Single and two-dose typhoid conjugate vaccine safety and immunogenicity in HIV-exposed uninfected and HIV-unexposed uninfected Malawian children

Abstract

Vaccine safety and immunogenicity data in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children are important for decision-making in HIV and typhoid co-endemic countries. In an open-label study, we recruited Malawian HEU and HIV unexposed uninfected (HUU) infants aged 9 - 11 months. HEU participants were randomized to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) at 9 months, Vi-TT at 15 months, or Vi-TT at 9 and 15 months. HUU participants received Vi-TT at 9 and 15 months. Safety outcomes included solicited and unsolicited adverse events (AE) and serious AEs (SAEs) within 7 days, 28 days, and 6 months of vaccination, respectively. Serum was collected before and at day 28 after each vaccination to measure anti-Vi IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Cohort 1 (66 participants) enrollment began 02 December 2019, and follow-up was terminated before completion due to the COVID-19 pandemic. Cohort 2 (100 participants) enrollment began 25 March 2020. Solicited AEs were mostly mild, with no significant differences between HEU and HUU participants or one- and two-dose groups. All six SAEs were unrelated to vaccination. Anti-Vi geometric mean titers (GMT) increased significantly from 4.1 to 4.6 ELISA units (EU)/mL at baseline to 2572.0 - 4117.6 EU/mL on day 28 post-vaccination, and similarly between HEU and HUU participants for both one- and two-dose schedules. All participants seroconverted (>4-fold increase in GMT) by the final study visit. Our findings of comparable safety and immunogenicity of Vi-TT in HUU and HEU children support country introductions with single-dose Vi-TT in HIV-endemic countries.

Keywords: HIV-exposed uninfected children; Typhoid fever; immunogenicity; safety; sub-Saharan Africa; typhoid conjugate vaccine; typhoid vaccine.

Figure 1.

Anti-vi antibody titers. 1A. Cohort 1. 1B. Cohort 2. Anti-vi IgG antibody titers before vaccination (day 0) and 28 days after at 9-month (V1) and 15-month (V2) visit. Colored shapes represent the log₁₀ transformed antibody titer result for each individual participant in each corresponding vaccine group. The bar in the middle of individual participant results for each timepoint represents the geometric mean antibody titer value on log₁₀ scale with 95% confidence interval. *using the paired t-test on log10 transformed data. **using two sample t-test with unequal variances on log10 transformed data. Using ANOVA on log10 transformed data, HEU(9) at Day 28 V2 and HEU(15) at Day 28 V1 statistically significant difference compared to other 3 groups; p < .0001. HEU = HIV exposed, uninfected. HUU = HIV unexposed uninfected. V1: 9-month visit. V2: 15-month visit. ^‡only HUU (9 + 15) had a blood sample collected on day 0 V2 document pre-second dose immunogenicity.