Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: Vaccines, Viral Vaccine
ATC code: J07BX02
Ervebo consists of a live, attenuated recombinant vesicular stomatitis virus-based vector expressing the envelope glycoprotein gene of Zaire Ebola virus (rVSV∆G-ZEBOV-GP). Immunisation of subjects with the vaccine results in an immune response and protection from Zaire Ebola Virus Disease (EVD). The relative contributions of innate, humoral and cell-mediated immunity to protection from Zaire Ebola virus are unknown.
The clinical development program included five Phase ⅔ (Protocols 009-012 and 018) clinical trials. All subjects received a single dose of vaccine.
Clinical efficacy of Ervebo was assessed in Protocol 010.
Protocol 010 (Ring vaccination study) was a Phase 3 open-label cluster-randomised trial of ring vaccination (vaccinating contacts and contacts of contacts [CCCs] of index Ebola cases) which evaluated efficacy and safety of Ervebo in Guinea. In this trial, 9,096 subjects ≥18 years of age who were considered CCCs of an index case with laboratory-confirmed EVD were randomised to immediate (4,539 subjects in 51 clusters) or 21 days delayed (4,557 subjects in 47 clusters) vaccination with Ervebo. Of those 9,096 subjects, 4,160 received Ervebo (2,119 subjects were vaccinated in the immediate arm and 2,041 subjects were vaccinated in the delayed arm). The median age of consenting CCCs was 35 years old. The final primary analysis included 2,108 subjects (51 clusters) vaccinated in the immediate arm and 1,429 subjects (46 clusters) eligible and consented on Day 0 in the delayed arm.
The final primary analysis was to assess efficacy against laboratory confirmed EVD by comparing incidence of cases occurring 10 to 31 days post-randomisation for those vaccinated in the immediate vaccination rings versus incidence of cases for subjects who consented on Day 0 in the delayed vaccination rings. Vaccine efficacy was 100% (unadjusted 95% CI: 63.5% to 100%; 95% CI adjusted for multiplicity: 14.4% to 100%) (0 cases in the immediate arm; 10 cases in 4 rings in the delayed arm). Randomisation was stopped after an interim analysis with a p=0.0036 that did not meet the prespecified alpha level of 0.0027. Of the 10 cases, 7 were in contacts, and 3 in contacts-of-contacts. Uncertainties remain as to the level, duration and type of protection given the methodological limitations and the exceptional circumstances experienced during the trial.
No immune correlates of protection have been defined.
Protocol 009 Partnership for Research on Ebola Vaccines in Liberia (PREVAIL) was a Phase 2 randomised, double-blind, placebo-controlled trial which evaluated the safety and immunogenicity of Ebola vaccine candidates including Ervebo. This trial compared Ervebo to normal saline placebo in 1,000 adults ≥18 years of age in Liberia.
Protocol 011 named Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE) was a Phase ⅔ randomised open-label trial which evaluated safety and immunogenicity of Ervebo in adults ≥18 years of age working in healthcare facilities or on frontline activities related to the Ebola response in Sierra Leone. In this trial, 8,673 adult subjects were enrolled and 8,651 with valid consents randomised to immediate (within 7 days of enrolment) or deferred (18 to 24 weeks after enrolment) vaccination with Ervebo. An immunogenicity sub-study included 508 subjects who were vaccinated and provided samples for the assessment of immunogenicity.
Protocol 012 was a Phase 3 randomised, double-blind, placebo-controlled trial which evaluated the safety and immunogenicity of three consistency lots and a high dose lot (approximately five times higher than the dose in consistency lots and dose used in other Phase ⅔ trials) of Ervebo compared to normal saline placebo. A total of 1,197 healthy subjects 18 to 65 years of age were enrolled in the US, Canada, and Spain.
Protocol 018 was a Phase 3 open-label trial conducted in Guinea to evaluate the safety and immunogenicity of Ervebo in vaccinated frontline workers 18 years of age and older that was implemented as Part B of the Phase 3 ring vaccination study for Protocol 010. In this trial, a total of 2,115 subjects were enrolled and 2,016 subjects were vaccinated with Ervebo. An immunogenicity sub-study included 1,217 subjects who were vaccinated and provided samples for the assessment of immunogenicity.
Immunogenicity testing has been performed in Protocol 009, Protocol 011, Protocol 012 and Protocol 018, and includes the assessment of binding immunoglobulin G (IgG) specific to purified Kikwit ZEBOV GP by validated enzyme linked immunosorbent assay (GP-ELISA) as well as validated neutralisation of vaccine virus by a plaque reduction neutralisation test (PRNT).
As shown in Tables 2 and 3, the geometric mean titers (GMT) of GP-ELISA and PRNT increased from pre-vaccination to post-vaccination. Over 93.8% of vaccine recipients met seroresponse criteria defined as a ≥2-fold increase from baseline and ≥200 EU/mL at any time post-vaccination by GPELISA and over 80.4% of subjects met seroresponse criteria defined as a ≥4-fold increase from baseline at any time post-vaccination by PRNT. Over 80.1% of subjects continued to meet the seroresponse criteria for GP-ELISA and over 63.5% of vaccine recipients continued to meet seroresponse criteria for PRNT at 12 months. The clinical relevance of the immunogenicity data is currently not known.
Immunogenicity data were obtained in Protocol 009 in Liberia, Protocol 011 in Sierra Leone, Protocol 012 in the United States, Canada, and Europe, and Protocol 018 in Guinea. Gamma irradiation of specimens (from regions involved in Ebola outbreaks) was performed to reduce risk of wild-type Ebola virus infection of laboratory workers, but increased pre-vaccination GP-ELISA immune responses by approximately 20% and decreased post-vaccination GP-ELISA and PRNT immune responses by approximately 20%. Gamma irradiation, baseline seropositivity and other factors result in a higher immune response in Protocol 012.
Table 2. Summary of Geometric Mean Titers for the GP-ELISA.from Protocols 009, 011, 012 and 018 Clinical Trials:
| Trial | Baseline GMT (n) [95% CI] | Month 1 GMT (n) [95% CI] | Month 6 GMT (n) [95% CI] | Month 12* GMT (n) [95% CI] | Month 24 GMT (n) [95% CI] |
|---|---|---|---|---|---|
| Protocol 009§ | 117.9 (464) [107.9, 128.7] | 994.7 (475) [915.0, 1,081.3] | 712.2 (477) [659.4, 769.3] | 661.4 (475) [613.2, 713.4] | NA |
| Protocol 011§ | 92.7 (503) [85.3, 100.9] | 964.3 (443) [878.7, 1,058.3] | 751.8 (383) [690.6, 818.4] | 760.8 (396) [697.6, 829.8] | NA |
| Protocol 012 | |||||
| Combined Consistency Lots Group | <36.11 (696) [<36.11, <36.11] | 1,262.0 (696) [1,168.9, 1,362.6] | 1,113.4 (664) [1,029.5, 1,204.0] | 1,078.4 (327) [960.6, 1,210.7] | 920.3 (303) [820.4, 1,032.3] |
| High Dose Group | <36.11 (219) [<36.11, <36.11] | 1,291.9 (219) [1,126.9, 1,481.2] | 1,189.5 (215) [1,036.7, 1,364.9] | 1,135.5 (116) [934.8, 1,379.3] | 1,009.1 (105) [830.0, 1,226.7] |
| Placebo Group | <36.11 (124) [<36.11, <36.11] | <36.11 (124) [<36.11, <36.11] | <36.11 (123) [<36.11, <36.11] | <36.11 (65) [<36.11, <36.11] | <36.11 (65) [<36.11, <36.11] |
| Protocol 018§ | 78.3 (1,123) [74.7, 82.0] | 1,106.5 (1,023) [1,053.4, 1,162.2] | 1,008.8 (75) [849.8, 1,197.6] | NA | NA |
The Full Analysis Set population was the primary population for the immunogenicity analyses in Protocols 009, 011 and 018 and consists of all vaccinated subjects with serology data and had a serum sample collected within an acceptable day range.
The Per-Protocol Immunogenicity Population was the primary population for the immunogenicity analyses in Protocol 012 and includes all subjects who were compliant with the protocol, received vaccination, were seronegative at Day 1, and had a serum sample at one or more timepoints collected within an acceptable day range.
n = Number of subjects contributing to the analysis.
CI = Confidence interval; GP-ELISA = Anti-Glycoprotein Human Enzyme-Linked Immunosorbent Assay (EU/mL); GMT = Geometric mean titer
* Protocol 011 from Month 9-12
§ Protocols 009, 011 and 018 used gamma irradiation of specimens to reduce risk of wild-type Ebola virus infection of laboratory workers
Table 3. Summary of Geometric Mean Titers for the PRNT from Protocols 009, 011, 012 and 018 Clinical Trials:
| Trial | Baseline GMT (n) [95% CI] | Month 1 GMT (n) [95% CI] | Month 6 GMT (n) [95% CI] | Month 12* GMT (n) [95% CI] | Month 24 GMT (n) [95% CI] |
|---|---|---|---|---|---|
| Protocol 009§ | <35 (428) [<35, <35] | 116.8 (477) [106.0, 128.8] | 76.8 (477) [69.9, 84.4] | 100.4 (476) [91.4, 110.3] | NA |
| Protocol 011§ | <35 (438) [<35, <35] | 116.0 (437) [105.7, 127.4] | 95.3 (382) [86.3, 105.3] | 119.9 (396) [107.9, 133.2] | NA |
| Protocol 012 | |||||
| Combined Consistency Lots Group | <35 (696) [<35, <35] | 202.1 (696) [187.9, 217.4] | 266.5 (664) [247.4, 287.0] | 271.4 (327) [243.4, 302.7] | 267.6 (302) [239.4, 299.2] |
| High Dose Group | <35 (219) [<35, <35] | 236.1 (219) [207.4, 268.8] | 302.1 (215) [265.2, 344.1] | 323.7 (116) [269.5, 388.8] | 342.5 (105) [283.4, 414.0] |
| Placebo Group | <35 (124) [<35, <35] | <35 (123) [<35, <35] | <35 (123) [<35, <35] | <35 (65) [<35, <35] | <35 (65) [<35, <35] |
| Protocol 018§ | <.35 (1,107) [<35, <35] | 160.0 (1,024) [151.6, 168.9] | 117.0 (75) [96.0, 142.6] | NA | NA |
Efficacy in children has not been assessed. In a Phase 1 trial in children 6 to 17 years of age (median age = 10), non-validated ELISA and Pseudovirion Neutralisation Assay (PsVNA) results at Day 28 and Day 180 post-vaccination were similar to those observed in adults in the same study (see sections 4.4 and 4.8).
The European Medicines Agency has deferred the obligation to submit the results of studies with Ervebo in one or more subsets of the paediatric population in prevention of Ebola disease (see section 4.2 for information on paediatric use).
Not applicable.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and toxicity to reproduction and development.
When Ervebo was administered to female rats, antibodies against the vaccine virus were detected in foetuses and offspring, likely due to trans-placental transfer during gestation and with the acquisition of maternal antibodies during lactation, respectively (see section 4.6).
Ervebo administered to female rats had no effects on mating performance, fertility, or embryonic/foetal development.
Ervebo administered to female rats had no effects on development or behaviour of the offspring.
The vaccine virus is a Genetically Modified Organism (GMO). An ERA was conducted to determine the potential impact of this vaccine on human health and the environment. Because this vaccine is based on VSV, a known pathogen in livestock (e.g. horses, cattle, pigs), the risk assessment included species that are relevant for the wild type (wt) VSV backbone of this vaccine.
In a biodistribution study conducted in non-human primates, vaccine virus RNA was detected in lymphoid organs up to 112 days post-vaccination. However, infectious virus was detected at Day 1 and persistent infectious virus was not detected at any subsequent timepoints measured (Days 56, 84 and 112).
Based on limited shedding in adults, the results of a toxicity study in non-human primates, and lack of horizontal transmission in pigs, the overall risk of Ervebo to human health and the environment is considered negligible. However, as a precaution, vaccinees should attempt to avoid exposure of livestock to blood and bodily fluids for at least 6 weeks following vaccination to avoid the theoretical risk of spread of the vaccine virus. People who develop vesicular rash after receiving the vaccine should cover the vesicles until they heal. Cover the vaccination site or any vesicles with an adequate bandage (e.g. any adhesive bandage or gauze and tape) that provides a physical barrier to protect against direct contact with vesicle fluid (see section 4.2). The bandage may be removed when there is no visible fluid leakage. To avoid unintended exposure to livestock, ensure medical waste and other cleaning materials do not come in contact with livestock.
See sections 4.4 and 6.6 for further information.
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