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

Abstract

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.

Keywords: BCG vaccination; T-cell proliferation; infants; intracellular cytokines; maternal HIV.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

CD4+ and CD8+ T-cell proliferation in response to BCG stimulation among infants who received BCG vaccine at birth (the early group) or 8 weeks of age (the delayed group). A, Longitudinal assessment of the median frequency of CD4+Ki67+ cells. Whiskers represent interquartile ranges. B, Frequency of CD4+ T cells expressing Ki67+ in the early group (black) and the delayed group (gray) at 14 weeks of age. Lines represent medians, and whiskers represent interquartile ranges. C, Frequency of CD4+ T cells expressing Ki67+ 6 weeks after vaccination (ie, at 6 weeks of age in the early group [black] and 14 weeks of age in the delayed group [gray]). D, Longitudinal assessment of the median frequency of CD8 + Ki67+ cells. Whiskers represent interquartile ranges. E, Frequency of CD8+ T cells expressing Ki67+ in the early group (black) and the delayed group (gray) at 14 weeks of age. F, Frequency of CD4+ T cells expressing Ki67+ 6 weeks after vaccination (ie, at 6 weeks of age in the early group [black] and 14 weeks of age in the delayed group [gray]). Lines represent medians, and whiskers represent interquartile ranges *P < .05 and **P < .01. Abbreviation: NS, nonsignificant.

Figure 2.

Frequency of proliferating CD4+ T-cell intracellular cytokine production among infants who received BCG vaccine at birth (the early group) or 8 weeks of age (the delayed group). A, Frequency of CD4+Ki67+ cells expressing interferon γ (IFN-γ) in the early group (black) and the delayed group (gray). B, Frequency of CD4+Ki67+ cells expressing interleukin 2 (IL-2) in the early group (black) and the delayed group (gray). C, Frequency of CD4+Ki67+ cells expressing interleukin 17 (IL-17) in the early group (black) and the delayed group (gray). Frequencies reported are calculated on the basis of the total number of CD4+ T cells. Abbreviation: NS, not significant.

Figure 3.

Frequency of proliferating T-cell intracellular cytokine production 6 weeks after vaccination among infants who received BCG vaccine at birth (the early group) or 8 weeks of age (the delayed group). Frequency of CD4 + Ki67+ and CD8 + Ki67+ cells expressing interferon γ (IFN-γ; A), interleukin 2 (IL-2; B), and interleukin 17 (IL-17; C) in the early group (black) and the delayed group (gray) 6 weeks after vaccination (ie, week 6 of age for the early group and week 14 of age for the delayed group). Frequencies reported are of total CD4+ T cells and total of CD8+ cells. Lines represent medians and whiskers interquartile ranges. Abbreviation: NS, nonsignificant.

Figure 4.

Proliferating CD4+ T cells making any combination of cytokine among infants who received BCG vaccine at birth (the early group) or 8 weeks of age (the delayed group). A, Pie chart of proliferating cells making 0 cytokines (pink), any single cytokine (green), any combination of 2 cytokines (yellow), or all 3 cytokines (red) in the early group (left) and the delayed group (right). B, Frequency of CD4 + Ki67+ T cells making the specific cytokines alone or in combination in the early group (blue) and the delayed group (red). Bars represent medians. *P < .05. Abbreviations: IFN, interferon; IL-2, interleukin 2; IL-17, interleukin 17.

Figure 5.

Proliferating CD8+ T cells making any combination of cytokines among infants who received BCG vaccine at birth (the early group) or 8 weeks of age (the delayed group). A, Pie chart of proliferating cells making 0 cytokines (pink), any single cytokines (green), any combination of 2 cytokines (yellow), or all 3 cytokines (red) in the early group (left) and the delayed group (right). B, Frequency of CD8 + Ki67+ T cells making the specific cytokines alone or in combination in the early group (blue) and the delayed group (red). Bars represent medians. Abbreviations: IFN, interferon; IL-2, interleukin 2; IL-17, interleukin 17.

Figure 6.

Polyfunctionality of T-cell cytokine responses 6 weeks after vaccination among infants who received BCG vaccine at birth (the early group) or 8 weeks of age (the delayed group). Pie chart of proliferating CD4+ (top) and CD8+ (bottom) T cells making 0 cytokines (pink), any single cytokine (green), any combination of 2 cytokines (yellow), or all 3 cytokines (red) in the early group (left) and the delayed group (right) 6 weeks after vaccination (ie, at 6 weeks of age for the early group and 14 weeks for the delayed group). Abbreviation: NS, nonsignificant.