Vaccines and Global Health: The Week in Review Ebola Vaccines Update

Vaccines and Global Health: The Week in Review

Ebola Vaccines Update
23 December 2016
Center for Vaccine Ethics & Policy (CVEP)

Editor’s Note:
    This is a special update on Ebola vaccine development and trials results as published in The Lancet – Online First on 22 December 2016, led with a 23 December 2016 news release by WHO.
    Vaccines and Global Health: The Week in Review will resume regular publication on 7 January 2017 following the end-of-year holiday period.

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WHO: Final trial results confirm Ebola vaccine provides high protection against disease
News release
23 December 2016 | GENEVA – An experimental Ebola vaccine was highly protective against the deadly virus in a major trial in Guinea, according to results published today in The Lancet. The vaccine is the first to prevent infection from one of the most lethal known pathogens, and the findings add weight to early trial results published last year.

The vaccine, called rVSV-ZEBOV, was studied in a trial involving 11 841 people in Guinea during 2015. Among the 5837 people who received the vaccine, no Ebola cases were recorded 10 days or more after vaccination. In comparison, there were 23 cases 10 days or more after vaccination among those who did not receive the vaccine.

The trial was led by WHO, together with Guinea’s Ministry of Health, Medecins sans Frontieres and the Norwegian Institute of Public Health, in collaboration with other international partners.
“While these compelling results come too late for those who lost their lives during West Africa’s Ebola epidemic, they show that when the next Ebola outbreak hits, we will not be defenceless,” said Dr Marie-Paule Kieny, WHO’s Assistant Director-General for Health Systems and Innovation, and the study’s lead author.

The vaccine’s manufacturer, Merck, Sharpe & Dohme, this year received Breakthrough Therapy Designation from the United States Food and Drug Administration and PRIME status from the European Medicines Agency, enabling faster regulatory review of the vaccine once it is submitted.

Since Ebola virus was first identified in 1976, sporadic outbreaks have been reported in Africa. But the 2013–2016 West African Ebola outbreak, which resulted in more than 11 300 deaths, highlighted the need for a vaccine.

The trial took place in the coastal region of Basse-Guinée, the area of Guinea still experiencing new Ebola cases when the trial started in 2015. The trial used an innovative design, a so-called “ring vaccination” approach – the same method used to eradicate small pox.

When a new Ebola case was diagnosed, the research team traced all people who may have been in contact with that case within the previous 3 weeks, such as people who lived in the same household, were visited by the patient, or were in close contact with the patient, their clothes or linen, as well as certain “contacts of contacts”. A total of 117 clusters (or “rings”) were identified, each made up of an average of 80 people.

Initially, rings were randomised to receive the vaccine either immediately or after a 3-week delay, and only adults over 18 years were offered the vaccine. After interim results were published showing the vaccine’s efficacy, all rings were offered the vaccine immediately and the trial was also opened to children older than 6 years.

In addition to showing high efficacy among those vaccinated, the trial also shows that unvaccinated people in the rings were indirectly protected from Ebola virus through the ring vaccination approach (so called “herd immunity”). However, the authors note that the trial was not designed to measure this effect, so more research will be needed.

“Ebola left a devastating legacy in our country. We are proud that we have been able to contribute to developing a vaccine that will prevent other nations from enduring what we endured,” said Dr KeÏta Sakoba, Coordinator of the Ebola Response and Director of the National Agency for Health Security in Guinea.

To assess safety, people who received the vaccine were observed for 30 minutes after vaccination, and at repeated home visits up to 12 weeks later. Approximately half reported mild symptoms soon after vaccination, including headache, fatigue and muscle pain but recovered within days without long-term effects. Two serious adverse events were judged to be related to vaccination (a febrile reaction and one anaphylaxis) and one was judged to be possibly related (influenza-like illness). All three recovered without any long term effects.

It was not possible to collect biological samples from people who received the vaccine in order to analyse their immune response. Other studies are looking at the immune response to the vaccine including one conducted in parallel to the ring trial among frontline Ebola workers in Guinea.

“This both historical and innovative trial was made possible thanks to exemplary international collaboration and coordination, the contribution of many experts worldwide, and strong local involvement,” said Dr John-Arne Røttingen, specialist director at the Norwegian Institute of Public Health, and the chairman of the study steering group.

In January, GAVI, the Vaccine Alliance provided US$5 million to Merck towards the future procurement of the vaccine once it is approved, prequalified and recommended by WHO. As part of this agreement, Merck committed to ensure that 300 000 doses of the vaccine are available for emergency use in the interim, and to submit the vaccine for licensure by the end of 2017. Merck has also submitted the vaccine to WHO’s Emergency Use and Assessment Listing procedure, a mechanism through which experimental vaccines, medicines and diagnostics can be made available for use prior to formal licensure.

Additional studies are ongoing to provide more data on the safety of the vaccine in children and other vulnerable populations such as people with HIV. In case of Ebola flare-ups prior to approval, access to the vaccine is being made available through a procedure called “compassionate use” that enables use of the vaccine after informed consent. Merck and WHO’s partners are working to compile data to support license applications.

The rapid development of rVSV-EBOV contributed to the development of WHO’s R&D Blueprint, a global strategy to fast-track the development of effective tests, vaccines and medicines during epidemics…

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The Lancet
Online First
22 December 2016

Articles
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!)
Ana Maria Henao-Restrepo, Anton Camacho, Ira M Longini, Conall H Watson, W John Edmunds, Matthias Egger, Miles W Carroll, Natalie E Dean, Ibrahima Diatta, Moussa Doumbia, Bertrand Draguez, Sophie Duraffour, Godwin Enwere, Rebecca Grais, Stephan Gunther, Pierre-Stéphane Gsell, Stefanie Hossmann, Sara Viksmoen Watle, Mandy Kader Kondé, Sakoba Kéïta, Souleymane Kone, Eewa Kuisma, Myron M Levine, Sema Mandal, Thomas Mauget, Gunnstein Norheim, Ximena Riveros, Aboubacar Soumah, Sven Trelle, Andrea S Vicari, John-Arne Røttingen, Marie-Paule Kieny
Open Access
PDF: http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)32621-6.pdf
PPT Images: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32621-6/ppt
Summary
Background
rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa.
Methods
We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×107 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6–17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193.
Findings
In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3–100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae.
Interpretation
The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters.
Funding
WHO, UK Wellcome Trust, Médecins Sans Frontières, Norwegian Ministry of Foreign Affairs (through the Research Council of Norway’s GLOBVAC programme), and the Canadian Government (through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development).

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Comment
First Ebola virus vaccine to protect human beings?
Thomas W Geisbert
Since the discovery of Ebola virus in 1976, researchers have attempted to develop effective vaccines. Early efforts were largely stalled as a result of the small global market for a vaccine for Ebola virus disease because of an absence of financial incentives for pharmaceutical companies. After the attacks in the USA on Sept 11, 2001, several governments invested in Ebola virus because they had concerns that it could be used as a biological weapon. These investments laid the groundwork for several candidate vaccines for Ebola virus disease that showed promise in preclinical studies in animals.1 Among the most promising vaccines showing protection in the gold standard non-human primate models of Ebola virus disease was a vaccine based on a recombinant vesicular stomatitis virus expressing the Ebola virus glycoprotein (rVSV-ZEBOV).2 Findings from preclinical studies in non-human primates jointly financed by the Public Health Agency of Canada and the US Defense Threat Reduction Agency showed that the rVSV-ZEBOV vaccine could completely protect non-human primates as a preventive vaccine against all medically relevant species of Ebola virus when given as a single-injection vaccine;2, 3 protect 50% of non-human primates against Ebola virus disease when given shortly after exposure;4 and seemed to be safe in non-human primates as evidenced by an absence of serious adverse events in severely immunocompromised animals5 and no evidence of neurovirulence in non-human primates.6

Outbreaks of Ebola virus disease have occurred sporadically, mostly in central Africa since 1976. These outbreaks have been small in size and generally well contained until December, 2013, when the largest recorded outbreak of Ebola virus disease began in the west African country of Guinea and quickly spread to surrounding countries with cases also being exported to Europe and the USA. As the outbreak grew in magnitude and appeared to be uncontained, efforts to use medical counter-measures to intervene intensified. In an Article published in The Lancet, Ana Maria Henao-Restrepo and colleagues follow-up their interim results7 and present the final results of their ring vaccination cluster-randomised trial in Guinea in 2015 to assess the efficacy of a single intramuscular dose of the rVSV-ZEBOV vaccine in the prevention of laboratory confirmed Ebola virus disease.8 The study involved vaccinating a ring of all contacts and contacts of contacts of confirmed cases of Ebola virus disease, either immediately or delayed to 21 days after randomisation. Briefly, 2119 contacts and contacts of contacts in 51 clusters randomly allocated, and 1677 contacts and contacts of contacts in 19 non-randomised clusters were immediately vaccinated, and 2041 contacts and contacts of contacts in 47 randomised clusters received a delayed vaccination 21 days after randomisation. Importantly, no cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters compared with 16 cases in those in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045). Vaccine efficacy was also 100% in the non-randomised clusters (95% CI 79·3–100·0, p=0·0033). These data strongly suggest that the rVSV-ZEBOV vaccine was effective in protecting against Ebola virus infection and probably contributed to controlling the 2013–16 outbreak of Ebola virus disease in Guinea.

Protective efficacy is clearly the strength of the study by Henao-Restrepo and colleagues. There have been concerns in the past regarding the safety profile of rVSV-ZEBOV because it is a replication-competent vaccine. In this study, the investigators identified 80 serious adverse events, of which only two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness), with all three cases recovering without sequelae. Conflicting safety results have been reported from phase I clinical trials of the rVSV-ZEBOV vaccine with oligoarthritis being reported in 13 of 51 low-dose vaccines in one study.9 No significant adverse events have been reported in other phase 1 studies.10 Although rVSV-ZEBOV seems to be highly efficacious and safe in the context of an outbreak, some questions remain. One question that has not been adequately addressed, even in non-clinical studies with any Ebola virus vaccine, is with regard to durability—is the vaccine long-lasting? Is it still protective, for example, 2–3 years after the vaccination? Another question is in regard to improvements in safety: clearly, the VSV-based Ebola virus vaccines appear to be the lead candidates for use in human beings, but can they be further attenuated to reduce the number of adverse events noted in phase 1 trials without reducing efficacy? Results of preclinical studies in non-human primates suggest that this attenuation might be possible.11

After 40 years we appear to now have an effective vaccine for Ebola virus disease to build upon. This success has been achieved by leveraging findings from published preclinical studies to justify the use of the rVSV-ZEBOV vaccine during an outbreak without the need for time-consuming and costly good laboratory practices (GLP) or GLP-like preclinical studies required by regulatory policies such as the US FDA Animal Rule,12 that although well intentioned, are impractical and inefficient in the context of the few high containment biosafety level 4 laboratories that exist worldwide (ie, laboratories that use the highest level of biosafety precautions and where, in most cases, workers wear positive pressure suits to work the with most hazardous viruses such as Ebola virus).

I have five US patents in the fields of filovirus and antiviral vaccines, including Ebola virus disease, and two provisional US patents: number 7635485, entitled “Method of accelerated vaccination against Ebola viruses” issued to G Nabel, N Sullivan, P Jahrling, and TW Geisbert on Dec 22, 2009, issued to the US government; number 7838658, entitled “siRNA silencing of filovirus gene expression” issued to I MacLachlan, V Sood, LE Hensley, E Kagan, and TW Geisbert on Nov 23, 2010, issued to Tekmira Pharmaceuticals and the US government; number 8017130 entitled “Method of accelerated vaccination against Ebola viruses” issued to G Nabel, N Sullivan, P Jahrling, and TW Geisbert on Sept 13, 2011, issued to US Government; number 8716464, entitled “Compositions and methods for silencing Ebola virus gene expression” issued to TW Geisbert, ACH Lee, M Robbins, V Sood, A Judge, LE Hensley, and I MacLachlan, on May 6, 2014, issued to Tekmira Pharmaceuticals and US Government; and number 8796013 entitled “Pre- or post-exposure treatment for filovirus or arenavirus infection” issued to TW Geisbert on Aug 5, 2014, issued to Boston University and Profectus Biosciences. I also have two patent provisional US patents: 61/014669 filed Feb 8, 2008, by TW Geisbert pending to Boston University, entitled “Compositions and methods for treating Ebola virus infection”, and 61/070748 filed March 25, 2008, by TW Geisbert, JH Connor, and H Ebihara pending to Boston University, entitled “Multivalent vaccine vector for the treatment and inhibition of viral infection.

References: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32618-6/fulltext

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Comment
Safety and immunogenicity of a recombinant adenovirus vector-based Ebola vaccine
Martin P Grobusch, Abraham Goorhuis
Summary
The 2013–16 epidemic of Ebola virus disease in west Africa was a game changer—not only in terms of the location and dimension of the outbreak and with regards to many painful lessons learnt about the epidemiology, features, and management of the disease, but also in terms of furthering the development of monoclonal antibody treatments1,2 and, most importantly, vaccines. Besides the replicative vector-based rVSV-ZEBOV vaccine,3,4 which has yielded high efficacy in an interim analysis of an open-label, cluster-randomised ring vaccination trial in Guinea,5 a range of other candidate vaccines have progressed into clinical development.

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Articles
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
Feng-Cai Zhu, Alie H Wurie, Li-Hua Hou, Qi Liang, Yu-Hua Li, James B W Russell, Shi-Po Wu, Jing-Xin Li, Yue-Mei Hu, Qiang Guo, Wen-Bo Xu, Abdul R Wurie, Wen-Juan Wang, Zhe Zhang, Wen-Jiao Yin, Manal Ghazzawi, Xu Zhang, Lei Duan, Jun-Zhi Wang, Wei Chen
Summary
Background
A recombinant adenovirus type-5 vector-based vaccine expressing the glycoprotein of Ebola Zaire Makona variant showed good safety and immunogenicity in a phase 1 trial of healthy Chinese adults. We aimed to assess the safety and immunogenicity of this vaccine in healthy adults in Sierra Leone and to determine the optimal dose.
Methods
We did a single-centre, randomised, double-blind, placebo-controlled, phase 2 clinical trial at Sierra Leone–China Friendship Hospital, Freetown, Sierra Leone. We recruited healthy adults aged 18–50 years who were HIV negative, had no history of Ebola virus infection, and had no previous immunisation with other Ebola vaccine candidates. Participants were sequentially enrolled and randomly assigned (2:1:1), by computer-generated block randomisation (block size of eight), to receive the high-dose vaccine (1·6 × 1011 viral particles), low-dose vaccine (8·0 × 1010 viral particles), or placebo (containing only vaccine excipients, with no viral particles). Participants, investigators, and study staff (except two study pharmacists) were masked from treatment allocation. The primary safety outcome was occurrence of solicited adverse reactions within 7 days of vaccination, analysed by intention to treat. The primary immunogenicity outcome was glycoprotein-specific antibody responses at days 14, 28, and 168 after vaccination, analysed in all vaccinated participants who had blood samples drawn for antibody tests. The trial is registered with the Pan African Clinical Trials Registry, number PACTR201509001259869, and is completed.
Findings
During Oct 10–28, 2015, 500 participants were enrolled and randomly assigned to receive the high-dose vaccine (n=250), low-dose vaccine (n=125), or placebo (n=125). 132 (53%) participants in the high-dose group, 60 (48%) in the low-dose group, and 54 (43%) in the placebo group reported at least one solicited adverse reaction within 7 days of vaccination. Most adverse reactions were mild and self-limiting. Solicited injection-site adverse reactions were significantly more frequent in vaccine recipients (65 [26%] in high-dose group and 31 [25%] in low-dose group) than in those receiving placebo (17 [14%]; p=0·0169). Glycoprotein-specific antibody responses were detected from day 14 onwards (geometric mean titre 1251·0 [95% CI 976·6–1602·5] in low-dose group and 1728·4 [1459·4–2047·0] in high-dose group) and peaked at day 28 (1471·8 [1151·0–1881·8] and 2043·1 [1762·4–2368·4]), but declined quickly in the following months (223·3 [148·2–336·4] and 254·2 [185·0–349·5] at day 168). Geometric mean titres in the placebo group remained around 6·0–6·8 throughout the study period. Three serious adverse events (malaria, gastroenteritis, and one fatal asthma episode) were reported in the high-dose vaccine group, but none was deemed related to the vaccine.
Interpretation
The recombinant adenovirus type-5 vector-based Ebola vaccine was safe and highly immunogenic in healthy Sierra Leonean adults, and 8·0 × 1010 viral particles was the optimal dose.
Funding
Chinese Ministry of Science and Technology and the National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology.

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