Duration of immune responses after Ebola virus vaccination
Authors: Steven B Bradfute
Journal: The Lancet Infectious Diseases (2015)

In The Lancet Infectious Diseases, Milagritos Tapia and colleagues1Tapia MD Sow SO Lyke KE et al.Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2015; (published online Nov 3.)http://dx.doi.org/10.1016/S1473-3099(15)00362-XPubMed Google Scholar address two important facets of Ebola virus immunity: longevity of vaccine-induced immune responses and correlates of immunity. Early attempts at Ebola virus vaccines on the basis of traditional methods, such as inactivated preparations and subunit vaccines, were not effective in animal studies2Geisbert TW Pushko P Anderson K Smith J Davis KJ Jahrling PB Evaluation in nonhuman primates of vaccines against Ebola virus.Emerg Infect Dis. 2002; 8: 503-507Crossref PubMed Scopus (220) Google Scholar (although later publications on these platforms are more promising3Marzi A Halfmann P Hill-Batorski L et al.Vaccines. An Ebola whole-virus vaccine is protective in nonhuman primates.Science. 2015; 348: 439-442Crossref PubMed Scopus (64) Google Scholar). Subsequent studies used a wide diversity of vaccine platforms that had not been used in approved human vaccines, such as non-pathogenic viral vectors engineered to express Ebola virus surface glycoprotein.4Ye L Yang C Development of vaccines for prevention of Ebola virus infection.Microbes Infect. 2015; 17: 98-108Crossref PubMed Scopus (24) Google Scholar Several vaccine platforms now exist that are effective against Ebola virus in non-human primates, such as the non-replicating chimpanzee adenovirus (ChAd3) platform expressing the Ebola virus glycoprotein, as reported by Tapia and colleagues.1Tapia MD Sow SO Lyke KE et al.Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2015; (published online Nov 3.)http://dx.doi.org/10.1016/S1473-3099(15)00362-XPubMed Google Scholar The ChAd3 vaccine was shown to be protective in non-human primate studies, but specific antibody and T-cell levels fell by 10 months, at which time the animals were less protected against Ebola virus challenge than before 10 months.5Stanley DA Honko AN Asiedu C et al.Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge.Nat Med. 2014; 20: 1126-1129Crossref PubMed Scopus (267) Google Scholar However, a modified vaccinia Ankara (MVA) booster vaccine provided protection against Ebola virus challenge 10 months after vaccination. The published scientific literature suggests that different vaccine platforms might have different correlates of immunity in Ebola virus infection.6Bradfute SB Bavari S Correlates of immunity to filovirus infection.Viruses. 2011; 3: 982-1000Crossref PubMed Scopus (31) Google Scholar The absence of standardised assays and the inherent difficulty with T-cell assays has limited side-by-side comparison of antibody and T-cell measurement in the different Ebola virus vaccines in both human and animal studies. For adenovirus-based vaccines, both Ebola virus-specific total antibody concentrations and polyfunctional T-cell responses (T cells that produce two or more of interferon γ, tumour necrosis factor α, and interleukin 2) are associated with protection in non-human primates, although exact correlation is still being analysed.5Stanley DA Honko AN Asiedu C et al.Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge.Nat Med. 2014; 20: 1126-1129Crossref PubMed Scopus (267) Google Scholar, 7Sullivan NJ Martin JE Graham BS Nabel GJ Correlates of protective immunity for Ebola vaccines: implications for regulatory approval by the animal rule.Nat Rev Microbiol. 2009; 7: 393-400Crossref PubMed Scopus (184) Google Scholar, 8Sullivan NJ Hensley L Asiedu C et al.CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates.Nature Med. 2011; 17: 1128-1131Crossref PubMed Scopus (172) Google Scholar The data presented by Tapia and colleagues1Tapia MD Sow SO Lyke KE et al.Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2015; (published online Nov 3.)http://dx.doi.org/10.1016/S1473-3099(15)00362-XPubMed Google Scholar substantially extend these studies in human volunteers, including four dose responses of the primary ChAd3 vaccination, with or without an MVA boost, in a large cohort. High-titre antibody responses were rapidly induced in most volunteers, with a significant increase at the highest vaccine dose. These titres increased after MVA boost and persisted for more than 6 months. T-cell responses were long lived in individuals receiving only the ChAd3 vaccination, but both the percentage of volunteers developing T-cell responses and the magnitude of polyfunctional T cells greatly increased after the MVA boost. The data suggest that both vaccines were well tolerated. The concentrations of anti-Ebola virus glycoprotein antibodies and polyfunctional T-cell responses after the MVA boost reached values associated with protection with adenovirus-based vaccines in non-human primates. At this point, how well non-human primate immune correlates relate to human protection is unknown. Future experiments that will be important to analyse correlates of immunity in Ebola virus vaccination will probably include analysis of both total anti-Ebola virus antibodies and functional antibody responses (such as neutralising antibody titres and other functional tests). Generally speaking, vaccines against one filovirus are not cross-protective against other filoviruses. Because six distinct filoviruses are pathogenic in human beings, research into use of proven vaccine platforms to cover additional filoviruses will be important. Further studies might focus on immune responses and adverse events after vaccination in different populations. Although direct comparison of field studies with clinical trials near research institutions is difficult, establishment of relative responses will be important. Genetic analysis of patients infected with a Sudan Ebola virus suggests that certain HLA haplotypes predispose patients to survival or lethality.9Sanchez A Wagoner KE Rollin PE Sequence-based human leukocyte antigen-B typing of patients infected with Ebola virus in Uganda in 2000: identification of alleles associated with fatal and nonfatal disease outcomes.J Infect Dis. 2007; 96: S329-S336Crossref Scopus (39) Google Scholar Genetic factors might contribute to immune responses and adverse events after vaccination,10Huttner 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 (214) Google Scholar including variability in presentation of glycoprotein peptides to T cells. A final point is that standardised antibody and T-cell measurements need to be developed for use in different vaccine studies so that immune responses can be directly compared between different studies and groups. Such work is underway by the Filovirus Animal Non-Clinical Group11Kilgore N Nuzum EO An interagency collaboration to facilitate development of filovirus medical countermeasures.Viruses. 2012; 4: 2312-2316Crossref PubMed Scopus (18) Google Scholar and other organisations and should be expanded to include a wide range of antibody and T-cell assays. I declare no competing interests. Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial1 × 1011 pu single-dose ChAd3-EBO-Z could suffice for phase 3 efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission. MVA-BN-Filo boosting, although a complex regimen, could confer long-lived protection if needed (eg, for health-care workers). Full-Text PDF Open Access