Human cytomegalovirus seropositivity and its influence on oral rotavirus vaccine immunogenicity: a specific concern for HIV-exposed-uninfected infants

Abstract

Oral rotavirus vaccines demonstrate diminished immunogenicity in low-income settings where human cytomegalovirus infection is acquired early in childhood and modulates immunity. We hypothesized that human cytomegalovirus infection around the time of vaccination may influence immunogenicity. We measured plasma human cytomegalovirus-specific immunoglobulin M antibodies in rotavirus vaccinated infants from 6 weeks to 12 months old and compared rotavirus immunoglobulin A antibody titers between human cytomegalovirus seropositive and seronegative infants. There was no evidence of an association between human cytomegalovirus serostatus at 9 months and rotavirus-specific antibody titers at 12 months (geometric mean ratio 1.01, 95% CI: 0.70, 1.45; P = 0.976) or fold-increase in RV-IgA titer between 9 and 12 months (risk ratio 0.999, 95%CI: 0.66, 1.52; P = 0.995) overall. However, HIV-exposed-uninfected infants who were seropositive for human cytomegalovirus at 9 months old had a 63% reduction in rotavirus antibody geometric mean titers at 12 months compared to HIV-exposed-uninfected infants who were seronegative for human cytomegalovirus (geometric mean ratio 0.37, 95% CI: 0.17, 0.77; P = 0.008). While the broader implications of human cytomegalovirus infections on oral rotavirus vaccine response might be limited in the general infant population, the potential impact in the HIV-exposed-uninfected infants cannot be overlooked. This study highlights the complexity of immunological responses and the need for targeted interventions to ensure oral rotavirus vaccine efficacy, especially in vulnerable subpopulations.

Keywords: Zambia; antibody; human cytomegalovirus; rotavirus; vaccine.

Graphical Abstract

Figure 1.

Study design. An illustration of the parent RCT study design and plasma collection timepoints.

Figure 2.

Flow diagram of infant samples included in the study. A schema of the participant flow and criteria used in the selection of plasma samples and infant subgroups included in analysis.

Figure 3.

Infant HCMV-IgM serostatus by age. The percentage of HCMV-IgM seropositive and seronegative infants (panel A) and cumulative HCMV-IgM seroconverters and non-seroconverters (panel B) at each age timepoint is shown as bars (n = 148).

Figure 4.

RV-IgA titres at 12 months infant age by point and cumulative HCMV-IgM serostatus at 9 months old stratified by infant HIV exposure. Each circle represents the log-transformed RV-IgA titer for a single infant (n = 146) among HIV-exposed-uninfected (HEU, n = 39) and HIV-unexposed (HU, n = 107) infants. Black and white circles indicate HCMV-IgM seropositive (+) and HCMV-IgM seronegative (−) infants at 9 months, respectively (panel A). Grey and white circle indicate cumulative HCMV-IgM seroconverting (s) and non-seroconverting (n.s.) infants at 9 months respectively (panel B). Solid horizontal bar and error bars indicates the mean value with 95% confidence intervals.

Figure 5.

Mean rotavirus antibody titers at 12 months infant age by point and cumulative HCMV-IgM serostatus at 9 months old stratified by vaccine dose schedule. Each circle represents the log-transformed RV-IgA titer for a single infant (n = 155) randomized to the intervention arm (n = 85) and control arm (n = 70). Black and white circle indicates HCMV-IgM seropositive (+) and seronegative (−) infants at 9 months, respectively (panel A). Grey and white circle indicates cumulative HCMV-IgM seroconverting (s) and non-seroconverting (ns) infants at 9 months, respectively (panel B). Solid horizontal bar and error bars indicates the mean value with 95% confidence intervals.

Figure 6.

Vaccine seroconversion by HCMV-IgM serostatus. Each bar represents the percent vaccine seroconverters at 14–20 weeks (1 month after two dose vaccination) among infants that were HCMV-IgM seropositive (n = 14) and HCMV IgM seronegative (n = 134) before vaccination at 6–12 weeks old (n = 148); HCMV IgM seropositive (n = 40) and HCMV IgM seronegative (n = 108) at 14–20 weeks old (n = 148); and cumulative HCMV-IgM seroconverting (n = 48) and non-seroconverting (n = 99) infants at 14–20 weeks old (n = 147). Black and white bars indicate HCMV-IgM seropositive (+) and seronegative (−) infants, respectively (panel A). Grey and white bars indicate cumulative HCMV-IgM seroconverting (s) and non-seroconverting (ns) infants respectively (panel B).