Lancet Infectious Diseases
Aug 2017 Volume 17 Number 8 p781-882 e235-e279
Advances in Ebola virus vaccination
Elizabeth C Clarke, Steven B Bradfute
The Ebola virus outbreak in western Africa between 2013 and 2016 was the largest and deadliest since the discovery of the virus in 1976. The epidemic provided the impetus to fast-track several promising vaccines into clinical trials during the tail-end of the outbreak, including the rVSVΔG-ZEBOV-GP viral vector vaccine, which was used in ring vaccination trials in Guinea.
In The Lancet Infectious Diseases, D Gray Heppner and colleagues2 report on the safety and immunogenicity of the rVSVΔG-ZEBOV-GP vaccine over a 6 log10 dose range. This study shows vaccine dose-dependent total and neutralising antibody titres among study participants, which persisted for up to 360 days. The rVSVΔG-ZEBOV-GP vaccine used in the study is a recombinant, replication-competent vaccine based on vesicular stomatitis virus in which the vesicular stomatitis virus glycoprotein (G) has been replaced with the Zaire Ebola virus surface glycoprotein (GP). The Ebola virus surface glycoprotein is the main antigen used in Ebola vaccine development, with the chimpanzee adenovirus (ChAd3)-based vaccine also expressing Ebola virus glycoprotein.3
The strength of this study lies in its demonstration of the longevity of neutralising antibody responses after vaccination. Previous studies with this vaccine showed sharp drop-offs in antibody titres after several months,4, 5 but in this study Ebola virus glycoprotein-specific antibodies were maintained for up to 360 days. Good longevity of immune responses is particularly positive for future development of Ebola virus vaccines, since it could increase the utility of the vaccine for health-care workers and people in endemic regions who are most likely to be exposed to the virus over a prolonged period.
This study examined a range of vaccine doses for immunogenicity. Although lower doses of the vaccine did develop neutralising antibody titres, the authors show that these responses were lower and emerged more slowly than with higher doses of the vaccine. These data are important because the rapidity of the development of immunity could have important repercussions on the value of the vaccine in an outbreak setting, where exposure to the virus is high and decreased time to onset of protection is essential.
Concerns have been raised previously regarding the safety profile of the rVSVΔG-ZEBOV-GP vaccine, particularly the high rates of post-vaccination arthralgia, which were reported in the phase 1 VSV-Ebola CONsortium (VEBCON) network vaccine study in Geneva, Switzerland.6 As with other live attenuated vector-based vaccines, adverse events in this study were more common at higher vaccine doses than at lower doses. This study also addresses many safety concerns, showing that the vaccine was well tolerated and that adverse events of transient arthritis were observed at a much lower rate than in some previous Ebola vaccine studies.
The correlates of protection for Ebola virus are currently unclear. Historically, different vaccine studies have shown that either robust virus-specific CD8+ T-cell responses, high antibody titres, or both are necessary for protection.7, 8, 9, 10 It is possible that correlates of protection for Ebola virus are different for each vaccine,11 or that variations in methodology for complex assays produce different outcomes.
The authors used IgG ELISA and neutralising antibody titres to assess the relevant immunogenicity of the vaccine. Antibodies are thought to be the necessary correlate of protection for the rVSVΔG-ZEBOV-GP vaccine, on the basis of results in non-human primate studies.8 However, it is unknown how well correlates of protection in non-human primates apply to human beings. Additionally, multiple methods can be used for assessment of antibody neutralisation and titre, and the absence of standard assays introduces uncertainty into comparisons of different vaccine platforms and clinical trials.
The prolonged antibody responses and increased understanding of the optimal vaccine doses shown in this study are important steps towards creating a safe and efficacious vaccine against Ebola virus disease. Future work should further describe the onset of protection after Ebola virus vaccination and characterise antibody isotype make-up and T-cell responses. We believe that efforts should be made to standardise the T-cell and antibody assays used in Ebola vaccine trials so that comparisons can be made between vaccines and the vaccines themselves can be improved upon.