HPV Roundup: Gardasil safety worries, Cervarix FDA delays, more on mandates

There's been a flurry of media coverage this week about possible safety issues related to Gardasil. It appears that the attention was initiated by this report released by Judicial Watch, the conservative watchdog group. Like its previous reports alleging numerous deaths and illnesses caused by vaccine, this Judicial Watch report is based on unconfirmed submissions to VAERS, the government's clearinghouse for reports of possible vaccine-related adverse events. Reports to VAERS -- widely described as a 'hypothesis-generating mechanism' -- are later examined by government officials to determine what, if any, role a vaccine may have had in the reported condition.

Numerous other outlets have raised questions about Gardasil's safety in the past few days, most notably this CBS News story by Sharyl Attkinson, the media member who is increasingly at the forefront of reporting on alleged vaccine risks. Other media outlets examining the topic include CNN and WebMD.

In the meantime, officials from CDC and FDA have assured the public that the vaccine remains safe and effective and that reports of possible adverse events will continue to be investigated. Merck responded similarly yesterday, noting the limitations of reports made to VAERS.

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Meanwhile, it appears that the U.S. head-to-head battle between Gardasil and GSK's Cervarix will most likely be delayed until late 2009. Last week, the Wall Street Journal and Reuters, among others, reported the GSK announcement of its timetable for submitting additional trial data requested by FDA. Here is the GSK press release. It notes that Cervarix is already approved in 67 countries, including the E.U., but it's no secret that the U.S. market is by far the most lucrative, as Merck's sales figures from earlier this year illustrated.

From a business standpoint, this is decidedly good news for Merck, as it extends its head start in the U.S. (The news has not all been good, however, as it was announced late last month that Merck's application to expand the indication for Gardasil for women through age 45 will face additional scrutiny and delays. Here's a story from Reuters and the Merck press release.)

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In other news, two papers have recently been published in academic journals on HPV mandates (joining a growing literature on this topic -- including papers by Schwartz, et al., Colgrove, and Zimmerman.) One paper, "Assessing Mandatory HPV Vaccination: Who Should Call the Shots?" (Javitt, et al.) appears in the Summer 2008 issue of the Journal of Law, Medicine & Ethics (subscription required). In short, the authors conclude, "...Mandating HPV vaccination at the present time would be premature and ill-advised."

Also, the May 2008 Harvard Law Review published a paper titled "Toward a 21st Century Jacobson v. Massachusetts (pdf), alluding to the 1905 case that is widely seen as the foundation for state public health powers. The authors argue that a distinction should be drawn between vaccines that are 'medically necessary' (such as smallpox) and those that are 'practically necessary' (such as hepatitis B and HPV, for which other preventive measures are available but not widely used). The paper suggests that current law and policy fail to acknowledge the implications of this distinction.

"Protecting public trust in immunization"

That's the title of an article in the current issue of Pediatrics (Vol. 122, No. 1, 149-153), a timely one given the ever-increasing rate of public attention to confirmed or alleged vaccine-related safety concerns. The authors present a persuasive account of the factors that are driving contemporary controversies as well as why they seem to have commanded greater attention in recent years.

The authors offer a set of policy recommendations aimed at preserving (and, in some cases, improving) public trust, suggesting improvements in public information and public engagement regarding new vaccines and vaccination programs. In particular, the authors call for increased attention and funding to the science of immunization safety, particularly by strengthening coordination efforts at the top levels of the Department of Health & Human Services.

It's a very interesting paper that offers an even-handed assessment of the successes, challenges, and present shortcomings of national vaccination efforts.

Perspectives on vaccine safety, exemptions, and autism links

Tuesday's Washington Post included a story about religious and other non-medical exemptions to state vaccine requirements. The article, "Faith lets some kids skip shots," examines the increase in personal belief exemptions by parents to forgo vaccination and its implications on disease rates as seen by the medical community. Interviewed for the story were Paul Offit, Saad Omer, and Barbara Loe Fisher.

This piece appears a few weeks after the cover story of Time magazine titled "The Truth about Vaccines." The story detailed the ongoing worries about alleged links between MMR or other vaccines with increases in autism rates and the response of the medical community to these concerns. Of particular note is the reporter's discussion of research using genetics and genomics to understand individual responses to vaccination. The story included a useful diagram (.pdf) tracing the recent increase in measles cases in the U.S., an increase suspected of being linked to trends in exemptions.

The Time cover story was likely motivated -- at least in part -- by the case of Hannah Poling which received significant attention this spring. In March, CDC acknowledged that vaccines Poling had received had exacerbated an underlying genetic condition related to mitochondria (a cellular component) leading to symptoms resembling those of autism. The case has been viewed by proponents of the vaccine-autism link as a 'smoking gun,' but CDC officials and others have noted that Poling's diagnosis and condition are exceptional and do not speak to a more general connection between vaccines and autism. The case was the subject of a commentary in the New England Journal of Medicine last month by Paul Offit that focused on the confusion surrounding many aspects of the decision.

Finally, returning to exemptions and their consequences, the New York Times' Ethicist column -- an often light-hearted Q&A on ethical dilemmas -- featured this question last weekend:

"My daughter’s play group consists of children ranging in age from infancy to 4 years old. One mother revealed that she does not vaccinate her son. After much frank but cordial discussion and opinions from pediatricians — some thought she endangered our vaccinated kids; others did not — she felt pressured to leave the group. Did the group behave ethically?"

Based on pediatricians' opinions that the unvaccinated child did not pose a significant threat to her vaccinated playmates (a view that is not held by all in the medical community), 'The Ethicist' concludes that the other parents were wrong to exclude the unvaccinated child.

From CDC: Zoster recommendations, measles outbreak, post-vaccine fainting, and more

Several items of note have been released by CDC in recent weeks, including:

• "Prevention of Herpes Zoster: Recommendations of the Advisory Committee on Immunization Practices" -- The publication making official the recommendations regarding the use of Merck's zoster vaccine, Zostavax. In short, routine vaccination of all persons age 60 and older is advised, except for those with specific contraindications.

• "Measles--United States, January 1-April 25, 2008" -- A report on the unexpectedly large number of measles cases confirmed in the U.S. in the early months of the 2008. Of the 64 cases, 63 occurred in people who were unvaccinated or were of undocumented vaccination status. The report notes that a large number of the cases occurred in children whose parents had received philosophical exemptions from vaccine requirements.

• "Syncope After Vaccination--United States, January 2005-July 2007" -- The arrival of newly recommended adolescent vaccines has led to an increase in fainting, particularly among 11-18 year old females, CDC reports. One fatality has been confirmed as a result of a head injury caused by a fainting-induced fall. The report reiterates a previous recommendation to observe patients for 15 minutes following vaccination to reduce the risk of falls and injuries caused by fainting.

• NCIRD Annual Report -- The 2008 annual report of the National Center for Immunization and Respiratory Diseases -- the administrative home of most of CDC's vaccination-related activities -- was released last month. Of interest to those interested in the breadth of CDC's immunization activities, it its own words.
  

No evidence of RotaTeq-intussusception link observed

Students of contemporary vaccine history are likely familiar with the story of RotaShield, a vaccine against rotavirus licensed in 1998 but withdrawn a year later following the apparent correlation between it and intussusception, a potential life-threatening bowel obstruction.

The clinical testing of RotaTeq, the Merck vaccine licensed in 2006, showed no such link, yet alarms were raised by a 'public health notification' titled "Information on RotaTeq and Intussusception" issued by FDA in February 2007. Despite its title, the announcement did not suggest that intussusception rates among vaccinees were any greater than what could be expected in the general population.

This month's issue of Pediatrics examines the topic in much greater detail, in a paper from CDC and FDA researchers titled, "Postlicensure Monitoring of Intussusception After RotaTeq Vaccination in the United States, February 1, 2006, to September 25, 2007". Based primarily on VAERS reports, the study concludes that there is no association between RotaTeq and intussusception.

Information about general trends in intussusception rates -- independent of a connection to vaccines -- appeared in a paper in the May issue of Pediatrics: "Trends in Intussusception Hospitalizations Among US Infants, 1993–2004: Implications for Monitoring the Safety of the New Rotavirus Vaccination Program".

"Science Progress" on Vaccine Policy

Our colleague Jonathan Moreno, also a Senior Fellow at the Center for American Progress, directs a project there on science and technology policy called "Science Progress." The project, consisting thus far of a web magazine and blog, celebrates its inaugural print edition this Friday. Last month, it published an interview with Dr. Saad Omer of Johns Hopkins, best known for his work on non-medical exemptions to vaccine requirements.

An excerpt from the interview:

SP: What do you think is most important for people who are both working in the public health community, people who are policymakers, people who might be hearing about this issue, and for parents to take away from this whole conversation in the public sphere at the moment?

Omer: One thing that people should realize is that we know that vaccines have some side effects. And we should acknowledge that, everyone who is involved. However, the risk and benefit calculus for all vaccines that are out there, based on our current knowledge, heavily favors not only getting your child vaccinated, but also getting them vaccinated according to the specified schedule.

N.Y. Times public editor examines coverage of vaccine-autism link

In today's New York Times, Public Editor Clark Hoyt takes a look at questions surrounding reporters' handling of contested topics (at least by some) in science and medicine, including allegations of the link between vaccines and autism.

As we wrote last month, the New York Times broke the story about the content of the premiere episode of ABC drama "Eli Stone", triggering a flurry of protest by the American Academy of Pediatrics and others. In his stories, Times reporter Edward Wyatt wrote that the issue was all but settled within the scientific and medical communities, with the possible link between vaccines and autism largely rejected. (A Times editorial published after the episode aired offered a similar point-of-view.)

In his piece today, Hoyt writes:

"Wyatt’s article made clear that there is a debate but did not give equal weight to the two sides. The Times has not since 2005, when two reporters investigated every scientific study and thousands of documents from parents convinced of a link between autism and vaccines, and came down pretty clearly on the side of the scientists.

Wyatt said he relied on that report and read extensively about autism when he got the first hint of what the “Eli Stone” episode would say. "The show seems to portray it as, ‘No one knows,’" he said. “My conclusion was that that is not the case."

Proponents of a possible link were not pleased with Wyatt's portrayal of the scientific debate last month and are likely to be similarly displeased with the concurrence of the Times' public editor today.

ABC drama with mercury-autism plot creates controversy

ABC, the same network that brought us 'Fatal Impact' -- the 2006 TV movie presenting a much-criticized dramatization of an avian flu pandemic -- is drawing fire from medical groups regarding the plot of the premiere episode of 'Eli Stone', a legal drama scheduled to debut on January 31.

As this New York Times story first reported last week, the plot of the first episode involves a 'ripped-from-the-headlines' case about a mercury-based vaccine preservative (called 'mercuritol' in the show) alleged to have caused autism in Eli Stone's client. At the end of the show, the jury apparently agrees that a link exists, deciding against the pharmaceutical industry and awarding the plaintiff $5.2 million.

News of the episode's plot has generated a remarkable amount of criticism from the medical community, including campaigns demanding ABC not air the episode. Here's a follow-up by the Times, "ABC Show Will Go On, Over Protests By Doctors." Leading the opposition has been the American Academy of Pediatrics -- here's a press release demanding the episode's cancellation and a letter to ABC from AAP President Renee Jenkins. Here is more coverage from the Associated Press, Reuters, and USA Today.

While all accounts suggest that 'Eli Stone' is a light-hearted series rather than a serious courtroom drama (commercials for the show prominently feature a singing-and-dancing George Michael, the 1980s pop singer who appears in 'visions' of the lead character), the medical community is still concerned that the show's plot will impact parents' decisions regarding vaccination. Today, the Immunization Action Coalition -- among the nation's most prominent advocates of vaccination -- encouraged readers of its e-mail newsletter to contact ABC and request that they cancel the episode.

More evidence against thimerosal-autism link; critics disagree

This paper in the Archives of General Psychiatry, part of the JAMA family of journals, reports that data "do(es) not show any recent decrease in autism in California despite the exclusion of more than trace levels of thimerosal from nearly all childhood vaccines. The DDS data do not support the hypothesis that exposure to thimerosal during childhood is a primary cause of autism."

Seemingly yet another piece of evidence refuting the thimerosal-vaccines-autism hypothesis, the paper led to coverage from ABC News, the Associated Press, the San Francisco Chronicle, and elsewhere.

Advocates of the link between thimerosal and autism were not swayed, as this Baltimore Sun story explains. SafeMinds, perhaps the most prominent organization focusing on mercury-related vaccine risks, published its own analysis of the paper arguing that the imprecision of the data in the study prevented any variable (including thimerosal) from being ruled out as a cause of increasing autism rates.

Study reports no link between thimerosal and neuropsychological outcomes

In what is sure to mark a new round in the debate regarding the impact of thimerosal in vaccines, a paper published in the latest issue of the New England Journal of Medicine reaches the following conclusion:

"Our study does not support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins and deficits in neuropsychological functioning at the age of 7 to 10 years."

The paper by CDC's William Thompson and (many) colleagues -- "Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years" -- is available for free at the NEJM website. The study compared children's performance on a battery of neuropsychological tests to their total exposures to thimerosal during vaccination as infants. The paper repeatedly states that autism was not a focus of this study, but there's little doubt that the findings here will find their way into the vaccines and autism debate, even despite efforts from CDC officials at today's teleconference to emphasize this distinction.

Tomorrow, we'll link to some of the media coverage that this news will surely receive -- it was already prominently featured on several of the national evening news broadcasts tonight. For now, here's coverage from the Associated Press, US News & World Report, and Reuters.

The New England Journal also published two related perspectives on thimerosal and vaccines. Paul Offit writes in "Thimerosal and Vaccines -- A Cautionary Tale" (free full text),

"The thimerosal controversy should stand as a cautionary tale of how not to communicate theoretical risks to the public; otherwise, the lesson inherent in the collateral damage caused by its precipitous removal will remain unlearned."

Stephen Sugarman also contributes a piece titled "Cases in Vaccine Court -- Legal Battles over Vaccines and Autism."

Autism advocates and proponents of a link between thimerosal and autism are already raising questions about the researchers, the study and its conclusions (despite the standards required for publication in the world's premier medical journal). For examples, here are statements from Autism Speaks and SafeMinds (which calls the study 'wrong').

More to come...

Federal hearing rekindles thimerosal-autism debate

As has been widely covered in the media, a significant hearing is underway in Washington, DC, this month, as three Special Masters hear claims from a group of 5,000 plaintiffs alleging a link between thimerosal-containing vaccines (prior to the preservative's removal in 1999) and autism. Directly at stake is whether autism should be included among diagnoses for which compensation can be awarded through the federal government's Vaccine Injury Compensation Program. Advocates of vaccination warn that a ruling in favor of the plaintiffs could bankrupt the compensation program, resulting in dire consequences for U.S. vaccination efforts.

The overwhelming consensus among the medical community remains that no link can be found between thimerosal and autism. (Here's the CDC site on mercury and vaccines.) Critics of this view -- many of whom have close links to children or families affected by autism -- respond that these conclusions are based on flawed or inadequate research, or worse, are the product of a medical and vaccination community with unacceptably close ties to the pharmaceutical industry.

Official information along with audio and transcripts of the proceedings can be found here.

An excellent preview of the proceedings appeared in this story by Shankar Vedantam in last Sunday's Washington Post.

Gardiner Harris of the New York Times reported here on the first day of testimony last Monday, as did this AP story. Over at Slate, Arthur Allen previewed the hearing, and the New Scientist reports on it as well. Both focus on the widely criticized research of Dr. Mark Geier -- undoubtedly the most controversial proponent of a thimerosal-autism link.

Sharyl Atkinson of CBS News offered some very provocative opinions in a web column titled, "Autism: Why The Debate Rages." In the Boston Globe, Paul Offit weighed in via an op-ed titled, "At risk: vaccines -- How a legal case could cripple one of modern medicine's greatest achievements". Offit's op-ed generated a number of critical letters which the Globe printed here.

An interesting sidebar to these proceedings is the reported rift among the autism advocacy community regarding the merits of thimerosal-based explanations for the rise in autism rates vs. other potential explanations. Both the New York Times ("Autism debate strains a family and its charity") and ABC News ("Emotions run high over autism's causes") highlighted the disagreement between members of the Wright family, founders of Autism Speaks, perhaps the most prominent and well-connected autism organization. At The Huffington Post, Robert F. Kennedy, Jr., takes issue with these portrayals of Katie Wright, who believes strongly in a thimerosal-autism link.

The hearing in Washington is scheduled to continue for another week and a half; a decision may take a year.

Info on Kawasaki disease added to RotaTeq label

A colleague from CDC alerted us to this announcement regarding a change to the label of RotaTeq, Merck's rotavirus vaccine recommended to all infants at 2, 4, and 6 months. Here's the first paragraph of the CDC statement:

"The Food and Drug Administration (FDA) approved today a revised label for RotaTeq, a rotavirus vaccine manufactured by Merck and Co., Inc., to include information on reports of Kawasaki disease occurring before and after the vaccine’s licensure in February 2006. FDA has not made any changes to its indications for use of RotaTeq nor has it issued new or revised warnings or precautions. Likewise, the Centers for Disease Control and Prevention (CDC) has not made any changes in its recommendations regarding the use of RotaTeq. Healthcare providers and parents should remain confident in using RotaTeq in infants."

Here's the FDA release and a related story from Reuters (the only media outlet to have reported on this item as of now.)

General info on Kawasaki disease can be found here and here. It's a rare and poorly understood inflammatory condition that affects 4,000 American children annually.

The "label" referred to in the announcements above is actually this document, an 11-page, single-spaced, data-laden product insert unlikely to top the reading lists of most parents (or pediatricians, for that matter).

The FDA statement notes, "The cases reported to date are not more frequent than what could be expected to occur by coincidence," a statement that could also describe its announcement in February regarding intussusception reports among recipients of RotaTeq.

Similar to that earlier occasion, this announcement was seemingly made so that providers and parents may be vigilant in looking for symptoms of Kawasaki disease, in case a connection to the vaccine does exist. However, calling attention to severe conditions for which no evidence suggests a vaccine link may create undue confusion and worry among parents still told to vaccinate their children with RotaTeq. Admittedly, it is a difficult balance that must be weighed by policy-makers, but one that merits further study.

Gardasil: CDC response on safety/efficacy; survey on parental support for mandates

The weekly news update from the Immunization Action Coalition alerted us to this CDC Q&A released last week titled "CDC Questions and Answers Concerning the Safety and Efficacy of Gardasil." The three-page document outlines the current status regarding safety monitoring, known safety concerns, the potential need for boosters, and the ongoing necessity of Pap screening.

It seems likely that the fact sheet was this breathless press release from JudicialWatch.org asserting (based on VAERS reports) that "three deaths were related to the vaccine." The CDC fact sheet clearly explains how and why this statement is a misinterpretation of VAERS data, reaching conclusions that are no possible from that information alone. Not surprisingly, a search of Google News suggests that the press release garnered virtually no attention from the print media. While safety concerns linked to Gardasil could still surface, there's no evidence at present to suggest such a connection.

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One other item related to Gardasil: The headline from a survey released by a group at the University of Michigan C.S. Mott Children's Hospital reads: "Majority of U.S. Parents Not in Favor of State HPV Vaccine Mandates." The report is available here, and here is coverage from CBS News and the Washington Times.

However, the headline -- while likely shrewdly written to generate the media coverage sampled above -- is very misleading. The report's own data (Table 1 in the report) lists 26% of parents disagreeing with an HPV mandate, 44% of parents agreeing, and a very significant 30% as 'neutral.'

Therefore, the same data could also carry the headline, "76% of parents not opposed to HPV mandate," which would actually more accurately capture the large percentage of respondents with no opinion for or against a mandate.

ABC "20/20" segment on risks of vaccination

On February 23, ABC News' 20/20 featured a series of reports by John Stossel under the heading "Scared Stiff: Worried in America." Among the topics he explored was the general question "are vaccines safe?" His conclusion: Yes, they are. An article closely based on the piece is available here.

Supporting Stossel's conclusion was Dr. Paul Offit; taking the other side, as usual, was Barbara Loe Fisher. She was hardly portrayed in a positive light by Stossel. Most damning was Fisher's unwillingness to acknowledge that, on balance, vaccines have done more good than harm for society throughout history, a position that all but the most fervent opponents of vaccination readily accept.

Needless to say, Fisher was less than pleased with the program's discussion, Stossel's assessment, and the way in which she and her organization were perceived. Her response can be viewed here.

Renewed attention to possible rotavirus vaccine link to intussusception

A fairly significant amount of alarm was raised by an FDA statement last week titled "Information on RotaTeq and Intussusception". The statement reports 28 cases of intussusception -- the significant intestinal complication that led to the removal of the first rotavirus vaccine, RotaShield, in 1998 -- in children following administration of RotaTeq.

But what may have seemed at first glance to be a major announcement about the vaccine's safety was clarified later in the statement...

"Intussusception can occur spontaneously in the absence of vaccination. Of the reported 28 cases of intussusception, the number that may have been caused by the vaccine, or occurred by coincidence, is unknown."

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"The number of intussusception cases reported to date after RotaTeq administration does not exceed the number expected based on background rates of 18-43 per 100,000 per year for an unvaccinated population of children ages 6 to 35 weeks (CDC, unpublished data)."

In other words, there's no reason to be alarmed about the number of cases reported to date, but the statement, not unsurprisingly, did just that. This AP story by Andrew Bridges originally did not include any information about the background rate, likely contributing to the Alliance for Human Research Protection (and others, no doubt) misinterpreting the FDA item. "Merck rotavirus vaccine linked to 28 reports of life-threatening effect," is how the AHRP item describes the announcement, not at all what the FDA said.

CDC promptly released a statement attempting to clear up confusion. Among the 'key facts' they list:

• "We are not surprised by the number of reported intussusception cases following RotaTeq vaccination."
• "Intussusception, a form of bowel obstruction, occurs spontaneously in the absence of vaccination."
  
• "This notice does not mean there is a problem with the RotaTeq vaccine."

There's been no detectable coverage of this topic in the media since the initial FDA statement last week. It will, however, be discussed at this week's meeting of the ACIP, the agenda for which can be viewed here.