Ebola Therapies and Vaccines Need Priority, Support

Veronica Hackethal, MD

August 22, 2014

The development of experimental therapies and vaccines for Ebola should receive priority, according to several editorials written by infectious disease experts and published in major medical journals this week. The urgency for such therapies and vaccines, however, some experts caution, should not trump the need for high-quality testing of those agents to ensure their value, or delay improvements in infrastructure and public health efforts that officials have used to stop Ebola outbreaks in the past.

One expert, currently working on the ground in Uganda, told Medscape Medical News that a silver lining from this large outbreak might be the increased priority wealthy countries put on infectious disease research. However, turning that attention into action and product will take commitment and money, and whether those last remains to be seen.

The current Ebola outbreak in West Africa is the largest and deadliest ever, with an estimated case fatality rate ranging between 50% and 90%. As of August 21, the US Centers for Disease Control and Prevention (CDC) report that the number of suspected and confirmed cases has climbed to 2473, with 1300 suspected deaths. The high mortality rate, coupled with a dearth of effective treatments, has focused attention on experimental therapies whose efficacy and safety in humans has yet to be tested.

A group of ethicists convened by the Wold Health Organization, although missing representation from countries affected by the current outbreak, write in a statement published on the organization's Web site that it is "ethical to offer unproven interventions with as yet unknown efficacy and adverse effects," and that "there is a moral duty to evaluate these interventions...in the best possible clinical trials."

In a perspective published online August 20 in the New England Journal of Medicine, Jesse L. Goodman, MD, MPH, from Georgetown University and the Veterans Affairs Medical Center, Washington, DC, notes that the highest priority remains infection control measures, but he also emphasizes the importance of developing effective treatments.

In particular, the use of ZMapp (Mapp Biopharmaceutical, Inc and LeafBio), the so-called "secret serum" given to American healthcare workers Kent Brantly, MD, and Nancy Writebol, who were infected with Ebola in West Africa, has generated much controversy. The drug, which contains 3 monoclonal antibodies, had been shown to improve survival in nonhuman primates but had never been tested for safety in humans. Although the 2 Americans survived, a third patient died after receiving the drug, depleting stores of the scarce therapy. Moreover, whether the Americans' improvement was a result of the drug itself or other factors remains unclear. High-quality supportive care — or simply surviving beyond the first few days of the illness — could have played a critical role, according to Dr. Goodman. The potential benefit associated with ZMapp is further muddied by the fact that Dr. Brantley also received a transfusion from a recovered patient, another therapy for which the efficacy remains unproven.

Good Trials Needed to Avoid Misleading Data

All this raises questions about how best to develop and test new drugs for diseases such as Ebola that occur as sporadic outbreaks in resource-poor settings. Therapies currently in development include RNA-based therapeutics (TkM-Ebola, AVI-7537) and an adenosine analogue (BCX-4430). Drugs approved for other indications, such as chloroquine and imatinib, might also have activity against Ebola.

Dr. Goodman proposes that experimental drugs be allowed for limited, compassionate use during a crisis. However, controlled clinical trials must also be conducted to avoid "misleading even harmful conclusions." For example, in acutely ill patients, severe adverse effects of the drug, such as organ failure and death, may be indistinguishable from the effects of the disease.

"The most promising [therapeutic candidates] are cocktails of monoclonal antibodies," Kartik Chandran, PhD, associate professor of microbiology and immunology at the Albert Einstein College of Medicine in New York City, told Medscape Medical News.

Dr. Chandran is part of a National Institutes of Health consortium created in March 2014 that has partnered academic, government, and industry researchers from 15 institutions in studying antibody "cocktails" in treating Ebola. Dr. Chandran is also one of the authors of a study by Gang Chen and colleagues, published online August 20 in ACS Chemical Biology. That study suggested that an antibody therapy developed by Dr. Chandran and colleagues could protect mice against the Sudan species of Ebola (the current outbreak has been caused by the Zaire strain).

"I believe therapeutics are a higher priority than vaccines," Dr. Chandran added. "Drugs against Ebola aren't the only things that are needed, but they should be a crucial component of the robust international response that this outbreak will hopefully engender."

In a related opinion published online August 21 in the Annals of Internal Medicine, Alison P. Galvani, PhD, from the Center for Infectious Disease Modeling, Yale School of Public Health, New Haven, Connecticut, and colleagues argue that untested vaccines should be deployed. No Ebola vaccines have been tested in late-stage human trials, and none are currently licensed, but several candidate vaccines exist. Phase 1 clinical trial results support the safety and immunogenicity of a DNA vaccine, the authors point out, and a therapeutic vaccine based on recombinant vesicular stomatitis viruses has also shown promise. Furthermore, the US Food and Drug Administration's "animal rule" allows for licensure and approval in unique circumstances, using results from animal models in conjunction with human safety and immunologic data.

"We believe that the safety risks of vaccines, particularly those found to be safe in phase 1 clinical trials, are probably negligible compared with the risks faced by health care workers in communities where the highly virulent Ebola virus is currently circulating," Dr. Galvani and colleagues write.

In yet another editorial published online August 20 in the New England Journal of Medicine, CDC Director Thomas Frieden, MD, MPH, and colleagues acknowledge the importance of moving forward with drug development and vaccines, but emphasize the absolute necessity of continued public health control efforts.

"Ethical issues have been raised about using experimental treatments and vaccines that are in very limited supply, but a vaccine that is safe and effective would further protect health care workers and potentially others in outbreak situations," they assert.

"In my view, all of these [vaccines and therapies] should continue to be advanced through the regulatory process. Ebola outbreaks are sporadic and difficult to predict, so even if a safe and effective vaccine could be developed, there would still be a need to have a therapy available as well," Jonathan R. Lai, PhD, associate professor of biochemistry at Albert Einstein College of Medicine, told Medscape Medical News. Dr. Lai is senior author on the study published this week in ACS Chemical Biology by Dr. Chen and colleagues. He is also part of the National Institutes of Health consortium.

In a counter-opinion published online August 21 in the Lancet, leading bioethicists Professor Ezekiel Emanuel, MD, from the University of Pennsylvania, Philadelphia, and Annette Rid, MD, from Department of Social Science, Health & Medicine, King’s College London, United Kingdom, argue that containment and strengthening health infrastructure should be the first priority.

"Although the prospect of specific Ebola treatments or vaccines is enticing, the current unproven interventions should have a marginal role in the global response," they write. "Fundamentally, this Ebola outbreak — and future ones — need focus on strengthening of health systems and basic infrastructure, rather than experimental treatments and vaccines."

Furthermore, they point out the vital importance of randomized controlled trials that adhere to a standard of 8 ethical principles of research. Fair distribution of these new drugs beyond the well-off or well-connected should also be ensured. If compassionate use outside of clinical trials does occur, the authors argue for full transparency of the results, overseen by a neutral body.

Multiple other perspective articles were published at the same time in various journals, highlighting other issues surrounding the current outbreak. In a perspective article published online August 20 in the New England Journal of Medicine, Margaret Chan, MD, director-general of the World Health Organization in Geneva, Switzerland, pointed to poverty as the single biggest reason explaining why the current outbreak has been "so large, so severe, and so difficult to contain." Fear also remains one of the biggest impediments to containment, and it could undermine surveillance and treatment efforts.

A View From the Frontlines

In a telephone call from Uganda, Leslie Lobel, MD, PhD, senior lecturer in the Department of Microbiology, Immunology and Genetics at Ben Gurion University of the Negev, Beer-Sheva, Israel, told Medscape Medical News about his own research efforts. Dr. Lobel is also part of the National Institutes of Health consortium. For the last 12 years, Dr. Lobel's group has researched antibodies from survivors with the strongest immunity against Ebola virus, as well as antibodies that can neutralize multiple Ebola strains at the same time. They have also identified survivors with little memory immunity and are trying to figure out how such patients managed to survive.

"We want to be ready for the next epidemic and for the unknown in terms of treatment of filoviruses," Dr. Lobel said. "Following all patients in the cohort, not just those with the strongest immune responses, will hopefully provide enough useful information to develop very effective vaccines."

However, science cannot provide all the answers, according to Dr. Lobel.

"The main challenge is bringing vaccines to market," Dr. Lobel stated. "Drug companies have done a great deal of good for society, it's just that they can't afford to lose huge sums of money on producing a product for these exotic diseases."

Another big challenge will be worldwide governmental coordination to secure funding.

"There are tremendous political and economic challenges that I think are just as great as the scientific challenges, if not greater," Dr. Lobel explained.

"The one thing that should be said, that most people aren't saying, is that if there is anything good coming out of this, [it is] that the world will realize that this is the tip of the iceberg. This should be a wakeup call that we can't sleep on infectious diseases," Dr. Lobel noted, while mentioning that challenges with funding for infectious disease research and lack of opportunity for virologists in academia are discouraging future generations from entering the field.

Continued support for developing these technologies and controlling Ebola needs to extend beyond the wake of the current epidemic.

"Governments need to wake up and realize that we need to rebalance the investment of funds so that infectious disease gets its fair share. Infectious diseases are actually a greater threat to global stability than any other disease in medicine today," Dr. Lobel emphasized. "They have molded the shape of civilizations in the past and can do so in the future."

Dr. Lai reports being a coinventor on 2 US patent applications covering antibodies for filovirus therapy. The other authors and Dr. Lobel have disclosed no relevant financial relationships.

N Engl J Med. Published online August 20, 2014. Goodman full text, Frieden full text, Chan full text

ACS Chem Biol. Published online August 20, 2014. Chandran extract

Ann Intern Med. Published online August 21, 2014. Full text

Lancet. Published online August 21, 2014. Full text

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