Sex-Differential Non-Vaccine-Specific Immunological Effects of Diphtheria-Tetanus-Pertussis and Measles Vaccination

Abstract

Vaccines can have nontargeted heterologous effects that manifest as increased protection against nonvaccine infections, as described for measles vaccine (MV), or increased susceptibility to infections and death, as described following diphtheria-tetanus-whole cell pertussis (DTP) vaccination. The mechanisms are unknown, and high-quality immunological studies are lacking. This study was designed to investigate the heterologous effects of MV and DTP in 302 Gambian infants. The results support a sex-differential immunosuppressive effect of DTP on innate proinflammatory responses and T-cell immunity. Males but not females receiving MV had enhanced proinflammatory innate responses. The results point to modified signaling via Toll-like receptor 4 (TLR4) as a possible mechanism for the effects on innate immunity. When both vaccines were administered together, purified protein derivative responses were enhanced in females but downregulated in males. Collectively, these data indicate immunological effects that could account for heterologous effects of MV and DTP, to take forward into prospective trials.

Negative Correlation between Circulating CD4+FOXP3+CD127− Regulatory T Cells and Subsequent Antibody Responses to Infant Measles Vaccine but Not Diphtheria–Tetanus–Pertussis Vaccine Implies a Regulatory Role

“…The MV + DTP group also experienced a decline in naïve CD4 and CD8 T cell frequencies, and increased CD4 T EM and CD4 T EMRA populations following vaccination, with some sex differences in this effect. These results are consistent with our previous findings that combining MV with DTP vaccination has immune suppressing effects on PPD cellular responses and RNA expression in males, but the opposite effect in females, compared to giving DTP or MV alone ( 17 ).…”

“…We previously showed that measles antibody titers 4 weeks after vaccination were not affected by simultaneous administration of DTP; nor were tetanus toxoid (Ttx), diphtheria toxoid (Dtx), and Ptx titers post-DTP vaccination altered by giving MV at the same time ( 17 ). To increase statistical power, we combined the MV and MV + DTP group to analyze for measles Ab correlations between baseline circulating Tregs and vaccine antibody levels 4 weeks later; and the DTP and MV + DTP groups to analyze for DTP Ab correlations.…”

“…This study was nested into a larger randomized study investigating the immunological effects of measles vaccination, DTP vaccination, or giving both vaccines together to 9-month-old Gambian infants, some of the results of which have been published previously ( 17 ). In this study, we focused on the role that Tregs play in regulating immune responses to these vaccines.…”

“…The cytokines analyzed were interferon-gamma (IFN-γ), tumor necrosis factor (TNF), interleukin-1 beta (IL-1β), IL-4, and IL-10. Out of range values were assigned twice the upper limit of detection or half the lower limit of detection for those above and below range, respectively, as in previous studies ( 17 ). Medium background was subtracted from the antigen-stimulated value to establish antigen-specific cytokine production.…”

Virus-Induced T Cell-Mediated Heterologous Immunity and Vaccine Development

“…Accordingly, time of vaccination has been linked to differences in T cell populations and strength and type of heterologous immune response (73,74). Sex-specific differences in terms of protective non-specific effects of vaccines such as measles and vaccinia (64,(75)(76)(77)(78)(79)(80) have also been described. Modification of vaccine composition (e.g., enrichment of particular proteins or epitopes) or conditions of administration (e.g., age, dose, number of immunizations) could potentially help us achieve the beneficial heterologous effects of vaccines without compromising their primary protective effects (vaccine specific).…”