- Email: [email protected]
Ebola vaccines: we have options
Comment
In the Lancet Infectious Diseases Olga De Santis and colleagues1 report promising safety and immunogenicity data after single immunisation of healthy volunteers with the chimpanzee adenovirus 3-based Ebola Zaire vaccine ChAd3-EBO-Z. The results of this phase 1/2a study closely mirror the outcomes of a similar trial done in a separate population,2 but add, for the first time, outcomes at 6 months post-vaccination. The findings come as the largest and longest Ebola virus outbreak, causing more than 28 000 cases and 12 000 deaths in West Africa, seems to be nearing its end, with both Guinea and Sierra Leone reporting no cases. The identification of three new Ebola cases at the end of November in Liberia, which had previously gone 122 days without an active case, shows the difficulties faced in ending this outbreak. Additional cases are likely to arise in Guinea and Sierra Leone in the coming months, but these will hopefully be rapidly identified and contained. The enormity of this outbreak finally provided the impetus to move promising vaccines against Ebola virus into human clinical trials with unprecedented speed, despite years of inaction. Results from clinical trials have now been reported for various vaccine platforms, including those based on human adenovirus (Ad5);3 chimpanzee adenovirus (ChAd3),4 with and without modified vaccinia Ankara (MVA-BN-Ebola)2 as part of the vaccination scheme; and recombinant vesicular stomatitis virus (rVSV-ZEBOV).5 Although the platforms differ, all of these vaccines use a similar Ebola antigen— the glycoprotein derived from viruses belonging to the Ebola (formerly Zaire) species. De Santis and colleagues report that after ChAd3EBO-Z vaccination, antibody response rates were near complete (96%), irrespective of vaccine dose (high vs low), whereas cell-mediated immunity response rates were lower (57–69%, depending on cell type). Protection from adenovirus-vectored Ebola vaccines was proposed to be cell-mediated;6 however, the correlates of protection in non-human primates are still debated.6,7 Importantly, the findings show that singleshot immunity is possible, whereas previous adenovirus vaccination schemes at lower doses than in the present study have relied on prime-boost strategies.2,6 Whether long-lasting (≥10 years) single-shot immunity is
possible is not known for this or any of the other Ebola virus vaccine platforms. As with all Ebola vaccines, proving efficacy in human populations will be difficult, and definitive data are unlikely to be obtained except in the context of another large outbreak. So far, only the rVSVZEBOV ring vaccination campaign has shown actual vaccine efficacy,8 albeit with relatively low numbers of individuals. Here, protection was apparent within 10 days of vaccination, in line with the rapid protection noted in non-human primates.9 In the context of reactive vaccination, rVSV-ZEBOV currently seems to set the standard. Unfortunately, with the observation of short-duration arthritis, dermatitis, and vasculitis in some individuals,10,11 population-wide vaccination seems unlikely. Fever was reported in almost 30% of vaccinated individuals in De Santis and colleagues’ study,1 compared with only 7% in a similar study2; however, this adverse event was not an impediment during the ring vaccination campaign. Mathematical modelling has suggested that even with a high response rate, reactive vaccination might only yield a small benefit early in an outbreak.12 Instead, prophylactic vaccination, especially of health-care workers in endemic and high-risk areas, is proposed to have the greatest effect on prevention of early disease transmission. Reactive vaccination (such as ring vaccination) could still have an important role, but is inherently less efficient than vaccination of specific populations before occurrence of an outbreak. For health-care workers in areas with high Ebola potential, the ChAd3-EBO-Z vaccine could play a part in limiting future outbreaks. The vaccine could also be suitable for mass vaccination campaigns should Ebola continue to circulate in west Africa. The ChAd3-EBO-Z vaccine adds another potential tool in our armamentarium to control future Ebola outbreaks. Decisions will have to be made as to which vaccines (if any) are considered for stockpiling for future outbreaks or preventive vaccination campaigns, or will strategies and interventions to combat the Ebola crisis only be addressed after another outbreak starts—a somewhat pitiful prospect in view of the apparent success of vaccines that have moved through clinical trials. The next time we face an Ebola outbreak (at least
www.thelancet.com/infection Published online December 22, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00534-4
National Institutes Of Health/Science Photo Library
Ebola vaccines: we have options
Lancet Infect Dis 2015 Published Online December 22, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)00534-4 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(15)00486-7
1
Comment
of the Zaire species) there should be something more to offer than isolation, contact tracing, and safe burials, which nevertheless will remain crucial components of outbreak response.
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Darryl Falzarano Vaccine and Infectious Disease Organization–International Vaccine Centre (VIDO–InterVac), University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada [email protected]
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I declare no competing interests. 1
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De Santis O, Audran R, Pothin E, et al. Safety and immunogenicity of the chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study. Lancet Infect Dis 2015; published online Dec 22. http://dx.doi. org/10.1016/S1473-3099(15)00486-7. Tapia 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 2016; 16: 31–42. Zhu FC, Hou LH, Li JX, et al. Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet 2015; 385: 2272–79.
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Rampling T, Ewer K, Bowyer G, et al. A monovalent chimpanzee adenovirus Ebola vaccine—preliminary report. N Engl J Med 2015; published online Jan 28. DOI:10.1056/NEJMoa1411627. Regules JA, Beigel JH, Paolino KM, et al. A recombinant vesicular stomatitis virus ebola vaccine—preliminary report. N Engl J Med 2015; published online April 1. DOI:10.1056/NEJMoa1414216. Sullivan NJ, Hensley L, Asiedu C, et al. CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates. Nat Med 2011; 17: 1128–31. Marzi A, Engelmann F, Feldmann F, et al. Antibodies are necessary for rVSV/ ZEBOV-GP-mediated protection against lethal Ebola virus challenge in nonhuman primates. Proc Natl Acad Sci USA 2013; 110: 1893–98. Henao-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: 857–66. Marzi A, Robertson SJ, Haddock E, et al. EBOLA VACCINE. VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain. Science 2015; 349: 739–42. Huttner 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: 1156–66. Agnandji ST, Huttner A, Zinser ME, et al. Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe—Preliminary Report. N Engl J Med 2015; published online April 1. DOI:10.1056/NEJMoa1502924. Coltart CE, Johnson AM, Whitty CJ. Role of healthcare workers in early epidemic spread of Ebola: policy implications of prophylactic compared to reactive vaccination policy in outbreak prevention and control. BMC Med 2015; 13: 271.
www.thelancet.com/infection Published online December 22, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00534-4
In the Lancet Infectious Diseases Olga De Santis and colleagues1 report promising safety and immunogenicity data after single immunisation of healthy volunteers with the chimpanzee adenovirus 3-based Ebola Zaire vaccine ChAd3-EBO-Z. The results of this phase 1/2a study closely mirror the outcomes of a similar trial done in a separate population,2 but add, for the first time, outcomes at 6 months post-vaccination. The findings come as the largest and longest Ebola virus outbreak, causing more than 28 000 cases and 12 000 deaths in West Africa, seems to be nearing its end, with both Guinea and Sierra Leone reporting no cases. The identification of three new Ebola cases at the end of November in Liberia, which had previously gone 122 days without an active case, shows the difficulties faced in ending this outbreak. Additional cases are likely to arise in Guinea and Sierra Leone in the coming months, but these will hopefully be rapidly identified and contained. The enormity of this outbreak finally provided the impetus to move promising vaccines against Ebola virus into human clinical trials with unprecedented speed, despite years of inaction. Results from clinical trials have now been reported for various vaccine platforms, including those based on human adenovirus (Ad5);3 chimpanzee adenovirus (ChAd3),4 with and without modified vaccinia Ankara (MVA-BN-Ebola)2 as part of the vaccination scheme; and recombinant vesicular stomatitis virus (rVSV-ZEBOV).5 Although the platforms differ, all of these vaccines use a similar Ebola antigen— the glycoprotein derived from viruses belonging to the Ebola (formerly Zaire) species. De Santis and colleagues report that after ChAd3EBO-Z vaccination, antibody response rates were near complete (96%), irrespective of vaccine dose (high vs low), whereas cell-mediated immunity response rates were lower (57–69%, depending on cell type). Protection from adenovirus-vectored Ebola vaccines was proposed to be cell-mediated;6 however, the correlates of protection in non-human primates are still debated.6,7 Importantly, the findings show that singleshot immunity is possible, whereas previous adenovirus vaccination schemes at lower doses than in the present study have relied on prime-boost strategies.2,6 Whether long-lasting (≥10 years) single-shot immunity is
possible is not known for this or any of the other Ebola virus vaccine platforms. As with all Ebola vaccines, proving efficacy in human populations will be difficult, and definitive data are unlikely to be obtained except in the context of another large outbreak. So far, only the rVSVZEBOV ring vaccination campaign has shown actual vaccine efficacy,8 albeit with relatively low numbers of individuals. Here, protection was apparent within 10 days of vaccination, in line with the rapid protection noted in non-human primates.9 In the context of reactive vaccination, rVSV-ZEBOV currently seems to set the standard. Unfortunately, with the observation of short-duration arthritis, dermatitis, and vasculitis in some individuals,10,11 population-wide vaccination seems unlikely. Fever was reported in almost 30% of vaccinated individuals in De Santis and colleagues’ study,1 compared with only 7% in a similar study2; however, this adverse event was not an impediment during the ring vaccination campaign. Mathematical modelling has suggested that even with a high response rate, reactive vaccination might only yield a small benefit early in an outbreak.12 Instead, prophylactic vaccination, especially of health-care workers in endemic and high-risk areas, is proposed to have the greatest effect on prevention of early disease transmission. Reactive vaccination (such as ring vaccination) could still have an important role, but is inherently less efficient than vaccination of specific populations before occurrence of an outbreak. For health-care workers in areas with high Ebola potential, the ChAd3-EBO-Z vaccine could play a part in limiting future outbreaks. The vaccine could also be suitable for mass vaccination campaigns should Ebola continue to circulate in west Africa. The ChAd3-EBO-Z vaccine adds another potential tool in our armamentarium to control future Ebola outbreaks. Decisions will have to be made as to which vaccines (if any) are considered for stockpiling for future outbreaks or preventive vaccination campaigns, or will strategies and interventions to combat the Ebola crisis only be addressed after another outbreak starts—a somewhat pitiful prospect in view of the apparent success of vaccines that have moved through clinical trials. The next time we face an Ebola outbreak (at least
www.thelancet.com/infection Published online December 22, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00534-4
National Institutes Of Health/Science Photo Library
Ebola vaccines: we have options
Lancet Infect Dis 2015 Published Online December 22, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)00534-4 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(15)00486-7
1
Comment
of the Zaire species) there should be something more to offer than isolation, contact tracing, and safe burials, which nevertheless will remain crucial components of outbreak response.
4
5
6
Darryl Falzarano Vaccine and Infectious Disease Organization–International Vaccine Centre (VIDO–InterVac), University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada [email protected]
7
8
I declare no competing interests. 1
2
3
2
De Santis O, Audran R, Pothin E, et al. Safety and immunogenicity of the chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study. Lancet Infect Dis 2015; published online Dec 22. http://dx.doi. org/10.1016/S1473-3099(15)00486-7. Tapia 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 2016; 16: 31–42. Zhu FC, Hou LH, Li JX, et al. Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet 2015; 385: 2272–79.
9
10
11
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Rampling T, Ewer K, Bowyer G, et al. A monovalent chimpanzee adenovirus Ebola vaccine—preliminary report. N Engl J Med 2015; published online Jan 28. DOI:10.1056/NEJMoa1411627. Regules JA, Beigel JH, Paolino KM, et al. A recombinant vesicular stomatitis virus ebola vaccine—preliminary report. N Engl J Med 2015; published online April 1. DOI:10.1056/NEJMoa1414216. Sullivan NJ, Hensley L, Asiedu C, et al. CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates. Nat Med 2011; 17: 1128–31. Marzi A, Engelmann F, Feldmann F, et al. Antibodies are necessary for rVSV/ ZEBOV-GP-mediated protection against lethal Ebola virus challenge in nonhuman primates. Proc Natl Acad Sci USA 2013; 110: 1893–98. Henao-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: 857–66. Marzi A, Robertson SJ, Haddock E, et al. EBOLA VACCINE. VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain. Science 2015; 349: 739–42. Huttner 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: 1156–66. Agnandji ST, Huttner A, Zinser ME, et al. Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe—Preliminary Report. N Engl J Med 2015; published online April 1. DOI:10.1056/NEJMoa1502924. Coltart CE, Johnson AM, Whitty CJ. Role of healthcare workers in early epidemic spread of Ebola: policy implications of prophylactic compared to reactive vaccination policy in outbreak prevention and control. BMC Med 2015; 13: 271.
www.thelancet.com/infection Published online December 22, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00534-4