Safety and Immunogenicity of an rVSV Lassa Fever Vaccine Candidate

Abstract

Background: No vaccine is currently available for Lassa fever, a viral hemorrhagic disease that is estimated to cause thousands of deaths each year in western Africa. A replication-competent recombinant vesicular stomatitis virus-vectored vaccine encoding a Lassa virus (LASV) glycoprotein complex, rVSVΔG-LASV-GPC, has been developed, but data on its safety and immunogenicity are limited.

Methods: In this phase 1, double-blind trial conducted in the United States and Liberia, we randomly assigned healthy adults (18 to 50 years of age) to receive rVSVΔG-LASV-GPC or placebo intramuscularly. Participants received a single vaccine dose of 2×10⁴ plaque-forming units (PFU), 2×10⁵ PFU, 2×10⁶ PFU, or 2×10⁷ PFU or placebo or received two vaccine doses of 2×10⁷ PFU or placebo, within a window of 6 to 20 weeks. The side-effect profile was assessed according to the incidence of solicited and unsolicited adverse events (primary end point). Because Lassa fever can cause sensorineural hearing loss, hearing acuity was measured before and after the injection. Secondary end points were levels of binding antibodies against LASV glycoprotein, neutralizing antibodies, and vaccine vector-derived viral RNA and PFU in plasma, urine, and saliva.

Results: A total of 114 adults were enrolled. No serious vaccine-related adverse events were reported. The vaccine caused minimal local reactions and dose-dependent, mild-to-severe early-onset systemic reactogenicity events that were transient. No hearing loss was detected. All doses induced robust long-lasting cellular and humoral (binding and neutralizing) responses that cross-reacted against common LASV lineages. No infectious vaccine virus particles were found in plasma, urine, or saliva.

Conclusions: The rVSVΔG-LASV-GPC vaccine resulted in transient local and systemic reactogenicity events but no hearing loss or serious adverse events. The vaccine had immunogenicity over a wide dose range in healthy adults in the United States and Liberia. (Funded by the Coalition for Epidemic Preparedness Innovations and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04794218; Pan African Clinical Trials Registry number, PACTR2021106625781067.).

Figure 1:. Proportion of participants experiencing the most common local and systemic solicited AEs by vaccine dose group and severity.

Proportion of participants with reactogenicity events detected after the single dose study vaccine or placebo in the United States (A) or in Liberia (B). The maximum severity for each event is shown.

Figure 2:. Antibody response (GM with 95% CI), according to vaccine dose and trial visit.

Anti-LASV GPC IgG binding responses are shown for Groups 1-4A and Placebo (US) (A) and Groups 5-7 and Placebo (Liberia) (B). Pseudo-virus neutralizing antibody responses are shown for Groups 1-4A and Placebo (US) (C) and Groups 5-7 and Placebo (Liberia) (D). Anti-LASV GPC IgG binding responses are shown for Groups 4A and 4B (E) and pseudo-virus neutralizing antibody responses are shown for Groups 4A and 4B in (F). Data points lying outside the 95% CI are shown as solid diamond shape dots. Red arrows indicate the time of the second vaccine dose administration to Group 4B participants. The red dashed lines indicate Lower Limit of Quantification values for each assay.

Figure 3:. LASV-GPC-specific T-cell response.

Data are GM (with 95% CI) GPC-specific T-cell responses detected by IFN-γ ELISPOT assay for each dose group and placebo recipients at baseline, and study days 29, 85, 169, 257 and 337 (A). Red dashed line indicates Limit of Detection of the assay. Heat map of fold change in spot forming units (SFU) to each LASV GPC peptide pool (LP) for every participant from day 0 to study day 85 is shown in (B).