Passive transfer of human sera from chikungunya virus virus-like particle vaccine (Vimkunya) recipients fully protects non-human primates from viremia

Abstract

Vimkunya, a chikungunya virus (CHIKV) virus-like particle (VLP) vaccine, is well-tolerated and induces a rapid, durable serum neutralizing antibody (SNA) response in individuals aged ≥12 years. This study evaluated the efficacy of human CHIKV VLP antisera to protect cynomolgus macaques from heterologous CHIKV challenge and determined an SNA titer that confers complete protection against viremia. Macaques receiving negative control sera had detectable viremia and RNAemia, whereas those receiving control anti-CHIKV IgG or CHIKV VLP antisera with pre-challenge NT₈₀ ≥ 25.7 had no detectable viremia/RNAemia through 10 days post-challenge. Logistic regression showed that pre-challenge NT₈₀s of 23.6 and 25.9 corresponded with 80% and 90% probability of protection, respectively. Data from seroepidemiology studies demonstrated that a neutralizing titer of >1:10 is protective in convalescent persons. The SNA NT₈₀ threshold of 100 selected by US and European regulators to predict protection against CHIKV disease in humans is conservative by a factor of ~4.

Fig. 1. Study design.

Study timeline showing day (D) of intravenous serum or IgG transfer, subcutaneous wildtype (WT) CHIKV challenge, blood draws for viremia by viral RNA (vRNA) by RT-qPCR or plaque assay (PFU), and antibody measured by CHIKV-luc NT₈₀ assay and CHIKV VLP ELISA.

Fig. 2. Pre-challenge SNA titers on study Day 0.

On Day -1, NHPs were given an IV injection with either a CHIKV VLP IgG preparation or a pooled CHIKV VLP serum from Vimkunya vaccinated human participants, or a pooled pre-immune serum from baseline seronegative study participants (control serum). Treatment dosages of serum or purified IgG are described as mL per kg body weight. Symbols represent the SNA results from individual NHPs and horizontal bars represent GMT. The dotted line represents the LOD and LLOQ of the assay (12.3).

Fig. 3. Rectal Temperature.

Symbols represent group means and bars indicate standard error.

Fig. 4. CHIKV RNAemia.

A CHIKV RNAemia by RT-qPCR of plasma. Group log₁₀ gc/mL results with symbols representing the mean log₁₀ gc/mL of the NHP groups shown and error bars representing standard error of the mean. The validated CHIKV RT-qPCR assay LOD (dashed line) and LLOQ (dotted line) were 292 and 931 gc/mL, respectively. Results <LOD were imputed to half-LOD ( ~ 146 gc/mL) and values between LOD and LLOQ were imputed to half (LOD + LLOQ) (611.5 gc/mL) for calculations and plotting. B Relationship between peak viremia by RT-qPCR vs pre-challenge Day 0 SNA titers. Day 0 NT₈₀ and maximum gc/mL results were log₁₀-transformed. Least squares linear regression was performed with the solid line and shading representing the regression result and 95% confidence interval, respectively. Each symbol represents an individual animal with the group shown in the key by test article and dose in mL/kg. Regression results of slope and 95% confidence interval in parenthesis. Dotted lines on the X and Y axes represent the LOD/LLOQ of the SNA assay (NT₈₀ 12.3) and LLOQ of the RT-qPCR assay (931gc/mL), respectively.

Fig. 5. Relationship between Day 0 SNA NT₈₀ and RNAemia.

Relationship between Day 0 SNA NT₈₀ and RNAemia as measured by RT-qPCR for CHIKV VLP immune sera- or IgG-treated NHPs with RNAemia ≥ LLOQ detected on at least 1 day (detectable viremia) or undetectable on all days (no viremia). Group 6 negative control animals are not shown.

Fig. 6. Logistic regression model fit to the binary response data where success is no viremia ≥ LOD for RT-qPCR results (0.0 for any viremia and 1.0 for no viremia) with log₁₀ Day 0 SNA titer as a predictor.

The y-axis represents the probability of immunity/protection from CHIKV, the x-axis represents the Day 0 NT₈₀, and each symbol is an individual NHP (Observed), with points jittered around 0.0 and 1.0 to view all animals. The solid curve represents the predicted probability of immunity/protection (Predicted), the shaded area represents the 95% confidence interval for the prediction (95% CI), the dotted black line represents the SNA assay LOD/LLOQ of 12.3, and dashed red lines represent the Day 0 SNA titers associated with 80% or 90% probabilities (shown by solid horizontal red lines at 0.8 and 0.9, respectively) of immunity/protection of 23.6 and 25.9, respectively. Day 0 SNA titers < LOD/LLOQ were imputed as LOD/LLOQ to be conservative.