Integrating Clinical Research into Epidemic Response The Ebola Experience (2017) / Chapter Skim
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4 Assessment of Vaccine Trials
4 Assessment of Vaccine Trials
Pages 113-154
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From page 113... ...
On September 29–30, 2014, with the international response just beginning in earnest, the World Health Organization (WHO) convened a meeting to coordinate the planned clinical trials for candidate Ebola vaccines.
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From page 114... ...
. With these vaccine candidates selected, debate shifted to concerns regarding the best trial designs for testing their efficacy.
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From page 115... ...
"The meeting was quite tense at moments," said Marie-Paule Kieny, WHO assistant director-general and vaccine expert (Cohen and Kupferschmidt, 2014a) , and determining the choice of control arm proved to be one of the most contentious points in designing Ebola vaccine trials.
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From page 116... ...
See Box 4-1 for WHO requirements for Ebola vaccine trials. At the October 23 WHO meeting the U.S.
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A Guinea Ebola vaccine trial working group2 was formed which determined the trial designs to be used in Guinea. The working group consisted of multiple stakeholders, including the WHO, academics, representatives from U.S.
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118 INTEGRATING CLINICAL RESEARCH INTO EPIDEMIC RESPONSE TABLE 4-1 October 2015 WHO Summary of the Phase 1 Ebola Vaccine Trials Product/Company Phase Trial Location Dates ChAd3-ZEBOV Phase 1 By VRC at NIH, USA September 2014 GlaxoSmithKline and By Oxford University in PHAC the UK By CVD in Mali October 2014 At the University of Lausanne, Lausanne, Switzerland rVSV-ZEBOV Phase 1 By WRAIR in the US October 2014 NewLink Genetics and By NIAID in the US Merck Vaccines USA By CTC North GmbH in November 2014 Hamburg, Germany At Albert Schweitzer Hospital in Lambarene, Gabon At the University of Geneva, Geneva, Switzerland At the IWK Health Center, Halifax, Canada By KEMRI Wellcome December 2014 Trust in Kilifi, Kenya Ad26.ZEBOV and Phase 1 By University of Oxford January 2015 MVA-BN-Filo in the UK and NIAID, Johnson & Johnson and USA Bavarian Nordic By University of Nairobi, Second half of 2015 Kenya By MRC, Uganda Virus Research Institute, Uganda By Mwanza Intervention Trials Unit, United Republic of Tanzania Recombinant protein Phase 1 Australia February 2015 Ebola vaccine candidate Novavax SOURCE: Adapted from WHO, 2015a.
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From page 119... ...
Among all of the therapeutic and vaccine trials conducted in West Africa during the outbreak, the ring vaccination trial came the closest to fulfilling the hope for a clinical trial "home run" (or a "six," its cricket equivalent)
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From page 120... ...
Centers for Disease Control and Prevention; EBOVAC = Ebola vaccine projects; STRIVE = Sierra Leone Trial to Introduce a Vaccine Against Ebola; PREVAIL = Partnership for Research on Ebola Vaccines in Liberia. a The Phase 2 and Phase 3 trials did not begin earlier in the course of the outbreak because the manufacturers did not have a clear view of the required doses and the investigators were still working on community engagement (Mohammadi, 2015)
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From page 121... ...
Based on the known incubation period of 2–21 days after infection before symptoms appear and on the fact that it takes some time for vaccine-induced protection to develop (if the vaccine actually works) , the period of observation for risk of infection -- or, conversely, protection from infection -- was set for both groups as the 21-day period from 10 to 30 days post-enrollment (Ebola ça Suffit Ring Vaccination Trial Consortium, 2015)
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From page 122... ...
of disease for eligible and vaccinated individuals in a ring who receive immediate vaccination and eligible individuals in a ring who receive delayed vaccination" (Ebola ça Suffit Ring Vaccination Trial Consortium, 2015)
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Slight imbalances in intrinsic TABLE 4-3 Calculations of Vaccine Efficacy and Vaccine Effectiveness Based on Different Study Populations -- Guinea Ring Vaccine Trial All Vaccinated in Immediate Versus All Eligible All Eligible in (eligible adults, All Delayed contacts and (all contacts (primary All Eligible contacts of and contacts analysis) and Consented contacts)
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From page 124... ...
Additionally, if the study team was convinced that the vaccine was effective, it might at the very least, however unintentional, raise the possibility that efforts might have been less intense to detect and report events in the clusters randomized to immediate vaccination. It should also be noted that the logistical considerations of the ring vaccination trial are complex, with numerous trial sites across a large geographic area (Logistical considerations for the trials are discussed further in Chapter 5.)
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From page 125... ...
. When an "on-treatment" analysis was applied to those in the immediate vaccination clusters who were actually vaccinated and this subset of participants was compared to all eligible in the delayed vaccination clusters, the trial results now showed statistically significant benefits (0 of 2,108 vaccinated persons in immediate clusters with a primary endpoint versus 16 of 3,075 persons in delayed clusters eligible for vaccination and a primary endpoint; vaccine efficacy 100 percent, 95% confidence interval, 69–100%)
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From page 126... ...
b Nonrandomized immediate clusters are excluded from this analysis. c From fitting a β-binomial distribution to the cluster-level numerators and denominators and using an inverted likelihood ratio test to identify the lower bound for vaccine efficacy (columns 1, 2, 5, and 6)
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ASSESSMENT OF VACCINE TRIALS 127 Randomized Clustersb 5 6 7 8 All vaccinated in All vaccinated in All eligible in immediate immediate immediate All contacts and (group A) (group A)
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For example, Donald McNeil of The New York Times wrote: "In a scientific triumph that will change the way the world fights a terrifying killer, an experimental Ebola vaccine tested on humans in the waning days of the West African epidemic has been shown to provide 100 percent protection against the lethal disease" (McNeil, 2016)
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From page 129... ...
If those who did not get the vaccine were more likely to be exposed, then by excluding them from the analysis but not excluding a comparable subset from the group assigned to delayed vaccination we would bias our results in favor of the immediate vaccination group. This is why the primary analysis in any RCT, including a cluster-randomized RCT, is almost always intention to treat, following the "once randomized, always analyzed" dictum (Hennekens et al., 1987)
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. If approved, it would become one of the world's first licensed Ebola vaccines, and Gavi would be able to begin purchasing the vaccine to create a stockpile for future outbreaks" (Gavi, 2016)
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From page 131... ...
. Partnership for Research on Ebola Vaccines in Liberia -- PREVAIL I; Liberia, cAD3-EBOZ, VSV-ZEBOV, Placebo The PREVAIL vaccine trial was a partnership between the Ministry of Health of Liberia and the National Institute of Allergy and Infectious Diseases of the U.S.
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Lines in orange, green, and blue show the breakdown of weekly reported cases that were classified as confirmed, probable, or suspected, respectively. On the right, the black dotted line shows the cumulative enrollment in the PREVAIL I vaccine trial, scaled to the axis on the right side of the graph.
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Pierson, Chief, Regulatory Compliance & Human Subjects Protection Branch, National Institute of Allergy and Infectious Disease (NIAID) , National Institutes of Health (NIH)
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Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE) ; Sierra Leone, VSV-ZEBOV The STRIVE trial was a collaboration among the College of Medicine and Allied Health Sciences of the University of Sierra Leone, the Sierra Leone Ministry of Health and Sanitation, and the CDC.
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135 TABLE 4-5 Preliminary Antibody Responses Following Vaccination -- PREVAIL I Trial Antibody Responses Following Vaccination P-value ChAd3 rVSV∆G Versus Versus ChAd3 rVSV∆G Placebo rVSV∆G Placebo Week 1 Number of 478 477 471 participants 88 (82–95)
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From page 136... ...
. Given these findings, STRIVE leaders modified the suspected Ebola case definition for trial participants for the first 48 hours to avoid potential confusion with adverse reactions to the 5 Presentation of Anne Schuchat, CDC, Clinical trial designs for emerging infectious diseases.
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From page 137... ...
and three or more of the following symptoms: headache, loss of appetite, fatigue, muscle/joint pain, diarrhea, unusual bleeding, difficulty breathing, nausea, vomiting, abdominal pain, difficulty swallowing, or hiccups; OR illness after direct, unprotected Ebola contact or a breach in personal protective equipment in the past 21 days. Modified case definition applied to vaccine recipients in the first 48 hours after vaccination: same as for standard suspected Ebola case except that at least one symptom had to be one of the following symptoms not consistent with a vaccine reaction: diarrhea, unusual bleeding, difficulty breathing, nausea, vomiting, abdominal pain, difficulty swallowing, or hiccups (Widdowson et al., 2016)
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The major contribution of the study was to expand safety information available for the rVSV-ZEBOV candidate vaccine, creating the largest safety database available on the vaccine and, ultimately, immunogenicity data. EBOVAC–Salone; Sierra Leone, Ad26.ZEBOV and MVA-BN-Filo The EBOVAC–Salone trial was originally designed as a large-cluster, randomized study in Sierra Leone to achieve and assess the efficacy of a prime boost vaccine approach.
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From page 139... ...
These began only 6 months after the WHO declared the epidemic a PHEIC, with the PREVAIL I trial starting in February 2015 in Liberia and both the STRIVE trial in Sierra Leone and the ring vaccination trial in Guinea starting in March 2015 (WHO, 2015c)
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From page 140... ...
For example, if the ring trial had been the only one conducted during the outbreak, an unfortunate situation could have emerged; because of the initial suggestion of its high degree of efficacy equipoise could have been preemptively eliminated despite the estimate of protection from the intention-to-treat analysis being much lower. Additionally, the results from the ring vaccination trial provide limited safety data and no data on the duration of the immune response beyond 84 days; fortunately, the PREVAIL I trial can address these important gaps in knowledge.
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From page 141... ...
For example, during an epidemic with a new pathogen in which the general population is at high risk of infection and a ring trial shows initial efficacy, it may be reasonable to forgo planning a placebo-controlled trial in order to vaccinate the entire population. Alternatively, it may be preferable to move quickly to implement a placebo-controlled trial as an epidemic begins to wane and it becomes clear that a ring trial may not give definitive answers.
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From page 142... ...
Ring Vaccine challenges -- including community unit for analysis, the Trial resistance, difficulty reaching remote trial was inconclusive. field sites, and vaccine transportation at If individual persons Ebola ça Suffit −80°C -- the Ebola ça Suffit trial forgoes eligible for vaccination Trial two of the routine practices of randomized within the clusters controlled trials.
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From page 143... ...
• Rings are randomly allocated before for benefit. Potential individual informed consent is obtained.
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18, 2015, >8,016 and Merck Leone; Sierra • Subjects were given only one dose of participants Vaccines USA Leone Trial to vaccine. vaccinated Introduce a Design considerations • those vaccinated, Of (FDA, 2015; Vaccine Against • Design was originally a step-wedge design 3,826 received Widdowson et al., Ebola (STRIVE)
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Of o these, 509 provided baseline blood samples, of whom 466 (92 percent) provided a day-28 blood sample and 411 (81 percent)
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From page 146... ...
, 1 placebo arm Ebola virus disease at NewLink Genetics Ebola Vaccines • Randomized 1:1:1 to ChAd3-EBO-Z, Redemption Hospital and Merck in Liberia VSVDG-ZEBOV, or saline placebo in Monrovia from Vaccines USA (PREVAIL I) • Following randomization, participants' February 2 through visits were scheduled at 1 week, 1 month, April 30, 2015.
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From page 147... ...
• Designs that will allow a rigorous The results as outlined assessment of safety and efficacy will document a robust provide confidence for future use if antibody response products are later used in wide-scale to either of the two vaccination programs. vaccines tested, that is maintained over a 12-month follow-up period and without evidence of adverse drug reactions other than the expected local injecting site reactions.
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(EBOVAC2, • The study is taking place in Sierra Leone 2016; EBOVAC, and consists of a screening phase, an active 2016; Milligan phase (vaccination) , and a follow-up phase.
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From page 149... ...
Design considerations: • Study was initiated in parallel track to multiple ongoing Phase 1 and Phase 2 studies across United States, Europe, and Africa as part of accelerated development plan for vaccine regimen. • The EBOVAC-Salone team's goal has been to conduct a study that meets Sierra Leone's Ebola prevention needs, has the support of the Sierra Leonean people, and can play a sustaining role in helping to restore the country's health infrastructure following the Ebola outbreak.
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a Personal communication, Barbara Mahon, CDC lead, Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE)
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Contemporary Clinical Trials Communications 4:68–73. Ebola ça Suffit Ring Vaccination Trial Consortium.
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From page 152... ...
2016. Safety and im munogenicity of novel adenovirus type 26- and modified vaccinia Ankara–vectored Ebola vaccines: A randomized clinical trial.
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2015a. Call for proposals: Mapping of the WHO coordinated international effort to develop Ebola vaccines, treatments and diagnostics and process for the Ebola vaccine trial in Guinea.
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2016. Implementing an Ebola vaccine study -- Sierra Leone.
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