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

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.

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

“…A randomized controlled trial in Australia showed that BCG Denmark and BCG Japan given at birth induced higher proportions of mycobacterialspecific polyfunctional [IFNγ(+)TNF(+)IL-2(+)] CD4 T cells than BCG Russia (Ritz et al, 2012). The impact of different BCG strains on the ontogeny of vaccine-specific and heterologous vaccine immunogenicity in the first 9 months of life was also examined in two African birth cohorts (Kiravu et al, 2019), where BCG Denmark vaccinated infants mounted significantly higher frequencies of polyfunctional CD4+ T cells, compared with infants vaccinated with BCG Bulgaria and BCG Russia. BCG-naïve adult volunteers immunized with BCG Denmark showed divergent whole blood pro-inflammatory and regulatory T cell responses, with significant induction of polyfunctional [IFNγ(+)TNF(+)IL-2(+)] CD4 T cells and IFNγ production confined to individuals with strong local skin inflammation, compared to regulatory-like CD8 T cell induction in individuals with mild skin inflammation (Boer et al, 2015).…”

A century of BCG: Impact on tuberculosis control and beyond

“…12 Similar results were reported in another clinical trial which compared BCG-Russia and Denmark. 13 Here too, BCG-Denmark induced a greater magnitude of mycobacteria-specific CD4 + T cell responses and polyfunctionality compared to BCG-Russia. 13 Finally, a very large clinical trial in infants in Guinea-Bissau that compared BCG-Denmark, Russia, and Japan found that BCG-Denmark and Japan were more immunogenic than BCG-Russia.…”

“…Apart from the absence of RD-1, propagation 10,11 There is evidence to suggest that anti-TB protection might vary with the strain of BCG used for vaccination (Table 1). [12][13][14] In Uganda, mycobacterial immune responses between infants vaccinated with BCG-Russia, Bulgaria, and Denmark were compared and it was found that vaccination with BCG-Denmark induced a higher percentage of scarring and anti-mycobacterial immune responses. 12 Similar results were reported in another clinical trial which compared BCG-Russia and Denmark.…”

Factors influencing maternal microchimerism throughout infancy and its impact on infant T cell immunity

“…The effect of MMc on the polyfunctionality of BCG vaccine responses (PFS) were assessed using GEE models clustered by individual, a gaussian outcome structure, and an exchangeable correlation matrix. We have previously shown that iHEU infants have altered T cell functionality to BCG (24) and that the type of BCG strain used for vaccination contributes strongly to the magnitude and polyfunctionality of vaccine response elicited in infants (29). We therefore adjusted for BCG strain, HIV exposure, and infant age in our analyses.…”