Fuller results from HIV vaccine trial suggest marginal benefit

That's the bottom line coming out of the AIDS Vaccine 2009 conference in Paris this morning, where detailed information was released on the results of the HIV vaccine trial in the news earlier this month. The announcement was timed with the online release of a paper and accompanying editorial in the New England Journal of Medicine.

Two stories written about today's news present sharply different perspectives about how to interpret the trial results. Marilynn Marchione of the Associated Press describes the findings at "exciting to scientists," and her story is peppered with quotes from the researchers and boosters of HIV vaccine research touting the study as a "landmark" in the long road toward a viable HIV vaccine.

A much more cautious tone is seen in a story by Gautam Naik of the Wall Street Journal. Naik writes:

"Now, two other analyses of the trial data suggests that the results could have been due to pure chance, and therefore the vaccine may not have conferred protection to people after all."

Naik's story looks closely at the various statistical analyses used to assess the benefit (if any) of the vaccine candidate being tested and the seemingly conflicting results that emerge from them. While digging into the finer points of study design and biostatistics, the story reveals the frequent difficulty in distinguishing meaningful research results from statistical flukes, a boundary that is often criticized as arbitrary. The research group involved in this study has been criticized by some for glossing over this ambiguity while initially publicizing their positive results earlier this month.

Two stories currently on the website of the BBC underscore the difficulty of interpreting scientific research results and conveying them to the public in an accessible way. One headline says, "HIV vaccine trial was significant," while another is titled "HIV vaccine: Doubts over trial." Despite seemingly contradicting themselves, both offer reasonable summaries of today's news and the reactions from experts.

In his New England Journal editorial, Raphael Dolin strikes a measured tone about what to take from the research results and its implications for future work toward an HIV vaccine:

"The clinical trial reported here represents an enormous effort by investigators, sponsoring institutions, and participants in the community. The findings raise a number of questions that have important implications for future directions in vaccine research. The answers to these and related questions will require the application of a balanced and coordinated research approach to the complex and difficult problem of the development of an HIV vaccine. This balanced approach includes fundamental laboratory and experimental-model studies, as well as rigorously designed and conducted clinical trials, such as the one reported on here."

H1N1 vaccines approved by FDA, to be available by mid-October

Today, FDA licensed four vaccines against H1N1 influenza (swine flu). Distribution of the initial doses is likely to begin within the next four weeks, according to HHS secretary Kathleen Sebelius. Here is coverage of today's announcement from the Associated Press and Wall Street Journal.

The vaccines approved today include MedImmune's nasal spray vaccine and injectable vaccines from SanofiPasteur, Novartis, and CSL Limited. Each of these manufacturers produces seasonal flu vaccines in the United States, as does GSK, whose H1N1 vaccine was not included in today's announcement. None of the vaccines contain adjuvants, a recent focus of concern among vaccine safety critics, and thimerosal-free vaccine will be available for those preferring it.

With respect to supply, CIDRAP News reports:

"The Department of Health and Human Services (HHS) has ordered about 195 million doses of H1N1 vaccine. According to a recent federal report, Novartis is expected to contribute 45.7% of that, Sanofi 26.4%, CSL 18.7%, MedImmune 5.8%, and GSK 3.4%."

Today's news is not at all surprising, especially following the favorable clinical trial results announced last week by NIH and published on the website of the New England Journal of Medicine. (Particularly encouraging were findings that only one dose of the vaccine was needed to produce immunity. This means that vaccine supply should be much larger and mass vaccination relatively less challenging than if two doses were required, as had been the expectation until last week's results.)

Over the past few days, the CDC H1N1 vaccination website has added increased information on vaccine safety, focusing particularly on concerns related to thimerosal and Guillain-Barre syndrome.

It bears repeating that the H1N1 vaccination program in the United States will be completely voluntary. (Vaccination will be required, however, for uniformed personnel in the U.S. military, according to this Department of Defense statement.)

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...

Positive data on Hepatitis E vaccine research

Regular readers are aware of our discomfort about reporting on news of vaccines years away from licensure, at best. But when the New England Journal of Medicine decides to include results of Phase I or II clinical trials, it's generally worth noting.

That's the case for the most recent issue of NEJM, which published a paper on the "Safety and Efficacy of a Recombinant Hepatitis E Vaccine." Hepatitis E, more information about which can be found here and here, is quite rare in the United States and is not known to cause chronic conditions. Far more common, of course, are hepatitis A, B, and C (with vaccines available for the first two). Hep E does, however, lead to outbreaks in many parts of the world, particularly in Asia.

The trial reported on here included nearly 1800 volunteers from the Army of Nepal, a population at high risk of contracting the virus. The result: the candidate vaccine's efficacy was 95.5%. No serious safety concerns were identified.

Included in the same issue of NEJM was an editorial titled "Hepatitis E Vaccine -- Ready for Prime Time?"

Seasonal flu: Healthcare workers, surplus doses, and more

A number of items in the news recently regarding seasonal (i.e., 'regular') influenza:

• Following up on our earlier post about the importance of vaccinating healthcare workers against seasonal flu, this story in the Houston Chronicle details CDC efforts to increase vaccination rates among this group.

• Regarding flu supply, we've noted several times this fall the very large supply of vaccine doses expected to be available this year -- as many as 20 million more doses that have ever been administered in a single season. This New York Times story ("After Shortage, Vaccine for Flu Goes Unused," 12/16) and this Cox News Service story examine the problems posed by the early delays in vaccine shipments this fall and the doses likely to be wasted as a result.

• The December 14 issue of the New England Journal of Medicine included three papers on flu vaccination. One article compares the efficacy of live attenuated flu vaccines (i.e., FluMist -- the nasal vaccine) vs. inactivated vaccines (the others that are injected). Another paper studies school-based vaccination programs, and a third is an editorial titled "Different approaches to influenza vaccination". All three papers are nicely summarized in this story by CIDRAP News' Lisa Schnirring.
  

AP and NEJM on potential hay fever vaccine

As regular visitors are aware, we're more than a bit reluctant to join the hype over whatever the next breakthrough vaccine is said to be. As the newly licensed vaccines over the past year have shown, getting a product from the lab to the doctor's office takes a few decades and, while not necessarily a good thing, fewer than a half dozen companies are capable of guiding vaccines through the large Phase III clinical trials. So when a story appears that refers to a vaccine trial with fewer than 100 research participants for a product made by a company you've never heard of, it's a safe bet that the vaccine in question has a long road to travel.

However, we've seen that news about nicotine vaccines and the like are of interest to many. So with that disclaimer in mind, here's a story from the Associated Press (where 'dummy pills' is apparently now an acceptable synonym for 'placebo') about a vaccine in development to lessen the symptoms of hay fever. The story piggybacks on a report in this week's New England Journal of Medicine of a 25-subject clinical trial (free abstract, subscription required for full access).

NEJM on measles in the U.S.

This week's issue of the New England Journal of Medicine includes two pieces that explore the status of measles in the U.S., particularly in relation to a 2005 outbreak in Indiana. That outbreak -- the largest in a decade -- was triggered by the return of a 17-year old unvaccinated girl who traveled to an orphanage in Romania as part of a church group.

One paper is a report tracing the spread of the virus from that individual through everyone she exposed. Titled "Implications of a 2005 Measles Outbreak in Indiana for Sustained Elimination of Measles in the United States" (available free), it concludes, in part:

"Measles was eliminated in the United States through high rates of routine childhood vaccination coverage. The outbreak in Indiana shows that states, localities, and health care organizations need to implement more effective policies to protect persons traveling abroad, home-schooled children, and health care workers against measles and other vaccine-preventable diseases. In addition, to preclude the experience of those countries where vaccine-preventable diseases have become epidemic through the refusal of vaccination, better communication strategies are needed concerning the adverse events associated with vaccines."

The second is a perspective essay by E. Kim Mulholland, M.D., from the London School of Hygiene and Tropical Medicine. Titled "Measles in the United States, 2006," Dr. Mulholland's conclusion is sure to raise the ire of critics of vaccine policy and safety. Putting the blame for outbreaks such as that in Indiana on those alleging vaccine safety issues, Mulholland writes:

"And as long as some groups within a given community respond to spurious claims about the risks of the vaccine by refusing to vaccinate their infants, further outbreaks will occur even in industrialized countries."

Questions of effectiveness surround avian flu vaccine

The March 30 issue of the New England Journal of Medicine reports on clinical trial results for the first-generation avian flu vaccine currently being stockpiled. The news? Not so good. Here's how the New York Times leads their story:

"A bird-flu vaccine being stockpiled by the government in preparation for a possible pandemic protects only about half the people who receive it, scientists are reporting. In addition, it must be given in such high doses that if a pandemic were to start soon, manufacturers could not begin to make enough vaccine for all who would need it."

You can read the full paper for yourself for free at the NEJM's site. The paper itself doesn't paint quite as gloomy a picture of the vaccine's prospects. Among other results, they report that it did not cause severe side effects among the 451 research subjects enrolled in the trial. Good news, yes, but that by no means assures a similar safety profile if/when it's administered on the order of millions of doses, as the history of vaccine development has shown repeatedly.

In fact, a potential ethical issue here is the all but certain lack of large-scale clinical testing of avian flu vaccines prior to their use in a pandemic. Testing of RotaTeq, the new Merck rotavirus vaccine, included a 70,000 person clinical trial, providing the kind of safety data that we almost certainly will not have for avian flu vaccines prior to needing them. Even if we had the time for such trials, by the time they were completed, the virus' continued mutation likely would have already rendered the vaccine in question ineffective. (Case in point, HHS has already announced plans to develop a 'second-generation' avian flu vaccine to replace the one being studied here. We discussed this in a previous post.)

The questions about this vaccine's effectiveness noted in the Times story and in an accompanying editorial in the NEJM differ from those we've pondered in the past (here, here, and here). There's no way of knowing with absolute certainty whether an avian flu vaccine (or any vaccine) trully provides protection against infection until those vaccinated are exposed to the virus.

As it would be wildly unethical to design a clinical trial in such a way, researchers rely on surrogate markers, such as the quantity of antibodies a vaccine produces in the immune system. More antibodies = greater likelihood of protection (generally). This clinical trial couldn't possibly answer the overall question of how the vaccine will stand up to a pandemic, yet it raised additional concerns over how well this vaccine can trigger the kind of activity in the immune system necessary to give it a decent chance against the virus.

More to come, no doubt...

New England Journal piece on HPV Vaccines

Judging from the early traffic to our site from search engines, it's clear that there is significant interest in the ethics of HPV vaccines. As we've written previously here, we share your interest and expect the topic to explode this spring when key decisions and recommendations from government committees are anticipated. We'll be monitoring developments closely and expect to post often on this topic, likely more frequently than on any other.

In the meantime, the current issue of the New England Journal has this piece (for free!) that sets the stage for the months ahead. It covers virtually identical terrain as our earlier post on HPV vaccines (likely because we both based our reviews on the same presentations at last month's ACIP meeting). Nevertheless, the piece is an excellent, comprehensive look at where we are and where we're headed with HPV vaccines. It is well worth a read.