ALTHOUGH there have been many preventive vaccines and therapeutic drugs for the Ebola virus disease (EVD) under development and investigation since the turn of the century, currently there is none that has been approved by any national regulatory authority for use in humans. On August 11, given the acuteness of the ongoing Ebola crisis in West Africa, the World Health Organisation (WHO) cleared such pipeline drugs and vaccines (with proven safety and efficacy in non-human primate studies) to be used for the purpose of compassionate care in emergency situations, particularly for health-care workers in the affected regions.
Since then, when the number of deaths were still in the hundreds ( Frontline , September 19), the situation has only escalated, and in fact, there was a sharp increase in the number of EVD cases in the last week of October. Guinea, Liberia and Sierra Leone are the worst-affected countries and where there is no perceptible decline in the number of cases. “Right now the epidemic is out of control. The situation is drastic and calls for drastic measures,” Marie-Paul Kieny, the WHO’s Assistant Director-General for Health Systems and Innovation, told the medical journal Lancet .
Accordingly, as a follow-up to the August 11 decision, the WHO convened a special consultation meeting on September 4 and 5 on potential therapies and vaccines for EVD. The meeting was attended by more than 200 experts from 29 countries, including some Ebola-affected West African countries. The objective of the meeting was to identify the most promising candidate vaccines and experimental therapies in the pipeline and map out the strategies to arrest the spread of the virus.
The meeting considered vaccines under development and experimental therapies, including drugs and “convalescent plasma” (whole blood and blood serum from survivors), for this fast-track initiative. But, as the WHO background document for the meeting correctly underlined, “evidence [based on immune responses in animal models] of their effectiveness is suggestive, but not based on solid scientific data from clinical trials. Safety is also unknown, raising the possibility of adverse side-effects when administered to humans. For most, administration is difficult and demanding.” (Phase 1 clinical trials screen the drugs/vaccines for safety. Phase 2 trials establish the efficacy of the vaccine, usually against a placebo in a randomised controlled trial (RCT). Phase 3 confirms safety and efficacy in a broader setting with a much larger sample size.)
Notwithstanding this fast-track approach, interventions using experimental therapeutic agents or vaccines may have only a marginal effect on the ongoing epidemic. For one, the supply of these interventions will only be limited as these are in the development phase. “While many efforts are under way to accelerate production, supplies will not be augmented for several months to come,” cautions the WHO document. “This is especially true for therapies, where expected supplies are not thought likely to have a significant immediate impact on the outbreak.” Secondly, the failure rate in clinical trials of compounds with great promise during the preclinical phase is high—the success rate from preclinical candidate selection to commercial launch is only around 10 per cent. “Although promising in non-human primates,” wrote Annette Rid and Ezekiel Emanuel of King’s College, London, in Lancet , “there is no reason to believe that the experimental Ebola interventions will be more successful [in humans].” There are also major ethical and regulatory issues to be considered in this accelerated drug and vaccine development that will be based on data from the infected and the diseased in a raging epidemic, and that too in a setting of poor health systems and infrastructure in some of the poorest countries of the world. In such a context there is, in fact, an ongoing debate within the medical community, and among the manufacturers, whether it is ethical to carry out RCTs in an epidemic setting where conventional care does not have any impact on clinical outcomes, and the fatality rate is as high as 70 per cent, the argument being that the ethical “equipoise” principle, a necessary condition for an RCT to provide reliable data, is not satisfied here.
Regulatory assessmentSince the initiative will be a concerted effort of multiple institutions based in different countries, harmonising clinical trial protocols and ethical review will also be an important issue. The data from the trials will then undergo regulatory assessment leading to product licensing for manufacture, and the manufacturer will take time to get scaling-up infrastructure in place. The meeting also discussed innovative models to expedite clinical trials and possible ways to ramp up production of the most promising products.
The WHO has estimated that it will take six to nine months to have the promising drugs and vaccines flowing into the affected areas. The WHO has also issued a road map, which details the steps to be taken to achieve that. It also needs to be borne in mind that in the worst case none of the potential therapies and vaccines may prove to be safe, efficacious and effective for EVD in humans.
Given these potential pitfalls, isolation of suspected Ebola cases, rigorous standards of practice in infection prevention and control (IPC), implementation of effective clinical care, contact tracing and follow-up, monitoring and surveillance, raising risk awareness of local communities and political mobilisation of collective international action will continue to be crucial to stem the epidemic, the WHO document notes. “However,” says the document, “at this stage of the outbreak, it is considered that the possible benefits of [clinical use of experimental therapies and vaccines] outweigh the risks for the individuals and communities concerned.”
At the end of the September 4-5 consultation, experts agreed that since, given the scale of the epidemic, there would be a large number of recovered patients, from among the experimental therapies, convalescent whole blood and plasma therapy should be accorded priority for further investigation. It was also decided that investigations with experimental therapies would run parallel to the accelerated clinical trials and licensure for the production of efficacious candidate vaccines. “[The] important thing is to stop it [the outbreak] with the tools we have today and at the same time make sure that when new products are available for tests, they be tested and they be tested in rigorous clinical trials because the only time you can study medicines or vaccines is during an outbreak,” David Heymann, former Assistant Director-General for Health Security and Environment in the WHO and currently Chairman of the Board in the Health Protection Agency (HPA), United Kingdom, said in a Lancet podcast interview. Heymann was part of the international team that investigated the first outbreak in 1976 in Zaire and had collected blood plasma from the survivors for later investigation and use. But the next outbreak happened much later, only in 1995, and the serum was no longer useful.
Studies suggest that transfusion of blood and blood serum (containing antibodies to the Ebola virus) from patients who have recovered from EVD might prevent or treat Ebola infection in others. However, from the results of these limited studies, it has been difficult so far to unambiguously conclude that antibodies in plasma of survivors are sufficient to be therapeutically useful. “What is the role of convalescent plasma? That study needs to be done right now in order to determine whether or not these are sustainable interventions and effective in Africa,” Heymann said.
In the 1999 outbreak, transfusion of locally collected convalescent blood is said to have helped decrease Ebola mortality. In the current outbreak, convalescent therapies have been used in a few patients but the numbers are too small to draw any conclusion about its efficacy. For instance, one American doctor working in Monrovia, Liberia, received convalescent whole blood and recovered while still in Monrovia, but since he also was administered the experimental medicine ZMapp and later received supportive care in the United States, it is difficult to attribute his recovery to convalescent therapy. There are a couple of other cases as well where convalescent therapy was effective.
There is, however, a theoretical concern in this therapy about “antibody-dependent enhancement” of Ebola infection. Studies as part of this fast-track initiative may throw light on this issue. Otherwise the associated risks are like those associated with the use of any blood product. In the case of Ebola, the donors have to be tested to see whether they are clinically and serologically free of the Ebola virus. This implies that capacity-building in Ebola-affected countries for the collection, and testing of sufficient convalescent blood from recovered patients is crucial. But, as Thierry Burnouf and others commented in Lancet , “paradoxically outbreaks are occurring in the countries that have the least capability for blood and plasma collection or viral screening”.
As the epidemic gets worse, the worst-affected countries apparently have already begun blood transfusions. The WHO has issued interim guidelines on the use of convalescent whole blood or plasma, addressed to national health authorities and blood transfusion services. The WHO is also in consultation with health experts and agencies in West Africa to see how this therapeutic intervention can be implemented effectively. “One great appeal of this drive,” the WHO noted, “… is the opportunity to strengthen basic public health infrastructures by helping these countries to develop good-quality blood services.” First batches of regular supply could begin from end-2014, according to the WHO. The other experimental therapies that were considered for testing in the meeting included: (i) the drug ZMapp and hyperimmune globulin, which target the Ebola virus before it enters the cell; (ii) the set of drugs (TKM-Ebola, AVI 7537, Favipiravir/T-705, BCX4430 and Brincidofovir) which interfere with viral production; (iii) interferons, which bolster human cells into antiviral action; and (iv) other existing drugs that have been approved for other purposes. ZMapp, which was developed by a U.S.-government-funded research and development (R&D) programme to counter the Ebola virus’ use as a biowarfare agent, is a cocktail of three humanised mouse monoclonal antibodies against the virus ( Frontline , September 19). The three antibodies in this mixture neutralise the virus by binding to a different site on the covering or “envelope” of the virus. Studies in monkeys showed a strong survival of up to five days after infection, when virus and/or fever was present. There have been no formal safety studies in humans so far though in the current epidemic a few EVD-infected individuals were given ZMapp on compassionate grounds and no safety issues have been reported. Only a very limited supply (fewer than 10 treatment courses) was used in the current epidemic. Increased supply following scaled-up production —a few hundred doses—may become available by 2014-end.
Hyperimmune globulin is prepared by purifying and concentrating the blood plasma or serum of immunised animals that are non-susceptible to Ebola or convalescent humans who have recovered with very high titres of neutralising antibody against EVD. But generally, hyperimmune globulin is derived from non-susceptible animals after multiple immunisations with live Ebola virus. The rationale for its use comes from the limited experience during the 1995 outbreak in Zaire and also from tests in non-human primates. There has been extensive experience with use of hyperimmune globulin against other infectious agents in humans. According to the WHO, large-scale good manufacturing practices (GMP)-compliant hyperimmune globulin batches for human use from horses or transgenic animals will not be available before mid-2015. Hyperimmune globulin studies in monkeys have shown that the therapy can be used to neutralise different strains of the virus if the treatment begins 48 hours after exposure to the virus.
The other five antiviral drugs included in (ii) above act by interfering with the replication mechanism of the virus in the host. TKM-Ebola is a nanoparticle drug carrying small interfering ribonucleic acid (siRNA) as its active ingredient. siRNA molecules typically interfere with the expression of certain genes. In this case, they interfere with two essential virus genes and stop the virus from replication. The drug has been found to be effective in guinea pigs and monkeys, and studies have shown 83 per cent and 67 per cent survival if administered 48 hours and 72 hours respectively after infection.
In monkey studies, doses of 14-40 mg/kg of the drug AVI 7537 for 14 days showed typical survival ranging from 60 to 80 per cent. Studies earlier have also demonstrated tolerability of the drug by humans. Favipivavir is an approved drug in Japan for use in viral influenza under special circumstances. No major side effects have been reported so far. However, efficacy studies against Ebola in animal models have not yielded unequivocal results: while it is effective in mice against EVD, in one monkey study, only one out of six survived. Also, according to the WHO document, the dose for Ebola in humans is likely to be two to five times higher and the treatment duration is also likely to be longer. The drug BCX4430 has been found to show 83 to 100 per cent survival in rodents with EVD. It is also effective against the lethal Marburg virus if given 48 hours after infection. Testing with EVD in monkeys is under way. No safety study has been done on humans and such studies are planned during the current outbreak.
Interferon drug formulations are based on proteins released by host cells when mounting an antiviral defence in the body. In therapy, they act by inducing an antiviral state in exposed cells and regulating the immune system. Various interferons have been in use to treat chronic hepatitis and multiple sclerosis where higher doses are associated with greater adverse effects but no greater efficacy. A study with EVD showed that interferons cause delayed death in monkeys but no overall increase in survival. Early administration enhances the effectiveness of the treatment in animals and lengthens the time after infection for which antibodies remain effective.
In the context of the current epidemic in West Africa, health researchers have increasingly come to realise that, even at this stage, an effective vaccine against EVD could be a potential game changer in the evolution of the epidemic in the months to come. A number of candidate EVD vaccines which have been tested in animals, exist (Table 1), but most are not available for clinical use. The September 4-5 consultation meeting also accorded high priority to expedited evaluation of the candidate vaccines with clinical grade material. The meeting identified two vaccines, which are available for Phase 1 clinical trials. The objective was to make these vaccines available as soon as possible—and in sufficient quantities—to protect critical front-line health workers so that it has an impact on the epidemic’s future evolution.
One vaccine, ChAd3-ZEBOV (ZEBOV stands for Zaire Ebola Virus), was developed collaboratively by the pharma company GlaxoSmithKline (GSK) and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), U.S. It is a chimpanzee-derived adenovirus vector (which does not grow in humans) with an Ebola virus gene inserted. The second (rVSV-Ebov) was developed by the Public Health Agency of Canada (PHAC) in Winnipeg. This vaccine uses an attenuated, or weakened, vesicular stomatitis virus (VSV), which is found in livestock. One of its genes has been replaced by an Ebola gene to induce an EVD-specific immune response. The licence for commercialisation of the vaccine is held by an American company, NewLink Genetics, located in Ames, Iowa.
In a study where animals were given a lethal dose of the Ebola virus, all 16 were protected by a single dose of ChAd3-ZEBOV vaccine. While the safety of an EVD vaccine in humans is yet to be established, more than 1,300 people—including 1,000 in Gambia, Senegal, Burkina Faso and Kenya—have received ChAd3-based vaccines for other diseases. The second vaccine was found to protect all 20 animals that had been given a lethal dose of the virus. The rVSV vaccine has also been found to be effective whether the animals were given the vaccine before or after the inoculation of the Ebola virus.
It was also found that animals with weakened immunity were not harmed by the vaccine. The vaccine was also found to be safe when directly injected into animal brains. However, it remains unknown whether the vaccine will grow in humans, especially in people with weak immunity. Too little growth, notes the WHO document, could make a weak vaccine and too much could lead to side effects. The PHAC had a stock of 1,500 vials, out of which it has donated 800 (which translate to 1,500-2,000 doses of the vaccine) to the WHO, and the rest are owned by NewLink. The WHO, in turn, has distributed the vaccine doses to different centres for the proposed trials.
Interestingly, both the vaccines were developed about a decade ago—the Canadian one, in fact, a little earlier, around 2000—but they did not go through clinical trials essentially for want of a sizable commercial market for the new vaccine. The licence with NewLink too has come under criticism because of the limitations of such a small company that has little experience in this area. The company was licensed to produce the vaccine when there was little interest in the vaccine among the big pharma companies as they did not see any emerging market for an Ebola vaccine.
Between the first outbreak in 1976 and before the current outbreak in 2014, EVD killed on an average about 40 people a year, points out Peter Piot, director of the London School of Health and Tropical Medicine and the co-discoverer of the Ebola virus in Zaire in 1976. All previous outbreaks have been sporadic, unpredictable and small in size, and it was never perceived to be a global public health issue until the current West African epidemic. Also, as Piot told Lancet , the vaccines could not have been rigorously tested in the absence of major epidemics and, more pertinently, without the virus circulating among humans, though he admitted that testing could have been done on a smaller scale.
However, as Medicins Sans Frontieres (MSF) has rightly observed: “Ebola is a disease that, until now, affected a small number of people in low-income countries in sub-Saharan Africa; the affected populations don’t represent a ‘market’ that could itself provide enough incentive for companies to develop a vaccine. Current development has been largely funded by governments motivated primarily by the need to protect against the possible use of Ebola in bioterrorism.”
Following the decision of the September 4-5 meeting, the WHO convened another meeting of experts during September 29-30 to assess the progress in the evaluation of the candidate vaccines. More than 70 experts, including many from the Ebola-hit West African countries, attended. Representatives of the companies manufacturing the two vaccines also attended. The key objective was to obtain an overview of the clinical trials under way and planned for the vaccines and to agree on a regulatory pathway to rapidly evaluate them for safety, immunogenicity and efficacy.
This was followed up by a high-level emergency meeting on October 23 that the WHO had convened at the request of several governments and representatives of the pharmaceutical industry to look at the many complex policy issues relating to the eventual production and supply of Ebola vaccines. The meeting included about 90 participants from governments, industry, and non-governmental and philanthropic organisations.
This meeting discussed ways to ensure fair distribution and financing of these vaccines, and the WHO underlined the sense of urgency in arriving at various milestones towards achieving the goal. For instance, the meeting decided to carry out the different phases of clinical trials in parallel rather than consecutively. The WHO also recommended partnerships to expedite the trials. Although RCTs are regarded as the gold standard for providing reliable scientific data for analysis and interpretation of efficacy from clinical trials, given the apprehensions around RCTs in the present context of the ongoing epidemic in West Africa, the meeting decided that a “randomised stepped-wedge” design could also be used to yield useful and meaningful data. In the stepped-wedge approach, different groups (wedge or slice of the study population pie) are randomly selected and included (stepwise) at different times and determine how the immune responses vary between the groups with the time of administration. Phase 1 trial of the ChAd3 vaccine began in late September in the U.S. and the U.K. and has since moved to Mali. In parallel, the NIH also has plans to carry out an advanced RCT in nearly 20,000 health workers in Liberia. The Phase 1 trial of the rVSV vaccine began in mid-October in the U.S. and is expected to begin soon in Gabon, Germany, Kenya and Switzerland. According to the WHO, the results of the Phase 1 trials should be available by December, and Phase 2 trials for efficacy will also begin alongside in December itself.
Funding issuesSignificantly, the meeting concluded that funding issues should not be allowed to dictate the vaccine agenda. “The funds will be found,” the WHO has stated. Funding for Phase 1 trials of both the vaccines came within a matter of weeks after the consultation meeting through a consortium of the Bill & Melinda Gates Foundation, the Wellcome Trust, the NIH and the European Commission. According to the Norwegian Institute of Public Health, the costs of trials beyond Phase 1, scaling up production over six to nine months, testing and immunisation campaigns that will follow will amount to about $150 million.
It was also concluded at the meeting that the timing of vaccine doses should not constrain the design of clinical trials, and industry representatives have apparently assured the supply of requisite quantities of vaccine. GSK expects to increase its monthly capacity for purified bulk vaccine from its current 24,000 doses to 230,000 doses —a 10-fold increase—by April 2015, if they can be filled for release. Indeed, filling vaccine vials at the rapid pace required may prove to be a bottleneck because, since the vaccines are genetically engineered, they are classified at biosecurity level 2, which limits the locations at which they can be processed. The meeting also noted that NewLink’s manufacturing capacity varied according to the dose selected. The company has targeted to increase its capacity from the present 52,000 doses to 5.2 million doses for the first quarter of 2015.
Given the limited supply of the vaccine, health-care workers, including medical staff, laboratory staff, burial teams and facility cleaners, will receive the first doses of the vaccine when the vaccination process gets under way. This, according to the WHO, should begin to happen in the first quarter of 2015. The October meeting concluded that all efforts to develop, test and approve the vaccines must be completed at an accelerated pace, “even if dramatic changes in the epidemic’s transmission dynamics meant that vaccines were no longer needed”.
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