Meta-analysis of hepatitis C virus vaccine efficacy in chimpanzees indicates an importance for structural proteins

Abstract

Background & aims: Studies in patients and chimpanzees that spontaneously cleared hepatitis C virus (HCV) infections demonstrated that natural immunity to the virus is induced during primary infections and that this immunity can be cross protective. These discoveries led to optimism about prophylactic HCV vaccines, and several studies were performed in chimpanzees, although most included fewer than 6 animals. To draw meaningful conclusions about the efficacy of HCV vaccines in chimpanzees, we performed statistical analyses of data from previously published studies from different groups.

Methods: We performed a meta-analysis that compared parameters among naïve (n = 63), vaccinated (n = 53), and rechallenged (n = 36) animals, including peak RNA titer postchallenge, time points of peak RNA titer, duration of viremia, and proportion of persistent infections.

Results: Each vaccination study induced immune responses that were effective in rapidly controlling HCV replication. Levels of induced T-cell responses did not indicate vaccine success. There was no reduction in the rate of HCV persistence in vaccinated animals, compared with naïve animals, when nonstructural proteins were included in the vaccine. Vaccines that contained only structural proteins had clearance rates that were significantly higher than vaccines that contained nonstructural components (P = .015).

Conclusions: The inclusion of nonstructural proteins in HCV vaccines might be detrimental to protective immune responses, and/or structural proteins might activate T-cell responses that mediate viral clearance.

Figure 1

Comparison of HCV kinetics during primary and secondary infections in chimpanzees. A) Maximum RNA titer detected in serum samples. B) Time post-challenge (days) that maximum RNA titer was measured. C) Duration of viremia (days; Log₂ scale). P<0.05 indicates a difference between primary and secondary infections (exact Wilcoxon Signed-Rank Test). Data obtained from^-;.

Figure 2

Comparison of HCV kinetics in naïve; rechallenged and vaccinated chimpanzees, regardless of infection outcome. A) Maximum RNA titer detected in serum samples. B) Time post-challenge (days) that maximum RNA titer was measured. Closed circles: naïve; open squares: rechallenged; closed triangles: vaccinated. Horizontal bars represent median values. P<0.017 indicates a difference between groups (Mann-Whitney U Test).

Figure 3

Comparison of HCV kinetics in naïve; rechallenged and vaccinated chimpanzees that cleared HCV. A) Maximum RNA titer detected in serum samples. B) Time post-challenge (days) that maximum RNA titer was measured. C) Duration of viremia (days; Log₂ scale). Closed circles: naïve; open squares: rechallenged; closed triangles: vaccinated. Horizontal bars represent median values. P<0.017 indicates a difference between groups (Mann-Whitney U Test).

Figure 4

Comparison of Elispot responses. A) Rechallenged and vaccinated at challenge. B) Rechallenged and vaccinated 2-4 weeks post challenge. C) Vaccinated animals at challenge. D) Vaccinated animals 4 weeks post challenge. Data is shown as IFN-γ spot forming units (SFU) per 10⁶ peripheral blood mononuclear cells (PBMCs). (A) and (B): Open squares: rechallenged; closed triangles: vaccinated. (C) and (D): Open diamonds: persistent infections; closed diamonds: cleared infections. Horizontal lines represent median values. P<0.05 indicates a difference between groups (Mann-Whitney U Test).