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...

"Most promising" HIV vaccine trial stopped; vaccine not effective

In what a colleague at Penn--an HIV researcher--describes as "very big and very disappointing news", Merck announced Friday that it was halting clinical trials on what was viewed as a highly promising HIV vaccine candidate, the most advanced vaccine that employed a new strategy attempting to stimulate T-cell immunity against the virus. An interim analysis of research data found that the vaccine was not effective.

Here's the front page story from Saturday's New York Times -- Failure of Vaccine Test is Setback in AIDS Fight, and more coverage from Scientific American, The Associated Press, and The Washington Post. Here are official statements from Merck, NIH, and IAVI.

Also of note is this editorial in today's Philadelphia Inquirer, "Starting fresh for an HIV vaccine."

More good news on Gardasil cross-protection?

An Associated Press story published last week began with what seemed to be remarkable news:

"New data show that a vaccine against the virus that causes cervical cancer partially blocks infection by 10 strains of the virus on top of the four types targeted. That boosts protection - at least partially - to 90 percent of strains causing the deadly cancer, according to data presented yesterday at a medical conference by Merck & Co., maker of Gardasil."

90% protection? Recalling that 70% had long been the number used to quantify the percentage of cervical cancer-causing HPV strains covered by the vaccine, this would be a major development.

As is often the case with unpublished data presented at medical conferences, specifics on the research results are difficult to come by. However, this WebMD story published at CBSNews.com adds more detail, explaining, "The new study, which involved about 11,000 young women aged 15 to 26, shows that the vaccine is also 38% effective against 10 additional HPV types, which are responsible for an additional 20% of cervical cancers."

The fact that the vaccine is only 38% effective against these additional strains is never clearly stated in the AP story. (Research has shown the vaccine to be 100% effective against the 70% of cancer-causing strains included in the vaccine.)

The findings are still good news, but readers of the AP story -- published in our hometown Philadelphia Inquirer and no doubt many other newspapers -- could be excused for thinking it was even more noteworthy.

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In other Gardasil news, Merck announced today plans to donate 3 million doses of the vaccine for use in the developing world. Here's coverage from the Associated Press and a Merck press release.

Seasonal flu: Record supply expected; FluMist approved for 2-4 year olds; Data shows low coverage in past

In what is becoming an annual tradition, CDC announced last week that a record supply of seasonal influenza vaccine is expected to be available for the approaching flu season. Once again, however, barring a massive increase in the number of Americans seeking the vaccine, millions of doses will very likely go unused.

As this AP story reports, current estimates are for 132 million doses to be available this year, an increase over last year's total of 121 million doses (itself a record). Despite the vaccine being recommended for 218 million Americans, 18 million doses were not used last year and were destroyed. Here's more coverage from CIDRAP News and the Washington Post.

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Last Wednesday, FDA approved FluMist -- the only flu vaccine that is administered nasally -- for use in children between the ages of 2-5. Previously, the vaccine had been approved for those age 5-49. Here's the FDA announcement, coverage from CIDRAP News, and a particularly detailed story from the Washington Post.

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Last week's MMWR included several papers detailing flu vaccination coverage in recent seasons. Here's state-by-state data of adults 18 and older, children age 6-23 months, and early data on children age 6-59 months (reflecting the new ACIP recommendation of June 2006). The editorial notes for all three papers explain that the observed vaccination rates are well below CDC goals.

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In related news, CDC announced a new-and-improved seasonal influenza website available at www.cdc.gov/flu/. The site contains extensive information for health professionals and the general public about the virus, prevention, and treatment.

Roundup: Gates TB vaccine grant; NEJM paper on renewed typhoid vaccination efforts

Two items in the news recently regarding vaccines against TB and typhoid...

-- Last week, the Gates Foundation announced a $200 million, 5-year grant to the Aeras Global TB Foundation, providing renewed support for its work next-generation tuberculosis vaccines. Here are press releases from Gates and Aeras and coverage from Reuters and the Seattle Times.

-- A perspective in last week's New England Journal of Medicine (dated September 13) advocated "Putting Typhoid Vaccination on the Global Health Agenda" (subscription required for full text). The paper notes that the number of deaths attributed to typhoid are comparable or greater than those caused by cervical cancer and meningococcal meningitis, yet typhoid vaccination "has largely fallen off the international radar screen" while HPV and meningococcal vaccines receive considerable attention. The paper reviews probable causes for this development and the potential of vaccination as part of global typhoid control efforts.

Ethical issues of "Grand Challenges in Global Health"

The Grand Challenges in Global Health Initiative is a Gates Foundation-sponsored program that aims "to achieve scientific breakthroughs against diseases that kill millions of people each year in the world’s poorest countries." Of the 14 'grand challenges', 6 are specifically related to vaccines and vaccination. The total amount awarded to date -- $436.6 million -- reflects the size of the initiative and the significant financial support behind it.

Amid the several dozen grants awarded was support to the University of Toronto for the study of ethical, social, and cultural issues related to these efforts. The work at Toronto is led by Peter A. Singer, MD (not the Princeton philosopher of the same name) and Jim Lavery, Ph.D.

Earlier this month, the Toronto group published four papers in PLoS Medicine. The papers (all available free at the PLoS Medicine website) review the work of the ethics group to date, future plans, and some of the key issues identified from their work thus far.

Caplan on college meningococcus vaccine requirements

Last week, MSNBC.com published a story titled, "Killer at college: Meningitis threatens students; Mandatory vaccine for deadly bacterial disease sparks debate." The story provides a detailed account of the threat posed by bacterial meningitis on college campuses and efforts by many states to require vaccination for college freshmen (or a signed waiver declining the vaccine). More information about meningococcal vaccination is available from this CDC website, and details about SanofiPasteur's Menactra (the vaccine recommended for adolescents) is available here.

In response to this story, Penn's Art Caplan wrote a commentary for MSNBC.com that was posted last Thursday: "Students' meningitis shots should be required." He writes, in part,

"Americans do love choice. But they also hate to lose a child, a sister or a granddaughter. Sometimes choice ought to yield to common sense and evidence. We ought [to] be doing all we can to get young people vaccinated against meningitis and to make sure that the costs of doing so are covered."

The importance of this issue was illustrated by tragic news on our own campus Sunday of the death of a Penn sophomore from bacterial meningitis. Here is coverage from The Daily Pennsylvanian and The Philadelphia Inquirer.

At Penn, all students living in on-campus dormitories are required to be vaccinated with Menactra or sign this waiver citing medical contraindications or religious objections to the vaccine. (This policy is in accordance with a 2002 Pennsylvania law.)

News reports note that the victim lived off-campus during the current school year, but nearly all Penn students live on-campus during their freshman year, making it likely that the vaccination requirement applied to the student one year ago. No information has been made public regarding her vaccination status.

Home-schooling and state vaccination requirements

A paper by our own Art Caplan and Penn Law student Donya Khalili in the current issue of The Journal of Law, Medicine, and Ethics explores the complicated landscape of vaccination requirements for home-schoolers. Titled "Off the Grid: Vaccinations among Home-schooled Children" (free abstract, subscription for full-text), the paper argues that extending state vaccination requirements to home-schooled children is ethically appropriate and legally justifiable.

From the authors' conclusion:

"While homeschooling and childhood vaccination laws vary substantially among states, the most direct way to encourage more parents to have their children vaccinated is to require that homeschoolers follow the same rules of mandatory immunization and standard exemptions that parents of public schooled students must follow. With improved vaccination rates, all Americans will be more protected against disease, and it is critical to the health and safety of our nation that we protect the health and safety of homeschooled children."

CDC National Immunization Survey Results Released

On Friday, the latest issue of MMWR included the 2006 data from the National Immunization Survey, the most reliable source for information on vaccination rates nationwide. MMWR (pdf) includes two reports. One looks at children age 19-35 months (the traditional study population of NIS since its inception in 1994). The other surveys teenagers age 13-17 years (a new 'spin-off' study appropriately dubbed NIS-Teen).

In the infant/toddler population, the news appears to be quite good. Based on a sample of over 21,000 children, 77% had received the full recommended series of vaccinations in 2006, a slight (though statistically insignificant) increase over 2005's figure of 76.1%. This year's data moves closer to the Healthy People 2010 goal of 80% coverage for the recommended series.

That said, there is a great variation in vaccination rates among states and clear differences among races and socioeconomic status. 73.9% of African-American children have received the complete series of recommended vaccinations, compared to 77.9% of white children and 77.4% of Hispanic children.

An accompanying CDC press release somewhat awkwardly explains the disparity this way:

"Children who live below the poverty level are less likely to be vaccinated than children who live at or above the poverty level. Because a substantial percentage of black children lived below the poverty level, coverage for black children overall was low compared with white children. Therefore, even though the 2006 survey found that black, non-Hispanic children had lower vaccination rates than white, non-Hispanic children for the series of routine vaccines, at [sic] the difference was likely related to socioeconomic status and household income rather than race."

As for teenagers, the NIS-Teen data was not as encouraging, as none of the recommended vaccines for this age group had coverage levels meeting the Healthy People 2010 goals. The accompanying editorial note and CDC press release point to the relative newness of several of the new recommendations for teenagers. Both look to the data as evidence for continued education of parents and health care providers about the benefits of these vaccines.

HIV, Malaria, TB: vaccine research issues and planning

Several items of note over the past few weeks on research for vaccines that would have the greatest potential benefit in the developing world:

-- HIV/AIDS: In the July-August issue of Health Affairs, a paper appears titled, "The Impact of An AIDS Vaccine In Developing Countries: A New Model and Initial Results." (free abstract). Among its findings, the paper notes that a vaccine with 50% effective administered to 30% of the developing world population (both reasonable estimates) could prevent 17 million infections in 15 years.

Speaking of HIV vaccines, the death of Dr. Edward Brandt was announced this weekend. Brandt was assistant secretary of HHS in the early 1980s when AIDS and HIV were first identified. His (and HHS secretary Margaret Heckler's) overly optimistic predictions of an HIV vaccine's arrival are featured prominently in Brandt's New York Times obituary. He opined that an HIV vaccine would be available by 1987, three years after HIV was identified.

-- Malaria: A news story in the current issue of JAMA reports on malaria vaccine development ("'Roadmap' AIDS Malaria Vaccine Efforts" -- free extract.) The story provides a very good summary of progress toward a malaria vaccine and challenges needing to be addressed. The 'roadmap' referred to is the Malaria Vaccine Technology Roadmap, the product of an international series of consultations.

-- Tuberculosis: We don't talk all that often about the development of new vaccines against tuberculosis, but a paper in PLoS Medicine ("Development of New Tuberculosis Vaccines: A Global Perspective on Regulatory Issues") summarizes the content of an international meeting on the topic. The paper summarizes many of the challenges facing vaccine development and offers recommend strategies to address them.

Vaccine business booming for pharma; Financing gaps for uninsured children

While we've been away in August working on the new VaccineEthics.org, a few items appeared that highlighted two very different angles of vaccine financing, cost, and profitability.

Last Sunday's New York Times noted how "Vaccines and Their Promise are Roaring Back." The story highlights the oft-repeated account of the surge in research interest from pharmaceutical companies, new products, and huge profit growth in vaccines in recent years.

Amid all this enthusiasm for new vaccine development, the story all but ignores the many challenges required to produce and deliver safe, effective, and affordable vaccines. Its conclusion captures the tone of the entire story:

"The allure of the silver bullet -- of wiping out an entire class of related diseases with a single injection -- remains a powerful symbol of technological advance. Fifty years ago, vaccine creators captivated the world's imagination. With the return of vaccine-making to the center of the pharmaceutical business, new sources of profits are emerging, and new heroes of innovation."

Speaking of challenges, a report published in JAMA earlier this month noted "Gaps in Vaccine Financing for Underinsured Children in the United States." (subscription required for full text). The CDC-sponsored study offers a useful overview of the varied programs that finance vaccines for uninsured or underinsured children. The authors' data confirm the long-standing belief that a significant percentage of underinsured children are not receiving all recommended vaccines due to shortfalls in state funding and federal discretionary spending. An accompanying editorial by Matthew Davis ("Reasons and Remedies for Underinsurance for Child and Adolescent Vaccines") examines the causes and possible solutions to this problem.

Avian flu: GSK vaccine contracts; NIH studying future pandemic strains

August brought a fair amount of news from GSK regarding their pre-pandemic influenza vaccine. At the start of the month, the company announced a new order from HHS for an additional 22.5 million doses of its avian influenza vaccine (in addition to the 5 million doses ordered in 2006). Here's the GSK press release. The total price of this new order is $97 million.

A few weeks later, GSK announced an agreement with the United Kingdom to deliver its vaccine "as soon as possible after a pandemic outbreak has been declared." Here's that announcement and coverage of both items from CIDRAP News.

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Unrelated to the GSK developments was news from NIH of research that could reduce the 6 month or longer delay between the start of a pandemic and the arrival of a specific vaccine against it. In the journal Science, Dr. Gary Nabel and colleagues report (free abstract) on a technique that could develop predicted variants of avian influenza before such mutations occur naturally, in effect giving vaccine development a head-start.

The background, methods, and possible implications of the research are all summarized nicely in this NIH announcement -- "NIH Scientists Target Future Pandemic Strains of H5N1 Avian Influenza." Here's coverage of the same news from Reuters, with a slightly bolder headline -- "New bird flu vaccine may prevent outbreak."

HPV: Is adolescent consent sufficient?; Data on vaccine effectiveness post-infection

The August issue of Pediatrics included a commentary related to HPV vaccine ethics and policy that is worth noting, even several weeks after its publication. Ruth Farrell and Ellen Rome from the Cleveland Clinic offer a well-reasoned argument in favor of adolescent consent being sufficient for HPV vaccination in their commentary, "Adolescents' Access and Consent to the Human Papillomavirus Vaccine: A Critical Aspect for Immunization Success." (free extract).

The authors argue that HPV vaccination could reasonably be given the same status as other reproductive health matters among teenagers, for which parental consent is not required. They outline some of the reasons why teenagers might seek the vaccine without parental involvement or knowledge and note the missed opportunity that would occur if physicians postpone discussion of the vaccine or vaccination itself until a future visit with a parent present. They write:

"Lack of parental authorization, whether because the adolescent's mother or father may not be reachable or the adolescent truly seeks confidentiality in immunization, should not overshadow the chance to initiate or continue immunization administration. By the time the adolescent returns for health care (with or without a parent), she may have initiated sexual activity, with the vaccine losing its maximum potential efficacy."

While these authors are not the first to suggest waiving parental consent for HPV vaccination, the publication of their argument in the nation's premier journal for pediatric medicine is likely to influence the policy discussion in the coming months.

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Data that could be seen as supporting Farrell and Rome's argument could be found in an August issue of JAMA. There, Allan Hildesheim and colleagues explore the "Effect of Human Papillomavirus 16/18 L1 Viruslike Particle Vaccine Among Young Women With Preexisting Infection" (In layman's terms, "Does Gardasil Help if a Woman Already Has HPV?") At the risk of oversimplifying a nuanced study, the answer is an unsurprising "NO!" This finding confirms what had long been known about the vaccine (and the reason why vaccination is recommended for 11-12 year old girls prior to first sexual contact).

An accompanying editorial "HPV Vaccines--Prophylactic, Not Therapeutic" reinforces this point and explains how the vaccine's lack of therapeutic action shaped the ACIP recommendations.

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Finally, a new issue of HPV Today was released earlier this summer. Included in it are status reports on HPV vaccination in the U.S. and worldwide and a short paper explaining why HPV subtype replacement is unlikely to occur as a result of widespread vaccination with Gardasil or Cervarix.

Seasonal flu: Benefits of childhood vaccination; '06-'07 flu season wrap-up

Among the many vaccine-related contributions to the latest issue of Pediatrics (dated September 1) is a paper titled "Childhood Influenza: Number Needed to Vaccinate to Prevent 1 Hospitalization or Outpatient Visit." (free abstract; subscription required for full text). The authors seek to evaluate the potential benefit of influenza vaccination of children ages 6-59 months following the ACIP decision last year to add this group to those for whom the vaccine is recommended annually.

Determining the "number needed to treat" is a common tool of epidemiologists and those interested in the cost-effectiveness of medical treatments. The methods and results of this study don't lend themselves well to summary, but here is the authors' one-sentence conclusion:

"With 1 outpatient visit being prevented through vaccination of [fewer than] 50 children, influenza vaccination can reduce influenza-attributable medical visits in children significantly, even in years with modest vaccine efficacy."

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Speaking of influenza vaccination, a report in MMWR in mid-August wrapped up the 2006-07 flu season and previewed the vaccine composition for the upcoming 07-08 season.

The report notes that the 2006-07 season was comparatively mild relative to the 3 flu seasons that preceded it, as mortality and pediatric hospitality rates were all below those of recent year.

The influenza vaccine for the upcoming season will include two of the same strains in last year's vaccine, with FDA advisers opting to include one different influenza A component. (Each season's vaccine includes two influenza A and one influenza B components.

Penn participating in study of brain cancer 'vaccine'

Over the past few years, we've been increasingly interested in the ways in which the definition of 'vaccine' has been broadened by researchers to describe a variety of new treatments that differ in form and function from vaccines of the past or present.

Tracing the evolution of the term 'vaccine' from the time of Edward Jenner to the present would be a great project for a historian or sociologist, as would attempting to understand why developers of new immunotherapies are eager to describe them as 'vaccines.' (One hypothesis -- unlikely to be palatable to critics of vaccination -- is that vaccines have a long-established record of safety and effectiveness, and classifying a new product as a 'vaccine' hopes to share in this positive connotation.)

Regardless, the latest example of this phenomenon comes from our own university, with a press release announcing, "Study Investigating Vaccine to Treat Brain Tumors Underway at Penn." As the press release and the web site of Celldex Therapeutics (the company testing the product) explain, the 'vaccine' (called CDX-110) is intended to target a particular molecule present in a significant portion of brain cancers (and other types of cancer, for that matter). The researchers' hypothesis is that administering CDX-110 to patients diagnosed with glioblastoma multiforme, the most serious form of brain cancer, will train the immune system to kill the cancer cells containing the specific target molecule.

Regardless of the branding issue, it's a very interesting and promising strategy worth following as research continues.