Delaying BCG vaccination until 8 weeks of age results in robust BCG-specific T-cell responses in HIV-exposed infants.

BACKGROUND: BCG vaccination prevents disseminated tuberculosis in children, but it is contraindicated for persons with human immunodeficiency virus (HIV) infection because it can result in severe disease in this population. In tuberculosis-endemic regions, BCG vaccine is administered soon after birth, before in utero and peripartum HIV infection is excluded. We therefore assessed the immunogenicity of BCG vaccine in HIV-exposed infants who received BCG at birth or at 8 weeks of age. METHODS: HIV-exposed, uninfected infants were randomly assigned to receive BCG vaccination at birth (the early vaccination arm) or 8 weeks of age (the delayed vaccination arm). BCG-specific proliferative and intracellular cytokine responses were assessed in 28 infants per arm at 6, 8, and 14 weeks of life. RESULTS: There was no difference in BCG-specific T-cell proliferation between the study arms 6 weeks after vaccination. However, at 14 weeks of age, the frequency of interferon γ-expressing CD4(+) T cells and multifunctional BCG-specific responses in the delayed vaccinated arm were significantly higher than those in the early vaccination arm (P = .021 and P = .011, respectively). CONCLUSIONS: The immunogenicity of BCG vaccination in HIV-exposed, uninfected infants is not compromised when delayed until 8 weeks of age and results in robust BCG-specific T-cell responses at 14 weeks of age. These findings support further evaluation of this modified BCG vaccination strategy for HIV-exposed infants. CLINICAL TRIALS REGISTRATION: NCT02062580.

Breastfeeding mitigates the effects of maternal HIV on infant infectious morbidity in the Option B+ era.

OBJECTIVE: The effects of in-utero HIV-exposure on infectious morbidity and mortality in settings with universal maternal treatment and high breastfeeding rates are unclear. Further, the benefits of exclusive feeding options have not been assessed in the Option B+ era. We investigated these in two African settings with high breastfeeding uptake and good HIV treatment infrastructure during the first year of life. METHODS: Cox regression with time-changing variables in a birth cohort of 749 HIV-exposed uninfected and HIV-unexposed uninfected infants from Cape Town, South Africa and Jos, Nigeria. RESULTS: There was no difference in infectious morbidity incidence between HIV-exposed uninfected and HIV-unexposed uninfected infants (hazard ratio 1.01; 95% CI 0.78-1.32) after adjusting for confounding variables. Formula-fed infants had significantly higher infectious morbidity incidence when compared with exclusively breastfed infants (hazard ratio 1.64; 95% CI 1.03-2.63) and mixed-breastfed infants (hazard ratio 1.42; 95% CI 1.00-2.02) after adjusting for potential confounding variables. There was no significant difference in mortality among HIV-exposed infants and HIV-unexposed infants during the first year of life in this cohort (2.04 versus 0.94%, P = 0.38). Notably, exclusive breastfeeding for only 4 months had protective effects on morbidity up to 1 year. CONCLUSION: In settings with universal antiretroviral coverage and high breastfeeding rates, breastfeeding mitigates the effects of in-utero HIV exposure among infants during the first year of life. These findings support previous recommendations for exclusive breastfeeding among HIV-infected women and highlight the role that breastfeeding plays on the health of infants in settings where exclusive breastfeeding is not always feasible or where replacement feeding is recommended.

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

BACKGROUND: Bacille Calmette-Guerin (BCG) is effective in preventing disseminated tuberculosis (TB) in children but may also have non-specific benefits, and is thought to improve immunity to unrelated antigens through trained innate immunity. In HIV-infected infants, there is a risk of BCG-associated adverse events. We aimed to explore whether delaying BCG vaccination by 8 weeks, in utero or perinatal HIV infection is excluded, affected T-cell responses to B. pertussis (BP) and tetanus toxoid (TT), in HIV-exposed, uninfected infants. METHODS: Infants were randomized to receive BCG vaccination at birth or 8 weeks of age. At 8 and 14 weeks, T cell proliferation and intracellular cytokine (IL-2, IL-13, IL-17, and IFN-γ) expression was analyzed in response to BP, TT and Staphylococcal enterotoxin B (SEB) antigens. RESULTS: Delaying BCG vaccination did not alter T-cell proliferation to BP or TT antigens. Infants immunized with BCG at birth had higher CD4+ T cell proliferation to SEB at 14 weeks of age (p=0.018). Birth-vaccinated infants had increased CD8+ IL-2 expression in response to BP, but not TT or SEB, at 8 weeks. Infants vaccinated with BCG at 8 weeks had significantly lower IL-13 expression by BP-specific CD4+ and CD8+ T cells at 14 weeks (p=0.032 and p=0.0035, respectively). There were no observed differences in multifunctional cytokine response to TT, BP or SEB between infants vaccinated with BCG at birth versus 8 weeks of age. CONCLUSION: Delaying BCG vaccination until 8 weeks of age results in robust T-cellular responses to BP and TT in HIV-exposed infants. CLINICAL TRIAL REGISTRY: NCT02062580.

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

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 CD8T-cell immune responses in infants to vaccines and nonspecific antigens.