Bioterror: VaxGen stops work on anthrax vaccine; smallpox contract awarded

A few recent items about efforts to develop vaccines against possible agents of bioterrorism:

-- We've been following the saga of the VaxGen anthrax vaccine contract since beginning this site in March 2006 (complete coverage here). When we last checked in -- in January -- the news was that HHS had finally canceled the $877.5 million contract awarded to VaxGen as part of Project Bioshield. Just before Memorial Day weekend (likely deliberately timed to reduce media coverage), VaxGen announced that is was ceasing further development of the vaccine, an all-but-inevitable development without new funding.

Here's the VaxGen press release and a story from CIDRAP News. The press release notes that VaxGen will be laying off 20 employees as a result of this decision, which, amazingly, accounts for 25% of its workforce. There's little doubt that this point will be noted by those who had long criticized the decision to award such a significant contract to a very small, unproven player in vaccine development.

Even more bad news is highlighted in this CQ.com story, which notes the new hurdles VaxGen faces is selling its anthrax vaccine technology developed thus far.

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-- Speaking of CQ.com and bioterror vaccines, following up on this previous post, the anticipated agreement between HHS and Bavarian Nordic for a second-generation smallpox vaccine was completed last week. Here's the HHS press release and an AP story, courtesy of CBSNews.com.

GSK gives to WHO bird flu vaccine stockpile; cell-based seasonal flu vaccine approved in EU

Some influenza-related goings-on this week:

• Yesterday, GSK announced via press release its plan to donate to WHO 50 million doses of its pre-pandemic avian influenza vaccine. WHO responded with a press release of its own, noting some of the many, many still-to-be-answered questions regarding if, when, and how such a stockpile would be used. Here's the AP story on the announcement. While a nice corporate gesture, vaccine doses for 25 million people -- delivered over 3 years, no less -- seems like a drop-in-the-bucket in the event that anything even resembling the estimates of policy-makers comes to fruition. Also, we've discussed the many uncertainties regarding the value of pre-pandemic vaccines previously, but suffice it to say, the benefit of such vaccines is uncertain today, much less three years from now in light of the viral mutation that would precede a pandemic in humans. All that said, this news can be seen as a good start, one could say, but by no means a major step in preparedness.

• In seasonal flu news, the EU approved a cell-based vaccine by Novartis, likely to be the first marketed flu vaccine produced without the use of eggs. Here's the AP story, courtesy of the Washington Post, and the Novartis press release. The story notes that the vaccine will not be available throughout the EU until the 2008-09 flu season and that U.S. approval will be sought next year. In light of the well-rehearsed problems with egg-based flu vaccine production (most notably the 2004 shortage), this may prove to be a major moment in flu vaccine development.

Smallpox: Vaccinia exposures linked to vaccinees; new vaccine updates

Somewhat unexpectedly, May has been a very busy month for news about smallpox and the vaccinia vaccine used against it. Here are the headlines:

• MMWR reported a vaccinia infection in the genital region of a woman reporting sexual contact with a U.S. military member who had received been vaccinated against smallpox. Here's the MMWR report, a related story from CIDRAP News, and the Reuters item. The woman's case was minor and resolved with minimal treatment.

• A similar story, albeit a much more severe event, was reported last week, also via MMWR and picked up by CIDRAP News and Reuters. A two-year old child developed a severe case of eczema vaccinatum from his father, a soldier vaccinated against smallpox prior to service in Iraq. After a 48-day hospitalization, the child is expected to suffer no long-term effects from his illness. It is the first case of the rare, potentially fatal condition in the U.S. since 1998.

• A new smallpox vaccine developed by Acambis received a positive vote from a key FDA advisory committee, all but assuring licensure in the near future. Here's the story from Forbes and the Chicago Tribune. The Tribune story acknowledges the very serious side-effects associated with this new vaccine, likely limiting its use to emergency scenarios only.

• The website of Congressional Quarterly reports that HHS is nearing a contract a Danish company called Bavarian Nordic for 20 million doses of a new smallpox vaccine. The vaccine is hoped to have a more favorable side-effect profile than the current vaccine or the Acambis product noted above.
  

• Finally, this MSNBC story notes that the WHO delayed a decision on the fate of the (known) stockpiles of smallpox -- the actual virus, not the vaccine -- held by the U.S. and Russia. The story reports that both countries are reluctant to destroy their stockpiles, citing their potential value if the virus is found elsewhere. Unclear from the story is the WHO or U.N. authority to enforce their decisions, whenever they may be made.
  

Evaluating the adequacy of pediatric vaccine stockpiles

While the Chiron-induced flu vaccine shortage in 2004 received far more public attention, there have been a number of shortages of universally-recommended pediatric vaccines since 2001. Among the vaccines in limited supply at some point in the past five years are measles/mumps/rubella, varicella, and diphtheria/tetanus/pertussis, among others. There's little doubt that the likelihood of temporary shortages is increased by the presence of only a single manufacturer of many recommended pediatric vaccines. Ensuring an adequate supply of those vaccines recommended to be administered to all children is very much an ethical issue.

The reasons for the current shape of the U.S. vaccine marketplace are many and well documented elsewhere. While some may hope for a wholesale redesign of the vaccine production marketplace, a more immediate response implemented by the CDC has been the creation of a 6-month stockpile of many recommended pediatric vaccines. The stockpile is intended to provide a buffer against short-term disruptions.

The current issue of Vaccine has an interesting paper that examines the adequacy of current stockpile levels to respond to shortages. The paper is titled "Stockpile levels for pediatric vaccines: How much is enough?" (free abstract, subscription required for full text). Using mathematical modeling, the authors' data validate the belief that current levels are adequate for a 6-month shortage of the vaccines included in the stockpile. Not surprisingly, the current stockpiles are very likely too small for a shortage of 8 months or longer, depending on how severe the shortage is. It should be noted that most recent pediatric vaccine shortages have lasted over one year.

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...