Impaired Bacillus Calmette–Guérin cellular immune response in HIV-exposed, uninfected infants

Mazzola, Taís Nitsch; Silva, Marcos T. N. da; Abramczuk, Beatriz Mariana; Moreno, Yara Maria Franco; Lima, S.C.B. Souza; Zorzeto, Tatiane Queiroz; Passeto, Andréa S.Z.; Vilela, M. M. S.

doi:10.1097/qad.0b013e32834bba0a

Cited by 55 publications

(45 citation statements)

References 32 publications

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“…Likewise, assessing T-cell responses to the superantigen SEB, which is used in many assays as a positive control, revealed important attributes of T-cell functionality in these infants. SEB stimulation results in signaling without the need for co-stimulatory molecules, and through multiple Vβ T-cell receptors (TCRS) [46,47]. When polyclonal stimulation with anti-CD3 and anti-CD28 was assessed in other studies, only HEU infants born to mothers with detectable plasma viral loads had increased proliferation compared to their unexposed counterparts [27].…”

Section: Discussionmentioning

confidence: 99%

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

Kidzeru

Hesseling

Passmore

et al. 2014

Aids

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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.

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Section: Discussionmentioning

confidence: 99%

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

Kidzeru

Hesseling

Passmore

et al. 2014

Aids

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“…Importantly, these children have been reported to have an increased risk of morbidity and mortality compared with children born to HIV-uninfected mothers [2-6]. This association is thought to be mediated through several factors, including impaired immunity[7-10], premature cessation of breastfeeding [11], and indirect factors such as increased parental mortality, exposure to maternal infections, and poverty.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children

Kamya

Kapisi²,

Bigira³

et al. 2014

Aids

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Objective Trimethoprim-sulfamethoxazole (TS) prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children. Design Open-label, randomized controlled trial. Setting Tororo, Uganda, a rural area with intense, year-round, malaria transmission. Participants 200 infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age). Intervention No chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily TS, or monthly dihydroartemisinin-piperaquine (DP) given from randomization to 24 months of age. Main outcome measures The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrheal illness, or respiratory tract infection; prevalence of anemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped. Results During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% (95% CI, 53-80%, p<0.001) for DP, 49% (95% CI, 23-66%, p=0.001) for TS, and 9% for SP (95% CI, −35 to 38%, p=0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the DP arm. Conclusions Monthly chemoprevention with DP was safe and associated with a significant reduction in malaria in young HIV-exposed children.

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“…However, other studies have not observed these differences when infants were BCG vaccinated at birth [13]. 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].…”

Section: Discussionmentioning

confidence: 99%

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

Blakney

Tchakoute

Hesseling

et al. 2015

Vaccine

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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, when in utero HIV 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

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Impaired Bacillus Calmette–Guérin cellular immune response in HIV-exposed, uninfected infants

Abstract: BCG-specific T-cell proliferation was reduced in HIV-exposed uninfected infants and IFN-γ concentration was lower in younger exposed infants, showing a delay in immune system maturation of HIV-exposed infants.

Cited by 55 publications

References 32 publications

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

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

Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children

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

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