Immunogenicity and Efficacy of a Measles Virus-Vectored Chikungunya Vaccine in Nonhuman Primates

Abstract

Background: Chikungunya virus (CHIKV) infection can result in chikungunya fever (CHIKF), a self-limited acute febrile illness that can progress to chronic arthralgic sequelae in a large percentage of patients. A new measles virus-vectored vaccine was developed to prevent CHIKF, and we tested it for immunogenicity and efficacy in a nonhuman primate model.

Methods: Nine cynomolgus macaques were immunized and boosted with the measles virus-vectored chikungunya vaccine or sham-vaccinated. Sera were taken at multiple times during the vaccination phase to assess antibody responses against CHIKV. Macaques were challenged with a dose of CHIKV previously shown to cause fever and viremia, and core body temperature, viremia, and blood cell and chemistry panels were monitored.

Results: The vaccine was well tolerated in all macaques, and all seroconverted (high neutralizing antibody [PRNT80 titers, 40-640] and enzyme-linked immunosorbent assay titers) after the boost. Furthermore, the vaccinated primates were protected against viremia, fever, elevated white blood cell counts, and CHIKF-associated cytokine changes after challenge with the virulent La Reunión CHIKV strain.

Conclusions: These results further document the immunogenicity and efficacy of a measles-vectored chikungunya vaccine that shows promise in Phase I-II clinical trials. These findings are critical to human health because no vaccine to combat CHIKF is yet licensed.

Keywords: chikungunya virus; measles virus; nonhuman primate; vaccine.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Anti-Chikungunya virus immunoglobulin titers in sera collected on days 0, 28, and 56 of the study as assayed by enzyme-linked immunosorbent assay. Sera yielding absorbance values that exceeded the means of negative control sera by more than 2 standard deviations were considered positive. The mean absorbance of the negative control sera was 0.08 at 450 nm. Error bars denote standard error.

Figure 2.

Body temperatures generated using a 2-hour moving average obtained from telemetric data. The vaccinated versus sham-vaccinated groups were compared statistically by one-way analysis of variance followed by Tukey’s test at each 2-hour time point beginning from 24 to 48 hours postchallenge. The mean temperature of the sham-vaccinated animals was significantly (P < .05) higher between 34 to 44 hours postchallenge as indicated by the asterisk.

Figure 3.

Nonhuman primate activity curves were generated using a 2-hour moving average. The vaccinated versus sham-vaccinated groups were compared statistically by one-way analysis of variance followed by Tukey’s test at each 2-hour time point beginning from 42 to 90 hours postchallenge. The mean activity of the sham-vaccinated animals was lower (P < .05) at hour 44 postchallenge as indicated by the asterisk. There are no units for activity.

Figure 4.

Viremia measured by quantitative real-time polymerase chain reaction assays. Ribonucleic acid (RNA) was isolated from sera and assayed using Chikungunya virus La Reunión (CHIKV-LR)-specific primers and probe. Cycle threshold (Ct) values were converted to plaque-forming units per milliliter (PFU/mL) from a standard curve generated from serially diluted RNA prepared from CHIKV-LR that was titered by plaque assay. Black symbols represent MV-CHIK vaccinated nonhuman primates (NHPs), whereas the red symbols indicate sham-vaccinated control animals.

Figure 5.

Mean levels of circulating cytokines in nonhuman primate serum assayed using the Monkey Cytokine Magnetic 29-Plex Panel (Invitrogen). Mean levels of interferon (IFN)-γ (A), interleukin (IL)-1RA (B), and monocyte chemoattractant protein-1 (MCP-1) are presented. One-way analysis of variance followed by Tukey’s multiple group comparisons were performed on the different time points for a given group; +, P < .05. Differences between groups were determined using an unpaired t test; *, P < .05 and **, P < .001. Bars indicate standard errors.