Accelerating clinical evaluation carries risks and benefits

Notification by the World Health Organization (WHO) of an outbreak of Ebola virus disease (EVD) in Guinea on March 23 was the starting point of an outbreak that now is of international concern. The statistics for the severity and transmission of this outbreak are tragic. According to a recent report from the WHO, EVD has an average case fatality rate of 70%. Assuming no change in control measures, the agency predicts that the number of people infected with the virus could exceed 20,000 in West African countries by the first week of November.1

EVD is spread through contact with bodily fluids and experts have termed it the ‘care-givers’ disease. Previous outbreaks of EVD have been controlled by rigorous containment measures. Unfortunately, these have failed with the current outbreak for several reasons including population density, major transport links, limited medical facilities and cultural practices. The potential for these infections, previously geographically isolated in regions of relatively low population density, to spread outside Africa and too high population densities in large cities is now a very real public health concern. International travel, ease of infection and lethality of these viruses have created the potential for a global pandemic.

In order to control this outbreak, there is a great deal of hope pinned to the development of vaccines to immunize against EVD, interrupt the chain of infection and contain the disease. However, a safe vaccine can take up to 10 years to develop, far too long a time frame to prevent the deaths of thousands more people. Fortunately a number of candidate vaccines against Ebola and other hemorrhagic members of the filoviridae have already been developed by government-based laboratories and pharmaceutical companies. In order to facilitate a rapid clinical evaluation of two potential vaccine candidates, a multinational effort is being coordinated by the WHO of two new Ebola vaccines currently in Phase 1 safety trials.

The vaccines

Many of the current Ebola vaccines being developed are based on recombinant viruses such as adenovirus, cytomegalovirus, modified vaccinia virus and plasmids—all foreign vectors to humans and therefore unlikely to have cross-reacting antibodies that would reduce the dose after administration. The preclinical testing pathway for vaccines, like other biological materials, does not follow one proscribed program, as the testing is tailored to the nature of the material. Generally however, a one or two species toxicology program, reprotoxicology, and with recombinant vaccines investigation of biodistribution and persistence, including germline and prenatal toxicology studies, are done.

The species choice for these studies will be dictated by susceptibility to the virus, with testing for humoral and cellular response and biodistribution and persistence studies. That some laboratory animal species are susceptible to Ebola virus was demonstrated during an outbreak among imported animals at Reston, Virginia in 1989 and at other sites in the US and Italy. However, there were no incidents of transfer to laboratory workers during this outbreak, leading to the conclusion that this particular strain (Reston Ebola) is non-pathogenic in man.2  The two viral vaccine candidates in clinical testing are:

  • cAd3-ZEBOV (cAd3) from GSK (GlaxoSmithKline) and NIAID (US National Institute of Allergy and Infectious Diseases). This vaccine is generated from an animal-specific adenoviral or ‘cold’ virus; it has been genetically engineered to express glycoproteins from the Zaire and Sudan species of Ebola virus. The adenoviral vector has been used in vaccines against other human diseases and so there is safety data available on this vector.
  • rVSV-ZEBOV (rVSV) from NewLink Genetics and the Public Health Agency of Canada. This vaccine is a ‘weakened’ vesicular stomatitis virus (VSV), a virus that normally infects livestock. It has been genetically engineered to express glycoproteins from the Zaire species of the Ebola virus. This VSV vector has not been previously administered to humans and so the safety data on the vaccine vector are limited at the current time.

The WHO also announced, late this month, that three more vaccine candidates should be ready for clinical testing in early 2015.

The trials

  • A Phase 1 trial evaluating the safety, tolerability and immunogenicity of the adenovirus vaccine (cAd3) candidate got underway last month in Oxford, UK, and Bethesda, USA. Other trials are planned for Mali, the Gambia and Switzerland. A total of 260 healthy volunteers are expected to be enrolled.
  • Another Phase 1 trial for the vesicular stomatitis virus (rVSV) vaccine candidate also recently began in the USA with additional trials planned in Germany, Kenya and Switzerland. Approximately 250 healthy volunteers will be vaccinated. Preliminary data from this trial and the Phase 1 cAd3 trial are expected in December.
  • Phase II and Phase III efficacy trials evaluating both these candidates are planned for early 2015.

It is hoped that Phase 1 data will identify a safe but effective dose to administer to at-risk populations and reduce the chance of infection without causing harm. However, there has been considerable discussion about the best way of ethically implementing Phase II trials while offering protection to workers in the affected regions. Phase II trials are normally run double-blind with placebo controls, in which two groups of individuals are identified; one group is given the trial vaccine while the other is given an irrelevant vaccine. This trial design ensures there is systematic data collection with the reduction of confounding factors that might bias the study outcome.

Proposals to implement this type of trial with a placebo group has resulted in controversy, since this would mean, if the vaccines are effective, that half of the most vulnerable trial participants will be without protection. While this study design has been assessed as the most rapid means of assessing the effectiveness, Doctors Without Borders/Médecins Sans Frontières (MSF) considers the double-blind trial unethical in this instance; MSF has stated that exposed and vulnerable people in the Ebola-affected and low-resource areas should not be led to believe they are being treated or protected when they are not.

Other trial designs have been suggested in which all participants receive vaccine—the so-called ‘Stepped Wedged Design’. In this design, a group or ‘wedge’ of the study population is selected for step-wise inclusion in the trials. Data from each trial ‘wedge’ informs the next group to be included in the study. Key to this design is that the entire study population eventually receives the vaccine if trials demonstrate sufficient efficacy.3

Looking ahead

Whichever trial design is selected to assess efficacy, there will be many logistical hurdles to cross, including availability of suitable quantity of vaccines doses, administration procedures, data collection and evaluation—all in countries with limited health-providing capabilities—before safety and efficacy data are available.

Once an effective vaccine has been identified, the WHO has estimated that a minimum of 50% of the people in at-risk communities will need to be vaccinated to eliminate the virus from the human population.4

Until such a time as one or more of these vaccines are proven effective and become widely available the only course of action, as experts at the NIAID describe, is the strengthening of traditional public health responses.5

Citations

  1. NEJM, 371, 1481-1495, 2014
  2. MMWR, 38(48);831-832,837-838 Dec. 08, 1989
  3. The Lancet, doi:10.1016/S0140-6736(14)61315-5 2014
  4. NEJM, 371, 1481-1495, 2014
  5. BMC Biology, 12:80, doi:10.1186/s12915-014-0080-6 2014