Abstract
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.
Highlights
Many TB endemic countries provide Bacille Calmette-Guérin (BCG) vaccine to infants routinely soon after birth [1,2,3,4]
Magnitude of Mycobacterial-Specific CD4+ T Cell Cytokine Responses Differ According to BCG Strain In January 2016, BCG-Denmark became unavailable and the South African Expanded Program on Immunization (EPI) program began using BCG-Russia (Supplementary Table 1)
Infant samples were re-stimulated in vitro with the matched antigen, except cells from Cape Town (CT) infants vaccinated with BCG-Russia were stimulated with BCG-Denmark culture (SSI) in vitro (Supplementary Table 2)
Summary
Many TB endemic countries provide Bacille Calmette-Guérin (BCG) vaccine to infants routinely soon after birth [1,2,3,4]. BCG-Denmark strain has been shown to induce a greater magnitude and polyfunctional CD4+ Th1 cytokine response [8] and has a range of heterologous effects [3, 15,16,17]. In adults, BCG-Denmark increases monocyte cytokine production against unrelated antigen stimulation; where such “trained immunity” after primary infection or vaccination has been shown to confer protection against secondary infection, independent of the adaptive immune system [16]. In low birth weight infants, BCG-Denmark vaccination has been associated with increased innate cytokine levels in whole blood stimulated with Toll-like receptor (TLR) ligands [19]. Whether vaccine strains other than BCG-Denmark have a similar effect on T cell responses to unrelated antigens in newborn infants in Africa has not been assessed. We show that BCG vaccine strain impacts significantly on CD4+ T cell polyfunction and memory maturation, and on heterologous T cell responses to other vaccines
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