Persistence of immune responses induced by Ebola virus ... - The Lancet

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Mar 5, 2017 - vaccines against this virus, with at least eight entering clinical trials in 2014–16.1 ... stomatitis virus genetically modified to express Ebola.
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Persistence of immune responses induced by Ebola virus vaccines The recent devastating outbreak of Ebola virus disease led to the accelerated development of multiple candidate vaccines against this virus, with at least eight entering clinical trials in 2014–16.1 Direct evidence of 100% effectiveness against disease has been demonstrated for VSV-EBOV, a vaccine based on a replicating vesicular stomatitis virus genetically modified to express Ebola virus glycoprotein.2 This vaccine has been granted Breakthrough Therapy Designation status by the US Food and Drug Administration and PRIME status by the European Medicines Agency, and its single-dose regimen and proof of effectiveness from 10 days postimmunisation make it an attractive candidate for use in a responsive campaign (whether it be through ring immunisation around identified cases or as a wholepopulation intervention). Where does this leave the other potential vaccines, and what additional information is required to inform their use? Many of these vaccines are based on a nonreplicating adenoviral vector modified to express the Ebola glycoprotein (eg, adenovirus 5 (Ad5-ZEBOV),3 chimpanzee adenovirus 3 (Chad3),4 or adenovirus 26 (AD26-ZEBOV),5 which could potentially be used in heterologous prime/boost schedules together with a vaccine that uses an alternative viral vector bearing the same or similar Ebola glycoproteins (eg, MVA-BN-Filo). Although most published clinical data on these vaccines are from phase 1 studies conducted in Europe, North America, and China, numerous studies are ongoing or recently completed in sub-Saharan Africa,1 including a phase 2 Ad5-ZEBOV study conducted in Sierra Leone, recently published in the Lancet.3 For all the candidate Ebola vaccines, a crucial, and as yet unknown, characteristic is the long-term persistence of the vaccine-induced response. Ebola virus has been detected in the seminal fluid of survivors of Ebola virus disease 401 days after infection,6 and sexual transmission has been documented.7 A review by the Wellcome Trust-CIDRAP Ebola Vaccine Team B initiative suggested that any vaccine used for responsive immunisation of disease contacts should optimally induce protection that lasts 2 years.8 The same review suggested that any immunisation schedule employed in www.thelancet.com/lancetgh Vol 5 March 2017

a pre-emptive campaign in at-risk populations such as health-care workers (an intervention that might curtail Ebola virus disease outbreaks more efficiently than responsive campaigns9) would ideally provide 10 years’ protection. No data are currently available on the duration of humoral immunity induced by immunisation with VSV-EBOV, although follow-on studies are underway.1 Data on the persistence of immune responses induced by other vaccine candidates are emerging, and in this issue of The Lancet Global Health, Jing-Xin Li and colleagues10 describe the persistence of humoral and cellular immunity for approximately 6 months following a single dose of Ad5-ZEBOV, and 1 year following a booster dose with the same vaccine (homologous prime/boost).10 Interpretation of these data is complicated by interlaboratory variability in the assays used in different clinical trials, the lack of a known immunological correlate of protection, and whether a correlate identified for the one vaccine with evidence of effectiveness (VSV-EBOV, using a replicating viral vector) would apply equally to immunity induced by a vaccine such as Ad5-ZEBOV that uses a non-replicating viral vector. Nevertheless, Li and colleagues’ study suggests that 6 months after a dose of Ad5-ZEBOV administered to healthy adults in China, Ebola-glycoprotein-specific IgG concentrations were less than half that of their postimmunisation peak. These data are concerning, but more concerning still is the eight-fold fall in specific IgG observed at the same dose in the Sierra Leonean study.3 Specific IgG concentrations were increased by a booster dose of Ad5-ZEBOV in the Chinese study; however, the specific T-cell response (measured by interferon gamma ELISPOT) following the Ad5-ZEBOV boosting appeared to be lower post-boost than post-prime. By 1-year post booster, specific IgG concentrations had fallen 14-fold from the post-boost peak, and were no higher than those at 28 days post priming. No data on a boosterdose response in the Sierra Leonean study are available. The rapid waning of immunity post-priming and post-booster might be related to high background immunity to the Ad5 viral vector in both the Chinese

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and Sierra Leonean population, and the rapid postboost decline could have been exacerbated by using AD5-ZEBOV for both priming and boosting. This postbooster response appears to be more persistent for schedules using the heterologous prime-boost schedules such as Ad26-ZEBOV/MVA-BN-Filo; when these vaccines were given 56 days apart, IgG concentrations at 180 days post boost had fallen three-fold from the post-boost peak but remained three to four times higher than at day 28 post-prime.5 Li and colleagues acknowledge that, given these concerns, a schedule of two doses of Ad5-ZEBOV given 6 months apart is unlikely to be employed in practice. Whether there will be a role for the other adenoviralvectored Ebola vaccines in schedules employing heterologous prime-boost vaccines might depend on whether these can induce more sustained immunity than the single-dose VSV-EBOV vaccine. In the welcome absence of ongoing disease outbreaks, evidence for this will need to be inferred from animal models and markers of immunity, as discussed above. Regardless, it would be unwise to rely on a single vaccine candidate, and it is reassuring that the assessment of other potential vaccine strategies is ongoing.

sponsored by Janssen Vaccines. I am also an investigator on a safety registry study for the Ad26-ZEBOV vaccine, which is funded and sponsored by Janssen Vaccines. I have previously been a Principal Investigator in vaccine clinical trials sponsored and funded by GlaxoSmithKline, who manufacture the Chad3 candidate Ebola vaccine. These activities are conducted on behalf of the University of Oxford and I receive no personal financial benefit. I acknowledge the assistance of Esha Sarkar for her preparatory work on this manuscript. Copyright © The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. 1

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Matthew D Snape Oxford Vaccine Group, Department of Paediatrics, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK [email protected] I was the Principal Investigator on a phase 1 study of the Ad26-ZEBOV candidate Ebola vaccine, which was funded by the EU Innovative Medicines Initiative and

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ClinicalTrials.gov. 2016. https://clinicaltrials.gov/ct2/results?term=ebola+v accine&type=Intr&hlth=Y&rcv_s=01%2F01%2F2014&rcv_ e=10%2F12%2F2017&pg=1 (accessed Dec 23, 2016). Henao-Restrepo AM, Caacho A, Longini I, 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 2016; published online Dec 22. http://dx.doi. org/10.1016/ S0140-6736(16)32621-6 Zhu F-C, Wurie AH, Liang Q, et al. Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2016; published online Dec 22, 2016. http://dx.doi.org/10.1016/S0140-6736(16)32617-4. Ewer K, Rampling T, Venkatraman N, et al. A monovalent chimpanzee adenovirus Ebola vaccine boosted with MVA. N Eng J Med 2016; 374: 1635–46. Milligan ID, Gibani MM, Sewell R, et al. Safety and immunogenicity of novel adenovirus type 26- and modified vaccinia Ankara-vectored Ebola vaccines: a randomized clinical trial. JAMA 2016; 315: 1610–23. Sissoko D, Duraffour S, Kerber R, et al. Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study. Lancet Glob Health 2017; 5: e80–e8. Mate SE, Kugelman JR, Nyenswah TG, et al. Molecular evidence of sexual transmission of Ebola virus. N Engl J Med 2015; 373: 2448–54. Osterholm M, Moore K, Ostrowsky J, Kimball-Baker K, Farrar J, Wellcome Trust CEVTB. The Ebola Vaccine Team B: a model for promoting the rapid development of medical countermeasures for emerging infectious disease threats. Lancet Infect Dis 2016; 16: e1–9. 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. Li J-X, Hou L-H, Meng F-Y, et al. Immunity duration of a recombinant adenovirus type-5 vector-based Ebola vaccine and a homologous prime-boost immunisation in healthy adults in China: final report of a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Glob Health 2016; published online Dec 22, 2016. http://dx.doi. org/10.1016/S2214-109X(16)30367-9

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