Examining future lessons of HIV vaccine trials

A recent issue of Vaccine included a paper that asked this question: "What can HIV vaccine trials teach us about future HIV vaccine dissemination?" (Newman, et al. Vaccine 26 (2008), 2528-2536 -- free abstract).

Based on focus groups conducted in the Los Angeles area, the researchers map the common barriers between participants' willingness to participate in vaccine trials and the acceptability of a hypothetical vaccine. In both cases, common themes emerged, including fear of vaccine-induced infection, false positives to HIV tests and associated consequences, side effects, partial vaccine efficacy, AIDS stigma, and mistrust of government, among others.

The authors conclude that these parallels provide a valuable opportunity to use HIV vaccine clinical trials to study issues related to acceptability of an approved vaccine. They write:

"...Rigorous sociobehavioral research conducted in conjunction with HIV vaccine trials, in addition to facilitating informed enrollment in safe and ethically conducted trials, may provide an empirical basis for targeted sociobehavioral interventions to ensure the effectiveness of future HIV vaccines in controlling the epidemic."

Updates: HIV vaccine reassessment; 2nd rotavirus vaccine approved; Avian flu vaccine supply

Here are a few updates on topics we've been covering over the past several months:

• HIV vaccine research -- Several months after the failure of what was billed as the 'most promising' HIV vaccine candidate, NIAID organized a meeting late last month to reassess the state of HIV vaccine research and plans for the future. The "Summit on HIV Vaccine Research and Development" garnered significant media attention from the Washington Post and New York Times, among other outlets. The apparent take-away message from the meeting was that renewed effort must be directed toward basic research and novel ideas. A subsequent Times editorial argued that the potential benefit of a vaccine is too great to give up hope. A webcast of the meeting is available at the NIAID summit website.

• Rotavirus vaccines -- As expected, on Thursday, FDA approved GSK's Rotarix, now the second rotavirus vaccine available in the United States. Here's a story from the Associated Press, the FDA press release and the GSK release. The major difference between Rotarix and Merck's RotaTeq is that Rotarix requires two doses compared to three for RotaTeq. No word yet on the price of Rotarix, which had already been licensed in over 100 countries. It is expected to be available in the U.S. later this year.
  

• Pandemic flu planning -- Another update on the federal government's pandemic flu planning was released by HHS Secretary Michael Leavitt late last month. Updates on vaccine development and stockpiling figure prominently in the report. It notes that enough pre-pandemic vaccine for 13 million people was stockpiled by the end of 2007. This CIDRAP News story has more details.

"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."

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.

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.

Hitting the bull's eye for pandemic flu vaccine development

In this month's Lancet Infectious Diseases, a commentary by Sambhara, Bridges, and Poland offers an update on progress toward pandemic influenza vaccine development in the wake of the licensure of Sanofi Pasteur's pre-pandemic vaccine this spring.

The title of the short commentary sums up the authors' assessment: "H5N1 vaccine hits the target, but not the bull's eye." (free abstract). Complementing this metaphor is a graphic which illustrates the specific areas that need to be addressed to produce the "ideal pre-pandemic vaccine." Such a vaccine would be safe (of course), require a single dose with a small amount of antigen, provide long-lasting immunity, and be stable (i.e., capable of remaining potent even if stored for some time).

Given that the Sanofi Pasteur vaccine licensed in April falls far short of these goals, the authors advocate directing research efforts toward these aims in particular.

Speaking of pandemic influenza research, WHO posted on their website late last week a series of tables summarizing the impressive number of vaccine candidates for which clinical trials are underway. As the tables show, while H5N1 is properly commanding the overwhelming majority of attention of late, it is not the only influenza strain with pandemic potential that has attracted the interest of researchers.

With respect to pandemic planning in the U.S., another update was issued late last week by HHS secretary Michael Leavitt. Here's the full report as well as coverage from CIDRAP News. In a brief section on vaccines, the report states that the current pre-pandemic stockpile includes sufficient doses for 6 million people, with a 5-year goal of building enough capacity to produce vaccine for all Americans within six months of 'the' pandemic virus' first appearance.

Research shows potential of edible vaccines

A potentially promising new strategy for vaccine delivery was highlighted in last week's edition of the Proceedings of the National Academy of Sciences (PNAS). In a paper by Nochi and colleagues, "Rice-based mucosal vaccine as a global strategy for cold-chain- and needle-free vaccination," (free abstract), the authors report on favorable immune responses in mice caused by rice genetically-engineered include a vaccine against cholera.

An editorial in the same issue of PNAS ("Vaccines are for dinner,") expresses great optimism about the potential for the Nochi, et al., method to address many of the logistical obstacles that hamper large-scale vaccination efforts, particularly the need to keep traditional vaccines refrigerated at all times from manufacture to delivery (known as the 'cold chain') and the difficulties of needle-based vaccination programs around the world.

Last week's issue of The Economist picked up the story -- "A new health food" -- providing a far more accessible summary of Nochi, et al.'s research for a lay audience.

It is an interesting and potentially important set of research findings, but as with most early-stage research, the journey to a viable human therapy employing rice-based vaccines is, at best, a decade or longer away.

Also in the news: new meningitis vaccine?; ethics of clinical trials

Two other odds-and-ends appearing in our inbox this week:

-- An AP story from late last week proclaims, "New meningitis shot could end fatal epidemics." Not surprisingly, "could" is very much the key word in that headline. As the story points out, the positive data being announced comes from a clinical trial of only 600 toddlers in Africa, and the successful introduction of the vaccine candidate is, at best, years away. More depressing, but no doubt accurate, is this point from the story:

"Even if the new vaccine becomes available, experts think there will be a lag of about 15 years before the majority of Africa’s at-risk population can be vaccinated."

Of course, this 'lag' is present for the introduction of any new vaccine in the developing world, often (as is the case for rotavirus and HPV vaccines) the parts of the world where the greatest vaccine-related benefit is possible.

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-- Speaking of vaccine research and testing in the developing word, the June 21 issue of Vaccine includes a paper titled, "Ethical considerations related to the provision of care and treatment in vaccine trials." (subscription required). Written by Daniel Tarantola, Ruth Macklin, and colleagues, the paper summarizes a meeting exploring the long-disputed question of the type and level of care due to research subjects in the developing world (where the standard of care is typically quite different from the home countries of research sponsors.)

Those looking for a clear recommendation will not find it here. The authors recommend "a structured approach" to decision-making, meaning, "a consultative process with trial communities and other stakeholders in research [that] will ensure that the needs and legitimate expectations of trial participants are appropriately met, obligations towards them are delivered and, as a result, ethical research is facilitated in the interest of public health."

Legal fears block vaccine research for pregnant women, newborns

That's the topic of this story in Friday's Baltimore Sun -- "Pregnant Pause." It examines the potential for a vaccine against Group B Streptococcus -- which affects thousands of newborns annually -- and the (seemingly justifiable) reluctance of the pharmaceutical industry to pursue a vaccine against it.

Why? Among other reasons, the story points to the regulatory difficulties of testing new product in pregnant women and newborns and the extreme legal vulnerability the companies would face if allegations of safety concerns come to light (real or alleged) even after a potential vaccine was licensed.

The story goes on to outline how legal worries influence physician attitudes regarding pertussis and influenza vaccination for pregnant women, contrary to the recommendations of the scientific and medical communities. It's a very interesting story for those thinking about how science, law, and policy interact.

Update on HIV Vaccine Research Strategies

Despite the many challenges facing the development of a safe and effective HIV vaccine (many of which we've discussed previously), we continue to be interested observers in the status of HIV vaccine research, cognizant of the incredible benefits a vaccine would bring.

The latest New England Journal of Medicine includes a review article by NIAID Director Dr. Anthony Fauci and researcher Dr. Margaret Johnston titled "An HIV Vaccine -- Evolving Concepts."

It's a science-laden paper, but its conclusion reflects the increasingly modest hopes for a potential first-generation HIV vaccine. Johnston and Fauci describe a different type of vaccine, one that would alter the common understanding of the protection vaccines provide and create additional implementation concerns along with the potential for tremendous benefits...

" A vaccine that conforms to the classic paradigm of viral vaccines remains the goal of efforts to develop an HIV vaccine. Such a vaccine would induce immune responses that prevented the establishment of HIV infection by clearing virus before latent viral reservoirs were produced. This goal may not be realized with first-generation vaccines. The development of an HIV vaccine may diverge from the classic paradigm for viral vaccines. There is optimism that even a less-than-perfect vaccine could benefit both individual recipients and the at-risk community. By blunting the initial burst of viremia and reducing virus levels, such a vaccine could prolong the disease-free period and also reduce transmission. If licensed, such a vaccine will have to be delivered as part of a comprehensive, multifaceted, prevention program."

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?"