- Email: [email protected]
Advances in Ebola virus vaccination
Comment
circumvent the lower efficacy of live oral vaccines observed in less developed regions, although that remains a conjecture until a study with clinical endpoints is done. Second, a more predictable advantage is that a parenteral vaccine is not expected to cause intussusception. Third, an inactivated vaccine could have some effect on reducing rotavirus shedding but, as for polio, it might be better at preventing disease while less effective at preventing shedding than live oral vaccines. Groome and colleagues11 indicate that a phase 2 trial with a formulation with additional rotavirus antigens is planned, with the hopes of broadening what appears to be a predominantly homotypic response. Hopefully when the phase 3 trial is designed, this vaccine will be compared with an established vaccine in a noninferiority trial, rather than to placebo. Such a study will be more difficult and will require substantially more infant participants, but would provide more definitive answers regarding comparative efficacy, and might be the only ethical choice with widespread vaccine use. Finally, implementation of a new parenteral vaccine in a crowded vaccine calendar might require antigen combinations, with old and possibly new targets such as norovirus, which is another major cause of childhood diarrhoeal disease.13
MO’R reports grants from Takeda Vaccines. BAL declares no competing interests. Copyright © The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY 4.0 license. 1 2 3 4 5 6
7
8
9 10 11
12
*Miguel O’Ryan, Benjamin A Lopman Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, University of Chile, Santiago 8380453, Chile (MO’R); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA (BAL) [email protected]
13
Tate JE, Burton AH, Boschi-Pinto C, Parashar UD. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000–2013. Clin Infect Dis 2016; 62 (suppl 2): S96–105. Centers for Disease Control and Prevention. Withdrawal of rotavirus vaccine recommendation. MMWR Morb Mortal Wkly Rep 1999; 48: 1007. Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354: 11–22. Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006; 354: 23–33. Yen C, Tate JE, Hyde TB, et al. Rotavirus vaccines: current status and future considerations. Hum Vaccin Immunother 2014; 10: 1436–48. Burnett E, Jonesteller CL, Tate JE, Yen C, Parashar U. Global impact of rotavirus vaccination on childhood hospitalizations and mortality from diarrhea. J Infect Dis 2017; published online April 18. DOI:10.1093/infdis/ jix186. Bhandari N, Rongsen-Chandola T, Bavdekar A, et al, for the India Rotavirus Vaccine Group. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet 2014; 383: 2136–43. Armah GE, Kapikian AZ, Vesikari T, et al. Efficacy, immunogenicity, and safety of two doses of a tetravalent rotavirus vaccine RRV-TV in Ghana with the first dose administered during the neonatal period. J Infect Dis 2013; 208: 423–31. Isanaka S, Guindo O, Langendorf C, et al. Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger. N Engl J Med 2017; 376: 1121–30. Aliabadi N, Tate JE, Parashar UD. Potential safety issues and other factors that may affect the introduction and uptake of rotavirus vaccines. Clin Microbiol Infect 2016; 22 (suppl 5): S128–35. Groome MJ, Koen A, Fix A, et al. Safety and immunogenicity of a parenteral P2-VP8-P[8] subunit rotavirus vaccine in toddlers and infants in South Africa: a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis 2017; published online may 5. http://dx.doi.org/10.1016/ S1473-3099(17)30242-6. O’Ryan M, Bandyopadhyay AS, Villena R, et al. Inactivated poliovirus vaccine given alone or in a sequential schedule with bivalent oral poliovirus vaccine in Chilean infants: a randomised, controlled, open-label, phase 4, non-inferiority study. Lancet Infect Dis 2015; 15: 1273–82. Lopman BA, Steele D, Kirkwood CD, Parashar UD. The vast and varied global burden of norovirus: prospects for prevention and control. PLoS Med 2016; 13: e1001999.
Advances in Ebola virus vaccination 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.1 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 www.thelancet.com/infection Vol 17 August 2017
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
Published Online June 9, 2017 http://dx.doi.org/10.1016/ S1473-3099(17)30320-1 See Articles page 854
787
Comment
Karsten Schneider/Science Photo Library
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 vectorbased 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.7–10 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 788
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. Elizabeth C Clarke, *Steven B Bradfute Center for Global Health, Division of Infectious Diseases, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA [email protected] We are supported by a grant from the US Defense Threat Reduction Agency (grant number HDTRA1-15-1-0061). The content of the information does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. 1
Henao-RestrepoAM, Camacho A, Longini IM, et al. 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!). Lancet 2017; 389: 505–18. 2 Heppner DG Jr, Kemp TL, Martin BK, et al, for the V920-004 study team. Safety and immunogenicity of the rVSV∆G-ZEBOV-GP Ebola virus vaccine candidate in healthy adults: a phase 1b randomised, multicentre, double-blind, placebo-controlled, dose-response study. Lancet Infect Dis 2017; published online June 9. http://dx.doi.org/S14733099(17)30313-4. 3 Ewer K, Rampling T, Venkatraman N, et al. A monovalent chimpanzee adenovirus Ebola vaccine boosted with MVA. N Engl J Med 2016; 374: 1635–46. 4 Khurana, S, Fuentes S, Coyle EM, Ravichandran S, Davey RT Jr, Beigel JH. Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies. Nat Med 2016; 22: 1439–47. 5 Dahlke C, Kasonta R, Lunemann S, et al. Dose-dependent T-cell dynamics and cytokine cascade following rVSV-ZEBOV immunization. EBioMedicine 2017; published online April 7. DOI:10.1016/j.ebiom.2017.03.045. 6 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 2016; 374: 1647–60. 7 Sullivan 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, 393–400. 8 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. 9 Warfield KL, Olinger G, Deal EM, et al. Induction of humoral and CD8+ T cell responses are required for protection against lethal Ebola virus infection. J Immunol 2015; 175: 1184–91. 10 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. 11 Bradfute SB, Bavari S. Correlates of immunity to filovirus infection. Viruses 2011; 3: 982–1000.
www.thelancet.com/infection Vol 17 August 2017
circumvent the lower efficacy of live oral vaccines observed in less developed regions, although that remains a conjecture until a study with clinical endpoints is done. Second, a more predictable advantage is that a parenteral vaccine is not expected to cause intussusception. Third, an inactivated vaccine could have some effect on reducing rotavirus shedding but, as for polio, it might be better at preventing disease while less effective at preventing shedding than live oral vaccines. Groome and colleagues11 indicate that a phase 2 trial with a formulation with additional rotavirus antigens is planned, with the hopes of broadening what appears to be a predominantly homotypic response. Hopefully when the phase 3 trial is designed, this vaccine will be compared with an established vaccine in a noninferiority trial, rather than to placebo. Such a study will be more difficult and will require substantially more infant participants, but would provide more definitive answers regarding comparative efficacy, and might be the only ethical choice with widespread vaccine use. Finally, implementation of a new parenteral vaccine in a crowded vaccine calendar might require antigen combinations, with old and possibly new targets such as norovirus, which is another major cause of childhood diarrhoeal disease.13
MO’R reports grants from Takeda Vaccines. BAL declares no competing interests. Copyright © The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY 4.0 license. 1 2 3 4 5 6
7
8
9 10 11
12
*Miguel O’Ryan, Benjamin A Lopman Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, University of Chile, Santiago 8380453, Chile (MO’R); and Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA (BAL) [email protected]
13
Tate JE, Burton AH, Boschi-Pinto C, Parashar UD. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000–2013. Clin Infect Dis 2016; 62 (suppl 2): S96–105. Centers for Disease Control and Prevention. Withdrawal of rotavirus vaccine recommendation. MMWR Morb Mortal Wkly Rep 1999; 48: 1007. Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354: 11–22. Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006; 354: 23–33. Yen C, Tate JE, Hyde TB, et al. Rotavirus vaccines: current status and future considerations. Hum Vaccin Immunother 2014; 10: 1436–48. Burnett E, Jonesteller CL, Tate JE, Yen C, Parashar U. Global impact of rotavirus vaccination on childhood hospitalizations and mortality from diarrhea. J Infect Dis 2017; published online April 18. DOI:10.1093/infdis/ jix186. Bhandari N, Rongsen-Chandola T, Bavdekar A, et al, for the India Rotavirus Vaccine Group. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet 2014; 383: 2136–43. Armah GE, Kapikian AZ, Vesikari T, et al. Efficacy, immunogenicity, and safety of two doses of a tetravalent rotavirus vaccine RRV-TV in Ghana with the first dose administered during the neonatal period. J Infect Dis 2013; 208: 423–31. Isanaka S, Guindo O, Langendorf C, et al. Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger. N Engl J Med 2017; 376: 1121–30. Aliabadi N, Tate JE, Parashar UD. Potential safety issues and other factors that may affect the introduction and uptake of rotavirus vaccines. Clin Microbiol Infect 2016; 22 (suppl 5): S128–35. Groome MJ, Koen A, Fix A, et al. Safety and immunogenicity of a parenteral P2-VP8-P[8] subunit rotavirus vaccine in toddlers and infants in South Africa: a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis 2017; published online may 5. http://dx.doi.org/10.1016/ S1473-3099(17)30242-6. O’Ryan M, Bandyopadhyay AS, Villena R, et al. Inactivated poliovirus vaccine given alone or in a sequential schedule with bivalent oral poliovirus vaccine in Chilean infants: a randomised, controlled, open-label, phase 4, non-inferiority study. Lancet Infect Dis 2015; 15: 1273–82. Lopman BA, Steele D, Kirkwood CD, Parashar UD. The vast and varied global burden of norovirus: prospects for prevention and control. PLoS Med 2016; 13: e1001999.
Advances in Ebola virus vaccination 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.1 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 www.thelancet.com/infection Vol 17 August 2017
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
Published Online June 9, 2017 http://dx.doi.org/10.1016/ S1473-3099(17)30320-1 See Articles page 854
787
Comment
Karsten Schneider/Science Photo Library
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 vectorbased 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.7–10 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 788
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. Elizabeth C Clarke, *Steven B Bradfute Center for Global Health, Division of Infectious Diseases, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA [email protected] We are supported by a grant from the US Defense Threat Reduction Agency (grant number HDTRA1-15-1-0061). The content of the information does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. 1
Henao-RestrepoAM, Camacho A, Longini IM, et al. 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!). Lancet 2017; 389: 505–18. 2 Heppner DG Jr, Kemp TL, Martin BK, et al, for the V920-004 study team. Safety and immunogenicity of the rVSV∆G-ZEBOV-GP Ebola virus vaccine candidate in healthy adults: a phase 1b randomised, multicentre, double-blind, placebo-controlled, dose-response study. Lancet Infect Dis 2017; published online June 9. http://dx.doi.org/S14733099(17)30313-4. 3 Ewer K, Rampling T, Venkatraman N, et al. A monovalent chimpanzee adenovirus Ebola vaccine boosted with MVA. N Engl J Med 2016; 374: 1635–46. 4 Khurana, S, Fuentes S, Coyle EM, Ravichandran S, Davey RT Jr, Beigel JH. Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies. Nat Med 2016; 22: 1439–47. 5 Dahlke C, Kasonta R, Lunemann S, et al. Dose-dependent T-cell dynamics and cytokine cascade following rVSV-ZEBOV immunization. EBioMedicine 2017; published online April 7. DOI:10.1016/j.ebiom.2017.03.045. 6 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 2016; 374: 1647–60. 7 Sullivan 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, 393–400. 8 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. 9 Warfield KL, Olinger G, Deal EM, et al. Induction of humoral and CD8+ T cell responses are required for protection against lethal Ebola virus infection. J Immunol 2015; 175: 1184–91. 10 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. 11 Bradfute SB, Bavari S. Correlates of immunity to filovirus infection. Viruses 2011; 3: 982–1000.
www.thelancet.com/infection Vol 17 August 2017