HUMAN VACCINES & IMMUNOTHERAPEUTICS 2016, VOL. 12, NO. 10, 2700–2703 http://dx.doi.org/10.1080/21645515.2016.1217372
COMMENTARY
Ebola vaccines – Where are we? Sara Viksmoen Watle, Gunnstein Norheim, and John-Arne Røttingen Domain for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
ABSTRACT
ARTICLE HISTORY
The 2014–16 Ebola outbreak in West Africa has by far been the largest and most devastating Ebola outbreak so far. At the start of the epidemic only 2 Ebola DNA vaccine candidates had been tested in clinical trials and the correlate of protection in humans was unknown. International stakeholders coordinated by the World Health Organization agreed to fast-track the development of 2 Ebola vaccine candidates, based on adenovirus and vesicular stomatitis virus (VSV) vectors. Phase I and II clinical trials were initiated in the autumn of 2014 and found both vaccines to be acceptable for proceeding to phase III trials. Despite the epidemic waning in the spring of 2015, by July 2015 preliminary results from a phase III trial in Guinea proved the Ebola VSV vaccine to be effective.
Received 18 July 2016 Accepted 22 July 2016
The largest Ebola outbreak to date Ebola is a filovirus and is divided into 5 species (with decreasing order of virulence): Zaire (ZEBOV), Sudan, Bundibugyo, Tai Forest and Reston ebolavirus. Bats are thought to be the natural reservoir.1 The first 2 Ebola viral disease (EVD) outbreaks occurred simultaneously in the Democratic Republic of Congo and Sudan in 1976.2 Since then, there have been multiple smaller, self-limiting outbreaks in East and Central Africa. The 2014–15 outbreak in West Africa has by far been the largest and most devastating Ebola outbreak with over 28,000 cases as of March 2016 and a case fatality rate averaging around 50%.3 For the first time, the virus was sustained in urban centers and spread beyond the African continent. The disease was first noticed in Gueckedou, a rural village in Guinea close to the borders with Liberia and Sierra Leone, in December 2013.4 In August 2014, the World Health Organization (WHO) declared the epidemic as a global public health emergency, followed by the United Nations declaring the disease a threat to international peace and security in September 2014.5
KEYWORDS
Ebola viral disease; efficacy trial; vaccine; vesicular stomatitis virus; West Africa
and cellular immunity,8-10 but the mechanisms for protection in humans are unknown. Based on the association between anti-GP antibodies and survival of Ebola viral disease, several vaccine candidates based on the GP antigen were developed and found promising in animal models.11 A large proportion of this vaccine research has been funded by the US government due to its aim of developing a pan-filovirus vaccine for biopreparedness against potential intentional spread of virus, bioterrorism.12 Protection at a threshold level of antibodies against the GP was shown in several studies of non-human primates immunized with an Ebola vaccine.13 However, due to the lack of a commercial market for Ebola vaccines, the opportunity to recruit funding for manufacturing of a clinical grade product (GMP) and to perform phase I trials was very limited. At the start of the epidemic in 2014, only 2 Ebola DNA vaccines had therefore been tested in humans in the US and Uganda, but these showed low ability to induce high titers of neutralizing antibodies.14-16
Fast tracking clinical trials The long road to an Ebola vaccine tested in humans The glycoprotein (GP) covering the viral surface is important for the immune response. Studies in different animal models have shown higher levels of both antibodies and T cell mediated responses against the surface protein in surviving animals.6 Immunity against Ebola antigens has also been seen in humans in several countries in Africa. In Gabon, a country which has experienced 4 EVD outbreaks, prevalence of ZEBOV specific IgG varied from 3 to 21%.7 The highest prevalence was found in forested areas possibly explained by exposure to ZEBOVinfected fruit bats or food contaminated by bat saliva and excrement. Studies in EVD survivors have shown both humoral CONTACT Sara Viksmoen Watle Nydalen, 0403 Oslo, Norway. © 2016 Taylor & Francis
[email protected]
During early autumn of 2014 the number of EVD cases in West Africa was rapidly increasing. Contact tracing and implementation of classical infection prevention control measures were challenging in these countries where health systems already were weak and the number of health workers low. With no precedent in the extent of transmission, policy makers were leaning on mathematical modeling to predict how the epidemic possibly could fold out. Estimates ranged widely from 20,000 (before November 2014) to 1.5 million cases (before January 2015) depending on the model.17 Regardless the number, it was assumed that an effective vaccine could contribute to controlling the epidemic.18
Domain for Infection Control and Environmental Health, Norwegian Institute of Public Health, P.O. Box 4404
HUMAN VACCINES & IMMUNOTHERAPEUTICS
A review of the available candidates was performed coordinated by the WHO in late 2014.19 The WHO facilitated international coordination among all relevant stakeholders, including academic institutions, pharmaceutical industry, policy makers, and biodefence research organizations. There was unanimous agreement to fast-track the clinical development of several Ebola vaccine candidates, with 2 live viral vector vaccines with an Ebola glycoprotein insert as frontrunners; the chimpanzee adenovirus (cAd3-EBOZ) and vesicular stomatitis virus (rVSV-ZEBOV). Both of these vaccine candidates had demonstrated 100% protection in non-human primate challenge models20,21 and were available as GMP vaccine product. Early access to safety and immunogenicity data To expedite clinical evaluation of vaccine candidates, parallel and sequential testing in phase I, II and III trials was critical. Phase I and II trials were initiated in US, Europe and Africa for the 2 leading candidates in September – December 2014, with one candidate releasing preliminary Phase I data as early as November 2014. Results from Phase I trials proved both candidates to be safe and immunogenic in humans.22-25 Previous data on human safety of the 2 platforms were disproportionate, with the adenovirus vector widely used in trials in contrast to the barely tested rVSV vector.26 The phase I trials results showing a weak immune response of the low dose (2 £ 1010 PFU) cAd3 vaccine however turned the balance in favor of the rVSV-ZEBOV vaccine. The early access to preliminary data from the phase I trials with the 2 vaccine platforms was critical to enable early and timely decisions by the phase III trial teams in terms of study design, choice of vaccine, and dose selection to have the highest chance of mounting a protective immune response. To further add to the complexity, no directly comparative data from sideto-side evaluation in the same trial, or immunogenicity assessment using directly comparable immunogenicity data were available at the time decisions had to be made. The extensive networks set up for the 2 platforms were exemplary and provided the foundation for the phase III trials to be initiated. The efficacy-studies in all 3 West African countries have included an embedded sub-study focusing on safety and immunogenicity assessment (n D 1500 in Liberia, n D 500 in Sierra Leone and n D 1200 in Guinea) providing essential data for potential regulatory approval of the cAd3-EBOZ and rVSV-ZEBOV vaccines. There are now 36 phase I and II clinical Ebola vaccine trials with 7 different vaccine platforms in US, Europe, Africa, Asia and Australia registered at clinicaltrials.gov. Efficacy trials in West Africa Three phase III trials were initiated in Liberia, Sierra Leone and Guinea in the midst of the Ebola outbreak. In Liberia, a LiberianUS consortium led by the NIH implemented a classical doubleblind 3-armed individually randomized controlled trial (iRCT), with a planned sample size of almost 28,000. The trial was testing the 2 vaccine candidates cAd3-EBOZ and rVSV-ZEBOV in addition to saline as placebo control group (PREVAIL I).27 In Sierra Leone, a Sierra Leone-US partnership led by the CDC initiated an
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unblinded, cluster randomized (cRCT) stepped wedge trial in front line workers (STRIVE).28,29 Planned sample size was 8,000. Due to the falling incidence of EVD in Sierra Leone, the design was modified to an unblinded iRCT with phased introduction of vaccine in the target population with 6 months deferred vaccination between the 2 clusters. Due to a rapid decline in number of cases in both Liberia and Sierra Leone it was not possible to conclude these trials with regard to efficacy testing. In Guinea, authorities and non-governmental organizations requested early access to vaccine in risk populations. Inspired by the smallpox eradication program in the 1970s, an efficacy trial based on a novel ring vaccination study design was planned and implemented by a consortium of WHO, Norwegian Institute of Public Health, Medecins Sans Frontieres, Guinea Ministry of Health and several academic institutions (Ebola c¸ a suffit).30 When a new Ebola case was diagnosed, all contacts (and contacts of these contacts) of the individual were identified forming a so called ring. Half of the rings were randomized to immediate vaccination and the other half to delayed vaccination after 21 d. The incidence of EVD between the 2 groups was compared after an expected ramp-up period of 10 d. The cRCT ring vaccination design ensured a high attack rate at the level of the ring, reducing the sample size and time for results. The choice of vaccine (rVSV-ZEBOV) was made using a rational framework based on recommendations made by the Scientific and Technical Advisory Committee on Ebola Experimental interventions (STAC-EE) and based on assessing preclinical data and the latest data from phase I trials. Interim results published 4 months after study initiation showed a vaccine efficacy of 75–100%.31 No cases of EVD were diagnosed in vaccinated participants from 6 d after vaccination. As a consequence, the study’s data safety and monitoring board recommended offering immediate vaccination to all rings/clusters. Randomization was stopped and all further clusters of contacts of new EVD cases were offered vaccine when assigned to a ring. Ultimately, the Ministries of Health in both Sierra Leone and Liberia requested the implementation of ring vaccination around newly defined EVD cases also in their countries. Future needs and plans The international actors in research and development (R&D) collectively managed to demonstrate efficacy of one vaccine candidate, and progressing several other candidates well into phase I and II trials in endemic countries. However, there is still no licensed vaccine against Ebola and regulatory approval will be attained by 2017 at the earliest. Gavi, the Vaccine Alliance, announced this January funding to Merck, the manufacturer of the rVSV-ZEBOV vaccine candidate, as an “advance purchase commitment” to help the manufacturer take the vaccine through licensure and enable Gavi procurement and stockpiling of the vaccine for future outbreaks.32 The agreement ensures 300,000 doses of the vaccine by May 2016 to use in clinical trials. In view of the unprecedented outbreak of EVD in West Africa, and while licensure is pending, WHO has issued a special procedure for the use of candidate vaccines during a public health emergency, the Emergency Use Assessment and Listing Procedure (EUAL).33 The procedure is a guide for procurement
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agencies and national regulatory authorities of affected WHO member states to ensure access to candidate vaccines during an outbreak where treatment and/or prevention options are limited. There are still research gaps to fill in terms of Ebola vaccines. The correlate of protection in humans is unknown. Data from current clinical trials on Ebola vaccines will hopefully contribute to elucidate these mechanisms. Even though one vaccine candidate has shown protective immunity, the duration of immunity is unknown. Furthermore, the vaccine needs to be stored at ¡70 C complicating storage conditions in endemic countries with weak infrastructure. However, stability studies indicate that the vaccine can sustain higher temperatures for a week or a day.34 Ongoing studies on heterologous prime-boost might point to vaccine regimens with stronger and more longlasting immunity.35 Several researchers are also exploring the possibility of a pan-filovirus vaccine that will induce protection against other Ebola species (in particular Sudan) as well as Marburg virus.36
Conclusion The experiences encountered during the Ebola vaccine clinical development point to the need for strong international coordination and cross-cutting collaborations in future epidemic emergencies. The extent and speed of the vaccine R&D was unprecedented, and may serve as an example for developing vaccines against other emerging infectious diseases. We are hopeful that the WHO Blueprint R&D Process will lead to an incremental improvement of the structures in place to prepare and respond to future epidemic crises.37
Disclosure of potential conflicts of interest The authors have no conflicts of interest to declare.
Acknowledgments We thank all members of the Guinea Ebola vaccine consortium for the unprecedented collaboration that led to the Guinea ring vaccination trial, as well as the following funding partners: Research Council of Norway through the Norwegian Institute of Public Health; the Canadian government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Center and Department of Foreign Affairs, Trade and Development; Medicins Sans Frontieres; and the WHO, with support from the Wellcome Trust, United Kingdom. A special thank also to Bjørg Dystvold Nilsson for her diligent and dedicated help in coordinating the project.
References [1] Mari Saez A, Weiss S, Nowak K, Lapeyre V, Zimmermann F, Dux A, K€ uhl HS, Kaba M, Regnaut S, Merkel K, et al. Investigating the zoonotic origin of the West African Ebola epidemic. EMBO Mol Med 2015; 7(1):17-23; http://dx.doi.org/10.15252/emmm.201404792 [2] Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet 2011; 377(9768):849-62; PMID:21084112; http://dx.doi.org/10.1016/ S0140-6736(10)60667-8 [3] WHO. Ebola virus disease Fact Sheet No 103 2016. [4] Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, Magassouba N, Soropogui B, Sow MS, Ke€ıta S, De Clerck H, et al. Emergence of zaire ebola virus disease in guinea. N England J Med 2014; 371(15):1418-25; PMID:24738640; http://dx.doi.org/10.1056/ NEJMoa1404505
[5] WHO. Statement on the 1st meeting of the IHR Emergency Committee on the 2014 Ebola outbreak in West Africa 2014. Available from: http://www.who.int/mediacentre/news/statements/2014/ebola20140808/en/ [6] Wong G, Richardson JS, Pillet S, Patel A, Qiu X, Alimonti J, Hogan J, Zhang Y, Takada A, Feldmann H, et al. Immune parameters correlate with protection against ebola virus infection in rodents and nonhuman primates. Sci Transl Med 2012; 4(158):158ra146; PMID: 23115355; http://dx.doi.org/10.1126/scitranslmed.3004582 [7] Becquart P, Wauquier N, Mahlakoiv T, Nkoghe D, Padilla C, Souris M, Ollomo B, Gonzalez JP, De Lamballerie X, Kazanji M, et al. High prevalence of both humoral and cellular immunity to Zaire ebolavirus among rural populations in Gabon. PloS one 2010; 5(2):e9126; PMID:20161740; http://dx.doi.org/10.1371/journal.pone.0009126 [8] McElroy AK, Akondy RS, Davis CW, Ellebedy AH, Mehta AK, Kraft CS, Lyon GM, Ribner BS, Varkey J, Sidney J, et al. Human Ebola virus infection results in substantial immune activation. Proc Natl Acad Sci U S A 2015; 112(15):4719-24; PMID:25775592; http://dx. doi.org/10.1073/pnas.1502619112 [9] Ksiazek TG, Rollin PE, Williams AJ, Bressler DS, Martin ML, Swanepoel R, Burt FJ, Leman PA, Khan AS, Rowe AK, et al. Clinical virology of Ebola hemorrhagic fever (EHF): virus, virus antigen, and IgG and IgM antibody findings among EHF patients in Kikwit, Democratic Republic of the Congo, 1995. J Infect Dis 1999; 179 (Suppl 1):S177-87; PMID:9988182; http://dx.doi.org/10.1086/514321 [10] Sobarzo A, Ochayon DE, Lutwama JJ, Balinandi S, Guttman O, Marks RS, Kuehne AI, Dye JM, Yavelsky V, Lewis EC, et al. Persistent immune responses after Ebola virus infection. N Engl J Med 2013; 369(5):492-3; PMID:23902512; http://dx.doi.org/10.1056/ NEJMc1300266 [11] Sridhar S. Clinical development of Ebola vaccines. Ther Adv Vaccin 2015; 3(5–6):125-38; PMID:26668751; http://dx.doi.org/10.1177/ 2051013615611017 [12] Klenk HD, Becker S. VACCINES. Ebola virus vaccines–preparing for the unexpected. Science (New York, NY). 2015; 349(6249):693-4; PMID:26273043 [13] 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(5):393-400; PMID:19369954; http://dx.doi.org/10.1038/nrmicro2129 [14] Martin JE, Sullivan NJ, Enama ME, Gordon IJ, Roederer M, Koup RA, Bailer RT, Chakrabarti BK, Bailey MA, Gomez PL, et al. A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine Immunol 2006; 13(11):1267-77; PMID:16988008; http://dx.doi.org/10.1128/CVI.00162-06 [15] Sarwar UN, Costner P, Enama ME, Berkowitz N, Hu Z, Hendel CS, Sitar S, Plummer S, Mulangu S, Bailer RT, et al. Safety and immunogenicity of DNA vaccines encoding Ebolavirus and Marburgvirus wild-type glycoproteins in a phase I clinical trial. J Infect Dis 2015; 211(4):549-57; PMID:25225676; http://dx.doi.org/10.1093/infdis/ jiu511 [16] Kibuuka H, Berkowitz NM, Millard M, Enama ME, Tindikahwa A, Sekiziyivu AB, Costner P, Sitar S, Glover D, Hu Z, et al. Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial. Lancet 2015; 385(9977):1545-54; PMID: 25540891; http://dx.doi.org/10.1016/S0140-6736(14)62385-0 [17] Chretien JP, Riley S, George DB. Mathematical modeling of the West Africa Ebola epidemic. eLife 2015; 4: 1–15; PMID:26646185 [18] WHO. WHO High-level meeting on Ebola vaccines access and financing. 2014 23 October 2014. Report No.: 1 [19] WHO. Ebola publications: Vaccines, research and development. Available from: http://www.who.int/csr/resources/publications/ebola/ vaccines/en/ [20] Jones SM, Feldmann H, Stroher U, Geisbert JB, Fernando L, Grolla A, Klenk HD, Sullivan NJ, Volchkov VE, Fritz EA, et al. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat Med 2005; 11(7):786-90; PMID:15937495; http://dx.doi.org/10.1038/nm1258
HUMAN VACCINES & IMMUNOTHERAPEUTICS
[21] Stanley DA, Honko AN, Asiedu C, Trefry JC, Lau-Kilby AW, Johnson JC, Hensley L, Ammendola V, Abbate A, Grazioli F, et al. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nat Med 2014; 20 (10):1126-9; PMID:25194571 [22] Ledgerwood JE, DeZure AD, Stanley DA, Novik L, Enama ME, Berkowitz NM, Hu Z, Joshi G, Ploquin A, Sitar S, et al. Chimpanzee Adenovirus Vector Ebola Vaccine - Preliminary Report. N Engl J Med 2014; PMID:25426834; http://dx.doi.org/10.1056/ NEJMoa1410863 [23] Ewer K, Rampling T, Venkatraman N, Bowyer G, Wright D, Lambe T, Imoukhuede EB, Payne R, Fehling SK, Strecker T, et al. A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA. N Engl J Med 2016; 374(17):1635-46; PMID:25629663; http://dx.doi. org/10.1056/NEJMoa1411627 [24] Agnandji ST, Huttner A, Zinser ME, Njuguna P, Dahlke C, Fernandes JF, Yerly S, Dayer JA, Kraehling V, Kasonta R, et al. Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe. N Engl J Med 2016; 374(17):1647-60; PMID:25830326; http://dx.doi.org/10.1056/ NEJMoa1502924 [25] Regules JA, Beigel JH, Paolino KM, Voell J, Castellano AR, Munoz P, Moon JE, Ruck RC, Bennett JW, Twomey PS, et al. A Recombinant Vesicular Stomatitis Virus Ebola Vaccine - Preliminary Report. N Engl J Med 2015; PMID:25830322; http://dx.doi.org/10.1056/ NEJMoa1414216 [26] Gilbert SC. Adenovirus-vectored Ebola vaccines. Exp Rev Vaccin 2015; 14(10):1347–57 [27] Kennedy SB, Neaton JD, Lane HC, Kieh MW, Massaquoi MB, Touchette NA, Nason MC, Follmann DA, Boley FK, Johnson MP, et al. Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges. Clin Trials. 2016; 13(1):49-56; PMID:26768572; http://dx.doi. org/10.1177/1740774515621037 [28] Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE) Overview 2015. Available from: http://www.fda.gov/downloads/Advi soryCommittees/CommitteesMeetingMaterials/BloodVaccinesandO
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therBiologics/VaccinesandRelatedBiologicalProductsAdvisoryCom mittee/UCM448002.pdf CDC. Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE) Q&A 2015. Available from: http://www.cdc.gov/vhf/ebola/ strive/qa.html The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola. BMJ (Clinical research ed) 2015; 351:h3740; PMID:26215666 Henao-Restrepo AM, Longini IM, Egger M, Dean NE, Edmunds WJ, Camacho A, Carroll MW, Doumbia M, Draguez B, Duraffour S, 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(9996):857-66; PMID:26248676; http://dx.doi. org/10.1016/S0140-6736(15)61117-5 GAVI tva. Ebola vaccine purchasing commitment from Gavi to prepare for future outbreaks 2016. Available from: http://www. gavi.org/Library/News/Press-releases/2016/Ebola-vaccine-purchas ing-commitment-from-Gavi-to-prepare-for-future-outbreaks/ WHO. Emergency Use Assessment and Listing Procedure (EUAL) for candidate vaccines for use in the context of a public health emergency 2015. Available from: http://www.who.int/medicines/news/ EUAL-vaccines_7July2015_MS.pdf Arnemo M, Viksmoen Watle SS, Schoultz KM, Vainio K, Norheim G, Moorthy V, Fast P, Røttingen JA, Gjøen T, et al. Stability of a Vesicular Stomatitis Virus-Vectored Ebola Vaccine. J Infect Dis. 2016; 213(6):930-3; PMID:26563239; http://dx.doi.org/10.1093/infdis/jiv532 Zhou Y, Sullivan NJ. Immunology and evolvement of the adenovirus prime, MVA boost Ebola virus vaccine. Curr Opin Immunol 2015; 35:131-6; PMID:26247875; http://dx.doi.org/10.1016/j.coi.2015.06.006 Ohimain EI. Recent advances in the development of vaccines for Ebola virus disease. Virus Res 2016; 211:174-85; PMID:26596227; http://dx.doi.org/10.1016/j.virusres.2015.10.021 WHO. An R&D Blueprint for Action to Prevent Epidemics. 2016.
COMMENTARY
Ebola vaccines – Where are we? Sara Viksmoen Watle, Gunnstein Norheim, and John-Arne Røttingen Domain for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway
ABSTRACT
ARTICLE HISTORY
The 2014–16 Ebola outbreak in West Africa has by far been the largest and most devastating Ebola outbreak so far. At the start of the epidemic only 2 Ebola DNA vaccine candidates had been tested in clinical trials and the correlate of protection in humans was unknown. International stakeholders coordinated by the World Health Organization agreed to fast-track the development of 2 Ebola vaccine candidates, based on adenovirus and vesicular stomatitis virus (VSV) vectors. Phase I and II clinical trials were initiated in the autumn of 2014 and found both vaccines to be acceptable for proceeding to phase III trials. Despite the epidemic waning in the spring of 2015, by July 2015 preliminary results from a phase III trial in Guinea proved the Ebola VSV vaccine to be effective.
Received 18 July 2016 Accepted 22 July 2016
The largest Ebola outbreak to date Ebola is a filovirus and is divided into 5 species (with decreasing order of virulence): Zaire (ZEBOV), Sudan, Bundibugyo, Tai Forest and Reston ebolavirus. Bats are thought to be the natural reservoir.1 The first 2 Ebola viral disease (EVD) outbreaks occurred simultaneously in the Democratic Republic of Congo and Sudan in 1976.2 Since then, there have been multiple smaller, self-limiting outbreaks in East and Central Africa. The 2014–15 outbreak in West Africa has by far been the largest and most devastating Ebola outbreak with over 28,000 cases as of March 2016 and a case fatality rate averaging around 50%.3 For the first time, the virus was sustained in urban centers and spread beyond the African continent. The disease was first noticed in Gueckedou, a rural village in Guinea close to the borders with Liberia and Sierra Leone, in December 2013.4 In August 2014, the World Health Organization (WHO) declared the epidemic as a global public health emergency, followed by the United Nations declaring the disease a threat to international peace and security in September 2014.5
KEYWORDS
Ebola viral disease; efficacy trial; vaccine; vesicular stomatitis virus; West Africa
and cellular immunity,8-10 but the mechanisms for protection in humans are unknown. Based on the association between anti-GP antibodies and survival of Ebola viral disease, several vaccine candidates based on the GP antigen were developed and found promising in animal models.11 A large proportion of this vaccine research has been funded by the US government due to its aim of developing a pan-filovirus vaccine for biopreparedness against potential intentional spread of virus, bioterrorism.12 Protection at a threshold level of antibodies against the GP was shown in several studies of non-human primates immunized with an Ebola vaccine.13 However, due to the lack of a commercial market for Ebola vaccines, the opportunity to recruit funding for manufacturing of a clinical grade product (GMP) and to perform phase I trials was very limited. At the start of the epidemic in 2014, only 2 Ebola DNA vaccines had therefore been tested in humans in the US and Uganda, but these showed low ability to induce high titers of neutralizing antibodies.14-16
Fast tracking clinical trials The long road to an Ebola vaccine tested in humans The glycoprotein (GP) covering the viral surface is important for the immune response. Studies in different animal models have shown higher levels of both antibodies and T cell mediated responses against the surface protein in surviving animals.6 Immunity against Ebola antigens has also been seen in humans in several countries in Africa. In Gabon, a country which has experienced 4 EVD outbreaks, prevalence of ZEBOV specific IgG varied from 3 to 21%.7 The highest prevalence was found in forested areas possibly explained by exposure to ZEBOVinfected fruit bats or food contaminated by bat saliva and excrement. Studies in EVD survivors have shown both humoral CONTACT Sara Viksmoen Watle Nydalen, 0403 Oslo, Norway. © 2016 Taylor & Francis
[email protected]
During early autumn of 2014 the number of EVD cases in West Africa was rapidly increasing. Contact tracing and implementation of classical infection prevention control measures were challenging in these countries where health systems already were weak and the number of health workers low. With no precedent in the extent of transmission, policy makers were leaning on mathematical modeling to predict how the epidemic possibly could fold out. Estimates ranged widely from 20,000 (before November 2014) to 1.5 million cases (before January 2015) depending on the model.17 Regardless the number, it was assumed that an effective vaccine could contribute to controlling the epidemic.18
Domain for Infection Control and Environmental Health, Norwegian Institute of Public Health, P.O. Box 4404
HUMAN VACCINES & IMMUNOTHERAPEUTICS
A review of the available candidates was performed coordinated by the WHO in late 2014.19 The WHO facilitated international coordination among all relevant stakeholders, including academic institutions, pharmaceutical industry, policy makers, and biodefence research organizations. There was unanimous agreement to fast-track the clinical development of several Ebola vaccine candidates, with 2 live viral vector vaccines with an Ebola glycoprotein insert as frontrunners; the chimpanzee adenovirus (cAd3-EBOZ) and vesicular stomatitis virus (rVSV-ZEBOV). Both of these vaccine candidates had demonstrated 100% protection in non-human primate challenge models20,21 and were available as GMP vaccine product. Early access to safety and immunogenicity data To expedite clinical evaluation of vaccine candidates, parallel and sequential testing in phase I, II and III trials was critical. Phase I and II trials were initiated in US, Europe and Africa for the 2 leading candidates in September – December 2014, with one candidate releasing preliminary Phase I data as early as November 2014. Results from Phase I trials proved both candidates to be safe and immunogenic in humans.22-25 Previous data on human safety of the 2 platforms were disproportionate, with the adenovirus vector widely used in trials in contrast to the barely tested rVSV vector.26 The phase I trials results showing a weak immune response of the low dose (2 £ 1010 PFU) cAd3 vaccine however turned the balance in favor of the rVSV-ZEBOV vaccine. The early access to preliminary data from the phase I trials with the 2 vaccine platforms was critical to enable early and timely decisions by the phase III trial teams in terms of study design, choice of vaccine, and dose selection to have the highest chance of mounting a protective immune response. To further add to the complexity, no directly comparative data from sideto-side evaluation in the same trial, or immunogenicity assessment using directly comparable immunogenicity data were available at the time decisions had to be made. The extensive networks set up for the 2 platforms were exemplary and provided the foundation for the phase III trials to be initiated. The efficacy-studies in all 3 West African countries have included an embedded sub-study focusing on safety and immunogenicity assessment (n D 1500 in Liberia, n D 500 in Sierra Leone and n D 1200 in Guinea) providing essential data for potential regulatory approval of the cAd3-EBOZ and rVSV-ZEBOV vaccines. There are now 36 phase I and II clinical Ebola vaccine trials with 7 different vaccine platforms in US, Europe, Africa, Asia and Australia registered at clinicaltrials.gov. Efficacy trials in West Africa Three phase III trials were initiated in Liberia, Sierra Leone and Guinea in the midst of the Ebola outbreak. In Liberia, a LiberianUS consortium led by the NIH implemented a classical doubleblind 3-armed individually randomized controlled trial (iRCT), with a planned sample size of almost 28,000. The trial was testing the 2 vaccine candidates cAd3-EBOZ and rVSV-ZEBOV in addition to saline as placebo control group (PREVAIL I).27 In Sierra Leone, a Sierra Leone-US partnership led by the CDC initiated an
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unblinded, cluster randomized (cRCT) stepped wedge trial in front line workers (STRIVE).28,29 Planned sample size was 8,000. Due to the falling incidence of EVD in Sierra Leone, the design was modified to an unblinded iRCT with phased introduction of vaccine in the target population with 6 months deferred vaccination between the 2 clusters. Due to a rapid decline in number of cases in both Liberia and Sierra Leone it was not possible to conclude these trials with regard to efficacy testing. In Guinea, authorities and non-governmental organizations requested early access to vaccine in risk populations. Inspired by the smallpox eradication program in the 1970s, an efficacy trial based on a novel ring vaccination study design was planned and implemented by a consortium of WHO, Norwegian Institute of Public Health, Medecins Sans Frontieres, Guinea Ministry of Health and several academic institutions (Ebola c¸ a suffit).30 When a new Ebola case was diagnosed, all contacts (and contacts of these contacts) of the individual were identified forming a so called ring. Half of the rings were randomized to immediate vaccination and the other half to delayed vaccination after 21 d. The incidence of EVD between the 2 groups was compared after an expected ramp-up period of 10 d. The cRCT ring vaccination design ensured a high attack rate at the level of the ring, reducing the sample size and time for results. The choice of vaccine (rVSV-ZEBOV) was made using a rational framework based on recommendations made by the Scientific and Technical Advisory Committee on Ebola Experimental interventions (STAC-EE) and based on assessing preclinical data and the latest data from phase I trials. Interim results published 4 months after study initiation showed a vaccine efficacy of 75–100%.31 No cases of EVD were diagnosed in vaccinated participants from 6 d after vaccination. As a consequence, the study’s data safety and monitoring board recommended offering immediate vaccination to all rings/clusters. Randomization was stopped and all further clusters of contacts of new EVD cases were offered vaccine when assigned to a ring. Ultimately, the Ministries of Health in both Sierra Leone and Liberia requested the implementation of ring vaccination around newly defined EVD cases also in their countries. Future needs and plans The international actors in research and development (R&D) collectively managed to demonstrate efficacy of one vaccine candidate, and progressing several other candidates well into phase I and II trials in endemic countries. However, there is still no licensed vaccine against Ebola and regulatory approval will be attained by 2017 at the earliest. Gavi, the Vaccine Alliance, announced this January funding to Merck, the manufacturer of the rVSV-ZEBOV vaccine candidate, as an “advance purchase commitment” to help the manufacturer take the vaccine through licensure and enable Gavi procurement and stockpiling of the vaccine for future outbreaks.32 The agreement ensures 300,000 doses of the vaccine by May 2016 to use in clinical trials. In view of the unprecedented outbreak of EVD in West Africa, and while licensure is pending, WHO has issued a special procedure for the use of candidate vaccines during a public health emergency, the Emergency Use Assessment and Listing Procedure (EUAL).33 The procedure is a guide for procurement
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agencies and national regulatory authorities of affected WHO member states to ensure access to candidate vaccines during an outbreak where treatment and/or prevention options are limited. There are still research gaps to fill in terms of Ebola vaccines. The correlate of protection in humans is unknown. Data from current clinical trials on Ebola vaccines will hopefully contribute to elucidate these mechanisms. Even though one vaccine candidate has shown protective immunity, the duration of immunity is unknown. Furthermore, the vaccine needs to be stored at ¡70 C complicating storage conditions in endemic countries with weak infrastructure. However, stability studies indicate that the vaccine can sustain higher temperatures for a week or a day.34 Ongoing studies on heterologous prime-boost might point to vaccine regimens with stronger and more longlasting immunity.35 Several researchers are also exploring the possibility of a pan-filovirus vaccine that will induce protection against other Ebola species (in particular Sudan) as well as Marburg virus.36
Conclusion The experiences encountered during the Ebola vaccine clinical development point to the need for strong international coordination and cross-cutting collaborations in future epidemic emergencies. The extent and speed of the vaccine R&D was unprecedented, and may serve as an example for developing vaccines against other emerging infectious diseases. We are hopeful that the WHO Blueprint R&D Process will lead to an incremental improvement of the structures in place to prepare and respond to future epidemic crises.37
Disclosure of potential conflicts of interest The authors have no conflicts of interest to declare.
Acknowledgments We thank all members of the Guinea Ebola vaccine consortium for the unprecedented collaboration that led to the Guinea ring vaccination trial, as well as the following funding partners: Research Council of Norway through the Norwegian Institute of Public Health; the Canadian government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Center and Department of Foreign Affairs, Trade and Development; Medicins Sans Frontieres; and the WHO, with support from the Wellcome Trust, United Kingdom. A special thank also to Bjørg Dystvold Nilsson for her diligent and dedicated help in coordinating the project.
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