In-utero exposure to maternal HIV infection alters T-cell immune responses to vaccination in HIV-uninfected infants

Abstract

Objective In sub-Saharan Africa, HIV-exposed uninfected (HEU) infants have higher morbidity and mortality than HIV-unexposed infants. To evaluate whether immune dysfunction contributes to this vulnerability of HEU infants, we conducted a longitudinal, observational cohort study to assess T-cell immune responses to infant vaccines (Mycobacterium bovis BCG and acellular pertussis) and staphylococcal enterotoxin B (SEB). In total, 46 HEU and 46 HIV-unexposed infants were recruited from Khayelitsha, Cape Town. Methods Vaccine-specific T-cell proliferation (Ki67 expression) and intracellular expression of four cytokines [interferon-γ, interleukin (IL)-2, IL-13 and IL-17] were measured after whole blood stimulation with antigens at 6 and 14 weeks of age. Results HEU infants demonstrated elevated BCG-specific CD4+ and CD8+ T-cell proliferative responses at 14 weeks (P = 0.041 and 0.002, respectively). These responses were significantly increased even after adjusting for birth weight, feeding mode and gestational age. Similar to BCG, increased CD4+ and CD8+ T-cell proliferation was evident in response to SEB stimulation (P = 0.004 and 0.002, respectively), although pertussis-specific T cells proliferated comparably between the two groups. Within HEU infants, maternal CD4+ cell count and length of antenatal antiretroviral exposure had no effect on T-cell proliferation to BCG or SEB. HIV exposure significantly diminished measurable cytokine polyfunctionality in response to BCG, Bordetella pertussis and SEB stimulation. Conclusion These data show for the first time, when adjusting for confounders, that exposure to HIV in utero is associated with significant alterations to CD4+ and CD8+T-cell immune responses in infants to vaccines and nonspecific antigens.

Incidence and Diagnosis of Pertussis in South African Children Hospitalized With Lower Respiratory Tract Infection

“…24 The observed increase in pertussis cases in these groups may relate to both reduced vaccine effectiveness and passive immunity associated with HIV infection or exposure. [25][26][27][28] Consistent with other studies, the risk of B. pertussis was higher in younger infants and decreased with each extra dose of vaccine received, with the lowest risk after a completed primary schedule. 18 A novel, important finding was the higher sensitivity for diagnosis of Bordetella spp.…”

Immunogenicity of BCG in HIV-exposed and non-exposed infants following routine birth or delayed vaccination

“…Several studies have described non-specific effects of in utero HIV exposure on immune responses in HIV-negative infants, 21,22,29,30 the long-term significance of which is still unknown. In the present study, HIV-exposed infants vaccinated at birth had lower IFN-γ responses to M. tuberculosis PPD and ESAT-6/CFP-10 at 14 weeks of age compared to non-HIV-exposed infants.…”

“…19,20 Data characterising the effect of delayed BCG vaccination or the influence of maternal HIV infection on infant immune responses against mycobacteria are limited; however, altered BCG immunogenicity has been described in HIV-exposed non-infected infants following routine BCG vaccination at birth. 21,22 BCG-induced immunity in infants is important in settings where there is a high risk of M. tuberculosis exposure early in life, and even more so in settings with high maternal HIV prevalence, which poses a risk of both vertical HIV transmission and M. tuberculosis exposure. 23,24 …”

Delayed BCG vaccination results in minimal alterations in T cell immunogenicity of acellular pertussis and tetanus immunizations in HIV-exposed infants

“…These studies were performed in HIV-unexposed populations, and there is evidence that HIV-exposed, uninfected infants may have different Th1 and Th2 cytokine profiles to BCG vaccination [35, 36]. We previously observed that HIV exposure results in reduced breadth and magnitude of cytokine production to BCG and acellular Pertussis vaccination in infants [19]. HIV-exposed infants also display increased monocyte and cDC production of pro-inflammatory cytokines in response to PAMPs [37], thus perhaps would have different epigenetics than unexposed infants.…”

“…The gating strategy has been previously described and is shown in Supplementary Figure 1 [19]. Cells expressing IFN-γ, IL-2, IL-13, and IL-17 were gated within the Ki67+CD8+ and Ki67+CD8− cell populations.…”