First Ebola virus vaccine to protect human beings?
Authors: Thomas W Geisbert
Journal: The Lancet (2016)

Since the discovery of Ebola virus in 1976, researchers have attempted to develop effective vaccines. Early efforts were largely stalled as a result of the small global market for a vaccine for Ebola virus disease because of an absence of financial incentives for pharmaceutical companies. After the attacks in the USA on Sept 11, 2001, several governments invested in Ebola virus because they had concerns that it could be used as a biological weapon. These investments laid the groundwork for several candidate vaccines for Ebola virus disease that showed promise in preclinical studies in animals.1Marzi A Feldmann H Ebola virus vaccines: an overview of current approaches.Expert Rev Vaccines. 2014; 13: 521-531Crossref PubMed Scopus (113) Google Scholar Among the most promising vaccines showing protection in the gold standard non-human primate models of Ebola virus disease was a vaccine based on a recombinant vesicular stomatitis virus expressing the Ebola virus glycoprotein (rVSV-ZEBOV).2Jones SM Feldmann H Ströher U et al.Live attenuated recombinant vaccine protects non-human primates against Ebola and Marburg viruses.Nat Med. 2005; 11: 786-790Crossref PubMed Scopus (544) Google Scholar Findings from preclinical studies in non-human primates jointly financed by the Public Health Agency of Canada and the US Defense Threat Reduction Agency showed that the rVSV-ZEBOV vaccine could completely protect non-human primates as a preventive vaccine against all medically relevant species of Ebola virus when given as a single-injection vaccine;2Jones SM Feldmann H Ströher U et al.Live attenuated recombinant vaccine protects non-human primates against Ebola and Marburg viruses.Nat Med. 2005; 11: 786-790Crossref PubMed Scopus (544) Google Scholar, 3Geisbert TW Geisbert JB Leung A et al.Single-injection vaccine protects nonhuman primates against infection with marburg virus and three species of ebola virus.J Virol. 2009; 83: 7296-7304Crossref PubMed Scopus (215) Google Scholar protect 50% of non-human primates against Ebola virus disease when given shortly after exposure;4Feldmann H Jones SM Daddario-DiCaprio KM et al.Effective post-exposure treatment of Ebola infection.PLoS Pathog. 2007; 3: e2Crossref PubMed Scopus (254) Google Scholar and seemed to be safe in non-human primates as evidenced by an absence of serious adverse events in severely immunocompromised animals5Geisbert TW Daddario-Dicaprio KM Lewis MG et al.Vesicular stomatitis virus-based Ebola vaccine is well-tolerated and protects immunocompromised non-human primates.PLoS Pathog. 2008; 4: e1000225Crossref PubMed Scopus (170) Google Scholar and no evidence of neurovirulence in non-human primates.6Mire CE Miller AD Carville A et al.Recombinant vesicular stomatitis virus vaccine vectors expressing filovirus glycoproteins lack neurovirulence in non-human primates.PLoS Negl Trop Dis. 2012; 6: e1567Crossref PubMed Scopus (90) Google Scholar Outbreaks of Ebola virus disease have occurred sporadically, mostly in central Africa since 1976. These outbreaks have been small in size and generally well contained until December, 2013, when the largest recorded outbreak of Ebola virus disease began in the west African country of Guinea and quickly spread to surrounding countries with cases also being exported to Europe and the USA. As the outbreak grew in magnitude and appeared to be uncontained, efforts to use medical counter-measures to intervene intensified. In an Article published in The Lancet, Ana Maria Henao-Restrepo and colleagues follow-up their interim results7Henao-Restrepo AM Longini IM Egger M et al.Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial.Lancet. 2015; 386: 857-866Summary Full Text Full Text PDF PubMed Scopus (597) Google Scholar and present the final results of their ring vaccination cluster-randomised trial in Guinea in 2015 to assess the efficacy of a single intramuscular dose of the rVSV-ZEBOV vaccine in the prevention of laboratory confirmed Ebola virus disease.8Henao-Restrepo AM Camacho A Longini IM et al.Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus diseaseexpressing Ebola virus surface glycoprotein: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!).Lancet. 2016; (published online Dec 22.)http://dx.doi.org/10.1016/S0140-6736(16)32621-6Google Scholar The study involved vaccinating a ring of all contacts and contacts of contacts of confirmed cases of Ebola virus disease, either immediately or delayed to 21 days after randomisation. Briefly, 2119 contacts and contacts of contacts in 51 clusters randomly allocated, and 1677 contacts and contacts of contacts in 19 non-randomised clusters were immediately vaccinated, and 2041 contacts and contacts of contacts in 47 randomised clusters received a delayed vaccination 21 days after randomisation. Importantly, no cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters compared with 16 cases in those in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045). Vaccine efficacy was also 100% in the non-randomised clusters (95% CI 79·3–100·0, p=0·0033). These data strongly suggest that the rVSV-ZEBOV vaccine was effective in protecting against Ebola virus infection and probably contributed to controlling the 2013–16 outbreak of Ebola virus disease in Guinea. Protective efficacy is clearly the strength of the study by Henao-Restrepo and colleagues. There have been concerns in the past regarding the safety profile of rVSV-ZEBOV because it is a replication-competent vaccine. In this study, the investigators identified 80 serious adverse events, of which only two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness), with all three cases recovering without sequelae. Conflicting safety results have been reported from phase I clinical trials of the rVSV-ZEBOV vaccine with oligoarthritis being reported in 13 of 51 low-dose vaccines in one study.9Huttner A Dayer JA Yerly S et al.The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial.Lancet Infect Dis. 2015; 15: 1156-1166Summary Full Text Full Text PDF PubMed Scopus (215) Google Scholar No significant adverse events have been reported in other phase 1 studies.10Regules JA Beigel JH Paolino KM et al.A recombinant vesicular stomatitis virus Ebola vaccine—preliminary report.N Engl J Med. 2015; (published April 1.)https://doi.org/10.1056/NEJMoa1414216Crossref PubMed Scopus (253) Google Scholar Although rVSV-ZEBOV seems to be highly efficacious and safe in the context of an outbreak, some questions remain. One question that has not been adequately addressed, even in non-clinical studies with any Ebola virus vaccine, is with regard to durability—is the vaccine long-lasting? Is it still protective, for example, 2–3 years after the vaccination? Another question is in regard to improvements in safety: clearly, the VSV-based Ebola virus vaccines appear to be the lead candidates for use in human beings, but can they be further attenuated to reduce the number of adverse events noted in phase 1 trials without reducing efficacy? Results of preclinical studies in non-human primates suggest that this attenuation might be possible.11Mire CE Matassov D Geisbert JB et al.Single-dose attenuated Vesiculovax vaccines protect primates against Ebola Makona virus.Nature. 2015; 520: 688-691Crossref PubMed Scopus (73) Google Scholar After 40 years we appear to now have an effective vaccine for Ebola virus disease to build upon. This success has been achieved by leveraging findings from published preclinical studies to justify the use of the rVSV-ZEBOV vaccine during an outbreak without the need for time-consuming and costly good laboratory practices (GLP) or GLP-like preclinical studies required by regulatory policies such as the US FDA Animal Rule,12US Food and Drug AdministrationCode of Federal Regulations title 21.https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314&showFR=1&subpartNode=21:5.0.1.1.4.9Google Scholar that although well intentioned, are impractical and inefficient in the context of the few high containment biosafety level 4 laboratories that exist worldwide (ie, laboratories that use the highest level of biosafety precautions and where, in most cases, workers wear positive pressure suits to work the with most hazardous viruses such as Ebola virus). I have five US patents in the fields of filovirus and antiviral vaccines, including Ebola virus disease, and two provisional US patents: number 7635485, entitled “Method of accelerated vaccination against Ebola viruses” issued to G Nabel, N Sullivan, P Jahrling, and TW Geisbert on Dec 22, 2009, issued to the US government; number 7838658, entitled “siRNA silencing of filovirus gene expression” issued to I MacLachlan, V Sood, LE Hensley, E Kagan, and TW Geisbert on Nov 23, 2010, issued to Tekmira Pharmaceuticals and the US government; number 8017130 entitled “Method of accelerated vaccination against Ebola viruses” issued to G Nabel, N Sullivan, P Jahrling, and TW Geisbert on Sept 13, 2011, issued to US Government; number 8716464, entitled “Compositions and methods for silencing Ebola virus gene expression” issued to TW Geisbert, ACH Lee, M Robbins, V Sood, A Judge, LE Hensley, and I MacLachlan, on May 6, 2014, issued to Tekmira Pharmaceuticals and US Government; and number 8796013 entitled “Pre- or post-exposure treatment for filovirus or arenavirus infection” issued to TW Geisbert on Aug 5, 2014, issued to Boston University and Profectus Biosciences. I also have two patent provisional US patents: 61/014669 filed Feb 8, 2008, by TW Geisbert pending to Boston University, entitled “Compositions and methods for treating Ebola virus infection”, and 61/070748 filed March 25, 2008, by TW Geisbert, JH Connor, and H Ebihara pending to Boston University, entitled “Multivalent vaccine vector for the treatment and inhibition of viral infection.” Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!)The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters. Full-Text PDF Open Access