Effect of a Chikungunya Virus-Like Particle Vaccine on Safety and Tolerability Outcomes: A Randomized Clinical Trial

Abstract

Importance: Chikungunya virus (CHIKV) is a mosquito-borne Alphavirus prevalent worldwide. There are currently no licensed vaccines or therapies.

Objective: To evaluate the safety and tolerability of an investigational CHIKV virus-like particle (VLP) vaccine in endemic regions.

Design, setting, and participants: This was a randomized, placebo-controlled, double-blind, phase 2 clinical trial to assess the vaccine VRC-CHKVLP059-00-VP (CHIKV VLP). The trial was conducted at 6 outpatient clinical research sites located in Haiti, Dominican Republic, Martinique, Guadeloupe, and Puerto Rico. A total of 400 healthy adults aged 18 through 60 years were enrolled after meeting eligibility criteria. The first study enrollment occurred on November 18, 2015; the final study visit, March 6, 2018.

Interventions: Participants were randomized 1:1 to receive 2 intramuscular injections 28 days apart (20 µg, n = 201) or placebo (n = 199) and were followed up for 72 weeks.

Main outcomes and measures: The primary outcome was the safety (laboratory parameters, adverse events, and CHIKV infection) and tolerability (local and systemic reactogenicity) of the vaccine, and the secondary outcome was immune response by neutralization assay 4 weeks after second vaccination.

Results: Of the 400 randomized participants (mean age, 35 years; 199 [50%] women), 393 (98%) completed the primary safety analysis. All injections were well tolerated. Of the 16 serious adverse events unrelated to the study drugs, 4 (25%) occurred among 4 patients in the vaccine group and 12 (75%) occurred among 11 patients in the placebo group. Of the 16 mild to moderate unsolicited adverse events that were potentially related to the drug, 12 (75%) occurred among 8 patients in the vaccine group and 4 (25%) occurred among 3 patients in the placebo group. All potentially related adverse events resolved without clinical sequelae. At baseline, there was no significant difference between the effective concentration (EC50)-which is the dilution of sera that inhibits 50% infection in viral neutralization assay-geometric mean titers (GMTs) of neutralizing antibodies of the vaccine group (46; 95% CI, 34-63) and the placebo group (43; 95% CI, 32-57). Eight weeks following the first administration, the EC50 GMT in the vaccine group was 2005 (95% CI, 1680-2392) vs 43 (95% CI, 32-58; P < .001) in the placebo group. Durability of the immune response was demonstrated through 72 weeks after vaccination.

Conclusions and relevance: Among healthy adults in a chikungunya endemic population, a virus-like particle vaccine compared with placebo demonstrated safety and tolerability. Phase 3 trials are needed to assess clinical efficacy.

Trial registration: ClinicalTrials.gov Identifier: NCT02562482.

Conflict of interest statement

Conflict of Interest Disclosures: Dr May reported being an employee of the Emmes Company. Ms Bray reported being an employee of the Emmes Company. Dr Cabié reported receiving grants from the French Health Ministry and FHI 360 and non-financial support from Gilead Sciences and ViiV Healthcare Ltd. Dr Diaz reported grant support from Leidos Biomedical for the study. Patents for the CHIKV virus-like particle vaccine have been licensed by the National Institutes of Health to Emergent BioSolutions. Drs Haney and Mr Mendy were employees of Emergent BioSolutions, the licensees at the time of the study. No other disclosures were reported.

Figures

Figure 1.. Recruitment, Randomization, and Follow-up of Participants in the Chikungunya Virus–Like Particle Vaccine Clinical Trial

aOther reasons includes that participants withdrew consent, enrolled after the study stopped or was paused at the site, exceeded protocol-defined maximum of 56 days between screening and enrollment, or lost interest in participation.

Figure 2.. Vaccination vs Placebo Response Among Participants Based on the Chikungunya Virus Focus Reduction Neutralization Test

Injections occurred on weeks 0 and week 4. Vaccine recipients developed a statistically significant response at week 8 compared with placebo, with the vaccine group response more than 46-fold higher than the placebo group response (both vaccine and placebo groups: n = 192, P < .001). The lower limit of detection for the assay is indicated by the dotted line and shown for week 0 for vaccine group and both time points for the placebo group. The number of participants with effective concentration 50 (EC50) values at the lower limit of detection for the placebo group at week 0 was 156 and week 8, 151; for the vaccine group at week 0, 156 and week 8, 1. The chikungunya virus focus reduction neutralization test (Chikungunya Virus Focus Reduction Neutralization Test [CHIKV FRNT] log10 of the EC50, defined as the reciprocal dilution of sera at half-maximal neutralization of viral activity) is presented for all vaccine and placebo recipients. The geometric mean titer and 95% CIs are indicated by horizontal bars.

Figure 3.. Chikungunya Virus Luciferase Neutralization Assay

Injections occurred on week 0 and week 4. The center line of the box for each time point represents the corresponding median titer, and the upper and lower edges of the box represent the 75th and 25th percentiles, respectively. The lengths of the whiskers extending above and below each box are equal to 1.5 times the interquartile range (75th percentile-25th percentile), or the distance between the most extreme data value and the corresponding quartile, whichever is shorter. Titers for individual samples that fall outside of the whiskers are represented as open circles. Postvaccination neutralization titers rose to a peak at week 8 (n = 153, P < .001), and remained well above baseline through week 72 (n = 144, P < .001). Lower limit of detection for the assay is 15, and data points for samples with titers below the assay detection of 15 are plotted at 7.5. All prevaccination titers were below the lower limit of detection. NT80 is defined as the reciprocal dilution of sera associated with an 80% reduction in viral activity.