This article was published in Scientific American’s former blog network and reflects the views of the author, not necessarily those of Scientific American
News is rapidly changing regarding Ebola. Even as I’ve been writing this post, we’ve gone from “There is no treatment except supportive care” to NIH’s Dr. Fauci saying a potential vaccine “could be given to health workers in affected African countries sometime in 2015.”
This optimistic projection was a surprise to me, as normally it takes years to develop and bring a drug or vaccine through all phases of clinical treatment.
The only way I can see this happening is by either the “animal rule,” where the FDA allows animal data to be used when clinical trials of efficacy are not practical, after safety testing is done in healthy volunteers (Phase 1, first in human) or by a “compassionate use,” when a drug’s use is allowed out of desperation, where there are no alternatives.
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There are several candidate treatments for Ebola:
Tekmira has an RNA interference drug in Phase 1 testing, but further testing was put on hold while the FDA was examining data about cytokine release, which could be deadly. (This is what happened in the disastrous TeGenero trial, where six healthy volunteers became critically ill with multi-organ failure from cytokine release).
BioCryst’s BCX4430, a nucleoside type of drug which blocks viral reproduction. It, like other drugs, is being co-developed by the government as bioterrorism protection. It is still in the animal testing phase.
Monoclonal antibodies—being developed by MAPP Biopharmaceutical, with the Public Health Agency of Canada and U.S. Army Medical Research Institute of Infectious Diseases, works by preventing virus from entering cells. They have shown good results in macaques infected with Ebola, even when administration was delayed for up to 48 hours. One huge plus for this approach is that production –in plants—can be ramped up with drug delivered within a few weeks. This ZMAPP drug was reportedly given to the two ill American missionaries, Dr. Kent Brantly and Nancy Writebol. Dr. Brantly also initially received a transfusion from a patient he had treated.
This older treatment—transfusion of “convalescent serum” from patients who have recovered from the same illness—seems obvious. This was used successfully to treat influenza in the 1918 pandemic, polio in 1934, and measles, among others. Transfusions were tried in the Kikwit Ebola outbreak in 1995, with apparently good results. The problem is these patients also received better supportive care, muddying the conclusions. Dr. Thomas Geisbert, an expert on Ebola virus at The University of Texas Medical Branch at Galveston, did not see the same good outcome in studies with rhesus macaques infected with Ebola, but these were small numbers. Given the long-standing successful history, the option of convalescent serum transfusion still seems worth pursuing as a potential, relatively low-tech treatment, at least in crisis situations like we have now.
Vaccines are also under development for Ebola. They will measure antibody response as a surrogate marker for efficacy—it would be hugely unethical to expose volunteers to the disease to test for protection from the vaccine. Dr. Geisbert is particularly enthusiastic about a recombinant vaccine. He has demonstrated use of a vesicular stomatitis vector to deliver the Ebola glycoprotein antigen to be moderately effective in animal models, even when given soon after exposure to the virus. This is similar to the way rabies vaccine is produced, he explained. Profectus is using this approach for treatments for a variety of viral pathogens.
One issue with vaccines is the question of what the source is. Live-attenuated vaccines (e.g., oral polio, measles) are the most effective, prompting a more robust immune response. Although they are weakened and are not dangerous, they tend to have more side effects than killed vaccines. There would likely be a lack of enthusiasm for one for hemorrhagic fevers. Killed vaccines (like influenza) have fewer side effects, but tend to require boosters.
Another problem is how to determine the effectiveness of the vaccine in the field. That could be done during an outbreak, offering the vaccine to some, but not others. There would certainly be an ethical outcry over that, although it is unknown whether the vaccine actually works. There are huge logistical concerns in doing a trial during an outbreak, as well as ethical concerns over the adequacy of consent. (A prime example was the suit against Pfizer over its use of Trovafloxacin in Nigeria during the midst of an epidemic of meningococcal meningitis.)
Widespread use of an Ebola vaccine among Africans will never occur—the disease occurs sporadically and infrequently. There were also cultural aversions to vaccines, even before the CIA’s vaccine ruse while seeking Bin Laden fueled mistrust and has led to a resurgence of polio. Any vaccine would be too costly, and there are other illnesses, such as measles and polio, that are far more important to target. Vaccines are likely to be used in two scenarios. One is for ring vaccination of exposed individuals, to prevent further spread. The other is pre-exposure vaccination of healthcare workers, as is done with hepatitis.
It’s important to remember that supportive care is vitally important. I was an investigator on a number of trials for sepsis drugs and, while none were shown to be effective, our mortality dropped from the predicted ~50%, to 10-15%. I emphasize—none of these drugs worked. Rather, we learned how to better manage critically ill, septic patients, thereby drastically reducing our mortality.
Some of the hurdles to be overcome follow.
Priorities and ethics
Perhaps the biggest problem in developing drugs for hemorrhagic fevers is that they occur infrequently, akin to rare diseases in the U.S., and therefore there is not much awareness of them. They don’t affect us, except from concerns over bioterrorism. More importantly, in a purely crass sense, they affect poor people, mostly in Africa. Drugs for illnesses there will not be profitable, therefore pharmaceutical companies don’t bother investing in the necessary drug development. This is the same problem affecting development of drugs for neglected tropical diseases (NTDs), which primarily affect poor, disenfranchised people. In fact, there are large swaths of America affected by many of these same illnesses, especially in the South, the Texas borderlands, and Appalachia, yet they receive similarly little attention and no public outcry.
The justifiable outrage that drugs are not being developed for poor people because they will not be profitable for pharma’s investors needs to be put in perspective with other drugs for bioterrorism and especially with the crisis in antibiotic development.
Ironically, because of profit incentives, a valuable medicine was unavailable last year in the U.S., while it was widely available in Europe. The vaccine, Novartis’ Bexsero, is effective against the strain of meningococcal meningitis that caused an epidemic in Princeton and Santa Barbara. That strain is serogroup B, and is not covered by the vaccines marketed in the U.S. Per the NY Times, “'Novartis had decided there wasn’t enough of a market for it here,” said Jason Schwartz, a fellow at the Princeton University Center for Human Values and an expert in vaccine policy. He added that it did not make sense for Novartis to spend millions of dollars to license a vaccine that would most likely be used only in scattershot outbreaks in the United States.”
President George Bush signed project Bioshield, which earmarked $5.6 billion for new drugs and vaccines to counter bioterrorism, in 2004. One of its beneficiaries is Emergent BioSolutions, which holds a lucrative and exclusive contract for anthrax vaccine production. I was particularly disturbed by its successful proposal to conduct pediatric anthrax vaccine trials. It has since won other juicy biodefense contracts.
While identifying effective treatment for Ebola is important, we should not forget the many multi-drug resistant infections that do not have treatments as well, and the frighteningly high and increasing toll MDR infections have both in the U.S. and globally. The lack of attention focused on antibiotic development is very disturbing.
“Each year in the United States, at least 2 million people become infected with bacteria that are resistant to antibiotics and at least 23,000 people die each year as a direct result of these infections. Many more people die from other conditions that were complicated by an antibiotic-resistant infection.”
For example, Clostridium difficile (aka C. Diff) causes 250,000 infections per year and 14,000 deaths, as well as $1,000,000,000 in excess medical costs per year. In my own limited practice, I’ve seen patients require emergency surgery to remove their colons in an attempt to save their lives, as well as patients dying.
Infections from carbapenem-resistant Enterobacteriaceae (CRE) bacteria are rapidly rising, and these bacteria are resistant to almost all antibiotics. According to the CDC, more than 9,000 healthcare-associated infections are caused by CRE each year, with 600 deaths. For some patients, we have to use toxic old drugs like IV polymixins, which cause renal failure.
Look at the needs:
“In 2012, an estimated 8.6 million people developed tuberculosis and 1.3 million died from the disease (including 320 000 deaths among HIV-positive people).” Drug resistant TB is growing at an alarming rate. In 2012 alone, About 450,000 people developed multi-drug resistant (MDR) TB in the world, with an estimated 9.6% being extremely drug resistant (XDR), resistant to the most effective and commonly used drugs.
Drug resistant malaria is another huge problem. According to WHO, there were an estimated 207 million cases of malaria in 2012, with 627,000 deaths. 1300 children die from malaria every day, or one child almost every minute. Yet by 2012, the incidence of malaria had been reduced by 25% from 2000. A recent study showed that 68% of patients in eastern Thailand showed evidence of resistance to artemesinin, the mainstay of anti-malarial treatment. Some of this is from inappropriate use of the drug as monotherapy; some is from counterfeiting, a profitable endeavor. If this resistance spreads to Africa, all the gains in treating malaria will likely be lost.
Now look at the antibiotic pipeline:
I believe we need to develop drugs for infections globally, especially those transmitted person-to-person (unlike anthrax). If the private market won’t address the problems of drugs for important diseases affecting public health, perhaps governments worldwide should fund development of these drugs. Imagine if there were such collaboration.
What do you think our priorities should be?
Credits:
Ebola in Guinea - Euro Comm DG ECHO/flickr
Timeline of Drug Development- Conducting Clinical Research
other images courtesy CDC
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