Safety of Ebola Virus Vaccines
On 1 August 2018, the Ministry of Health of the Democratic Republic of the Congo (DRC) reported an outbreak of Ebola virus disease (EVD) in North Kivu province. As of 4 June 2019, a total of 2008 EVD cases, including 1832 confirmed cases and 1346 deaths had been recorded. SAGE has recommended extending ring vaccination with the rVSV-ZEBOV vaccine should an EVD outbreak occur. This vaccine was used in a ring vaccination study conducted in Guinea during the outbreak of EVD in West Africa in 2015, with high efficacy. It is currently the only vaccine for which data on clinical effectiveness are available.
Nevertheless, GACVS considered use of other licensed and investigational Ebola vaccines. There are currently 2 licensed Ebola vaccines: a single-dose Ad5-EBOV vaccine in China and a 2-dose rVSV/Ad5 vaccine licensed in the Russian Federation “for emergency use”. In addition, there are 2 investigational vaccines, the rVSV-ZEBOV vaccine made by Merck and the Ad26.ZEBOV/MVA-BN-Filo vaccine by Janssen.
GACVS members were presented with preliminary information on these vaccines, including their characteristics, source of viral strains, dose, schedule, storage conditions, nonclinical and clinical development and licensure status. The Ad5-EBOV (China) and the rVSV/Ad5 vectored vaccine (Russian Federation) “for emergency use” were licensed on the basis of tests in animal models and data on human immunogenicity from phase 1 and 2 clinical trials, which included studies in African populations. The effectiveness of the Ad26.ZEBOV/MVA-BN-Filo vaccine made by Janssen is based on studies in non-human primates in phase 1 and 2 clinical safety and immunogenicity trials; a phase 3 study is planned. Data on the safety of this vaccine are available for about 4000 people. Data on use of any of the 3 vaccines in elderly or immune-compromised people, children and pregnant or lactating women are not yet available.
The product characteristics and nonclinical and clinical data available for the rVSV-ZEBOV made by Merck were reviewed in the context of the viral vector template, clinical safety data presented by Merck and data from studies of clinical efficacy. In brief, the rVSV-ZEBOV was evaluated in several phase 2 and 3 clinical studies in over 15 000 people. Interim data on the impact of the ring vaccination strategy used during the current outbreak in the DRC were presented, which confirmed high vaccine efficacy. The safety of the vaccine is being followed up in all the recipients in this ring vaccination study 30 minutes and 3 and 21 days after vaccination. If enrolment of infants and pregnant women is approved, safety will be followed up on day 21 after vaccination for infants aged 6–11 months and pregnant women and also at delivery for the pregnant women; their offspring will not be followed up. As of 5 June 2019, more than 130 000 individuals in the DRC had consented and were vaccinated. Of the 228 serious adverse events (SAEs) identified between 7 August 2018 and 5 June 2019), only a few, including 1 case of anaphylaxis, were attributed to the vaccine.
The GACVS was presented with an overview of the standard template for the recombinant vesicular stomatitis virus (rVSV) vector developed by the Brighton Collaboration Viral Vector Vaccines Safety Working group, which is being explored as a platform for multiple vaccines. The rVSV causes self-limited disease in horses, pigs and cattle, but humans are generally asymptomatic. Other advantages include a low prevalence of vector immunity, the inability of viral RNA to integrate and the ability to express large foreign genes. The rVSV-ZEBOV vaccine constitutes the live, replication-competent VSV vector with the VSV glycoprotein G gene replaced by the glycoprotein gene of ZEBOV. Deletion of the G protein, the principal Ebola virus virulence factor, causes attenuation and also removes the primary target for anti-vector immunity. Preclinical data on the rVSV-ZEBOV showed no toxic effects in mice, rats or non-human primates and no neurovirulence in non-human primates; however, rVSV-ZEBOV is neurotropic in neonatal mice. VSV and rVSV-ZEBOV are highly sensitive to interferon and are relatively thermostable; associated viraemia occurs for the first 24–72 hours but is rarely detectable by 72 hours. The rVSV-ZEBOV elicits innate immune responses and adaptive immune responses within 7–14 days.
Merck updated the clinical safety profile of the investigational rVSV-ZEBOV-GP (V920) vaccine. The safety of the vaccine was evaluated in 8 phase 1 clinical trials in various countries and populations and in 5 phase 2 and 3 studies in Liberia (PREVAIL), Sierra Leone (STRIVE), Guinea (Ebola Ça Suffit! and Frontline Workers) and in Canada, Spain and the USA. Data on its safety are available for 15 996 people, including 234 children (> 6 months to < 18 years), 536 elderly people (> 65 years), 261 pregnant women and 22 HIV-positive patients. The most common local reactions were pain (70.3%), swelling (16.7%) and erythema (13.7%), which were limited in duration and of mild to moderate severity. Systemic reactions that were more common in vaccinated people than in recipients of placebo included headache, pyrexia, myalgia, fatigue, arthralgia, nausea, chills, arthritis, rash, hyperhidrosis, abdominal pain and rare cases of anaphylaxis. The results of an integrated analysis of the double-blinded trials showed SAEs in 3.4% of vaccine recipients and 7.8% of placebo recipients (1-year follow up), the most common reported SAE in the vaccine group being malaria, which was reported in 1.5% of those receiving the vaccine and 5.6% receiving placebo. Arthralgia of short duration occurred in up to 50% of vaccinated people during the first 14 days after vaccination. In blinded trials, the median time to onset of arthritis events was approximately 10 days, and the mean duration was 6 days; most cases were mild to moderate, although a few persisted for months to years. Vesicular lesions and oral ulcers occurred in a few people. Among the 261 pregnant women who received the vaccine in the trials in Sierra Leone, the frequency of pregnancy loss was higher in the group that was vaccinated immediately than in the deferred crossover or unvaccinated group; the reasons for the differences are not clear. Although these findings are of concern, their interpretation is difficult, as there were few exposures and limited data on the outcomes of the pregnancies, and the timing of vaccination in relation to gestational age was difficult to establish. Reliable background rates of pregnancy and neonatal outcomes are also lacking. Data on safety in the 234 children (ages 6 to <18 years) enrolled in 2 studies suggest that the adverse events reported were in general consistent with those observed in adults. Post-vaccination viraemia was detected more often in children than adults. Viral shedding in saliva and urine was also reported more frequently in children (71.8% overall versus 2% overall); however, no data are yet available on secondary transmission.
Data on the safety and efficacy of the rVSV-ZEBOV vaccine in infants (<1 year) are not available, and there are no data on lactating women. A clinical study with children aged 1–17 years and a study in HIV-positive people are under way. GACVS noted that more data are needed on the pregnancy outcomes. Concern was expressed about the possible implications of viral shedding and viraemia, the latter especially in infants. For the review of the safety of Ebola virus vaccines planned for the GACVS meeting in December 2019, it was decided that the vector template should be used, as it offers a structured approach to evaluating the safety of the vector-based Ebola virus vaccines. Additional information on safety from current vaccination initiatives in the DRC and, if available, from additional clinical trials with the V920 vaccine and other Ebola virus vaccines should be made available for review by the GACVS.