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| Ebola virus. Image from |
Everyone is very worried about Ebola right now, so it seems like a good choice of topic. The news story I'm going to talk about is from today's NY Times, Testing for Ebola Vaccines to Start Soon, W.H.O. Says.
This story is about the World Health Organization's plan to start vaccinating people at risk for contracting Ebola in January. Now, I know that seems like a long wait, but there's a reason for the delay. Actually there are multiple reasons. The first is purely practical, these vaccines have not yet made it beyond phase I clinical trials, so up to this point only small batches of vaccine have been produced. It takes 6-9 months to produce a single large batch of vaccine. October is already nearly gone, drug companies will have to bust their butts to get a batch ready for January.
The next reason is related to ethics, the CDC and WHO have already decided that it is appropriate to bypass phase II clinical trials and go straight to phase III (i.e. go ahead and give a large number of people this vaccine and then monitor them) with a few of the Ebola vaccines in the late stages of development. But now there is disagreement about the best way to do the phase III trial. Some groups, including the WHO, would like to set up a randomized control trial. This is where some percentage of study participants will receive a placebo vaccination so that researches can compare the out comes of vaccinated and un-vaccinated individuals who receive the same medical care in every other way at the same time without being biased by knowing who has and who has not be vaccinated (We can imagine that, in spite of their best efforts to be fair, doctors might subconsciously work harder to save vaccinated people than un-vaccinated people because the doctors think the vaccinated individuals have a better chance; they could "give up" on people they knew to be un-vaccinated. Or the opposite could happen, doctors could try harder with the people they think need more help. Either of these biases would damage the validity of the study results.) Randomized control trials are the gold standard for such research; however, there is a big ethical problem with giving people a "fake" placebo vaccine to such a deadly disease: how can we knowingly give some people less than their best chance at survival? Doctors without Boarder is one of the groups that feels these ethical problems are too large to ignore and that a randomized control trial (RCT) is not appropriate. A group of scientists writing to The Lancet also wisely point out that there is another practical problem with using an RCT in this case: there is a big problem in Africa with distrust of Western intervention/medicine. This problem has already likely cost many many lives. If the people of west Africa find out that some percentage of study participants are being given "fake" (placebo) vaccines, distrust will likely increase and further complicate both the study of the vaccine and control of the outbreak. And they will find out, because ethics demands that study participants give informed consent, and thus they will be told there is a chance they are getting a placebo. It's a real ethical quandary. Is it better to do the RCT and get the best research data and the most certainty about the efficacy and side effects of the tested vaccines, or is it better to try to save as many people as possible even at the expense of knowing some specifics about the vaccines for next time? And how sure are we that this vaccine is really the best chance people have; several promising HIV vaccine studies being done in west Africa had to be halted because vaccination was increasing the infection risk! (Update 10/29: For more, see here)
Let's leave those important considerations for a moment and talk a bit more about these vaccines and the research behind them. There was another news story a few days ago where Dr. Francis Collins, the head of the National Institutes of Health (NIH) told Huff Po that a vaccine had been in the works for over 10 years but that budget cuts had hampered research progress. Conservative news outlets have attacked this claim saying that a) funding has held steady with inflation accounted for and increased in actual dollars and that b) the CDC gave out millions in annual bonuses in 2013 and 2014. Firstly, the CDC is not the NIH; they have different rolls so even if B is true it doesn't mean the NIH doesn't need more money. Secondly, even if A is true, the funding rate for grant proposals submitted to the NIH in 2013 was 16.8%, but 29.9% in 2003. Now, I think it's unlikely that grant proposals have gotten worse in the last decade, these are all written by scientists with PhDs and are the life blood of their careers. So a more reasonable explanation is that $3.5 billion just doesn't go as far as it used to. We could talk about the issues that contribute to that, such as "overhead" and if/how we could fix that, but this post is about vaccines, not politics. So I'll get back to that.
Back in November of 2000 researchers at the NIH published a paper in the journal Nature about a vaccine for the Zaire strain of Ebola. This vaccine was a DNA vaccine with an adenovirus vector. The adenovirus family is one you know quite well, if not by that name, they are the cause of many common viral infections including colds, upper respiratory infections, and tummy flu (gastroenteritis). They are a favorite of researchers because they have a small, simple genome that is very well understood--at this point scientists know basically what every single nucleotide in that virus does. To make a DNA vaccine using this vector scientists carefully remove specific genes from the viral genome (particularly those that cause high virulence, i.e. illness) and add genes that encode proteins from some other virus that they want to make a vaccine against (Ebola in this case). The result is a low-virulence (unlikely to make you feel sick or be contagious) adenovirus that contains genes encoding the surface proteins of a different, dangerous, virus (Ebola). When these viruses are introduced to the host (when you get the vaccine), they infect a few cells and hijack the cellular machinery to make all the proteins encoded in the viral genome, just like a normal viral infection. The body then naturally raises an immune response, and because some of the proteins are from the dangerous virus the immune response will work against an encounter with the dangerous virus. Here's an explanation from the NIH about how vaccines work.
The vaccine described in the paper was not tested in humans, but instead, macaques. Testing in primates (or other appropriate large mammal) is one of the last research steps before trials in humans can begin. Macaques are very much like humans in that they get Ebola and it is very deadly. In the study all the un-vaccinated macaques were dead within one week while all the vaccinated ones were still alive and healthy six months later. The vaccinated macaques also showed no detectable virus a few days after the initial exposure, showing that their immune system had fought off the virus.
By 2003 the NIH researchers had come up with another vaccine for Ebola in macaques, one that required a shorter vaccine schedule to reach adequate effectiveness. And by 2006 the first phase I clinical trial of an Ebola vaccine in humans had been completed. This trial looked for two things: was the vaccine safe and were there measurable anti-ebola antibodies in the blood of individuals who had received the vaccine. The trail was not able to test one very important thing: were these people now safe from Ebola?
The 2006 phase I trial of the Ebola vaccine was done on 27 healthy adults living in Bethesda, Maryland. They were separated into 4 groups, each of which received a different number of vaccine does (including 6 control individuals, who received all placebo shots). The participants were then monitored for 2 weeks for negative vaccine reactions. A mild fever was observed frequently, and one person broke their foot, but no other worrisome side effects were observed (yes, it's a small sample, so rare side-effects could have gone unnoticed, that's what phases 2-4 of clinical trial are meant to discover). At the end of the two weeks, blood was taken to look for evidence of an immune response to the vaccine. All participants who received at least one dose of real vaccine had antibodies to at least one of the three Ebola antigens included in the vaccine. This suggests that these individuals MAY be protected against Ebola, but there's only one way to know for sure. And no one is going to agree to that!
From 2006 to today the trail starts to thin, more studies were published suggesting alternative vaccine delivery methods or dosing schedules but no further clinical trials have been published. This is likely due to two problems 1) the money problem that Dr. Collins talked about: phase 2 and 3 trials are very expensive and because there is not really any money in vaccine production (especially not for one against a virus that is mainly a problem in the developing world), private drug companies have been disinterested in spending the money leaving it to the government to pay for (if it gets done at all). And 2) without an actual large-scale Ebola outbreak to study this vaccine with we can only test for safety and immune response, not for actual effectiveness. Even with an outbreak, an ethical experimental design for such a vaccine is tricky as I explained above.
So what do you think? Whose right, the WHO or Doctor's without Boarders?
References (gray references require a subscription to view)
Adebamowo, Clement, et al. "Randomised controlled trials for Ebola: practical and ethical issues." The Lancet (2014).
Falzarano, Darryl. "Progress in filovirus vaccine development: evaluating the potential for clinical use." Expert Review of Vaccine 10.1 (2011): 63-77.
Feldmann, Heinz, et al. "Ebola virus: from discovery to vaccine." Nature Reviews Immunology 3.8 (2003): 677-685.
Jones, Steven M., et al. "Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses." Nature medicine 11.7 (2005): 786-790.
Martin, Julie E., et al. "A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial." Clinical and vaccine immunology 13.11 (2006): 1267-1277.
Reardon, Sara. "HIV vaccine raised infection risk" Nature News. (October 2013): http://www.nature.com/news/hiv-vaccine-raised-infection-risk-1.13971
Sullivan, Nancy J., et al. "Development of a preventive vaccine for Ebola virus infection in primates." Nature 408.6812 (2000): 605-609.
Sullivan, Nancy J., et al. "Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates." Nature 424.6949 (2003): 681-684.
Sullivan, Nancy J., et
al. "Correlates of protective immunity for Ebola vaccines: implications
for regulatory approval by the animal rule." Nature Reviews Microbiology 7.5 (2009): 393-400.
Tatsis, Nia, and Hildegund CJ Ertl. "Adenoviruses as vaccine vectors." Molecular Therapy 10.4 (2004): 616-629.
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