Did budget cutting in Washington stop the progress of an Ebola vaccine? Not according to the World Health Organization and doctors developing the vaccines.
In an interview published Sunday, NIH Director Francis Collins said, “Frankly, if we had not gone through our 10-year slide in researchsupport, we probably would have had a vaccine in time for this thatwould’ve gone through clinical trials and would have been ready.” Collins makes it sound as if human trials are just the final stages of a vaccine development process that NIH runs in house. Pour federal dollars in one end and vaccines come out the other end. In reality, the process by which vaccines are developed and brought to market is far more complex and ultimately subject to both human prioritization and market forces.
The Need for Speed
Recently the World Health Organization held the kind of emergency meeting one might see in a Hollywood movie. Twelve doctors from around the world with expertise in bioethics and Ebola research were invited to participate in a 3-hour teleconference. The meeting’s agenda was built around a series of questions which boileddown to one big decision. Should the WHO make an exception to normalprotocol and allow people to be inoculated with drugs which have not yet completed human trials.
The meeting began by highlighting the extraordinary nature of the current Ebola outbreak in Africa, which by early August was already “the largest ever recorded of a filovirus disease,” the category of viruses that includes Ebola and the equally deadly Marburg virus. The panelists noted that antiviral drugs and vaccines already exist which “are at an advanced preclinical stage,” with some of these treatments, “ready for testing in humans.”
The normal process of human drug and vaccine testing is a process that can take years. But because of the severity of the African outbreak, it was unanimously decided that existing Ebola treatments needed to be tested immediately. In fact, the panelists asked the WHO to do something it does not do, expand promising drugs to greater numbers of people before initial human safety testing was complete.
Two different Ebola vaccine candidates are being tested in small numbers of volunteers at sites around the world. The full results of those tests won’t be available fornearly a year but, per the WHO decision, researchers will look at theinitial results and, if they are positive, begin distributing thevaccine more broadly.
In order to avoidany additional delay, GSK is producing 10,000 doses of the vaccine right now, in the hope that the early test results will bepositive. If they are, GSK will turn the vaccine over to the WorldHealth Organization for immediate distribution, primarily in Africaamong front-line health workers.
A World Health Organization presentation on the distribution plan indicates that 10,000 doses is still only about halfof the estimated 20,000 doses needed to inoculate at-riskhealth care workers. But the same document suggests vaccine productioncould ramp up to 100,000 doses as soon as February of 2015. At the announcement of the trials in August, a spokesman for GSK focused on speed, saying, “We are encouraged by progress so far and will dothe best we can, along with WHO and our partners, to speed updevelopment.”
Dr. Samba Sow, Director of the Mali center for vaccine development, one of the sites where the vaccine is being tested, told the Voice of America, “I have never seen such a rapid response in developing a vaccine against any disease before.”
Prioritization
In the midst of the life or death discussion hosted by WHO in August, the 12 assembled experts explained why there were so many Ebola drugs and vaccines ready for human trials but none which had passed through the trials already. In the published report on the meeting this was the second key point [emphasis added]:
Before the outbreak, there was no commercial incentive to develop treatments or vaccines for filovirus diseases, and the lack of any such intervention has left public health authorities and clinicians in the affected countries with no specific prevention or treatment options, despite the fact that outbreaks have been occurring for nearly four decades.
In June of this year, before the WHO meeting, Nature published a story titled, “Ebola treatments caught in limbo.” The story quotes Dr. Heinz Feldmann, creator of one of the two Ebola vaccines currently being rushed through human testing. Dr. Feldman tells Nature that compared to diseases like malaria, “Ebola is just not that much of apublic-health problem worldwide.” As a result, Ebola drugs and vaccines do not draw the attention or funds required to go through human trials. Dr. Feldmann’s vaccine platform was originally published in 2005.
In terms of sheer numbers of people impacted, Dr. Feldmann is right. A list of Ebola outbreaks going back to 1976 shows that the number of people infected has often been a few hundred per outbreak. When compared to diseases like malaria and HIV the impact is relatively small. According to the WHO, 1.6 million people died from AIDS in 2012 alone, roughly 1,000 times the number who died from all Ebola outbreaks worldwide prior to last year.
Of course every death from Ebola is a genuine tragedy and no one wants to say that an Ebola vaccine is not a priority, especially in the midst of the worst outbreak in history. But people in the business of saving lives with drugs and vaccines are aware of the simple mathematics behind some of their decisions. Simply put, because some diseases are deadlier than others some drugs and vaccines are a greater priority. And, as experts at the WHO meeting pointed out, the more widespread the disease the more likely a drug will be taken to market.
Slow Path to the Fast Track
The other vaccine currently in human trials was developed in a partnership between a division of NIH called the National Institute of Allergy and Infectious Diseases (NIAID) and a biotech company called Okairos (now owned by GlaxoSmithKline). As Director Collins noted in his interview, NIAID has been working on this vaccine since 2001.
At various times in the past NIH has announced successful animal trials. A version of the vaccine even went through phase 1 human trials back in 2006. It was a success according to the abstract for that study which states, “This Ebola virus DNA vaccine was safe and immunogenic in humans.” However, the abstract also adds, “Further assessment…will facilitateevaluation and potential licensure of an Ebola virus vaccine under theAnimal Rule.”
What is the Animal Rule? In the development of a vaccine, the normal human testing procedure would be to inoculate a small group of patients and then test the vaccine by presenting the subjects with the disease to see if the vaccine works. For obvious reasons, that kind of testing can’t be done with Ebola. The Animal Rule allows researchers to use animals in place of humans. The efficacy of the drug in humans is then inferred from its success in animals.
In the case of this particular vaccine, that’s exactly what happened. The researchers tested a variation of the vaccine on monkeys in 2009. NIH published a press release summarizing the success of the new research in 2010:
Four cynomolgus macaques received the DNAprime vaccine. A year later, the animals were boosted with the vectorvaccine. Shortly after the boost, the four vaccinated monkeys and fourunvaccinated ones serving as controls were exposed to lethallevels of BEBOV [A strain of Ebola]. All the unvaccinated animals became ill, and threedied. None of the vaccinated animals showed any sign of illness.
In the wake of this success, the lead researcher at NIAID partnered with a private firm called Okairos and patented a vaccine which uses a virus found in chimpanzees as a vector to prime the human immune system for Ebola. The patent was issued in October 2011.
A fact sheet published by Okairos in September 2011 has a graphic of their product pipeline. It shows that the company hoped to enter phase 1 trials with the Ebola vaccine in 2013. In May 2013, Okairos parent company was bought by drug manufacturer GlaxoSmithKline.
At some point the GSK-owned Okairos and NIAID teamed up for another round of animal testing. A paper summarizing the results was published last month. This latest iteration of the research is the one now being tested and already being produced by GSK.
No Guarantees
Bringing a drug or vaccine to market is a long, slow and expensive process. Often the initial research is undertaken by government entities who publish results and then look for public or private partners who can advance the work and potentially help attract a manufacturer willing to fund expensive human trials and eventually manufacture a product. But not every vaccine candidate is rushed to market.
This is not a problem unique to Ebola. The Sabin Vaccine Institute was founded in 2000 with a large grant from the Bill & Melinda Gates Foundation. Sabin specializes in creating vaccines for what they call NTDs, neglected tropical diseases. The Institute’s goal is to help develop, “low-cost vaccines that have essentially no commercial market for diseases that primarily impact the world’s poorest populations.” For example, Sabin is currently part of a consortium working to create a vaccine for SARS.
Contrary to the claim made by Director Collins, there is no guaranteethat another year or another billion dollars dumped on the NIH budgetwould have resulted in a ready-for-market Ebola vaccine. As the WHO andDr. Feldmann have indicated, there are other factors involved which probably had as much or more to do with this than the NIH’s budget.
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