Bacille Calmette-Guérin Vaccine Strain Modulates the Ontogeny of Both Mycobacterial-Specific and Heterologous T Cell Immunity to Vaccination in Infants.

Differences in Bacille Calmette-Guérin (BCG) immunogenicity and efficacy have been reported, but various strains of BCG are administered worldwide. Since BCG immunization may also provide protection against off-target antigens, we sought to identify the impact of different BCG strains on the ontogeny of vaccine-specific and heterologous vaccine immunogenicity in the first 9 months of life, utilizing two African birth cohorts. A total of 270 infants were studied: 84 from Jos, Nigeria (vaccinated with BCG-Bulgaria) and 187 from Cape Town, South Africa (154 vaccinated with BCG-Denmark and 33 with BCG-Russia). Infant whole blood was taken at birth, 7, 15, and 36 weeks and short-term stimulated (12 h) in vitro with BCG, Tetanus and Pertussis antigens. Using multiparameter flow cytometry, CD4+ T cell memory subset polyfunctionality was measured by analyzing permutations of TNF-α, IL-2, and IFN-γ expression at each time point. Data was analyzed using FlowJo, SPICE, R, and COMPASS. We found that infants vaccinated with BCG-Denmark mounted significantly higher frequencies of BCG-stimulated CD4+ T cell responses, peaking at week 7 after immunization, and possessed durable polyfunctional CD4+ T cells that were in a more early differentiated memory stage when compared with either BCG-Bulgaria and BCG-Russia strains. The latter responses had lower polyfunctional scores and tended to accumulate in a CD4+ T cell naïve-like state (CD45RA+CD27+). Notably, BCG-Denmark immunization resulted in higher magnitudes and polyfunctional cytokine responses to heterologous vaccine antigens (Tetanus and Pertussis). Collectively, our data show that BCG strain was the strongest determinant of both BCG-stimulated and heterologous vaccine stimulated T cell magnitude and polyfunctionality. These findings have implications for vaccine policy makers, manufacturers and programs worldwide and also suggest that BCG-Denmark, the first vaccine received in many African infants, has both specific and off-target effects in the first few months of life, which may provide an immune priming benefit to other EPI vaccines.

Compromised Growth Among HIV-exposed Uninfected Compared With Unexposed Children in Nigeria.

BACKGROUND: HIV-exposed but uninfected (HEU) children may be at an increased risk of impaired growth when compared with their HIV-unexposed and uninfected (HUU) counterparts. We compared the growth patterns of HEU to HUU children in Nigeria. METHODS: Pregnant women with and without HIV infection were enrolled at the Plateau State Specialist Hospital, Jos, Nigeria. Infants born to these mothers were recruited at birth and the mother-infant pairs followed up for 18 months. Weight, length and head circumference of the infants were measured at each visit. Age- and sex-standardized Z scores were generated for each anthropometric measure using the World Health Organization Child Growth Standards. Children with length-for-age, weight-for-age and weight-for-length Z scores <-2 were classified as stunted, underweight and wasted, respectively. RESULTS: Of 415 children (307 HEU and 108 HUU) recruited for this study, 117 (28.4%), 9 (2.2%) and 32 (7.8%) infants were stunted, underweight and wasted, respectively, at birth. In a multivariable longitudinal analysis, the odds of stunting were higher among HEU as compared with HUU children [adjusted odds ratio: 2.4 (95% confidence interval: 1.4-4.1)]. Similarly, odds of being underweight were higher among the HEU children [adjusted odds ratio: 1.6 (95% confidence interval: 1.1-2.2)]. CONCLUSIONS: Linear and ponderal growth were more impaired among HEU as compared with HUU children in Nigeria during the first 18 months of life. Further studies are needed to explore the causal basis for these differences.

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.

Development of a prospective cohort of HIV Exposed Sero-Negative (HESN) individuals in Jos Nigeria.

BACKGROUND: HIV/AIDS continues to be a global health problem. With currently no cure, it is critical to get an effective vaccine to add to the arsenal of prevention and treatment tools. HIV Exposed Sero-Negative (HESN) individuals were enrolled and followed for 2 years. METHODS: A prospective observational cohort study to enroll HESN volunteers and their partners was developed with a 2-year follow up. This was a vaccine preparedness study and designed as a Phase IIb trial. We provided counseling, lab testing and conducted medical examinations for all enrollees. RESULTS: A total of 534 HESN were enrolled with 48 % (256) females and 52 % (278) males, a mean age of 37 ± 9 years. Three female HESN enrollees seroconverted giving this cohort a HIV incidence rate [95 % coefficient interval (CI)] of 3.2 (2.3-4.2) per 100,000 person-months of observation. Baseline analysis showed that female HESN are 24 % more likely to have their spouse consistently use condoms (RR 1.24; p = 0.04); 16 % more likely to have HIV+ partners with detectable viral load (RR 1.16, p = 0.03) and 28 % more likely that their HIV+ partners has a CD4 count less than 350cells/µl (RR 1.28, p = 0.03) when compared to male HESN. CONCLUSIONS: Our findings suggest that female HESN are more at risk of HIV acquisition due the low CD4 counts and detectable viral load among their HIV+ spouses. Moreover, we provide additional information on incidence and risk factors among naturally exposed persons, which might impact biomedical prevention research and immune responses to HIV vaccines.

Social determinants of mixed feeding behavior among HIV-infected mothers in Jos, Nigeria.

Mixed feeding confers excess risk of mother-to-child transmission (MTCT) of HIV compared with exclusive breastfeeding and exclusive formula feeding. We undertook a qualitative and quantitative cross-sectional survey to identify the social determinants of mixed feeding among a subset of the 469 HIV-infected women enrolled in a MTCT prevention program in Jos, Nigeria. Formula was provided free-of-cost. Of the 91 participants, 68 (75%) exclusively formula fed, 7 (8%) exclusively breastfed, and 16 (18%) practiced mixed feeding. Of the mixed feeding women, seven primarily formula fed and nine primarily breastfed. Women who primarily formula fed described family pressure as the reason for mixed feeding, while women who primarily breastfed reported insufficient breast milk. In a multivariate analysis, lack of partner support of the feeding decision predicted mixed feeding behavior (OR: 4.2; 95% CI: 1.2-14.9; p=0.03). Disclosure of HIV status was significantly correlated (p<0.001) with partner support. HIV prevention interventions aimed at reducing mixed feeding should encourage supportive partner relationships that facilitate disclosure of HIV status. Attention should also be made to the differing pressures faced by women attempting to exclusively breast feed and exclusively formula feed.

Timing and determinants of mother-to-child transmission of HIV in Nigeria.

OBJECTIVE: To characterize the timing and determinants of mother-to-child transmission (MTCT) of HIV among mothers receiving single-dose nevirapine to prevent MTCT in Nigeria. METHODS: Three hundred and seventy-one HIV-infected mothers and their infants were followed from birth, at 1 week, and at 1, 3, 6, and 12 months. Risks of in utero (IU), intrapartum (IP/EPP), and postnatal (PP) transmission were quantified using conditional Cox regressions. RESULTS: Maternal viral load was the only risk factor for IU transmission after controlling for known risk factors. Low birth weight, premature birth, mixed feeding, and maternal viral load were associated with IP/EPP transmission. Increased PP transmission was associated with low birth weight and mixed feeding. At 6 months, mixed-fed infants were more likely to acquire infection than formula-fed infants (hazard ratio=5.74; 95% CI, 1.26-26.2). CONCLUSION: Risk factors for IU transmission differed from those of IP and PP transmission. Reducing mixed feeding and low birth weight delivery among HIV-infected mothers can further decrease IP and PP transmission.

Reference values of CD4 T lymphocytes in human immunodeficiency virus-negative adult Nigerians.

A cross-sectional study that involved secondary analysis of data collected from 681 pregnant women and 183 miners (94 men and 89 women; ratio of men to women, 1:0.95) in Jos, Nigeria, was carried out to determine the reference ranges for CD4(+)-cell counts in healthy HIV-negative adult Nigerians. The main results of interest were CD4(+)-cell counts and odds ratios (ORs) of low CD4(+)-cell counts, defined as below 350 cells per microl. CD4(+)-cell counts were similar in men and nonpregnant women, with a mean (standard deviation) of 828 (203) cells per microl, but pregnant women had a lower value of 771 (250) cells per microl. None of the factors assessed was related to the odds of having a low CD4(+)-cell count among men and nonpregnant women, but age, age of marriage, and alcohol usage were significant predictors in pregnant women. Compared to pregnant women less than 20 years old, older women had significantly lower odds of a low CD4(+)-cell count (ORs were 0.06 for women aged 20 to 29 years and 0.22 for those aged 30 to 39 years). When compared with those pregnant women who were married before 20 years of age, those who married at 20 to 29 years and 30 to 39 years had odds ratios of 6.41 and 9.40, respectively. Previous alcohol use was also associated with low CD4(+)-cell counts (OR, 5.15). The 95% confidence interval for CD4(+)-cell counts in healthy adult Nigerians is 547 to 1,327 cells per microl, and this is the first time this has been determined.