The Live Attenuated Cholera Vaccine CVD 103-HgR Primes Responses to the Toxin-Coregulated Pilus Antigen TcpA in Subjects Challenged with Wild-Type Vibrio cholerae

Abstract

One potential advantage of live attenuated bacterial vaccines is the ability to stimulate responses to antigens which are only expressed during the course of infection. To determine whether the live attenuated cholera vaccine CVD 103-HgR (Vaxchora) results in antibody responses to the in vivo-induced toxin-coregulated pilus antigen TcpA, we measured IgA and IgG responses to Vibrio cholerae O1 El Tor TcpA in a subset of participants in a recently reported experimental challenge study. Participants were challenged with V. cholerae O1 El Tor Inaba N16961 either 10 days or 90 days after receiving the vaccine or a placebo. Neither vaccination nor experimental infection with V. cholerae alone resulted in a robust TcpA IgG or IgA response, but each did elicit a strong response to cholera toxin. However, compared to placebo recipients, vaccinees had a marked increase in IgG TcpA antibodies following the 90-day challenge, suggesting that vaccination with CVD 103-HgR resulted in priming for a subsequent response to TcpA. No such difference between vaccine and placebo recipients was observed for volunteers challenged 10 days after vaccination, indicating that this was insufficient time for vaccine-induced priming of the TcpA response. The priming of the response to TcpA and potentially other antigens expressed in vivo by attenuated V. cholerae may have relevance to the maintenance of immunity in areas where cholera is endemic.

Keywords: TcpA; challenge; cholera; priming; vaccines.

FIG 1

CtxB-specific IgG response for vaccine and placebo recipients before and after cholera challenge. Mean fold change of anti-CtxB IgG antibodies for placebo and vaccine recipients challenged at day 10 (A) and day 90 (B). To the left of the dashed line are days before cholera challenge, and to the right are days following challenge. Error bars represent standard errors of the means, and an asterisk denotes differences between placebo and vaccine recipients with a P value of <0.05.

FIG 2

TcpA-specific IgG and IgA response for vaccine and placebo recipients before and after cholera challenge. Mean fold change of anti-TcpA IgG (A and B) and IgA (C and D) antibodies for placebo and vaccine recipients challenged at day 10 (A and C) and day 90 (B and D). To the left of the dashed line are days before cholera challenge, and to the right are days following challenge. Error bars represent standard errors of the means, and an asterisk denotes differences between placebo and vaccine recipients with a P value of <0.05.

FIG 3

TcpA-specific IgG response for vaccinees following challenge with V. cholerae. Mean fold change relative to day 0 for anti-TcpA IgG antibodies for vaccinees challenged either 10 or 90 days following vaccination. Error bars represent standard errors of the means, and an asterisk denotes differences between challenge cohorts with a P value of <0.05.

FIG 4

Correlation of maximum fold change before 90-day challenge relative to diarrhea volume following cholera challenge. Shown are the vaccinee maximum (max) fold changes for anti-TcpA IgG (A), anti-TcpA IgA (B), and anti-CtxB IgG (C) antibodies before 90-day challenge relative to cumulative diarrhea volume following 90-day challenge. The line represents a linear regression with R² and P values for normalized data.