Anybody else Not trust the H1N1 Vaccine?

[Ashley]

Originally Posted by Timber Loftis

Second of all, the vaccines are such a moneymaker... I mean, really, things like the HPV vaccine really make me think twice -- should we really be vaccinating 12-13 yr. old women from an STD?

Why not? I haven't had the shot, but I'm sure that if I wasn't in a long-term, monogamous relationship I would have. HPV is an extremely common virus, and if I can provide myself extra protection against cervical cancer, why wouldn't I?

I guess maybe my opinion is different because I am a woman and of a different generation, but I sometimes have difficulty understanding why someone wouldn't want protection against something as scary as cancer.

[Timber Loftis]

Originally Posted by Ashley

Why not?

Well, there may be side effects:
http://www.americanchronicle.com/articles/view/122199

http://www.myfoxla.com/dpp/health/HP...fects_20091006

Again, I'm just trying to choose what's right for my kids. This isn't about advocacy one way or the other, it's about information.

[Omega_Precision]

Originally Posted by Timber Loftis

I appreciate your input, and the link for further information.

I apologize, but I tend to be skeptical of vaccines. I know that in your view that is probably tragic -- vaccines have been a wonderful thing for the world, generally, wiping out polio and whatnot. They have been a boon to society.

But, I'm still skeptical of many of the modern vaccines being pushed on us. First off, you have to admit (I think) that the general flu vaccine is based off of the "best guess" the industry has as to what will be the most prevalent strain of the flu this year -- it's part historical analysis, part guesswork, as I understand it. Second of all, the vaccines are such a moneymaker... I mean, really, things like the HPV vaccine really make me think twice -- should we really be vaccinating 12-13 yr. old women from an STD?

Of course, I readily recognize that the H1N1 vaccine is specific and targeted, so it doesn't suffer from the randomness factor.

That said, both the regular flu vaccine and the H1N1 vaccine have thimerosol in them, and from what I've read thimerosol is roughly 50% mercury, the kind that metabolizes into ethyl mercury, an organic form of mercury (i.e., a bioaccumulator) whose toxicological effects have not been studied.

I'm not trying to challenge the assertions of doctors on here, nor am I trying to thwart them, I'm trying to understand more.

As a personal note, I'll say that my two kids are aged 2 yrs. and 7 mos. I went with the regular vaccine regiment up to about the 1 yr. stage for both. I recognize that studies have shown that the presence of thimerosol in the MMR vaccine has not indicated a link to autism. However, I also recognize that the MMR vaccination contains upwards of 32 different vaccines in a cocktail. Lacking information on the effects of this, I suspended and intend to suspend vaccinations on my kids between the ages of 1.5 yrs. and 4 yrs. Then I will pick up the regiment again -- we don't know what causes autism, basically, but we do know that it occurs between 2-4 yrs. so I want to just take everything off the table during that timeframe for them.

Timber,

I respect your views further than a wristwatch. You have studied or tried to obtain knowledge about vaccination. I, myself, believe that vaccination is the cause of autism in kids.

I admire your perseverance(if spelled correctly) to gain more knowledge on the subject before you have someone injecting your kids with a chemical, whether right or not.

Always remember, the future of our society or the kids, never have a right to say whether they want these shots but as parents, perhaps, we can educate ourselves whether CERTAIN, and not all, vaccinations are necessary for them.

[Earl]

Originally Posted by sexner

Henry, we were vaccinated against Polio in Elementary school in the 50's and early 60's.

I had a grade 5 teacher that had Polio.

And yes as far as I know it is now eradicated.

Please, don't forget about all the disease (and I mean it) coming north into the USofA from 3rd world countries south of our boarders. Outbreaks are happening and this is what scares me! They have not immunized against the many "eradicated" disease's that did not exist here for over 40 or 50 years but, they are coming back and from where?

Thank you for letting me vent.

[AIKO]

Originally Posted by Brunotheboxer

But out of those 30 million how many were healthy with strong immune systems. For unhealthy people the vaccine is probably worth the risk. For a healthy person I just dont feel it is.

Most of those who die each year are old and sick from something else. But this new flu is not attacking those people. It is attacking people like you and me (40) and younger and the healthy. This new vaccine is made teh exact way the seasonal vaccine has been made for years and years-just a new strain of flu. They may only allow <25 to be vaccinated and healthcare workers. I have read so many conflicting things, CDC still has no final guidelines.

[steelers]

I hate to post this.But I passed on the shot! I hope I did not bring myself bad luck,as I'm in Asia now.

[TheDude]

I'm a technologist, and I'm thinking about the vaccine (and my body) in the same manner that I think of my technology adoption:


I wouldn't be an early adopter for technology, a software patch, a firmware, etc... If something is too new, I sit back and watch to see what problems arise before I put it on my phone, computer, etc...

Same thing goes for my body... why on earth would I put a 1.0 vaccine in the only body I have? I can't hit the reset button if something goes wrong. They're rushing to get this thing out the door, and with all pharma - it's not about zero risk to the patient, it's about making sure the benefits of a treatment outweigh the risk.

I'll get a standard flu shot and probably a pneumonia vaccine (per CDC recommendation)

[Dr.B]

Fact: Everyone has an opinion. However, we should respect each others opinions. Lets help each-other get educated. (just like you guys help me on watches)

Here are some sites where you can find some information on infectious diseased and associated facts.

http://www.nfid.org/factsheets/index.shtml

http://www.cancer.gov/cancertopics/hpv-vaccines

http://www.cdc.gov/vaccines/

http://www.cdc.gov/flu/professionals...background.htm

[Dr.B]

2009-10 Influenza Prevention & Control Recommendations
ACIP Recommendations: Introduction and Biology of Influenza

In the United States, annual epidemics of seasonal influenza occur typically during the late fall through early spring. Influenza viruses can cause disease among persons in any age group, but rates of infection are highest among children. Rates of serious illness and death are highest among persons aged 65 years and older, children aged <2 years, and persons of any age who have medical conditions that place them at increased risk for complications from influenza. An annual average of approximately 36,000 deaths during 1990—1999 and 226,000 hospitalizations during 1979--2001 have been associated with influenza epidemics.

Annual influenza vaccination is the most effective method for preventing influenza virus infection and its complications. Influenza vaccine can be administered to any person aged >6 months who does not have contraindications to vaccination to reduce the likelihood of becoming ill with influenza or of transmitting influenza to others. Trivalent inactivated influenza vaccine (TIV) can be used for any person aged 6 months and older, including those with high-risk conditions (Boxes 1 and 2). Live, attenuated influenza vaccine (LAIV) may be used for healthy, nonpregnant persons aged 2—49 years. No preference is indicated for LAIV or TIV when considering vaccination of healthy, nonpregnant persons aged 2—49 years. Because the safety or effectiveness of LAIV has not been established in persons with underlying medical conditions that confer a higher risk for influenza complications, these persons should be vaccinated only with TIV. Influenza viruses undergo frequent antigenic change (i.e., antigenic drift); to gain immunity against viruses in circulation, patients must receive an annual vaccination against the influenza viruses that are predicted on the basis of viral surveillance data. Although vaccination coverage has increased in recent years for many groups targeted for routine vaccination, coverage remains low among most of these groups, and strategies to improve vaccination coverage, including use of reminder/recall systems and standing orders programs, should be implemented or expanded.

Antiviral medications are an adjunct to vaccination and are effective when administered as treatment and when used for chemoprophylaxis after an exposure to influenza virus. However, the emergence since 2005 of resistance to one or more of the four licensed antiviral agents (oseltamivir, zanamivir, amantadine and rimantadine) among circulating strains has complicated antiviral treatment and chemoprophylaxis recommendations. Updated antiviral treatment and chemoprophylaxis recommendations will be provided in a separate set of guidelines later in 2009. CDC has issued interim recommendations for antiviral treatment and chemoprophylaxis of influenza, and these guidelines should be consulted pending issuance of new recommendations.

In April 2009, a novel influenza A (H1N1) virus that is similar to influenza viruses previously identified in swine was determined to be the cause of an influenza respiratory illness that spread across North America and was identified in many areas of the world by May 2009. The symptoms of novel influenza A (H1N1) virus infection are similar to those of seasonal influenza, and specific diagnostic testing is required to distinguish novel influenza A (H1N1) virus infection from seasonal influenza. The epidemiology of this illness is still being studied and prevention issues related to this newly emerging influenza virus will be published separately.
Biology of Influenza

Influenza A and B are the two types of influenza viruses that cause epidemic human disease. Influenza A viruses are categorized into subtypes on the basis of two surface antigens: hemagglutinin and neuraminidase. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have circulated globally. Influenza A (H1N2) viruses that probably emerged after genetic reassortment between human A (H3N2) and A (H1N1) viruses also have been identified in some influenza seasons. In April 2009, human infections with a novel influenza A (H1N1) virus were identified; as of June 2009, infections with the novel influenza A (H1N1) virus have been reported worldwide. This novel virus is derived partly from influenza A viruses that circulate in swine and is antigenically distinct from human influenza A (H1N1) viruses in circulation since 1977. Influenza A subtypes and B viruses are further separated into groups on the basis of antigenic similarities. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations and recombination events that occur during viral replication. Recent studies have begun to shed some light on the complex molecular evolution and epidemiologic dynamics of influenza A viruses.

Currently circulating influenza B viruses are separated into two distinct genetic lineages (Yamagata and Victoria) but are not categorized into subtypes. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses. Influenza B viruses from both lineages have circulated in most recent influenza seasons.

Immunity to the surface antigens, particularly the hemagglutinin, reduces the likelihood of infection. Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype of influenza virus. Furthermore, antibody to one antigenic type or subtype of influenza virus might not protect against infection with a new antigenic variant of the same type or subtype. Frequent emergence of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and is the reason for annually reassessing the need to change one or more of the recommended strains for influenza vaccines.

More dramatic changes, or antigenic shifts, occur less frequently. Antigenic shift occurs when a new subtype of influenza A virus appears and can result in the emergence of a novel influenza A virus with the potential to cause a pandemic. New influenza A subtypes have the potential to cause a pandemic when they are able to cause human illness and demonstrate efficient human-to-human transmission and little or no previously existing immunity has been identified among humans. Novel influenza A (H1N1) virus is not a new subtype, but because the large majority of humans appear to have no pre-existing antibody to key novel influenza A (H1N1) virus hemagglutinin epitopes, substantial potential exists for widespread infection
BOX 1. Summary of seasonal influenza vaccination recommendations, 2009: children and adolescents aged 6 months--18 years

All children aged 6 months--18 years should be vaccinated annually.

Children and adolescents at higher risk for influenza complications should continue to be a focus of vaccination efforts as providers and programs transition to routinely vaccinating all children and adolescents, including those who:

* are aged 6 months--4 years (59 months);
* have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, cognitive, neurologic/neuromuscular, hematological or metabolic disorders (including diabetes mellitus);
* are immunosuppressed (including immunosuppression caused by medications or by human immunodeficiency virus);
* are receiving long-term aspirin therapy and therefore might be at risk for experiencing Reye syndrome after influenza virus infection;
* are residents of long-term care facilities; and
* will be pregnant during the influenza season.

Note: Children aged < 6 months cannot receive influenza vaccination. Household and other close contacts (e.g., daycare providers) of children aged < 6 months, including older children and adolescents, should be vaccinated.

BOX 2. Summary of influenza vaccination recommendations, 2009: adults

Annual vaccination against influenza is recommended for any adult who wants to reduce the risk of becoming ill with influenza or of transmitting it to others. Vaccination is recommended for all adults without contraindications in the following groups, because these persons either are at higher risk for influenza complications, or are close contacts of persons at higher risk:

* persons aged 50 years and older;
* women who will be pregnant during the influenza season;
* persons who have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, cognitive, neurologic/neuromuscular, hematological or metabolic disorders (including diabetes mellitus);
* persons who have immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus;
* residents of nursing homes and other long-term care facilities;
* health-care personnel;
* household contacts and caregivers of children aged <5 years and adults aged 50 years and older, with particular emphasis on vaccinating contacts of children aged <6 months; and
* household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza.

[BarkMaster]

Originally Posted by Dr.B

Fact: Everyone has an opinion. However, we should respect each others opinions. Lets help each-other get educated. (just like you guys help me on watches)

Here are some sites where you can find some information on infectious diseased and associated facts.

http://www.nfid.org/factsheets/index.shtml

http://www.cancer.gov/cancertopics/hpv-vaccines

http://www.cdc.gov/vaccines/

http://www.cdc.gov/flu/professionals...background.htm

Thanks for the info!!

[Dr.B]

Sorry for the long article, but some of you may be interested.....

Autism and chronic disease: Little evidence for vaccines as a contributing factor

Author
Jan E Drutz, MD
Section Editor
Teresa K Duryea, MD
Deputy Editor
Mary M Torchia, MD



Last literature review for version 17.2: May 1, 2009 | This topic last updated: September 23, 2008



INTRODUCTION — Since the 1980s, there appears to have been an increase in the number of cases of autism diagnosed in the United States and other parts of the world [1-6]. Rates of autistic spectrum disorders in studies from the late 1990s are consistently greater than 10 per 10,000 compared to four to five per 10,000 in previous decades [7].

This real or perceived increase in autism cases has occurred at a time when there has been a significant increase in the number of recommended childhood vaccines. In the search for a causal relationship, parents of autistic children and some professionals have identified a temporal association between immunizations and the onset of more evident symptoms of autism in the second year of life [8]. It has been suggested that certain vaccines (eg, measles, mumps, and rubella, MMR) and vaccine constituents (eg, thimerosal) play a role in the development of autism [9-14]. Vaccines and vaccine constituents have also been linked with the development of other chronic diseases such as multiple sclerosis [15-17] and diabetes [18,19].

Research to prove or disprove a possible relationship between the various components of recommended childhood vaccines and chronic diseases such as autism is ongoing. However, to date, no scientific linkage has been established. The evidence for and against an association between vaccines and autism and chronic disease will be presented here. The evidence for and against an association between thimerosal and autism and chronic disease is discussed separately. (See "Autism and chronic disease: Little evidence for thimerosal as a contributing factor").

The clinical features and diagnosis of autism spectrum disorders are discussed separately. (See "Clinical features of autism spectrum disorders" and see "Diagnosis of autism spectrum disorders").

APPARENT INCREASE IN AUTISM — In the past decades, there appears to have been an increase in the number of cases of autism diagnosed in the United States and other parts of the world [1-6]. Much attention was generated when the California Department of Developmental Services reported a 210 percent increase in the number of persons with autism between 1987 and 1998 [1]. Adequate explanation for the increase was not clear, though there was speculation that changes in diagnostic criteria and an increased awareness of the conditions among health-care providers and developmental specialists may have been contributing factors. Subsequent reports analyzing data from cohorts of children with autism from regional developmental centers in California reached opposite conclusions about whether the apparent rise in cases of autism were attributable to changes in diagnostic criteria, misclassification, or in-migration to a generous service system [20,21]. (See "Clinical features of autism spectrum disorders", section on Epidemiology).

Comparing studies with different case definitions, methods of case finding, and sample populations is problematic unless there is rigorous control for these variables [22]. Systematic reviews of the epidemiologic studies of autism have found evidence that changes in case definition and increased awareness account for much of the increased prevalence [23-25]

POSSIBLE ASSOCIATION BETWEEN AUTISM AND MMR — The real or perceived increase in autism cases occurred at a time when the number of recommended childhood vaccines also increased (to include Haemophilus influenza type b (Hib), hepatitis B, varicella, and pneumococcal vaccines, as well as a second dose of the MMR vaccine). (See "Standard childhood immunizations"). In the search for a causal relationship, parents of autistic children and some professionals identified a temporal association of immunizations with the onset of more evident symptoms of autism in the second year of life [8].

In addition to the temporal association, concern about a potential association between autism and MMR vaccine comes primarily from two reports describing a link between MMR vaccine, gastrointestinal complaints, and autism [9,26]. The first report described chronic enterocolitis in children with neuropsychiatric dysfunction, including autism [9]. The second report described increased presence of persistent measles virus in the intestinal tissue of children with developmental disorders compared to controls [26]. Taken together, these reports describe a phenotype of autism that involves gastrointestinal symptoms, is associated with the persistence of persistent measles virus, and accounts for the apparent increase in the incidence of autism [27].

Enterocolitis and regression — The potential association between MMR, enterocolitis, and autism was first reported in a study of 12 children who were consecutively referred to a pediatric gastroenterology unit in the United Kingdom for evaluation of abdominal pain, diarrhea, and loss of acquired skills following previously normal development [9]. Nine of these children were ultimately diagnosed with autism or an autistic spectrum disorder (ASD), and eight of the nine had lymphoid nodular hyperplasia on endoscopy. The onset of symptoms in six of these children was associated with recent injection of MMR vaccine, according to the child's parent(s) or physician.

The authors of the report hypothesized that the MMR vaccine introduced a series of events, including colitis, intestinal inflammation, increased intestinal permeability, and absorption of encephalopathic proteins into the bloodstream that eventually entered the brain and caused autism [9].

Limitations of the report include the small number of patients, the lack of a control group, and potential selection bias [28]. Subsequent review of the children's histories revealed that behavioral symptoms preceded the gastrointestinal symptoms in all cases [29]. In addition, age-appropriate levels of immunoglobulin A (IgA) were described as "abnormal." Finally, like childhood tonsillar hypertrophy, ileal and colonic lymphoid hyperplasia is a normal variant [29].

Since 90 percent of children in Great Britain had received MMR vaccine at the time of this report, and since autism is typically diagnosed at about the same age as the recommended dose for vaccine administration, it is not surprising that children with a diagnosis of autism/ASD had received a recent dose of the vaccine [29]. Thus, the temporal association is not necessarily causal.

The authors clearly state that their report "did not prove an association between measles, mumps, and rubella vaccine and the syndrome described" [9]. However, they did raise the possibility of a link between the two, an interpretation that contributed to a lack of confidence in the MMR vaccination program [30]. Ten of the 13 authors of the report describing the possible association between gastrointestinal disease and developmental regression [9] have published a statement retracting that interpretation [31].

Persistent intestinal measles virus — A second study compared the presence of persistent measles virus in the intestinal tissue of 91 children with developmental disorders, including autism, and 70 controls [26]. Persistent measles virus particles were more prevalent among the children with developmental disorders (82 versus 7 percent). The authors concluded that the data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder.

This study and its conclusions have been criticized and contradicted [27-29,32,33]. The criticisms include a number of methodologic flaws [29]:

It is plausible that in the natural course of response to the live-attenuated measles vaccine, including the virus being taken up by antigen-presenting cell, that measles virus genome could be detected in the intestine and other body tissues, particularly with a very sensitive assay (as was used).
Information about whether and when cases and controls had received the MMR vaccine was not reported; such information is critical in determining whether the MMR vaccine causes autism [32].
It was not determined whether the virus genome that was detected was from vaccine virus or natural measles virus (which is still circulating in England).
Measures to prevent false-positive results from natural measles virus contamination in the laboratory were not described, nor was blinding of the laboratory personnel.
LACK OF EVIDENCE FOR ASSOCIATION BETWEEN AUTISM AND MMR

Biologic mechanisms — One of the criteria for establishing causality is that there is a coherent explanation that accounts for the findings (ie, a plausible biologic mechanism) [34]. Decreased viral immunity, caused by the MMR vaccine, has been proposed as a mechanism for the association between MMR and ASD [10]. However, there is insufficient evidence to support this view [28,35].

Autoimmunity, persistent GI measles virus [26,36], and opioid excess [9] have been proposed to explain the association between MMR, bowel disease, and autism/ASD [28]. However, evidence to support these mechanisms is lacking:

Characteristic markers for immune injury or inflammation are not present in patients with autism [28,37].
Although there is support for persistent CNS measles vaccine virus causing neuropsychiatric dysfunction in immunocompromised individuals as a possible mechanism [38,39], the presence of vaccine-strain measles virus mRNA has not been demonstrated in the CNS or other tissues of healthy individuals [28].
Using PCR technology, several investigators have reported the presence of measles virus in intestinal or blood samples of children with autism spectrum disorders [26,36,40]. However, subsequent studies using highly sensitive and specific assays and enhanced laboratory techniques failed to detect measles virus nucleic acids in the white blood cells of children with autism who had received MMR vaccine, suggesting that the findings in the earlier studies may have been false positives [41-43].
A case-control study evaluated the presence of measles virus RNA (with PCR) and/or inflammation in bowel tissue and the temporal relation between MMR administration and onset of ASD and/or gastrointestinal (GI) disturbances in 23 children with GI disturbances and ASD and 9 children with isolated GI disturbances [44]. The presence of measles virus RNA was assayed in three laboratories, including the one from which the findings suggesting a link between MMR and autism were reported [9]. The laboratories were blinded to the diagnosis. The results were consistent across laboratories: measles virus RNA was detected in one patient in each group. The timing of MMR, onset of GI disturbances, and onset of autism was not consistent with MMR vaccine as a trigger of GI disturbances or ASD.
Another case-control study found no differences in the excretion of opioid peptides in the urine of children with ASD or controls [45]. Cerebrospinal beta-endorphins in patients with autism are not consistently elevated [46-48]. Nor do social and stereotypic behaviors in children with ASD improve with administration of opioid antagonists [49-51].
Persistent measles infection or abnormally persistent immune response to MMR is another mechanism that has been proposed to explain an association between MMR and autism. Support for this hypothesis was lacking in a case-control study in which measles virus and measles antibody were measured in 98 children (aged 10 to 12 years) with ASD, 52 children with special needs without ASD, and 90 typically developing children [52]. Measles virus nucleic acid was detected in peripheral blood mononuclear cells of one child with ASD and two typically developing children. Antibody response did not differ between cases and controls and there was no correlation between antibody levels and autism symptoms.

Epidemiologic studies — To determine whether the MMR vaccine actually causes autism, it is necessary to compare the relative risk of developing autism among children who did and did not receive the MMR vaccine [29,32]. Such epidemiologic methods have been used to detect associations between the swine flu vaccine and Guillain-Barre syndrome [53], the Rotashield vaccine and intussusception [54], and the MMR vaccine and idiopathic thrombocytopenic purpura [55]. In contrast, several large epidemiologic studies have failed to detect an association between MMR vaccine and autism [3,56-62]. As examples:

The incidence of autism among vaccinated and unvaccinated children was compared in a retrospective cohort study of all children born in Denmark between January 1991 and December 1998 [3]. Among the 537,303 children in the cohort, 838 (<1 percent) had autism or ASD, and 82 percent had received the MMR vaccine. After adjustment for potential confounders, the relative risk of autism among the vaccinated children was 0.92 (95% CI, 0.68-1.24), and the relative risk of ASD among the vaccinated children was 0.83 (95% CI, 0.65-1.07). In addition to the lack of association between MMR vaccine and autism/ASD, no association was found between the age at the time of vaccination, the time since vaccination, or the date of vaccination and the development of autism or ASD.
A population-based study from the United Kingdom investigated the incidence of autism before and after the introduction of MMR vaccine in 1988 [56]. Although there was a steady increase in the number of cases of autism by year of birth, there was no sudden change in the trend after the introduction of the MMR vaccine. Moreover, there was no difference in the age of diagnosis of autism between the cases vaccinated before or after 18 months of age and those never vaccinated. The analysis failed to support a causal relationship between receipt of the MMR vaccine and subsequent development of autism [56]. A similar retrospective analysis in the United States came to the same conclusion [2].
In a population-based study from Montreal, rates of ASD increased as MMR vaccination coverage decreased [62]. In addition, the rate of increased prevalence of ASD was similar before and after the introduction of a second dose of MMR vaccine to the routine childhood immunization schedule [62].
A population-based case-control study in the United States, which hypothesized that earlier age at vaccination might be associated with an increased risk for autism, failed to detect such an association [57].
A matched case-control study using the UK General Practice Research Database found no association between receipt of the MMR vaccine and autism or pervasive developmental disorder [61].
After the introduction of the MMR vaccine in Finland in 1982, a countrywide surveillance program was established to determine the incidence and nature of serious adverse events [58-60]. Among children who received the vaccine between 1982 and 1986, there was no clustering of hospitalizations for autism related to MMR administration; nor was there an increase in cases of encephalitis or aseptic meningitis [58]. Among 31 children who reported gastrointestinal symptoms after the vaccine, no cases of ASD were reported or identified; mean follow-up was 9.25 years (range of 1.3 to 15.1 years) [60].
In a population study, bowel problems and developmental regression among 473 children with autism or ASD were examined between 1979 and 1998, and related to MMR vaccine (which was introduced in 1988) [56]. The proportion of children with bowel symptoms or developmental regression did not change after the introduction of the MMR vaccine. In addition, the rates of bowel problems and regression among children who received the MMR vaccine before their parents were concerned about their development were similar to the rates among children who received the vaccine after their parents were concerned about their development and those who did not receive the vaccine. These findings do not support an association between MMR vaccine and autism.
In a total population study in Yokohama, Japan, the incidence of ASD among 31,426 children born between 1988 and 1996 increased from 48 to 117 cases per 10,000 children [63]. The increased incidence in ASD occurred despite decline in MMR vaccination rate from 70 to 0 percent in 1993, after which MMR vaccination was replaced with monovalent measles and rubella vaccines (mumps vaccination was terminated because of concerns regarding aseptic meningitis as a possible side-effect).
Systematic reviews of the epidemiologic evidence also have failed to find support for an association between the MMR vaccine and autism/ASD [28,64]. As an example, the Immunization Safety Committee of the Institute of Medicine (IOM) reviewed evidence for an association between MMR vaccine and autism in 2001 and 2004 and concluded that existing epidemiologic evidence failed to reveal any causal association between the vaccine and autism [28,35]. Evidence for a plausible biologic mechanism was fragmentary and insufficient [8,28,35].

Summary — Research to prove or disprove a possible relationship between MMR and autism is ongoing. However, to date, no scientific linkage has been established.

The proposed biologic mechanisms that have been generated are only theoretical [35].
Multiple large, well-designed epidemiologic studies [2-5,27,56,58,65] and systematic reviews [28,35,64] have found insufficient evidence to support an association between the MMR vaccine and autism.
The inability to absolutely exclude an association between the MMR vaccine and autism stems from the limitations of the scientific method [32], in which the null hypothesis (ie, that MMR vaccine does not cause autism) can be rejected or not rejected, but cannot be accepted. Thus, in strict adherence to the scientific method, one cannot accept the null hypothesis and conclude that the MMR vaccine does not cause autism, because this would imply that the MMR vaccine never causes autism, something that cannot be proven. However, in its latest review, the Immunization Safety Review Committee of the IOM concludes that the evidence favors rejection of a causal relationship between MMR vaccine and autism [35].

OTHER CHRONIC DISEASES — In addition to autism, other chronic diseases, including multiple sclerosis and diabetes, have been attributed to the proximate receipt of vaccines in certain individuals.

Multiple sclerosis — There has been a concern that onset or relapse of multiple sclerosis was precipitated by hepatitis B or other vaccines. The relationship between multiple sclerosis and vaccines is discussed separately. (See "Epidemiology, risk factors, and clinical features of multiple sclerosis in adults" section on Role of immune system stimuli).

Type 1 diabetes mellitus — There have been reports of clustering of cases of type 1 diabetes mellitus (DM) linked temporally to hemophilus influenza type b vaccine, pertussis vaccine, MMR, and BCG vaccine [18] and concerns that the timing of the first dose of vaccine may affect the risk of development of type 1 diabetes mellitus [19].

The studies linking type 1 diabetes mellitus and various vaccines were performed by comparing the rates of diabetes and vaccination schedules among various countries, and searching databases on the incidence of type 1 diabetes in various regions and then determining whether changes in immunization occurred during the time the incidence of DM was recorded [18].

Such ecologic studies may provide the basis for a hypothesis that a vaccine is associated with a particular disease, but do not provide evidence for the association. Many factors may affect the rates of diabetes between various countries (eg, genetic predisposition, environmental exposures, breastfeeding, etc). (See "Pathogenesis of type 1 diabetes mellitus").

To provide evidence of an association between a particular vaccine and diabetes mellitus, it is necessary to compare the relative risk of developing type 1 diabetes among children who did and did not receive the particular vaccine (as described above). Two large, population-based, case-control studies found no association between any of the routinely recommended childhood vaccines and an increased risk of type 1 diabetes mellitus [66,67]. Nor has an association between type 1 diabetes and childhood vaccination been detected in large population-based cohort studies in Sweden, Finland, and Denmark [68-70].

One potential mechanism for an association between vaccine administration and development of type 1 diabetes is that the vaccines stimulate beta cell autoimmunity. However, in a prospective cohort of children who had a first-degree relative with type 1 diabetes mellitus, development of beta-cell autoimmunity was not associated with HBV, Hib, polio, or DTP vaccines administered before nine months of age, time of receipt of first HBV vaccine, or median age at first HBV, Hib, polio, or DTP vaccination [71]. In another study, vaccination against tuberculosis, smallpox, tetanus, pertussis, rubella, and mumps had no effect on the risk of developing type 1 diabetes [72]. On the other hand, there is some evidence that measles vaccine may decrease the risk of diabetes mellitus [72,73]. (See "Pathogenesis of type 1 diabetes mellitus").

PROVEN BENEFITS OF VACCINES — As discussed above, there is a lack of evidence for an association between vaccines and chronic disease [74]. On the other hand, the benefits of vaccines are clear. As illustrated below, several infectious diseases that were once associated with significant morbidity and mortality have been almost completely eliminated through the development, distribution, and almost universal administration of protective vaccines:

Wild-strain poliomyelitis has been eliminated from the Western hemisphere. No case has been reported in the United States since 1979. The last known case in the Western hemisphere was reported in Peru in 1992. (See "Poliovirus vaccination").
The number of reported measles cases in the United States has fallen substantially since the early 1990s, when the uniform recommendation was made that all children, adolescents, and young adults without history of natural measles disease receive two doses of measles vaccine. (See "Clinical presentation and diagnosis of measles").
Between 1987 (when the Hib conjugate vaccine was introduced in the United States) and 2000, the number of invasive Hib cases in children younger than five years of age declined by >99 percent [75,76]. (See "Microbiology, epidemiology and treatment of Haemophilus influenzae").
With the declining incidence of these once-common infectious diseases, parents of young children may no longer appreciate the potential severity or dire consequences of the illnesses. Parents who lack such appreciation may be willing to forego immunizations for their children, particularly if unproven risks (eg, autism/ASD) are highly publicized [77]. When this occurs, immunization rates decline and outbreaks of infectious diseases, such as measles and pertussis, may occur with significant morbidity and mortality [32,78-82].

As an example, between 35 and 100 of every 100,000 patients with measles disease develop acute encephalitis, which has a mortality rate of 10 percent and causes neurologic damage in 25 percent of survivors [58,80,83,84]. In addition to acute encephalitis, meningitis, subacute sclerosing panencephalitis, and acute disseminated encephalomyelitis have been reported [58,83,85]. Even in uncomplicated cases of measles, as many as 50 percent of patients may have EEG changes [58,86]. (See "Clinical presentation and diagnosis of measles").

SUMMARY AND CONCLUSIONS — Based upon the above discussion, several conclusions can be drawn:

The prevalence of autism and ASD appears to have increased over the last several decades. Much of this trend is accounted for by changes in case definition and increased awareness of autism [24]. Whether or not the actual incidence of autism has increased is unclear.
Multiple large, well-designed epidemiologic studies [2-5,27,56,58,65] and systematic reviews [28,35,64] have found insufficient evidence to support an association between the MMR vaccine and autism. In its latest review, the Immunization Safety Review Committee of the IOM concludes that the evidence favors rejection of a causal relationship between MMR vaccine and autism [35].
Similarly, well-designed epidemiologic studies have failed to find an association between vaccines and multiple sclerosis or type 1 diabetes mellitus.
The administration of childhood vaccines has led to a decline in the incidence of childhood diseases that can have severe sequelae. Withholding vaccines from a child because of a hypothetical risk places the child at risk for actual infection that may have actual sequelae.
Though neither specific childhood vaccines nor vaccine components, such as thimerosal, have been proven by scientific study to have a causal relationship with the development of autism, there is evidence that other factors, including genetics, are important in the development of autism. These factors are discussed separately. (See "Terminology, epidemiology, and pathogenesis of autism spectrum disorders", section on Pathogenesis).

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Childhood immunizations" and see "Patient information: Autism spectrum disorders"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.

The following Web sites from the US Centers for Disease Control and Prevention (CDC), the United Kingdom's Department of Health, and Australian National Centre for Immunisation Research and Surveillance (NCIRS) provide additional information about vaccines and autism and diabetes. They include sections on frequently asked questions that may be helpful when discussing these issues with parents.

www.cdc.gov/nip/vacsafe/concerns/autism
www.cdc.gov/nip/vacsafe/concerns/Diabetes
www.mmrthefacts.nhs.uk
www.ncirs.usyd.edu.au/facts/f-diabetes.html


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Peltola, H, Patja, A, Leinikki, P, et al. No evidence for measles, mumps, and rubella vaccine-associated inflammatory bowel disease or autism in a 14-year prospective study. Lancet 1998; 351:1327.
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Fombonne, E, Zakarian, R, Bennett, A, et al. Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations. Pediatrics 2006; 118:e139.
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[Dr.B]

Adolescent Immunization Questions & Answers
Are there vaccines that protect against communicable diseases?
Yes! Vaccines are available to protect against tetanus (lockjaw)-diphtheria-pertussis (whooping cough), meningococcus,
influenza (flu), hepatitis B, measles-mumps- rubella (German measles), varicella (chickenpox), and human papilloma
virus (HPV) are recommended for all unimmunized or incompletely immunized adolescents. In addition, vaccines against
hepatitis A and pneumococcal disease are available and recommended for use by some adolescents in special
circumstances.
Should all adolescents be immunized?
This depends on which vaccines they have received as children. All adolescents should receive a tetanus-diphtheriapertussis
(Tdap) booster, the meningococcal conjugate vaccine, and an annual seasonal influenza vaccine. Girls and
women aged 11-26 years should receive the HPV vaccine to prevent cervical cancer and genital warts. Hepatitis B
vaccine and measles, mumps, rubella (German measles) vaccine is indicated for all adolescents who have not been
vaccinated previously. Varicella (chickenpox) vaccine is recommended for those not previously vaccinated and do not
have proof of immunity such as history of having had the disease. All adolescents with diabetes or chronic heart, lung,
liver or kidney disorders need protection against pneumococcal disease and should consult their healthcare providers
regarding their need for these vaccines. Hepatitis A vaccine is recommended for adolescents traveling to or working in
countries where the disease is common, living in communities with outbreaks of the disease, and living in states that have
rates that exceed the national average, and for any person wishing to obtain immunity. It is also recommended for
adolescents who have chronic liver disease or clotting-factor disorders, are injection drug users, or are male and have sex
with other males.
How often do I need to be immunized?
Meningococcal conjugate vaccine is routinely recommended for adolescents aged 11-18 years and for certain high-risk
children from 2 through 10 years of age. A single booster dose of Tdap is recommended at ages 11-12 years to maintain
immunity against tetanus, diphtheria, and pertussis. Females aged 11-26 should receive 3 doses of the HPV vaccine.
Adolescents not previously vaccinated against hepatitis B should receive three doses of hepatitis B vaccine. Depending
on how many doses they have previously received, one or 2 doses of the MMR vaccine is required for protection against
measles, mumps and rubella. Two doses of chickenpox vaccine are recommended for adolescents 11-12 years of age if
there is no proof immunity such as history of having had chickenpox or immunization. Adolescents who received one
dose of varicella vaccine during childhood are recommended to receive a second dose. Seasonal influenza vaccine
should be administered yearly to adolescents. A single dose of pneumococcal polysaccharide vaccine is recommended
for adolescents with certain underlying medical conditions and who are at increased risk for this disease or its
complications. For adolescents recommended to receive Hepatitis A vaccine, the vaccine is administered in 2 doses.
Are there side effects to these immunizations?
Vaccines are among the safest medical products available. Some common side effects are a sore arm or low grade fever.
As with any medical product, there are very small risks that serious problems could occur after getting a vaccine.
However, the potential benefits associated with the diseases that these vaccines prevent are much greater than the
potential risks associated with the vaccines themselves. Report any adverse events following immunization to your parent
or guardian who will contact your provider or send a report to the Vaccine Adverse Event Reporting System (VAERS)
through their VAERS website at www.vaers.hhs.gov or to receive a form to complete by mail call 1-800-822-7967.
Should I have a personal immunization record?
Yes! This record will help you and your health care provider ensure that you are protected against vaccine-preventable
diseases. Ask your provider for this record, and be sure to take it with you every time you visit your provider so that it
can be reviewed and updated.
National Foundation for Infectious Diseases
4733 Bethesda Avenue, Suite 750, Bethesda, MD 20814
(301) 656-0003. Web site: www.nfid.org August 2009
Facts About Adolescent Immunization
FACT: Vaccines are among the safest medical products available.
FACT: Approximately 6.8 million children and adolescents aged 2 to 18 years have chronic illnesses,
placing them at risk for influenza and pneumococcal diseases and their complications.
FACT: Although no longer a very common disease in the U.S., diphtheria remains a problem in other
countries and can pose a serious threat to those in the U.S. who may not be fully immunized and
who travel to other countries with diphtheria or have contact with immigrants or international
travelers coming to the U.S from countries with diphtheria.
FACT: Forty to fifty cases of tetanus (lockjaw) occur each year, resulting in approximately five deaths
annually in the U.S.
FACT: The majority of the estimated 43,000 new hepatitis B infections each year strike adolescents and
young adults. The hepatitis B virus is 100 times more infectious than HIV, the virus that causes
AIDS.
FACT: The hepatitis B vaccine is recognized as the first anti-cancer vaccine because it can prevent
primary liver cancer caused by hepatitis B infection.
FACT: In 2007, rates of hepatitis A infection among children and adolescents 5 to 14 years old who live
in some parts of the United States were dramatically reduced by vaccination.
FACT: Of the 140 confirmed cases of measles reported in 2008, approximately 75% occurred in people
younger than 20 years of age.
FACT: In 2006, an outbreak of mumps occurred in the United States and affected over 6000 people. The
highest incidence occurred among college-aged persons, but younger adolescents were also
affected.
FACT: At least 50% of sexually active women will be infected with human papilloma virus (HPV), the
virus that causes cervical cancer. There are on average 9,710 new cases and 3,700 deaths from
cervical cancer in the United States every year.
FACT: About 25-30% of reported pertussis cases are in adolescents.

[Dr.B]

Autism and chronic disease: Little evidence for thimerosal as a contributing factor

Author
Jan E Drutz, MD
Section Editor
Teresa K Duryea, MD
Deputy Editor
Mary M Torchia, MD



Last literature review for version 17.2: May 1, 2009 | This topic last updated: January 28, 2009



INTRODUCTION — Since the 1980s, there appears to have been an increase in the number of cases of autism diagnosed in the United States and other parts of the world [1-6]. Rates of autistic spectrum disorders in studies from the late 1990s are consistently greater than 10 per 10,000 compared to four to five per 10,000 in previous decades [7].

This real or perceived increase in autism cases has occurred at a time when there has been a significant increase in the number of recommended childhood vaccines. In the search for a causal relationship, parents of autistic children and some professionals have identified a temporal association between immunizations and the onset of more evident symptoms of autism in the second year of life [8]. It has been suggested that certain vaccines (eg, measles, mumps, and rubella, MMR) and vaccine constituents (eg, thimerosal) play a role in the development of autism and other chronic diseases [9-14].

Research to prove or disprove a possible relationship between the various components of recommended childhood vaccines and chronic diseases such as autism is ongoing. However, to date, no scientific linkage has been established. The evidence for and against an association between thimerosal and autism and chronic disease will be presented here. The evidence for and against an association between vaccines and autism is discussed separately. (See "Autism and chronic disease: Little evidence for vaccines as a contributing factor").

The clinical features and diagnosis of autism spectrum disorders are discussed separately. (See "Clinical features of autism spectrum disorders" and see "Diagnosis of autism spectrum disorders").

APPARENT INCREASE IN AUTISM — In the past decades, there appears to have been an increase in the number of cases of autism diagnosed in the United States and other parts of the world [1-6]. Much attention was generated when the California Department of Developmental Services reported a 210 percent increase in the number of persons with autism between 1987 and 1998 [1]. Adequate explanation for the increase was not clear, though there was speculation that changes in diagnostic criteria and an increased awareness of the condition among health-care providers and developmental specialists may have been contributing factors. Subsequent reports analyzing data from cohorts of children with autism from regional developmental centers in California reached opposite conclusions about whether the apparent rise in cases of autism was attributable to changes in diagnostic criteria, misclassification, or in-migration to a generous service system [15,16]. (See "Clinical features of autism spectrum disorders", section on Epidemiology).

Comparing studies with different case definitions, methods of case finding, and sample populations is problematic unless there is rigorous control for these variables, even when the studies being compared occur during the same time period [17]. Systematic reviews of the epidemiologic studies of autism have found evidence that changes in case definition and increased awareness account for much of the apparent increase in the prevalence of autism [18-21].

BACKGROUND — Thimerosal, or sodium ethylmercury thiosalicylate, is an organic compound that has been used as a preservative since the 1930s. Thimerosal has been used as a preservative in hepatitis B, diptheria-tetanus-acellular-pertussis, and Haemophilus influenzae type b vaccines, as well as other vaccines that are no longer part of the routine childhood vaccination schedule for children in the United States. In the United States, Rh immune globulin also contained thimerosal until 2001 [22]. The dose of ethylmercury per dose of vaccine has ranged from <0.03 to 25 mcg (http://www.fda.gov/BiologicsBloodVac...fety/UCM096228). At such low doses, the only identified risk of thimerosal in humans has been a hypersensitivity reaction [23,24].

In 1999, the US Food and Drug Administration (FDA) released a statement that some infants who received thimerosal-containing vaccines at multiple visits could potentially receive cumulative doses of ethylmercury that would exceed Environmental Protection Agency (EPA) guidelines for methylmercury [25,26]. After the release of this statement, the American Academy of Pediatrics (AAP) and the US Public Health Service (USPHS) issued a joint statement recommending that thimerosal-containing vaccines be reduced or eliminated [27]. The statement also recommended that, until thimerosal-free hepatitis B vaccines were available, the first dose of hepatitis B vaccine for infants of mothers seronegative for hepatitis B surface antigen (HBsAg) be delayed until the infants reached 2 to 6 months of age [27,28].

The AAP/USPHS recommendation was taken as a precautionary measure, since there was no evidence of any harm caused by the low levels of mercury in the vaccines [29]. An advisory committee to the World Health Organization in a 2002 report concluded that the continued use of thimerosal in vaccines was safe, particularly in developing countries [30].

The FDA statement and AAP/USPHS recommendations led to concerns regarding a possible association between thimerosal and neurologic disability, including autism [31]. The neurotoxicity of mercury at high doses underlies these concerns [32].

By July 2000, children in the United States had access to thimerosal-free hepatitis B, Haemophilus influenzae type b, and diptheria-tetanus-acellular-pertussis vaccines [33]. Measles-mumps-rubella, varicella, inactivated polio, and pneumococcal conjugate vaccines never contained thimerosal [33].

Impact of controversy — When increased supplies of thimerosal-free hepatitis B vaccine became available in September 1999, the USPHS recommended resumption of newborn hepatitis B immunization [34]. Despite the availability of thimerosal-free vaccine and the USPHS recommendation, there has been a decline in the routine administration of hepatitis B vaccine to newborns of HBsAg-negative mothers before discharge from the newborn nursery [35-37]. As examples,

By March 2000, in Wisconsin, the number of hospitals with written policies or standing orders for newborn hepatitis B vaccination fell from 81 to 10 percent, and routine immunization prior to discharge declined from 84 to 43 percent [35].
In Cook County, Illinois, there was a 35 percent decrease in the number of hospital nurseries offering routine HBV vaccine to neonates one year after the recommendation to resume immunization [36].
The proportion of infants in the United States who received the first dose of hepatitis B vaccine at birth declined from 47 percent 7 to 12 months before the suspension to 33 percent one year after the suspension was lifted [37].
In addition, some hospitals misinterpreted the guideline and discontinued administration of hepatitis B vaccine to all newborns, resulting in delayed immunization of some infants born to HBsAg-positive mothers or mothers whose HBsAg status was unknown [35,38-40]. One such unvaccinated infant died from fulminant hepatitis B infection [35].

Mercury toxicity — The toxicity of mercury is complex, and is dependent on the form of mercury (methylmercury versus ethylmercury), the route of entry (ie, ingested versus injected), the dose, and the age at exposure [28,32,41]. Thimerosal contains 50 percent ethylmercury by weight and has a toxicologic profile that is thought to be similar to ethylmercury from other sources [42]. The main route of environmental exposure to organic mercury (eg, methylmercury or ethylmercury) is through the consumption of predatory fish, particularly shark and swordfish. Clinically significant poisoning from mercury is unlikely if blood and urine concentrations are below 100 mcg/L.

Little is known about the pharmacokinetics of ethylmercury in human infants. One small study measured blood mercury concentration before and after administration of hepatitis B vaccine in 15 preterm and five term infants [43]. Mean mercury concentrations before vaccination were similar between both groups (0.54 and 0.04 mcg/L, respectively). However, mean mercury concentrations after vaccination were greater among the preterm infants (7.36 versus 2.24 mcg/L).

Two additional studies measured blood, urine, and stool mercury concentrations before and after vaccination of infants with thimerosal-containing vaccines [44,45]. In the larger of these studies, blood, urine, and stool mercury concentrations were measured 12 hours to 30 days after vaccination in 216 healthy infants with gestational age >32 weeks (72 newborns, 72 two-month-olds, and 72 six-month-olds) who received thimerosal-containing vaccines [45]. The following findings were reported:

Mercury dose ranged from 12.5 to 32.5 mcg in the newborns, 37.5 to 57.5 mcg in the two-month olds (with a cumulative dose between 50 and 90 mcg), and 37.5 and 57.5 mcg in the six-month-olds (with a cumulative dose between 112.5 and 162.5 mcg).
Blood mercury levels peaked at 0.5 to 1 day after vaccination and returned to prevaccination levels within a few weeks. The estimated blood mercury half-life was calculated to be 3.7 days 95% CI 2.9-4.5).
The maximal mean blood mercury levels were 5 ng/mL, 3.6 ng/mL, and 2.8 ng/mL in the newborns, two-month-olds, and six-month-olds, respectively.
Prevaccination blood mercury levels in six-month olds were not higher than those in two-month-olds, suggesting that exposure to thimerosal-containing vaccines does not result in an accumulation of mercury in the blood.
For all infants, the concentration of mercury in the blood was less than the concentration that is thought to be safe in cord blood (29 nmol/L) [46].
Stool mercury levels peaked on day 5 after vaccination; maximal mean stool mercury levels were 19.1 ng/mL, 37 ng/mL, and 44.3 ng/mL in the newborns, two-month-olds, and six-month-olds, respectively.
Mercury was virtually undetectable in urine in all samples.
These studies indicate that younger infants with lower body weights have higher blood mercury concentrations after immunization with thimerosal-containing vaccines than do older, heavier infants. However, the concentrations do not exceed those thought to be safe in cord blood. Furthermore, ethylmercury is rapidly eliminated from the blood of infants who receive thimerosal-containing vaccines [44,45].

Methylmercury versus ethylmercury — Ethylmercury (CH3CH2Hg+) and methylmercury (CH3Hg+) have similar chemical structures and similar initial distribution in the body [32]. At toxic doses, they cause similar damage to the brain. High-dose exposure to ethylmercury (≥3 mg/kg) can cause severe toxicity including local necrosis, acute hemolysis, disseminated intravascular coagulation, acute tubular necrosis, and central nervous system injury [47-52].

There is little information regarding the clinical effects of low-dose exposure to mercury. The only studies describing low-dose exposure to organic mercury are those involving prenatal exposure to methylmercury from fish consumption in the Seychelles and Faroe islands [53-55]. The results of these studies are inconsistent.

Studies from the Faroe islands, where mercury exposure was primarily through whale consumption [56], report subtle and long-term cognitive deficits at methylmercury levels previously thought to be safe [55,57]. However, children from these islands may have been exposed to additional toxins (eg, polychlorinated biphenyls) [58,59].
Studies of children from the Seychelles, evaluating more global outcomes, failed to find significant cognitive or behavioral effects in offspring of women with high fish consumption when other factors, such as social and environmental developmental modifiers and postnatal mercury exposure, were considered [53,54].
Extrapolating the neurotoxic effects of low-dose methylmercury exposure to low-dose ethylmercury exposure is problematic because the two compounds have different half-lives (50 versus 7 days, respectively) and biologically distinct behaviors [42,60,61]. Whereas methylmercury is actively transported across the blood-brain barrier [62], ethylmercury is not [63]. The transport of ethylmercury into the central nervous system is further hindered by its larger molecular size and rapid decomposition. The lack of transport of ethylmercury across the blood-brain barrier is supported by the following observations:

After equivalent doses of ethylmercury and methylmercury were administered to different groups of rodents, greater concentrations of mercury were detected in the blood than in the brain of the rodents that had received ethylmercury [61,64]
In experimental studies in rats, postnatal exposure to ethylmercury caused patchy damage in the cerebellar granule cell layer, whereas postnatal exposure to methylmercury caused diffuse abnormality [61]
Compared to methylmercury, ethylmercury exposure produced more lesions of the spinal cord, skeletal muscle, and myocardium [65].
Although both methylmercury and ethylmercury have neurotoxic effects, methylmercury appears to be a more potent toxin, with a longer half-life, and greater access to the central nervous system.

POSSIBLE ASSOCIATION BETWEEN THIMEROSAL AND AUTISM — Because mercury is known to be a neurotoxin, the concern regarding the neurologic effects of thimerosal is a biologically plausible one [63]. However, as mentioned above, data regarding low-dose mercury toxicity are limited and primarily related to prenatal methylmercury, rather than postnatal ethylmercury, exposure [63].

Some authors [11,12] hypothesize that autism is an expression of mercury poisoning. They base this hypothesis on their observations that mercury toxicity and autism appear to have similar clinical manifestations, that the apparent increase in the number of cases of autism parallels the increased exposure to thimerosal, and that a temporal association may be perceived between the onset of autism and immunization. These observations are discussed in detail and refuted below. (See "Lack of evidence for association between thimerosal and autism" below).

Additional concern regarding an association between thimerosal and autism stems from anecdotal and unpublished reports of improvement in children with autism and abnormal blood metal levels following chelation therapy [8,66-68]. However, systematic review of the peer-reviewed literature found no publications reporting an abnormal burden of mercury or an excess of mercury in hair, urine, or blood of patients with autism [69], and published evidence that chelation therapy improves autism is lacking [63].

Other reports of an association between thimerosal and autism are derived from data from the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance that relies on clinicians and others to voluntarily report possible vaccine adverse events [13,14,70]. The AAP issued a response to these reports [41], critiquing their methods and conclusions (www.aap.org/profed/thimaut-may03.htm). Highlights of the AAP response include [41]:

VAERS data, although useful for generating hypotheses about causal associations, cannot be used to verify causal associations because of the lack of information about the comparison group (ie, the group of individuals who were immunized and did not report problems) [41]. (See "Epidemiologic studies" below).
The method for calculation of thimerosal exposure was not revealed (necessary data for this calculation are not available in VAERS reports).
The authors of the report make assumptions about possible exposure to thimerosal for early (1984-1985) and late (1990-1994) cohorts that are contrary to the timing of introduction of thimerosal-containing vaccines to the routine childhood immunization schedule.
LACK OF EVIDENCE FOR ASSOCIATION BETWEEN THIMEROSAL AND AUTISM

Comparison of clinical features — The clinical features, diagnosis, and treatment of mercury poisoning and autism are discussed in detail separately. A brief overview of the clinical manifestations of each disorder is provided here to highlight the differences between them (show table 1). The clinical feature of autism are discussed in detail separately. (See "Clinical features of autism spectrum disorders").

Common characteristic motor findings in high-dose mercury poisoning include ataxia, dysarthria, tremor, muscle pain, and weakness [52,71,72]. In contrast, the characteristic motor finding in children with autism is repetitive behavior such as flapping, circling, or rocking [63]. Hypotonia has been noted in some infants with autism, and clumsiness in some cases of Asperger syndrome. However, other motor manifestations are uncommon. The presence of ataxia or dysarthria in a child whose behavior has autistic features should prompt a careful medical evaluation for an alternative or additional diagnosis [63].

Individuals with mercury poisoning typically have dysarthric speech. In contrast, individuals with autism or an autistic spectrum disorder (ASD) typically have delayed speech or echolalia.

Sensory findings in mercury poisoning include bilateral visual field constriction, which is highly specific [71-73], and paresthesias. In addition, infants with mercury poisoning may have erythema and pain in the hands and feet from peripheral neuropathy [63]. Sensory findings in autism include decreased responsiveness to pain and hypersensitivity to other sensory stimuli, including sounds [63]. In addition, children with autism/ASD may have "sensory defensiveness", which appears to be caused by abnormalities in central sensory processing [74-76].

Other manifestations of mercury poisoning include hypertension [77], skin eruption [78,79], and thrombocytopenia [80]. In addition, patients with mercury poisoning may have toxic psychosis or, in milder cases, nonspecific depression, anxiety, or irritability [81-83]. Hypertension, rash, and thrombocytopenia are not features of autism/ASD [63].

Children with prenatal or early childhood exposure to mercury typically have decreased head circumference [84]. In contrast, patients with autism often have macrocephaly [85-88].

Neuropathology — Pathologic findings in the brains of individuals who died as a result of mercury poisoning include [65,89]:

Severe atrophy and gliosis of the calcarine cortex
Diffuse neuronal loss and gliosis of the auditory, motor, and sensory cortices
Extensive cerebellar atrophy
Demyelination of ninth and 10th cranial nerve roots
Atrophy of the cerebellar granule cell layer with relative sparing of Purkinje cells
The brains of autistic children examined at autopsy or with magnetic resonance imaging (MRI) are typically enlarged in weight and volume compared to those of controls [90,91]. Additional findings include [90,92,93]:

Unusually small, closely packed neurons and increased cell-packing density in portions of the limbic system, consistent with curtailment of development of this circuitry
Reduction in the number of Purkinje cells in the cerebellum, primarily in the posterior inferior hemispheres
Involvement of granule cells has rarely been reported
Biologic mechanisms — A causal association between thimerosal-containing vaccines and neurodevelopmental disorders, including autism, has not been established. Although biologic mechanisms for such an association have been proposed, the information upon which the hypotheses are based is indirect and incomplete [66] and the potential mechanisms are considered theoretical [94]:

Low-dose thimerosal exposure in humans has not been demonstrated to be associated with effects on the nervous system [66].
Neurodevelopmental effects have been demonstrated in some populations [55] for prenatal but not postnatal exposures to low doses of methylmercury.
Thimerosal exposure from vaccines has not been proven to result in mercury levels associated with toxic responses; after exposure to thimerosal-containing vaccines, ethylmercury appears to be rapidly eliminated from the blood of infants with gestational age >32 weeks, with an estimated half-life of 3.7 days [45].
There is no evidence that ethylmercury causes any of the pathophysiologic changes that are known to be associated with autism.
Epidemiologic studies — To determine whether thimerosal is associated with autism, it is necessary to compare the relative risk of developing autism among children who were and were not exposed to thimerosal. Such epidemiologic methods have been used to detect associations between the swine flu vaccine and Guillain-Barre syndrome [95], the Rotashield vaccine and intussusception [96], and the MMR vaccine and idiopathic thrombocytopenic purpura [97].

In contrast, several large epidemiologic studies have failed to detect an association between thimerosal and autism [4,98-102] or other developmental disorders [103-105], as illustrated below:

The annual and age-specific incidence of autism among children between 2 and 10 years of age was compared before and after discontinuation of the use of thimerosal-containing vaccines in Denmark [4]. There was no trend toward an increase in autism during the time period when thimerosal was used (1971 to 1990). The discontinuation of the use of thimerosal-containing vaccines in 1992 was followed by an increase in the incidence of autism. Similar findings were noted in reports from Montreal [102] and California [106].
In a similar study, the incidence and prevalence of autism in California, Sweden, and Denmark were compared to the average exposure to thimerosal-containing vaccines [99]. In each region, the incidence and prevalence of autism/ASD began to increase after 1985 and increased at an accelerated rate in the early 1990s. However, exposure to thimerosal-containing vaccines during this period varied by location, decreasing in Sweden and Denmark, and increasing in the United States. These results are inconsistent with the hypothesis that increased exposure to thimerosal accounts for the apparent increase in the rates of autism.
The potential toxicity of thimerosal-containing vaccines among infants was evaluated in a two-phase retrospective cohort study using computerized health maintenance organization databases [100]. No association between thimerosal-containing vaccines and autism was detected. However, conflicting results regarding an association between thimerosal-containing vaccines and tics or language delay were found at different health maintenance organizations.
A population-based cohort study compared the rate ratio of autism/ASD among Danish children vaccinated with thimerosal-containing and thimerosal-free preparations of the same vaccine in Denmark [101]. The risk of autism/ASD was similar in both groups and no dose-response association was detected.
A prospective population based cohort study in the United Kingdom compared measures of mercury exposure from thimerosal containing vaccines at three, four, and six months with measures of cognitive and behavioral development from 6 to 91 months of age [103]. No convincing associations between exposure to thimerosal and neurologic or psychologic outcome were detected.
A survey and review of medical records of 214 families of children with ASD found that Rh-negative status was no more common among mothers of children with ASD than in the general population [98]. In addition, exposure to thimerosal containing Rh immune globulin was not increased in children with ASD compared to children with de novo chromosome disorders, and pregnancies resulting in children with ASD were no more likely to be Rh-incompatible than those in the general population.
The association between current neuropsychological performance (as assessed by 42 outcomes) and exposure to thimerosal during the prenatal period and first seven months of life was evaluated in 1047 children (7 to 10 years of age) [105]. The associations that were detected were small and almost equally divided between positive and negative effects, suggesting that they were chance findings related to the large number of statistical tests performed. The overall pattern of findings did not support a causal association between thimerosal and deficits of neuropsychological function at 7 to 10 years of age.
One of the associations that was detected was between early exposure to thimerosal and tics in boys. This association has been described previously, although inconsistently [100,104], and warrants further attention in future studies.

A similar study evaluated neuropsychological performance (as assessed by 24 outcomes) in 1403 children 10 years after participation in a vaccine study in which they received vaccines that contained 62.5 or 137.5 mcg of thimerosal [107]. Only two outcomes were associated with increased thimerosal exposure. The associations were based on small differences in mean test scores, of doubtful clinical significance, and inconsistent with findings from other studies, suggesting that they were chance findings related to the large number of statistical tests performed.
Summary — Research to prove or disprove a possible relationship between thimerosal and autism is ongoing. However, to date, no scientific linkage has been established.

The characteristic features of mercury poisoning have little in common with those of autism (show table 1).
Although the hypothesis that thimerosal-containing vaccines can cause neurodevelopmental disorders, including autism, is biologically possible, the information upon which the hypothesis is based is indirect and incomplete and the potential mechanisms are considered theoretical [94].
Multiple, large, well-designed epidemiologic studies [4,99-101,103,104] and systematic reviews [63,66,94,108] have found insufficient evidence to support an association between thimerosal-containing vaccines and autism or other developmental disorders.
In its latest review, the Immunization Safety Review Committee of the Institute of Medicine concludes that the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism [94].

OTHER CHRONIC DISEASES — Statistical associations between cardiovascular effects and exposure to mercury, primarily methylmercury, have been reported [56,109-112]. One study described a direct relation between mercury concentration and the risk of myocardial infarction [109]. However, a nested case-control study among male health professionals found no such association [113]. The reasons for these conflicting results are unclear. (See "Overview of the risk factors for cardiovascular disease").

PROVEN BENEFITS OF VACCINES — As discussed above, there is a lack of evidence for an association between exposure to thimerosal-containing vaccines and autism. On the other hand, the benefits of vaccines are clear. As illustrated below, several infectious diseases that were once associated with significant morbidity and mortality have been almost completely eliminated through the development, distribution, and almost universal administration of protective vaccines:

Wild-strain poliomyelitis has been eliminated from the Western hemisphere. No case has been reported in the United States since 1979. The last known case in the Western hemisphere was reported in Peru in 1992. (See "Poliovirus vaccination").
The number of reported measles cases in the United States has fallen substantially since the early 1990s, when the uniform recommendation was made that all children, adolescents, and young adults without history of natural measles disease receive two doses of measles vaccine. (See "Clinical presentation and diagnosis of measles").
Between 1987 (when the Hib conjugate vaccine was introduced in the United States) and 2000, the number of invasive Hib cases in children younger than five years of age declined by >99 percent [114,115]. (See "Microbiology, epidemiology and treatment of Haemophilus influenzae").
With the declining incidence of these once-common infectious diseases, parents of young children may no longer appreciate the potential severity or dire consequences of vaccine-preventable illnesses. Parents who lack such appreciation may be willing to forego immunizations for their children, particularly if unproven risks (eg, autism/ASD) are highly publicized. When this occurs, immunization rates decline and outbreaks of infectious diseases, such as measles or pertussis, may occur with significant morbidity and mortality [116-119].

As an example, between 35 and 100 of every 100,000 patients with measles disease develop acute encephalitis, which has a mortality rate of 10 percent and causes neurologic damage in 25 percent of survivors [118,120-122]. In addition to acute encephalitis, meningitis, subacute sclerosing panencephalitis, and acute disseminated encephalomyelitis have been reported [120,121,123]. Even in uncomplicated cases of measles, as many as 50 percent of patients may have EEG changes [120,124]. (See "Clinical presentation and diagnosis of measles").

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Childhood immunizations" and see "Patient information: Autism spectrum disorders"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.

The following Web sites of the US Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) provide additional information about thimerosal and vaccines. They include sections on frequently asked questions that may be helpful when discussing these issues with parents.

www.cdc.gov/nip/vacsafe/concerns/thimerosal
http://www.fda.gov/BiologicsBloodVac...fety/UCM096228
SUMMARY AND CONCLUSIONS — It remains questionable whether thimerosal contained in childhood vaccines in the past, and in the minute amounts contained in a small number of vaccines at present, increases the risk of neurologic disability or autism in children. Nonetheless, several conclusions can be drawn from the discussion above:

The prevalence of autism and ASD appears to have increased over the last several decades. Much of this trend is accounted for by changes in case definition and increased awareness of autism [19]. Whether or not the actual incidence of autism has increased is unclear.
Multiple large, well-designed epidemiologic studies [4,99-104] and systematic reviews [63,66,94,108] have found insufficient evidence to support an association between thimerosal and autism or other developmental disorders.
Similarly, a well-designed epidemiologic study failed to find an association between thimerosal and cardiovascular disease [113].
The administration of childhood vaccines has led to a decline in the incidence of childhood diseases that can have severe sequelae. Withholding vaccines from a child because of a hypothetical risk places the child at risk for actual infection that may have actual sequelae.
Although the AAP/USPHS recommend the use of thimerosal-free vaccines for children whenever possible, they believe that the risk of not vaccinating children because thimerosal-free vaccines are not available exceeds the risk of exposure to thimerosal-containing vaccines [24,28,33]. The World Health Organization advisory committee concluded in a report published in 2002 that it was safe to continue using thimerosal in vaccines [30]. The Institute of Medicine has concluded that evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism [94].
Though neither specific childhood vaccines nor vaccine components, such as thimerosal, have been proven by scientific study to have a causal relationship with the development of autism, there is evidence that other factors, including genetics, are important in the development of autism. These factors are discussed separately. (See "Terminology, epidemiology, and pathogenesis of autism spectrum disorders", section on Pathogenesis).



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[Dr.B]

If anyone has specific inquiries please let me know and I will do my best to find the info........
I hope some of this stuff helps....

[ijen0311]

Originally Posted by Ashley

Why not? I haven't had the shot, but I'm sure that if I wasn't in a long-term, monogamous relationship I would have. HPV is an extremely common virus, and if I can provide myself extra protection against cervical cancer, why wouldn't I?

I guess maybe my opinion is different because I am a woman and of a different generation, but I sometimes have difficulty understanding why someone wouldn't want protection against something as scary as cancer.

I second this. In our child welfare system, we have many caregivers who do not want their children to take this vaccine because it has a sexual connotation. This is a very naïve way of thinking and it drives me nuts...

[Nick1959]

I do not like this or any othe vaccine period. Try to improve our own immunity.

[unclesallie]

Fernando: thanks for the information , but as you may note , attempts at education are greatly over valued; people would rather hold on to their belief systems, even in the face of overwhelming scientific data to the contrary.

[Dr.B]

Originally Posted by ijen0311

I second this. In our child welfare system, we have many caregivers who do not want their children to take this vaccine because it has a sexual connotation. This is a very naïve way of thinking and it drives me nuts...

HPV and VACCINE INFO:

Human papillomavirus vaccines

Author
Barbara H McGovern, MD
Section Editor
Martin S Hirsch, MD
Deputy Editor
Barbara H McGovern, MD



Last literature review for version 17.2: May 1, 2009 | This topic last updated: June 12, 2009



INTRODUCTION — Human papillomaviruses (HPV) are highly prevalent, tissue-specific, DNA viruses that infect epithelial cells [1]. Persistent viral infection with oncogenic types of HPV leads to cancer of the cervix, anus, vagina, vulva, penis, mouth, and sinuses [2-4]. Cervical cancer is the second most common malignant disease in women worldwide and has a bimodal onset in the third and sixth decades of life [2].

Use of cervical cytology has reduced the incidence of cervical cancer by 70 percent. However, cervical cancer remains a leading cause of death in countries without screening programs. Vaccines that prevent these persistent HPV infections have the potential to further reduce the burden of disease [5-8].

Clinical data on the use of these candidate vaccines will be reviewed here. The epidemiology, virology, pathogenesis, clinical manifestations, and treatment of HPV are discussed separately. (See "Clinical presentation and diagnosis of human papillomavirus infections" and see "Epidemiology of human papillomavirus infections" and see "Virology of human papillomavirus infections and the link to cancer" and see "Treatment and prevention of human papillomavirus infections").

HPV TYPES — Specific HPV types are associated with squamous intraepithelial lesions. HPV 16, 18, 45, and 31 cause over half of the low-grade lesions, and about 65 percent of the high-grade lesions. HPV 6 and 11 cause 12 percent of low-grade lesions [9] and approximately 80 percent of genital warts [9-15]. Up to 40 percent of patients are infected with more than one HPV type. (See "Epidemiology of human papillomavirus infections").

HPV 16 and HPV 18 are associated with approximately 50 and 20 percent of cervical cancers, respectively [16,17]. HPV 45 and 31 are the next most common HPV types associated with cervical cancer, accounting for another 5 percent each. The first peak of oncogenic HPV infection occurs between the ages of 15 to 25 years, with a secondary peak in the sixth decade of life [18].

It is estimated that targeted HPV protection with the bivalent or quadrivalent vaccine would prevent half of the high-grade precancerous lesions (CIN 2 or 3) and two-thirds of the invasive cancers. The quadrivalent vaccine would also prevent most genital warts [19].

LIFE CYCLE AND THE IMMUNE RESPONSE — Human papillomaviruses are small, nonenveloped viruses, whose circular genome encodes the encapsulating structural proteins, L1 and L2 [20]. The life cycle of the virus is integrally linked to the maturation of the keratinocyte. Initial infection occurs in the basal stem cell. Specific gene products are transcribed at every level of differentiation of the squamous keratinocyte [20]. At the most superficial level, the L1 protein coat is transcribed, and upon desquamation of this short-lived cell, HPV virions are infective for transmission to the next basal stem cell in the adjacent mucosal epithelium. (See "Virology of human papillomavirus infections and the link to cancer").

HPV infection evades the immune system through a variety of mechanisms. HPV infection leads to down regulation of interferon expression and regulatory pathways, which subsequently prohibits the activation of cytotoxic T-lymphocytes [21]. No associated cytolysis or release of pro-inflammatory cytokines occurs as a result of basal cell infection [21]. In the absence of the usual signals that identify a virally-infected cell, the cellular immune system is not activated and HPV infection persists [21]. The importance of cellular immunity is clinically apparent in HIV-infected patients and in renal transplant patients, who have a higher incidence of HPV-related disease [22]. (See "Preinvasive and invasive cervical neoplasia in HIV-infected women").

Approximately 75 to 90 percent of HPV infections will clear within a year of initial infection [17]. Clearance is mediated by the natural desquamation of epithelial cells, cell-mediated immunity and in part, by low-levels of neutralizing antibody responses to the specific HPV L1 epitope [23]. There is a limited antibody response from natural infection and a significant loss of these antibodies within three years [24,25].

HPV infection induces a time-limited, type-specific immunity to HPV infections [26]. Individuals who are infected with one HPV type may develop protective antibodies against future infection for a limited period of time with that specific type, but remain immunologically naive to other HPV types. Thus, vaccine design strategies need to incorporate the most common disease-causing HPV types in order to protect against the majority of cervical intraepithelial neoplasias and cervical cancers. The interval between acquisition of incident HPV infection and malignancy usually takes ten years or longer [27].

ANAMNESTIC RESPONSE — HPV infects only the epithelium and does not have a viremic phase. HPV actively evades immune recognition. In vaccinated women, therefore, it is unlikely there will be any antibody response with reinfection of type specific HPV. Protective antibody levels will be dependent on initial and sustained vaccine responses or requisite booster shots.

At this time, most alum-based vaccinations have booster shots recommended at 7- to 10-year intervals, to maintain disease protection. This concept is important for HPV disease, since the benefits of vaccination are to prevent long term cancer development, and not immediate epidemic protection, as has been the standard for infectious diseases, such as pertussis, meningitis, or polio.

Sustained antibody titers have been reported with use of an ASO4 adjuvant system in the bivalent vaccine, which specifically is designed to prime antigen presenting cells and may lengthen B cell memory response [28].

TOOLS FOR ASSESSMENT OF VACCINE EFFICACY — Vaccine efficacy is measured only by the prevention of virologic infection or clinical events. The immunogenicity of the vaccines are not equated with vaccine efficacy for three reasons:

The antibody titers are unique for each HPV type and not comparable across types.
The antibody titers for each vaccine are in different noncomparable assay units (milli-ELISA units/mL and milli-Merck units/mL).
There is no established correlate between a titer level and protection against HPV infection or the development of CIN/cancer.
Absolute values of antibody titers are not comparable within or between studies. Therefore, immunogenicity is measured by comparing type-specific, vaccine-induced titers to natural infection titers and then expressed as a ratio at a specific point in time after vaccination. HPV antibody titer levels at or above infection titers are generally considered to be protective.

Vaccine efficacy for cervical cancer is defined for several natural history events that all serve as surrogate markers for the development of cervical cancer:

Incident HPV infection
Persistent type-specific HPV infection (>6 or >12 months)
Abnormal cytology
Abnormal histologic changes
VACCINE DEVELOPMENT — The HPV L1 major capsid protein self-assembles into virus-like particles (VLPs) for each HPV type [29]. Because the VLPs are hollow, without inner HPV DNA cores, the vaccine itself is not infectious. Preclinical research demonstrated that L1 is highly immunogenic with and without an adjuvant [29]. The major capsid protein, L1, is the only portion of HPV used in vaccine design [30].

The proof-of-concept vaccine trial with HPV 16 VLP [31] demonstrated that HPV infection could be prevented. This vaccine, which is no longer being used in population-based clinical trials, led to the development of the following immunizations: the bivalent HPV 16/18 VLP vaccine, and the quadrivalent HPV 6/11/16/18 VLP vaccine.

BIVALENT HPV 16/18 L1 VIRUS-LIKE PARTICLE VACCINE

Safety and efficacy — The efficacy of a bivalent HPV 16/18 L1 virus-like particle vaccine was demonstrated in a double blind, randomized, placebo-controlled trial in 1113 women, 15 to 25 years of age [32,33]. Study participants were randomly assigned to receive 20 micrograms each of HPV type 16 and 18 VLPs with ASO4 adjuvant or placebo at months 0, 1 and 6 with follow-up to 6.5 years [34]. The trial results were significant for the following observations:

Protection against incident HPV 16/18 infection occurred in 95 percent of women who received vaccination according to protocol and in 91 percent of all participants, including those who received vaccine doses at irregular times.
Protection against persistent HPV 16 and 18 infections (≥12 months) occurred in 100 percent of women who received vaccination and follow-up visits according to protocol; and in 96 percent of all participants.
Greater than 98 percent of the vaccine recipients sustained seroconversion for more than 6.5 years for both HPV types.
No cases of CIN caused by HPV 16/18 were reported in the vaccine group, compared to 15 cases in the placebo group.
Protection against incident HPV 45 and HPV 31 infections occurred in 78 and 60 percent of all women enrolled in the trial, respectively (show table 1).
In another study in women 15 to 55 years of age, the bivalent HPV vaccine was safe and immunogenic for at least two years, including those women in the oldest age group (46 to 55 years of age) [35].

An interim analysis of the phase III efficacy trial of the bivalent HPV vaccine was conducted when 23 cases of CIN 2 or greater with HPV 16 or 18 DNA were identified among 18,644 women who had been randomly assigned to HPV vaccine or control vaccine (hepatitis A vaccine) [36]. Cases of CIN 2 or greater were noted in two participants in the HPV vaccine group and in 21 participants in the control group. Based on this interim analysis with a mean length of follow-up of 14.8 months, HPV vaccine efficacy was estimated to be greater than 90 percent among women who did not have evidence of HPV 16/18 infection at baseline.

The vaccine was generally safe and well tolerated. Detailed information regarding vaccine safety in the post-marketing experience is discussed in detail below. (See "Vaccine safety" below).

QUADRIVALENT HPV 6/11/16/18 L1 VIRUS-LIKE PARTICLE VACCINE

Safety and efficacy — The efficacy of a quadrivalent HPV 6/11/16/18 L1 VLP vaccine has been demonstrated in a number of trials (show table 2A-2D), including a double blind, placebo-controlled trial in 552 women (mean age 20 years) [23]. Participants were given either alum placebo or vaccine, composed of 20 micrograms each of HPV types 6 and 18 VLPs and 40 micrograms each of HPV types 11 and 16 VLPs with alum, at months 0, 2, and 6 with follow-up through three years. This study did not exclude subjects with prior or ongoing HPV infection of any type [23]. Thus, women who were anti-HPV-seropositive and women who were HPV DNA-positive were eligible for enrollment. The trial was significant for the following results:

Overall protection against persistent HPV 16/18 infection (>4 months) occurred in 89 percent of women who received vaccination and follow-up visits according to protocol, with 100 percent, 86 percent, and 89 percent efficacy for HPV 6, 16, and 18, respectively. There were no cases of HPV 11 infection reported.
Protection against CIN caused by HPV 6/11/16/18 occurred in 100 percent of all participants who were not infected with these types at first vaccination while seven cases occurred in the placebo group.
Protection against all external genital warts caused by HPV 6/11 occurred in 100 percent of all participants with four cases occurring in the placebo group.
The vaccine was generally safe and well tolerated.
After three vaccine doses, seroconversion rates were 94, 96, 100, and 76 percent for HPV types 6, 11, 16, and 18 at month 36, respectively [37].
Two hundred forty-one of these study participants were subsequently enrolled in an extension trial to obtain an additional two years of follow-up data [38]. The combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced by 96 percent in vaccine recipients (two cases in the vaccine group versus 46 in the placebo group). Seropositivity for HPV 18 declined to 65 percent.

FUTURE II trial — In a phase III, multinational prospective, double-blind, placebo-controlled trial (FUTURE II), more than 12,000 women, aged 15 to 26 years (with a lifetime number of no more than four sexual partners), were randomly assigned to receive a three-dose regimen of vaccine or placebo [39,40]. The majority of the study participants were from Europe (65 percent) and Latin America (26 percent). At baseline, cervical cytology was abnormal in 11 percent of both vaccine and placebo groups; approximately 16 and 7 percent had evidence of HPV 16 and 18 infection, respectively.

The primary efficacy analysis was performed in those subjects who did not have evidence of either HPV 16 or 18 infection (by DNA or serologic testing) through one month after the third dose of vaccine; these patients were referred to as "HPV susceptible" per protocol. The primary composite end point was CIN 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV 16 or HPV 18. The mean duration of follow-up was three years. The study demonstrated the following results:

Vaccine efficacy for the prevention of the primary composite end point was 98 percent in study participants who were "HPV susceptible".
Vaccine efficacy remained high (95 percent) in those HPV-negative participants who did not receive all doses of vaccine according to protocol, suggesting some flexibility in the timing of the vaccine schedule.
Seroconversion rates at 24 months among 1512 vaccinated women in the immunogenicity substudy were 96, 97, 99, and 68 percent for HPV types 6, 11, 16, and 18, respectively.
The vaccine was well tolerated and there were no serious adverse events.
However, vaccine efficacy for CIN 2 or 3 disease due to all HPV types was significantly lower (44 percent) in the overall population of women who had undergone randomization, which included participants with baseline or incident HPV infection by one month after the last dose of vaccine.

FUTURE I trial — A similarly designed phase III placebo-controlled trial was conducted in 5455 women aged 16 to 24 years to assess the efficacy of quadrivalent vaccine to prevent HPV-related anogenital disease (FUTURE I) [41]. The primary aim of the trial was to determine vaccine efficacy in reducing the combined incidence of anogenital warts, vulvar or vaginal intraepithelial neoplasia grades 1 to 3 or cancer associated with HPV vaccine types 6, 11, 16, or 18. A secondary aim was to observe whether the administration of vaccine reduced the combined incidence of CIN grades 1 to 3, adenocarcinoma in situ, or cancer associated with vaccine-type HPV.

The following results were demonstrated after a mean follow-up of three years:

The vaccine was 100 percent effective in preventing anogenital disease in women who were "HPV susceptible" (ie, no cases were identified in the vaccine group versus 60 cases in the placebo group).
Vaccine efficacy was 100 percent in preventing CIN grades 1 to 3 or adenocarcinoma in situ with vaccine-type HPV in those women who were "HPV susceptible" (ie, no cases were diagnosed in the vaccine group, whereas 65 cases were diagnosed in placebo group).
As noted in the FUTURE II trial, vaccine efficacy was lower when women with baseline HPV infection were included in the intent-to-treat analysis (ie, 73 percent efficacy in prevention of external anogenital or vaginal lesions and 55 percent efficacy in the prevention of CIN).
There was no clear evidence that vaccination altered the course of disease or infection present before administration of the first dose of vaccine in both FUTURE I and II trials. These data reinforce the use of the HPV vaccine as a prophylactic, and not a therapeutic immunization. (See "Vaccine utilization" below).

A summary of the efficacy data from four placebo-controlled, double-blind, randomized Phase II and III clinical studies of the quadrivalent vaccine may also be viewed on the website for the US Food and Drug Administration (www.fda.gov).

VACCINE IMMUNOGENICITY — Natural infection induces antibody titers, most of which wane after three years [24] and are not protective against future infections of the same HPV type [42].

In the study of quadrivalent HPV vaccine discussed above [23], subjects with prior or ongoing HPV infection of any type were not excluded [23]. Thus, women who were anti-HPV-seropositive and women who were HPV DNA-positive were eligible for enrollment. An analysis of primary immunogenicity demonstrated the following [37]:

All of the subjects had detectable HPV 6, 11, 16, and 18 antibodies after completion of the vaccine series.
Anti-HPV geometric mean titers (GMT) were 27- to 145-fold higher than those observed in placebo recipients who were HPV-seropositive at baseline, suggesting that HPV vaccine leads to higher antibody titers than natural infection.
At month 36 of follow-up, vaccine-induced antibody titers were comparable or higher than that of natural infection.
In the subset of women with detectable HPV antibodies at baseline, HPV vaccine led to rapid inclines, higher peaks, and longer persistence of antibody levels compared to HPV-seronegative women, suggesting that HPV vaccine may induce amamnestic responses.
Similar excellent antibody responses have been reported for the bivalent HPV vaccine [43].

Cross-protection — Although certain HPV types share capsid epitopes that can elicit serologic cross-reactivity, it was uncertain as to whether vaccination would lead to only type-specific neutralizing antibodies. However, preliminary data suggest that both vaccines can also induce antibody formation to other phylogenetically related HPV types, some of which are associated with cervical cancer [44,45]. For example, two analyses of the 17,622 women who were enrolled in the FUTURE 1 and 2 trials demonstrated that vaccination with quadrivalent vaccine significantly reduced both the incidence of non-vaccine types (eg, HPV-31) and associated lesions of CIN and adenocarcinoma in situ [46,47]. These observations were true for women who were HPV-naive and for those who had preexisting HPV infection or HPV disease. Bivalent HPV vaccine also induced cross-protection against HPV-45, which is also associated with cervical cancer [48].

Duration of protection — The quadrivalent vaccine induces five-year antibody titers for HPV 16 that are 10-fold higher than natural infection titers, with more than 98 percent of women remaining seropositive [37]. On the other hand, the five-year antibody titers for HPV 18 are at natural infection titers with 65 percent of women remaining seropositive [37].

Preliminary data demonstrate that the bivalent vaccine induces 6.5-year antibody titers for HPV 16 and 18 that are 11-fold higher than those seen in natural infection with more than 98 percent of women maintaining their seropositivity for both types [32,33,49].

Because the antibody titers induced by the quadrivalent and bivalent vaccines are measured in type-specific and product-specific assays, the absolute GMTs cannot be compared. A relative ratio of vaccine to natural infection titers is currently in use until both vaccines can be evaluated by one assay system.

Recommendations — The Federal Food and Drug Administration has approved the use of quadrivalent HPV vaccine in girls and women 9 to 26 years of age.

The Advisory Committee on Immunization Practices (ACIP) recommends that HPV vaccine should be routinely offered to females between the ages of 11 through 26 (and may begin at age 9 years), and to anyone who has not completed their vaccination series [50-52]. A history of genital warts, abnormal Papanicolaou test result, or positive HPV DNA test result is not evidence of prior infection with all vaccine HPV types; the ACIP recommends HPV vaccine for persons with such histories. For full benefit, HPV vaccine should be administered before onset of sexual activity. Females who are sexually active should still be vaccinated consistent with age-specific recommendations; however, immunization is less beneficial for females who have already been infected with one of more of the HPV vaccine types [52].

The American College of Obstetricians and Gynecologists (ACOG) also suggests that routine inquiries regarding past HPV immunization should be made at an initial clinic visit with adolescents and young adults to facilitate "catch up" doses for those who missed earlier vaccination opportunities. (See "Human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine: Drug information").

The ACIP immunization schedule of 2009 also indicates that health care personnel are not at increased risk of HPV infection due to occupational exposure; age-based recommendations noted above still apply [52].

HPV vaccine is not specifically recommended for persons with immunodeficiency, HIV infection, or other chronic medical diseases, but can be considered, according to the ACIP guidelines, since it is not a live vaccine [52]. It should be noted, however, that the efficacy and safety of the HPV vaccine in these risk groups has not been established. Furthermore, cervical screening for HPV infection and disease continues to play an important role in preventing CIN and cervical cancer in these high-risk patients. (See "Cervical intraepithelial neoplasia: Definition; incidence; and pathogenesis" and see "HIV and women" and see "Immunizations in HIV-infected patients").

Other vaccine approaches have been considered for immunotherapy of cervical cancer as well as prevention of the acquisition of HPV infection. (See "Virology of human papillomavirus infections and the link to cancer").

VACCINE SAFETY — Virus-like particles (VLPs) are recombinant proteins, manufactured in biologic systems (yeast and Baculovirus), that, in general, are safe [19].

The clinical trials of the bivalent and quadrivalent vaccines have demonstrated mild injection site reactions [23,32]; no serious adverse events have been recorded, including one study with more than five years of follow-up [53]. Furthermore, HPV vaccine has been studied in diverse populations of women in both developed and developing countries [39,41].

Since 2006, more than 16 million doses of the vaccine have been distributed, with about one in four US adolescent girls receiving the vaccine [54]. In post-marketing surveillance, the vaccine adverse events reporting system (VAERS) has registered over 10,000 adverse events, most of which (94 percent) were not considered to be serious, including fainting, headache, nausea, fever, and pain and swelling at the injection site [54]. Due to reports of fainting, the manufacturer added a warning to monitor vaccinees for 15 minutes in the office after immunization [55].

The remaining 6 percent of adverse events reports after quadrivalent vaccine (Gardasil™) administration were classified as serious, including two cases of Guillain-Barre syndrome (GBS), seizures, thromboembolism, and 17 deaths (in 9 of which causation is inconclusive; 8 are unrelated). Analysis of the reports has not identified any pattern, suggesting that these events were not related to the vaccine itself [54]. A preliminary analysis from the CDC's Vaccine Safety Datalink regarding 375,000 doses of vaccine did not find an increased risk for these serious outcomes in persons who received vaccine compared to placebo [54]. Additional data on the Vaccine Adverse Event Reporting System are available on the web [56].

Ongoing reporting also continues for adverse events from coadministration of the quadrivalent vaccine with other vaccines, as there have been limited data available prior to regulatory approval.

Anaphylaxis has been reported following administration of the quadrivalent vaccine. In a mass school-based national vaccination program, the incidence of anaphylaxis was 2.6 per 100,000 doses; although this complication is rare, the incidence is higher than that associated with most other routinely administered vaccines [57]. (See "Allergic reactions to vaccines").

Neither HPV vaccine contains live virus; the quadrivalent vaccine has been classified as a category B drug by the FDA. However, use in pregnancy is not recommended because of limited data on safety in this setting. In the FUTURE II trial, pregnancy occurred in 1053 women in the vaccine group and 1106 in the placebo group; no obvious anomalies attributable to vaccine were observed [39].

Instructions for reporting adverse events to the Vaccine Adverse Event Reporting System are available at www.vaers.hhs.gov or by calling 800-822-7967 in the United States.

The manufacturer maintains a pregnancy registry to monitor fetal outcomes of pregnant women exposed to the vaccine. Exposures can be reported by calling 800-986-8999 [58]. However, lactating women can receive the immunization series since subunit vaccines do not affect the safety of infant breast-feeding. (See "Immunizations in pregnant women").

SPECIFIC ISSUES

Cost-effectiveness — Mathematical models have examined the cost-effectiveness of HPV vaccination [59-62]. One study suggested that vaccination of the entire United States population of 12-year-old girls would prevent more than 200,000 HPV infections, 100,000 abnormal cervical cytology examinations, and 3300 cases of cervical cancer if cervical cancer screening continued as currently recommended [59]. Studies have demonstrated that the effectiveness of HPV vaccination will depend on the duration of vaccine immunity, including one study that supported continued cost-effectiveness when the vaccine was given to 12- to 26-year-old females [63].

In models, vaccinating both men and women is predicted to be more beneficial in reducing HPV infection and disease than by vaccinating only women, but at a higher cost [64,65]. However, models of cost-effectiveness are plagued by substantial uncertainty regarding major issues such as duration of protection [66], the effect of herd immunity, and the prevalence of vaccine-specific HPV types circulating in age-specific populations [67]. (See "Epidemiology of human papillomavirus infections").

Vaccine utilization — Clinical trials of the HPV vaccines suggest high efficacy and an excellent safety profile in women who do not have abnormal cervical cytology or HPV infection at the time of immunization.

Several questions remain regarding vaccine utilization including [19]:

The duration of protection is unknown; protective antibodies persist for at least five years. Duration of protection is important in determining when booster vaccines will be needed [68].
The precise level of antibody needed for protection against infection is also unknown.
HPV exposure occurs at all ages of life, starting in infancy [69,70]. The risk of HPV exposure increases with the number of sexual partners, regardless of the age at which new partners are acquired [71]. Decisions about the age at which to initiate HPV immunization have been guided by epidemiologic data regarding ages of peak HPV acquisition and estimated duration of vaccine protection [4,18,26]. HPV vaccination has been recommended by the ACIP in girls and women 9 to 26 years of age.

The American Cancer Society (ACS) guidelines are in general agreement with the ACIP recommendations about the need for vaccination [71]. Studies are ongoing to determine vaccine efficacy in women older than 26 years.

Effective vaccination strategies will require further education of the public on the importance of HPV infection and its consequences [72]. A study of 400 women in a university setting demonstrated that awareness and knowledge of HPV was very limited [73]. Vaccination against cervical cancer will be especially important in developing countries, where nearly 80 percent of cancer cases are reported, and where screening cytologies are rarely used [74].

Molecular-based testing for HPV detection is NOT recommended prior to immunization [75]. (See "Clinical presentation and diagnosis of human papillomavirus infections", section on Diagnosis).

Efficacy in established infection — Since there are many HPV types that can infect the cervix, there are important distinctions that need to be made about the efficacy of the HPV vaccine in women with prior versus current HPV infection.

The HPV vaccine does not clear HPV infection that is present at the time of vaccination [75].
The absence of therapeutic efficacy for established infection was illustrated in a trial of 2189 women with cervical HPV DNA who were randomly assigned to receive either three doses of bivalent HPV 16/18 L1 virus-like particle vaccine or a control (hepatitis A) vaccine [76]. There was no evidence of increased viral clearance of established infection at 6 or 12 months in the group that received HPV vaccine. Likewise, in FUTURE II, there was no therapeutic efficacy of three doses of the quadrivalent vaccine to prevent CIN 2/3 in women with established infection compared to placebo [77].

The HPV vaccine can still protect women with current HPV infections from acquisition of additional HPV types (ie, HPV 6,11,16,18) [77].
The HPV vaccine can prevent women with past exposure (serologically positive, but cytologically DNA-negative) from acquiring the same HPV-type infection in the future at the same 100 percent efficacy [41].
The vaccine was effective in preventing CIN 2/3 or adenocarcinoma in situ in a subgroup of 4722 women from the FUTURE 1 and FUTURE 2 studies who had evidence of current infection with at least one cancer-causing HPV vaccine type (16 or 18) at the time of vaccination, but were naive to the other vaccine type [77]. These data suggest that vaccinating a woman currently infected with 16 or 18 can still confer benefit in preventing infection with the other oncogenic HPV types.

IMPORTANCE OF CERVICAL SCREENING — Appropriate use of cervical cytology has reduced the death rate from cervical cancer by 74 percent in the past five decades [78]. However, there are limitations to cervical screening:

Many women do not seek or receive cervical screening, especially minority groups and recent immigrants.
The results of cervical cytology smears cannot be used to make a definitive diagnosis or to initiate treatment (See "Cervical cytology report").
Despite optimal cytologic screening strategies, cervical cancers still occur [79].
Cytologic screening is of paramount importance since HPV immunization is NOT effective in clearing cytologically evident disease or infection. Furthermore, neither vaccine can prevent all types of cervical cancers. Strategic linking of immunization initiatives to cervical screening programs may be effective in reducing the number of abnormal cytology results and in reducing the number of cervical cancers not detected by cervical cytology [10]. (See "Cervical cytology report" and see "Epidemiology of human papillomavirus infections", section on Prevalence).

Cytologic screening is recommended for any woman who has been sexually active for three or more years or is 21 years of age. A preventive health care visit in which vaccination is discussed or offered represents an ideal opportunity to offer Pap screening to sexually active patients as well [71].

In contrast, in the young child or adolescent, the pubertal, physiologic, and psychological development of the young child or adolescent needs to be considered; thus cervical screening should not be considered until at least three years have passed after the onset of sexual activity.

PREVENTION OF VULVAL AND VAGINAL LESIONS — Vulvar and vaginal cancers are uncommon complications of HPV infection, which are preceded by vulva intraepithelial neoplasia (VIN2-3) and vaginal intraepithelial neoplasia (VaIN2-3). Data from three placebo-controlled clinical trials evaluating the quadrivalent HPV vaccine for cervical cancer were combined to assess the potential effect of immunization on the prevention of moderate to severe vulvar intraepithelial neoplasia (VIN-2 and VIN-3) [36]. Among 15,596 women who were naive to HPV 16 or 18 infection through one month after the final dose of vaccine, immunization was 100 percent effective against the development of VaIN-2/3 and VIN-2/3 caused by HPV 16/18 over a mean follow-up time of three years (ie, no cases demonstrated in vaccinated group; 13 in the placebo group). In the intention to treat population of 18,174 women, vaccine efficacy was 49 percent for VaIN or VIN grades 2 or 3, irrespective of HPV type (27 cases in the vaccinated group; 53 cases in the placebo group).

VACCINATION IN MEN — Studies of male vaccination to prevent HPV-associated genital warts and cancers occurring in men are ongoing [19,80], but mathematical models suggest that male vaccination may not be cost-effective for the prevention of cervical cancer in women [59,71,81].

VACCINATION IN OLDER WOMEN — Epidemiologic studies have shown that there are two peaks of incident HPV infections; the first occurs in those younger than 25 years, followed by a second peak after menopause [82].

However, the vast majority of studies of HPV vaccine have been performed in young women 25 years of age and younger. As discussed above, studies have shown that those who were naive to all four vaccine HPV types (by serologic and HPV DNA testing) derive full benefit of vaccine, whereas women who are infected with one or more vaccine types before immunization will only derive partial benefit (ie, protection from the types that the participants were not infected with at baseline).

A phase III placebo-controlled trial was performed in 3819 women aged 24 to 45 years with no history of genital warts or cervical disease who were randomly assigned to quadrivalent HPV vaccine (types 5, 11, 16, 18) versus placebo [83]. The coprimary endpoints were the combined incidence of infection and cervical and external genital disease (including cervical, vulvar, or vaginal intraepithelial neoplasia; adenocarcinoma in situ; cervical, vulvar, or vaginal cancer; and genital warts) related to HPV 6, 11, 16, or 18; and to HPV 16 or 18 alone. The secondary efficacy endpoint was the combined incidence of infection related to HPV types 6 or 11 and genital disease. For evaluation of disease, all participants underwent a complete gynecologic examination at day 1 and months 7, 12, 24, 36, and 48; HPV infection was assessed by multiplex PCR testing at baseline and follow-up.

To be eligible for the per-protocol efficacy analyses, the study participants had to be HPV-seronegative and PCR-negative for the relevant HPV types and completed all three doses of vaccine with follow-up visits. The intention-to-treat analysis included all women who received at least one dose of vaccine or placebo and had one follow-up visit. The trial demonstrated the following:

Approximately one-third had evidence of HPV infection by serologic testing; however, only 8 percent were infected with a vaccine HPV type at baseline as determined by DNA testing.
Vaccine-induced antibody titers were similar in women aged 24 to 34 years and 35 to 45 years.
Efficacy against infection or disease with any vaccine HPV type was 91 percent in the per-protocol analysis. In the intention-to-treat population, efficacy was 31 percent.
Efficacy against the combined incidence of infection or disease with HPV types 16 or 18 was 83 percent, while efficacy against HPV types 6 or 11 was 100 percent.
The vaccine was generally well tolerated.
These results suggest that the quadrivalent HPV vaccine is efficacious in women aged 24 to 45 years who are uninfected with the relevant HPV types before immunization.

FUTURE IMPACT OF HPV VACCINE — The impact of HPV vaccination programs on reduction of cervical cancer in the future will be dependent on multiple issues, such as the amount of circulating HPV types in the population, the percent of patients vaccinated, and the duration of protection [71]. Another important factor will be whether patients and providers continue to adhere to recommendations for cervical screening, since premature cessation of these preventive interventions could lead to an increase in cervical cancer rates.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Human papillomavirus (HPV) vaccine" and see "Patient information: Condyloma (genital warts) in women" and see "Patient information: Cervical cancer screening"). We encourage you to print or e-mail these topic reviews, or to refer patients to our public web site, www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS

Persistent infection with high-risk oncogenic HPV types may lead to cervical intraepithelial neoplasia and cervical cancer [84], the second most common malignant disease in women worldwide. (See "Introduction" above).
Multicenter, double blind, placebo-controlled trials for both quadrivalent and bivalent HPV vaccines demonstrate efficacy against incident and persistent HPV infection and abnormal histology. Bivalent HPV 16/18 L1 VLP AS04 adjuvanted vaccine has been submitted to the FDA for approval; quadrivalent HPV 6/11/16/18 L1 VLP vaccine is available for use and distribution. The quadrivalent vaccine also prevents most genital warts. (See "Vaccine development" above).
Both vaccines in general are safe. Post-marketing side effects have been reported for the quadrivalent vaccine. (See "Vaccine safety" above).
We recommend immunization with HPV vaccine, as suggested by the ACIP and ACOG (Grade 1A). The currently suggested immunization schedule is in girls and women 9 to 26 years of age. Quadrivalent HPV 6/11/16/18 L1 VLP vaccine (Gardasil™) is administered in three doses at 0, 2, and 6 months. The duration of immunity is unknown. (See "Vaccine development" above).
Cytologic screening is recommended for any woman who has been sexually active for three or more years or is 21 years of age. Clinicians need to be aware that HPV immunization is NOT effective in clearing cytologically evident disease or infection. A preventive health care visit in which vaccination is discussed or offered represents an ideal opportunity to offer Pap screening to sexually active patients as well. (See "Vaccine utilization" above).
Vaccination can be offered to females as young as nine years of age. Cervical screening is not appropriate until pubertal, physiologic, and psychological development has been established and at least three years from onset of sexual activity has passed.
HPV vaccine is a major advance in the prevention of cervical cancer, but it will not replace the need for other preventive strategies, such as cervical screening. (See "Importance of cervical screening" above).
ACKNOWLEDGMENT — The editors of UpToDate would like to acknowledge Diane M Harper, MD, MPH, MS, who contributed to earlier versions of this topic review.



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[Dr.B]

Human Papillomaviruses and Cancer: Questions and Answers

Key Points

* Human papillomaviruses (HPVs) are a group of more than 100 related viruses (see Question 1).
* Genital HPV infections are very common and are sexually transmitted. Most HPV infections occur without any symptoms and go away without any treatment over the course of a few years (see Question 1, 4 and 5).
* However, HPV infection sometimes persists for many years. Such infections are the primary cause of cervical cancer. HPVs may also play a role in cancers of the anus, vulva, vagina, penis, as well as oropharyngeal cancer (see Question 3).
* In 2006, the U.S. Food and Drug Administration approved Gardasil®, a vaccine that is highly effective in preventing infection with two high-risk HPVs that cause most cervical cancers and genital warts (see Question 6).
* The warts and other benign lesions caused by HPV infection can be treated (see Question 10).
* Researchers at the National Cancer Institute and elsewhere are conducting research on HPV-related cancers (see Question 11).

1. What are human papillomaviruses, and how are they transmitted?

Human papillomaviruses (HPVs) are a group of more than 100 related viruses. They are called papillomaviruses because certain types may cause warts, or papillomas, which are benign (noncancerous) tumors. The HPVs that cause the common warts which grow on hands and feet are different from those that cause growths in the throat or genital area. Some types of HPV are associated with certain types of cancer (1). These are called high-risk, oncogenic, or carcinogenic HPVs.

Genital HPV infections are very common and are sexually transmitted. Of the more than 100 types of HPV, more than 30 types can be passed from one person to another through sexual contact. Although HPVs are usually transmitted sexually, doctors cannot say for certain when infection occurred. Most HPV infections occur without any symptoms and go away without any treatment over the course of a few years. However, HPV infection sometimes persists for many years, with or without causing cell abnormalities. This can increase a woman’s risk of developing cervical cancer.
2. What are genital warts?

Some types of HPV may cause warts to appear on or around the genitals or anus. Genital warts (technically known as condylomata acuminata) are most commonly associated with two HPV types, HPV–6 and HPV–11. Warts may appear within several weeks after sexual contact with a person who is infected with HPV, or they may take months or years to appear, or they may never appear. HPVs may also cause flat, abnormal growths in the genital area and on the cervix (the lower part of the uterus that extends into the vagina). However, HPV infections of the cervix usually do not cause any symptoms.
3. What is the association between HPV infection and cancer?

Persistent HPV infections are now recognized as the major cause of cervical cancer. In 2007, it was estimated that 11,000 women in the United States would be diagnosed with this type of cancer and nearly 4,000 would die from it. Cervical cancer strikes nearly half a million women each year worldwide, claiming a quarter of a million lives. Studies also suggest that HPVs may play a role in some cancers of the anus, vulva, vagina, and penile cancer (cancer of the penis) (2).

Studies have also found that oral HPV infection is a strong risk factor for oropharyngeal cancer (cancer that forms in tissues of the oropharynx, which is the middle part of the throat and includes the soft palate, the base of the tongue, and the tonsils) (2, 3). Researchers found that an oral HPV infection and past HPV exposure increase the risk of oropharyngeal squamous cell cancer, regardless of tobacco and alcohol use, two other important risk factors for this disease. However, combining HPV exposure and heavy tobacco and alcohol use did not have an additive effect (3).
4. Are there specific types of HPV that are associated with cancer?

Some types of HPV are referred to as “low-risk” viruses because they rarely cause lesions that develop into cancer. HPV types that are more likely to lead to the development of cancer are referred to as “high-risk.” Both high-risk and low-risk types of HPV can cause the growth of abnormal cells, but only the high-risk types of HPV lead to cancer. Sexually transmitted, high-risk HPVs include types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 73 (4). These high-risk types of HPV cause growths on the cervix that are usually flat and nearly invisible, as compared with the external warts caused by low-risk types HPV–6 and HPV–11. HPV types 16 and 18 together cause about 70 percent of cervical cancers (4, 5). It is important to note, however, that the great majority of high-risk HPV infections go away on their own and do not cause cancer (5).
5. What are the risk factors for HPV infection and cervical cancer?

Having many sexual partners is a risk factor for HPV infection. Although most HPV infections go away on their own without causing any type of abnormality, infection with high-risk HPV types increases the chance that mild abnormalities will develop and progress to more severe abnormalities or cervical cancer. However, even among the women who do develop abnormal cell changes with high-risk types of HPV, only a small percentage would develop cervical cancer if the abnormal cells were not removed. As a general rule, the more severe the abnormal cell change, the greater the risk of cancer. Studies suggest that whether a woman develops cervical cancer depends on a variety of factors acting together with high-risk HPVs. The factors that may increase the risk of cervical cancer in women with HPV infection include smoking and having many children (5).
6. Can HPV infection be prevented?

The surest way to eliminate risk for genital HPV infection is to refrain from any genital contact with another individual.

For those who choose to be sexually active, a long-term, mutually monogamous relationship with an uninfected partner is the strategy most likely to prevent genital HPV infection. However, it is difficult to determine whether a partner who has been sexually active in the past is currently infected.

HPV infection can occur in both male and female genital areas that are covered or protected by a latex condom, as well as in areas that are not covered. Although the degree of protection provided by condoms in preventing HPV infection is unknown, condom use has been associated with a lower rate of cervical cancer.

In 2006, the U.S. Food and Drug Administration (FDA) approved Gardasil®, a vaccine that is highly effective in preventing infection with types 16 and 18, two “high-risk” HPVs that cause most (70 percent) cervical cancers (4), and types 6 and 11, which cause most (90 percent) genital warts (5).
7. How are HPV infections detected?

Testing samples of cervical cells is an effective way to identify high-risk types of HPV that may be present. The FDA has approved an HPV test as a follow-up for women who have an ambiguous Pap test (a screening test to detect cervical cell changes) and, for women over the age of 30, for general cervical cancer screening. This HPV test can identify at least 13 of the high-risk types of HPV associated with the development of cervical cancer. This test, which looks for viral DNA, is performed by collecting cells from the cervix and then sending them to a laboratory for analysis. The test can detect high-risk types of HPV even before there are any conclusive visible changes to the cervical cells. There are currently no approved tests to detect HPV infection in men.
8. How are cervical cell abnormalities classified?

A Pap test is used to detect abnormal cells in the cervix. It involves the collection of cells from the cervix for examination under the microscope. Various terms have been used to describe the abnormal cells that may be seen in Pap tests.

The major system used to report the results of Pap tests in the United States is the Bethesda System. In this system, samples with cell abnormalities are divided into the following categories:

• ASC—Atypical Squamous Cells. Squamous cells are the thin, flat cells that form the
surface of the cervix. The Bethesda System divides this category into two groups:

1. ASC–US—Atypical Squamous Cells of Undetermined Significance. The squamous cells do not appear completely normal, but doctors are uncertain what the cell changes mean. Sometimes the changes are related to HPV infection. An HPV test may be done to clarify the findings.

2. ASC–H—Atypical Squamous Cells cannot exclude a High-grade squamous
intraepithelial abnormality. Intraepithelial refers to the layer of cells that forms the surface of the cervix. The cells do not appear normal, but doctors are uncertain what the cell changes mean. ASC–H may indicate a higher risk of being precancerous compared with ASC–US.

• AGC—Atypical Glandular Cells. Glandular cells are mucus-producing cells found in
the endocervical canal (opening in the center of the cervix) or in the lining of the uterus. The glandular cells do not appear normal, but doctors are uncertain what the cell changes mean.

• AIS—endocervical Adenocarcinoma In Situ. Precancerous cells are found in the
glandular tissue.

• LSIL—Low-grade Squamous Intraepithelial Lesion. Low-grade means there are early changes in the size and shape of the cells. The word lesion refers to an area of abnormal tissue. LSILs are considered mild abnormalities caused by HPV infection and are a common condition, especially among young women. The majority of LSILs return to normal over months to a few years.

• HSIL—High-grade Squamous Intraepithelial Lesion. High-grade means that the cells look very different in size and shape from normal cells. HSILs are more severe abnormalities and may eventually lead to cancer if left untreated.

Pap test results may also be described using an older set of categories called the “dysplasia scale.” Dysplasia is a term used to describe abnormal cells. Although dysplasia is not cancer, it may develop into very early cancer of the cervix. The cells look abnormal under the microscope, but they do not invade nearby healthy tissue.
There are four degrees of dysplasia: mild, moderate, severe, and carcinoma in situ. Carcinoma in situ is a precancerous condition that involves only the layer of cells on the surface of the cervix, and has not spread to nearby tissues. In the Bethesda System, mild dysplasia is classified as LSIL; moderate or severe dysplasia and carcinoma in situ are combined into HSIL.

Cervical intraepithelial neoplasia (CIN) is another term that is sometimes used to describe abnormal tissue findings. Neoplasia means an abnormal growth of cells. The term CIN along with a number (1, 2, or 3) describes how much of the thickness of the lining of the cervix contains abnormal cells. CIN–3 is considered to be a precancerous condition that includes carcinoma in situ.
9. What tests are used to screen for and diagnose precancerous cervical conditions?

A Pap test is the standard way to check for any cervical cell changes. A Pap test is usually done as part of a gynecologic exam. The U.S. Preventive Services Task Force guidelines recommend that women have a Pap test at least once every 3 years, beginning about 3 years after they begin to have sexual intercourse, but no later than age 21.

Because the HPV test can detect high-risk types of HPV in cervical cells, the FDA approved this test as a useful addition to the Pap test to help health care providers decide which women with ASC–US need further testing, such as colposcopy and biopsy of any abnormal areas. (Colposcopy is a procedure in which a lighted magnifying instrument called a colposcope is used to examine the vagina and cervix. Biopsy is the removal of a small piece of tissue for diagnosis.) In addition, the HPV test can be a helpful addition to the Pap test for general screening of women age 30 and over.
10. What are the treatment options for HPV infection?

Although there is currently no medical cure for human papillomavirus infection, the lesions and warts these viruses cause can be treated. Methods commonly used to treat lesions include cryosurgery (freezing that destroys tissue), LEEP (loop electrosurgical excision procedure, the removal of tissue using a hot wire loop), and conventional surgery. Similar treatments may be used for external genital warts. In addition, some drugs may be used to treat external genital warts (6). More information about treatment for genital warts can be found on the Centers for Disease Control and Prevention’s (CDC) Sexually Transmitted Diseases Treatment Guidelines Web page at http://www.cdc.gov/STD/treatment/ on the Internet.
11. What research is being done on HPV-related cancers?

Researchers at the National Cancer Institute (NCI), a part of the National Institutes of Health (NIH), and elsewhere are studying how HPVs cause precancerous changes in normal cells and how these changes can be prevented (7). Scientists are also developing HPV vaccines that will be stable at room temperature and that protect against more HPV types.
The goal is to develop a vaccine that does not require refrigeration for storage and distribution, which could allow for its use in many climates and locations.

Laboratory research has indicated that HPVs produce proteins known as E5, E6, and E7. These proteins interfere with the cell functions that normally prevent excessive growth. For example, HPV E6 interferes with the human protein p53. This protein is present in all people and acts to keep tumors from growing (8). This research is being used to develop ways to interrupt the process by which HPV infection can lead to the growth of abnormal cells.

Researchers at the NCI and elsewhere are also studying what people know and understand about HPV infection and cervical cancer, the best way to communicate the latest research results to the public, and how doctors are talking with their patients about HPV infection. This research will help to ensure that the public receives accurate information about HPV that is easily understood and will facilitate access to appropriate tests for those who need them.
12. How can people learn more about HPV infection?

The following Federal Government agencies can provide more information about HPV infection:

The NCI’s HPV (Human Papillomavirus) Vaccines for Cervical Cancer Digest Page provides links to NCI materials about HPV vaccines as well as general information about HPV, cancer vaccines, and cervical cancer. This Web site can be found at http://www.cancer.gov/cancertopics/hpv-vaccines on the Internet.

The National Institute of Allergy and Infectious Diseases (NIAID), another part of the NIH, supports research on HPV infection and offers printed materials. NIAID can be contacted at:
Organization: National Institute of Allergy and Infectious Diseases
Address: Office of Communications and Public Liaison
6610 Rockledge Drive, MSC 6612
Bethesda, MD 20892–6612
Telephone: 301–496–5717
TTY: 1–800–877–8339
Web site: http://www3.niaid.nih.gov

The CDC-INFO Contact Center provides information on sexually transmitted infections, including HPV, and how to prevent them. The center can be reached by calling toll-free 1–800–CDC–INFO (1–800–232–4636). Both English- and Spanish-speaking specialists are available 24 hours a day, 7 days a week, 365 days a year. Staff provide information about sexually transmitted diseases (STDs) and referrals to free or low-cost clinics nationwide. Free educational literature about sexually transmitted infections and prevention methods is also available. More information from the CDC about sexually transmitted infections is available at http://www.cdc.gov/std on the Internet. The CDC’s Division of STD Prevention Web site also has information about HPV, including treatment guidelines and surveillance statistics. This Web site can be found at http://www.cdc.gov/std/hpv/ on the Internet.

Selected References

1. Division of STD Prevention. Prevention of genital HPV infection and sequelae: Report of an external consultants’ meeting. Atlanta, GA: Centers for Disease Control and Prevention, 1999.

2. Parkin DM. The global health burden of infection-associated cancers in the year 2002. International Journal of Cancer 2006; 118:3030–3044.

3. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. New England Journal of Medicine 2007; 356:1944–1956.

4. Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. International Journal of Cancer 2004;111:278–285.

5. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. The Lancet 2007; 370:890–907.

6. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report 2002; 51(RR-6):1–78.

7. National Cancer Institute. Future directions in epidemiologic and preventive research on human papillomaviruses and cancer. Proceedings of a workshop. Bethesda, Maryland, June 2002. Journal of the National Cancer Institute Monographs 2003; 31:1–130.

8. Howley PM, Ganem D, Kieff E. Etiology of cancer: Viruses. Section 2: DNA Viruses. In: DeVita VT Jr., Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. Vol. 1 and 2. 6th ed. Philadelphia: Lippincott Williams and Wilkins, 2004.

# # #

Related NCI materials and Web pages:

* National Cancer Institute Fact Sheet 4.21, Human Papillomavirus (HPV) Vaccines: Questions and Answers
(http://www.cancer.gov/cancertopics/f...on/HPV-vaccine)
* National Cancer Institute Fact Sheet 5.16, The Pap Test: Questions and Answers
(http://www.cancer.gov/cancertopics/f...ction/Pap-test)
* NCI’s HPV (Human Papillomavirus) Vaccines for Cervical Cancer Digest Page
(http://www.cancer.gov/cancertopics/hpv-vaccines)
* Understanding Cervical Changes: A Health Guide for Women
(http://www.cancer.gov/cancertopics/u...ervicalchanges)
* What You Need To Know About™ Cancer of the Cervix
(http://www.cancer.gov/cancertopics/wyntk/cervix)

For more help, contact:

NCI's Cancer Information Service
Telephone (toll-free): 1–800–4–CANCER (1–800–422–6237)
TTY (toll-free): 1–800–332–8615
LiveHelp® online chat: https://cissecure.nci.nih.gov/livehelp/welcome.asp

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[Dr.B]

ACOG = American College of Obstetricians & Gynecologysts

HPV Vaccine - ACOG Recommendations

The U.S. Food and Drug Administration recently approved a quadrivalent human papillomavirus (HPV) vaccine for females aged 9–26 years. The American College of Obstetricians and Gynecologists (ACOG) recommends the vaccination of females in this age group. The Advisory Committee on Immunization Practices has recommended that the vaccination routinely be given to girls when they are 11 or 12 years old. Although obstetrician–gynecologists are not likely to care for many girls in this initial vaccination target group, they are critical to the widespread use of the vaccine for females aged 13–26 years. Specific recommendations regarding the use of the quadrivalent HPV vaccine will be published in the September 2006 issue of Obstetrics & Gynecology. Because of the urgent nature of this information, excerpts of the recommendations are being posted online in advance of publication.
Recommendations
Vaccination of Girls, Adolescents, and Young Women
The ACOG Committee on Adolescent Health Care and the ACOG Working Group on Immunization recommend the vaccination of females aged 9–26 years against HPV. The Advisory Committee on Immunization Practices has recommended the initial vaccination target of females aged 11 or 12 years (1). Although obstetrician–gynecologists are not likely to care for many girls in this initial vaccination target group, they are critical to the widespread use of the vaccine for females aged 13–26 years. The American College of Obstetricians and Gynecologists has recommended that the first adolescent reproductive health care visit take place between ages 13 years and 15 years (2). Adolescents and young women aged 16–26 years who are in the vaccination age groups visit obstetrician–gynecologists for primary care, contraceptive or other gynecologic needs, or pregnancy-related services. These visits are a strategic time to discuss HPV and the potential benefit of the HPV vaccine and to offer vaccination to those who have not already received it. During a health care visit with a girl or woman in the age range for vaccination, an assessment of the patient’s HPV vaccine status should be conducted and documented in the patient record.
Cervical Cytology Screening
Current cervical cytology screening recommendations remain unchanged and should be followed regardless of vaccination status (2–6). Cervical cancer screening should begin approximately 3 years after the onset of vaginal intercourse or no later than age 21 years (5). After the first screening, annual cervical cytology screening should be conducted for women younger than 30 years (6). It must be emphasized that the currently approved quadrivalent vaccine protects against acquisition of HPV genotypes that account for only
70% of HPV-related cervical cancer and only 90% of genital warts cases (7). The vaccine is a preventive tool and is not a substitute for cancer screening.
Human Papillomavirus Testing
Testing for HPV is currently not recommended before vaccination. Testing for HPV DNA would not identify past HPV infections, only current HPV infections. Serologic assays for HPV are unreliable and currently not commercially available. Requiring any type of screening test would raise the cost of vaccination programs dramatically and reduce the cost-effectiveness of vaccination.
Vaccination of Sexually Active Women
Sexually active women can receive the quadrivalent HPV vaccine. Women with previous abnormal cervical cytology or genital warts also can receive the quadrivalent HPV vaccine. These patients should be counseled that the vaccine may be less effective in women who have been exposed to HPV before vaccination than in women who were HPV naive at the time of vaccination (8, 9). Women with previous HPV infection will benefit from protection against disease caused by the HPV vaccine genotypes with which they have not been infected. The need for annual cervical cytology screening should be emphasized.
Vaccination of Women With Previous Cervical Intraepithelial Neoplasia
There is concern that provision of the vaccination to women with previous cervical intraepithelial neoplasia may create a false sense of protection, potentially deterring patients from continuing their regular screening and management. The quadrivalent vaccine can be given to patients with previous cervical intraepithelial neoplasia, but practitioners need to emphasize that the benefits may be limited, and cervical cytology screening and corresponding management based on ACOG recommendations must continue.
Vaccination Is Not Treatment
The quadrivalent HPV vaccine is not intended to treat patients with cervical cytologic abnormalities or genital warts. Patients with these conditions should undergo the appropriate evaluation and treatment. It is important to note that many early cytologic abnormalities can be detected and managed conservatively given the significant rate of regression. This is especially true in adolescents and young women (4, 10).
Vaccination of Pregnant and Lactating Women
The quadrivalent HPV vaccine has been classified by the FDA as pregnancy category B. Although its use in pregnancy is not recommended, no teratogenic effects have been reported in animal studies. In clinical studies, the proportion of pregnancies with an adverse outcome was comparable in women who received the quadrivalent HPV vaccine
and in women who received a placebo (8). The manufacturer’s pregnancy registry should be contacted if pregnancy is detected during the vaccination schedule. Completion of the series should be delayed until pregnancy is completed. It is not known whether vaccine antigens or antibodies found in the quadrivalent vaccine are excreted in human milk (8). Lactating women can receive the quadrivalent HPV vaccine because inactivated vaccines such as this vaccine do not affect the safety of breastfeeding for mothers or infants (11).
Vaccination of Immunosuppressed Patients
The presence of immunosuppression, like that experienced in patients with HIV infection, is not a contraindication to the quadrivalent HPV vaccine. However, the immune response may be smaller in the immunocompromised patient than in immunocompetent patients (8).
Vaccination of Women Older Than 26 Years and Males
Research regarding vaccination of women older than 26 years and males is currently under way. Data available are insufficient to make recommendations for these populations.
For additional information prior to the release of the September 2006 issue of Obstetrics & Gynecology, please refer to the following web sites:
􀂾
Product approval information for GARDASIL www.fda.gov/cber/products/hpvmer060806.htm
􀂾
FDA Office of Women's Health Fact Sheet—HPV www.fda.gov/womens/getthefacts/hpv.html
􀂾
HPV Vaccine Questions and Answers www.cdc.gov/std/hpv/STDFact-HPV-vaccine.htm
􀂾
The Society for Adolescent Medicine held a webcast on “HPV: Human Papillomavirus: What You Need to Know” in March 2006, which contained information on how to talk to parents about the vaccine for their children. It is available at: www.adolescenthealth.org/cme/program_hpv .
References
1. Centers for Disease Control and Prevention. HPV vaccine [human papillomavirus (HPV) and the HPV vaccine]. Atlanta (GA): CDC. Available at: www.cdc.gov/nip/vaccine/hpv/ . Retrieved July 26, 2006.
2. American College of Obstetricians and Gynecologists. Primary and preventive health care for female adolescents. In: Health care for adolescents. Washington, DC : ACOG; 2003. p. 1–24.
3. Human papillomavirus. ACOG Practice Bulletin No. 61. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005;105:905–18.
4. Evaluation and management of abnormal cervical cytology and histology in the adolescent. ACOG Committee Opinion No. 330. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006:107:963–8.
5. Cervical cancer screening in adolescents. ACOG Committee Opinion No. 300. American College of Obstetricians and Gynecologists. Obstet Gynecol 2004;104:885–9.
6. Cervical cytology screening. ACOG Practice Bulletin No. 45. American College of Obstetricians and Gynecologists. Obstet Gynecol 2003;102:417–27.
7. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995;87:796–802.
8. Prescribing information for GARDASIL. Whitehouse Station (NJ): Merck & Co., Inc.; 2006. Available at: http://www.merck.com/product/usa/pi_...ardasil_pi.pdf . Retrieved June 26, 2006.
9. Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley DJ, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial [published erratum appears in Obstet Gynecol 006;107:1425]. Obstet Gynecol 2006;107:18–27.
10. Moscicki AB, Shiboski S, Broering J, Powell K, Clayton L, Jay N, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr 1998;132:277–84.
11. Atkinson WL, Pickering LK, Schwartz B, Weniger BG, Iskander JK, Watson JC. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51(RR-2):1–35.

[Numismatist]

Originally Posted by Brunotheboxer

That waiver thing alone scares me.

To say nothing of the Vaccine Court you have to go through if you want to try and sue them for anything...

[redshirt1957]

Just to be safe I had my wife get two H1N1 shots. The third breast she grew really comes in handy.


What is funny is that I lived in Salt Lake City and heard the same arguments for and against treating water with fluoride. Lots of dentist in SLC as they do not add fluoride to the water supply. Made me remember the movie Dr. Strangelove. If you get the shot fine. If you don't fine. Those with childern need to decide for their kids. Whatever you do, if you are sick.....stay HOME.

[Dr.B]

"Just to be safe I had my wife get two H1N1 shots. The third breast she grew really comes in handy"

[zseriessub]

Originally Posted by Dr.B

John:
Be insulting...? We are all ignorant in many aspects.
Being ignorant is not a bad thing per say.
Ignorant:
1. lacking in knowledge or training; unlearned: an ignorant man.
2. lacking knowledge or information as to a particular subject or fact: ignorant of quantum physics.
3. uninformed; unaware.
4. due to or showing lack of knowledge or training: an ignorant statement.

Unless you are a physician with the training then you can't compare what I know to what you know with anything to do with medicine. Just like many here are experts in watches, I am quite ignorant in watches....but I do strive to learn.

I do apologize if I offended you....but facts are facts.

I work at a hospital and what you are saying pretty much echoes what the docs I work with are saying. So I guess, I'll be getting mine.

[Dr.B]

Originally Posted by Omega_Precision

If vaccines wiped out polio, then polio should be extinct, therefore there is no need for anymore polio vaccinations. Unless a case occured?......I have never knew or heard of anyone catching polio in my life.

Just wanted to share some info.

Polio in the USA has essentially been eradicated, however it does continue in selected countries.

Here is some info from the "WHO"



Fact sheet N°114
Updated January 2008

Poliomyelitis


Key facts

* Polio (poliomyelitis) mainly affects children under five years of age.
* One in 200 infections leads to irreversible paralysis (usually in the legs). Among those paralysed, 5% to 10% die when their breathing muscles become immobilized.
* Polio cases have decreased by over 99% since 1988, from an estimated 350 000 cases then, to 1997 reported cases in 2006. The reduction is the result of the global effort to eradicate the disease.
* In 2008, only four countries in the world remain polio-endemic, down from more than 125 in 1988. The remaining countries are Afghanistan, India, Nigeria and Pakistan.
* Persistent pockets of polio transmission in northern India, northern Nigeria and the border between Afghanistan and Pakistan are the current focus of the polio eradication initiative.
* As long as a single child remains infected, children in all countries are at risk of contracting polio. Between 2003 and 2005, 25 previously polio-free countries were re-infected due to imports of the virus.
* In most countries, the global effort has expanded capacities to tackle other infectious diseases by building effective surveillance and immunization systems. Knowledge of the poliovirus has expanded with aggressive research carried out under the eradication effort.
* Success for the effort hinges on closing a substantial funding gap to finance next steps of the global eradication initiative.

Polio and its symptoms

Polio is a highly infectious disease caused by a virus. It invades the nervous system, and can cause total paralysis in a matter of hours. The virus enters the body through the mouth and multiplies in the intestine. Initial symptoms are fever, fatigue, headache, vomiting, stiffness in the neck and pain in the limbs. One in 200 infections leads to irreversible paralysis (usually in the legs). Among those paralysed, 5% to 10% die when their breathing muscles become immobilized.

People most at risk

Polio mainly affects children under five years of age.

Prevention

There is no cure for polio, it can only be prevented. Polio vaccine, given multiple times, can protect a child for life.

Global caseload

Polio cases have decreased by over 99% since 1988, from an estimated 350 000 cases in more than 125 endemic countries then, to 1997 reported cases in 2006. In 2008, only parts of four countries in the world remain endemic for the disease - the smallest geographic area in history.

The Global Polio Eradication Initiative

Launch

In 1988, the forty-first World Health Assembly, consisting then of delegates from 166 Member States, adopted a resolution for the worldwide eradication of polio. It marked the launch of the Global Polio Eradication Initiative, spearheaded by the World Health Organization (WHO), Rotary International, the US Centers for Disease Control and Prevention (CDC) and UNICEF. This followed the certification of the eradication of smallpox in 1980, progress during the 1980s towards elimination of the poliovirus in the Americas, and Rotary International’s commitment to raise funds to protect all children from the disease.

Progress

Overall, in the 20 years since the Global Polio Eradication Initiative was launched, the number of cases has fallen by over 99%. In 2008, only four countries in the world remain polio-endemic.

In 1994, the World Health Organization (WHO) Region of the Americas (36 countries) was certified polio-free, followed by the WHO Western Pacific Region (37 countries and areas including China) in 2000 and the WHO European Region (51 countries) in June 2002.

In 2007, more than 400 million children were immunized in 27 countries during 164 supplementary immunization activities (SIAs). Globally, polio surveillance is at historical highs, as represented by the timely detection of cases of acute flaccid paralysis.

Persistent pockets of polio transmission in northern India, northern Nigeria and the border between Afghanistan and Pakistan are key epidemiological challenges.

Objectives

The objectives of the Global Polio Eradication Initiative are:

* To interrupt transmission of the wild poliovirus as soon as possible;
* To achieve certification of global polio eradication;
* To contribute to health systems development and strengthening routine immunization and surveillance for communicable diseases in a systematic way.

Strategies

There are four core strategies to stop transmission of the wild poliovirus in areas that are affected by the disease or considered at high risk of re-infection:

* high infant immunization coverage with four doses of oral poliovirus vaccine (OPV) in the first year of life;
* supplementary doses of OPV to all children under five years of age during SIAs;
* surveillance for wild poliovirus through reporting and laboratory testing of all acute flaccid paralysis (AFP) cases among children under fifteen years of age;
* targeted “mop-up” campaigns once wild poliovirus transmission is limited to a specific focal area.

Before a WHO region can be certified polio-free, three conditions must be satisfied: (a) there are at least three years of zero polio cases due to wild poliovirus; (b) disease surveillance efforts in countries meet international standards; and (c) each country must illustrate the capacity to detect, report and respond to “imported” polio cases. Laboratory stocks must be contained and safe management of the wild virus in inactivated polio vaccine (IPV) manufacturing sites must be assured before the world can be certified polio-free.

The Advisory Committee on Polio Eradication, the independent, technical body providing strategic guidance to the Global Polio Eradication Initiative, is overseeing a programme of research and consensus-building that will lead to the development of post-eradication polio immunization policy options, which will be considered by the World Health Assembly.

Coalition

The Global Polio Eradication Initiative (GPEI) is spearheaded by WHO, Rotary International, the US Centers for Disease Control and Prevention (CDC) and the United Nations Children’s Fund (UNICEF).

The polio eradication coalition includes governments of countries affected by polio; private sector foundations (e.g. United Nations Foundation, Bill & Melinda Gates Foundation); development banks (e.g. the World Bank); donor governments (e.g. Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Iceland, Ireland, Italy, Japan, Luxembourg, Malaysia, Monaco, the Netherlands, New Zealand, Norway, Oman, Portugal, Qatar, the Republic of Korea, the Russian Federation, Saudi Arabia, Spain, Sweden, Switzerland, Turkey, United Arab Emirates, the United Kingdom and the United States of America); the European Commission; humanitarian and nongovernmental organizations (e.g. the International Red Cross and Red Crescent societies) and corporate partners (e.g. Sanofi Pasteur, De Beers and Wyeth). Volunteers in developing countries also play a key role: 20 million people have participated in mass immunization campaigns.

Countries at risk

As long as a single child remains infected with polio, children in all countries are at risk of contracting the disease. The poliovirus can easily be imported into a polio-free country and can spread rapidly among unimmunised populations. Between 2003 and 2005, 25 previously polio-free countries were re-infected due to importations.

The four polio-endemic countries are Afghanistan, India, Nigeria and Pakistan.

Priorities for polio eradication

To stop transmission of the wild poliovirus and optimize the benefits of polio eradication, the global priorities are:

Closing the funding gap: Substantial external financial resources are required to support the efforts of endemic countries to eradicate polio. Economic modelling in 2007 demonstrated the financial and humanitarian benefits of polio eradication. Success in carrying out the necessary vaccination campaigns and surveillance hinges on sufficient funds being made available by the financial stakeholders.

Stopping wild poliovirus transmission in endemic countries: Polio is today more geographically restricted than ever before. The highest priority is reaching all children during SIAs in the remaining four endemic countries. To succeed, high levels of political commitment must be maintained at national, state/provincial and district levels. In 2007 an intensified effort to eradicate polio occurred in each of these four countries, with tailored eradication approaches to address the unique challenges of each of the infected areas. Efforts fully exploited new monovalent vaccines and diagnostics that are significantly more effective in detecting and stopping polio transmission.

IMPACT OF THE INITIATIVE

The Global Polio Eradication Initiative was launched in 1988. More than five million people who would otherwise have been paralysed are today walking because they have been immunized against polio since the initiative began.

By preventing a debilitating disease, the Global Polio Eradication Initiative is helping to reduce poverty, and is giving children and their families a greater chance of leading healthy and productive lives.

By establishing the capacity to access children everywhere, more than two billion children worldwide have been immunized during SIAs, demonstrating that well-planned health interventions can reach even the most remote, conflict-affected or poorest areas.

Planning for SIAs provides key demographic data – “finding” children in remote villages and households for the first time, and "mapping" their location for future health services.

In most countries, the Global Polio Eradication Initiative has expanded the capacity to tackle other infectious diseases, such as avian influenza or Ebola, by building effective disease-reporting and surveillance systems, training local epidemiologists and establishing a global laboratory network. This capacity has also been deployed in post-disaster health emergencies such as the aftermath of the 2004 tsunami in south-east Asia.

Routine immunization services have been strengthened by bolstering the cold chain, transport and communications systems for immunization. Improving these services helped to lay the groundwork for highly successful measles vaccination campaigns that have saved millions of young lives.

Vitamin A is often administered during polio SIAs. Since 1988, more than 1.2 million childhood deaths have been prevented through provision of vitamin A during polio SIAs.

On average, one in every 250 people in a country has been involved in polio immunization campaigns. More than 20 million health workers and volunteers have been trained to deliver OPV and vitamin A, fostering a culture of disease prevention.

Through the synchronization of SIAs, many countries have established a new mechanism for coordinating major cross-border health initiatives aimed at reaching all people – a model for regional and international cooperation for health.

Future benefits of polio eradication

Once polio is eradicated, the world can celebrate the delivery of a major global public good – something that will equally benefit all people, no matter where they live. Economic modelling published in 2007 established that significant financial benefits will also accrue from eradication.

[AIKO]

Originally Posted by Dr.B

2009-10 Influenza Prevention & Control Recommendations
ACIP Recommendations: Introduction and Biology of Influenza

In the United States, annual epidemics of seasonal influenza occur typically during the late fall through early spring. Influenza viruses can cause disease among persons in any age group, but rates of infection are highest among children. Rates of serious illness and death are highest among persons aged 65 years and older, children aged <2 years, and persons of any age who have medical conditions that place them at increased risk for complications from influenza. An annual average of approximately 36,000 deaths during 1990—1999 and 226,000 hospitalizations during 1979--2001 have been associated with influenza epidemics.

Annual influenza vaccination is the most effective method for preventing influenza virus infection and its complications. Influenza vaccine can be administered to any person aged >6 months who does not have contraindications to vaccination to reduce the likelihood of becoming ill with influenza or of transmitting influenza to others. Trivalent inactivated influenza vaccine (TIV) can be used for any person aged 6 months and older, including those with high-risk conditions (Boxes 1 and 2). Live, attenuated influenza vaccine (LAIV) may be used for healthy, nonpregnant persons aged 2—49 years. No preference is indicated for LAIV or TIV when considering vaccination of healthy, nonpregnant persons aged 2—49 years. Because the safety or effectiveness of LAIV has not been established in persons with underlying medical conditions that confer a higher risk for influenza complications, these persons should be vaccinated only with TIV. Influenza viruses undergo frequent antigenic change (i.e., antigenic drift); to gain immunity against viruses in circulation, patients must receive an annual vaccination against the influenza viruses that are predicted on the basis of viral surveillance data. Although vaccination coverage has increased in recent years for many groups targeted for routine vaccination, coverage remains low among most of these groups, and strategies to improve vaccination coverage, including use of reminder/recall systems and standing orders programs, should be implemented or expanded.

Antiviral medications are an adjunct to vaccination and are effective when administered as treatment and when used for chemoprophylaxis after an exposure to influenza virus. However, the emergence since 2005 of resistance to one or more of the four licensed antiviral agents (oseltamivir, zanamivir, amantadine and rimantadine) among circulating strains has complicated antiviral treatment and chemoprophylaxis recommendations. Updated antiviral treatment and chemoprophylaxis recommendations will be provided in a separate set of guidelines later in 2009. CDC has issued interim recommendations for antiviral treatment and chemoprophylaxis of influenza, and these guidelines should be consulted pending issuance of new recommendations.

In April 2009, a novel influenza A (H1N1) virus that is similar to influenza viruses previously identified in swine was determined to be the cause of an influenza respiratory illness that spread across North America and was identified in many areas of the world by May 2009. The symptoms of novel influenza A (H1N1) virus infection are similar to those of seasonal influenza, and specific diagnostic testing is required to distinguish novel influenza A (H1N1) virus infection from seasonal influenza. The epidemiology of this illness is still being studied and prevention issues related to this newly emerging influenza virus will be published separately.
Biology of Influenza

Influenza A and B are the two types of influenza viruses that cause epidemic human disease. Influenza A viruses are categorized into subtypes on the basis of two surface antigens: hemagglutinin and neuraminidase. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have circulated globally. Influenza A (H1N2) viruses that probably emerged after genetic reassortment between human A (H3N2) and A (H1N1) viruses also have been identified in some influenza seasons. In April 2009, human infections with a novel influenza A (H1N1) virus were identified; as of June 2009, infections with the novel influenza A (H1N1) virus have been reported worldwide. This novel virus is derived partly from influenza A viruses that circulate in swine and is antigenically distinct from human influenza A (H1N1) viruses in circulation since 1977. Influenza A subtypes and B viruses are further separated into groups on the basis of antigenic similarities. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations and recombination events that occur during viral replication. Recent studies have begun to shed some light on the complex molecular evolution and epidemiologic dynamics of influenza A viruses.

Currently circulating influenza B viruses are separated into two distinct genetic lineages (Yamagata and Victoria) but are not categorized into subtypes. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses. Influenza B viruses from both lineages have circulated in most recent influenza seasons.

Immunity to the surface antigens, particularly the hemagglutinin, reduces the likelihood of infection. Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype of influenza virus. Furthermore, antibody to one antigenic type or subtype of influenza virus might not protect against infection with a new antigenic variant of the same type or subtype. Frequent emergence of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and is the reason for annually reassessing the need to change one or more of the recommended strains for influenza vaccines.

More dramatic changes, or antigenic shifts, occur less frequently. Antigenic shift occurs when a new subtype of influenza A virus appears and can result in the emergence of a novel influenza A virus with the potential to cause a pandemic. New influenza A subtypes have the potential to cause a pandemic when they are able to cause human illness and demonstrate efficient human-to-human transmission and little or no previously existing immunity has been identified among humans. Novel influenza A (H1N1) virus is not a new subtype, but because the large majority of humans appear to have no pre-existing antibody to key novel influenza A (H1N1) virus hemagglutinin epitopes, substantial potential exists for widespread infection
BOX 1. Summary of seasonal influenza vaccination recommendations, 2009: children and adolescents aged 6 months--18 years

All children aged 6 months--18 years should be vaccinated annually.

Children and adolescents at higher risk for influenza complications should continue to be a focus of vaccination efforts as providers and programs transition to routinely vaccinating all children and adolescents, including those who:

* are aged 6 months--4 years (59 months);
* have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, cognitive, neurologic/neuromuscular, hematological or metabolic disorders (including diabetes mellitus);
* are immunosuppressed (including immunosuppression caused by medications or by human immunodeficiency virus);
* are receiving long-term aspirin therapy and therefore might be at risk for experiencing Reye syndrome after influenza virus infection;
* are residents of long-term care facilities; and
* will be pregnant during the influenza season.

Note: Children aged < 6 months cannot receive influenza vaccination. Household and other close contacts (e.g., daycare providers) of children aged < 6 months, including older children and adolescents, should be vaccinated.

BOX 2. Summary of influenza vaccination recommendations, 2009: adults

Annual vaccination against influenza is recommended for any adult who wants to reduce the risk of becoming ill with influenza or of transmitting it to others. Vaccination is recommended for all adults without contraindications in the following groups, because these persons either are at higher risk for influenza complications, or are close contacts of persons at higher risk:

* persons aged 50 years and older;
* women who will be pregnant during the influenza season;
* persons who have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, cognitive, neurologic/neuromuscular, hematological or metabolic disorders (including diabetes mellitus);
* persons who have immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus;
* residents of nursing homes and other long-term care facilities;
* health-care personnel;
* household contacts and caregivers of children aged <5 years and adults aged 50 years and older, with particular emphasis on vaccinating contacts of children aged <6 months; and
* household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza.

Thanks doc. I typoed 30-40 million annual flu deaths Obviously incorrect, 30,000-40,000 flu related deaths per year.

[JBat]

Originally Posted by Dr.B

John:
Be insulting...? We are all ignorant in many aspects.
Being ignorant is not a bad thing per say.
Ignorant:
1. lacking in knowledge or training; unlearned: an ignorant man.
2. lacking knowledge or information as to a particular subject or fact: ignorant of quantum physics.
3. uninformed; unaware.
4. due to or showing lack of knowledge or training: an ignorant statement.

Unless you are a physician with the training then you can't compare what I know to what you know with anything to do with medicine. Just like many here are experts in watches, I am quite ignorant in watches....but I do strive to learn.

I do apologize if I offended you....but facts are facts.

And I appreciate your efforts at education, Fernando, but you must realize that calling people ignorant does not usually go over very well. I am also very familiar with the definition of the word. You are correct, everyone is ignorant about something, it's just your usage I took umbrage with.

Vaccinations are always a sticky topic. Many just don't feel comfortable getting them. I tend to be one of them. It's a decision I make for myself alone.

[JBat]

Originally Posted by unclesallie

Fernando: thanks for the information , but as you may note , attempts at education are greatly over valued; people would rather hold on to their belief systems, even in the face of overwhelming scientific data to the contrary.

Again, this is insulting and presumes facts not in evidence. Belief systems? Which belief systems are you referring to? Your "belief system" dictates one must get a flu shot to be safe. My personal experience has been different. The flu is a virus and virus' mutate. People who get flu shots can and do get the flu anyway because of this. I have had the flu a couple of times in my 48 years and I don't get regular flu shots. The vast majority of my years have been flu-free.

The one time I was forced to get a flu shot, during my time in the army, I was stricken with the worst case of influenza I've ever had some two months later. Laid me up in bed for a week. Anecdotal experience? Perhaps. But I go with what I know.

Again, as a medical professional, I appreciate Fernando's efforts regarding educating people about flu shots. I believe he does so with the best of intentions, and that speaks well to his character. They are just not for me.

[Paulie]

Anyone miss Smallpox? It only exists in a couple of highly secure freezers, not in people. I'd like to see more diseases in the same location...

[redshirt1957]

The current wife has been trying to put my little small pox in the freezer for years.