Delayed BCG Vaccination: Effect on the Infant Immune Response, Unrelated Pathogens and Other EPI Vaccines

Darboe, Fatoumatta (2015). Delayed BCG Vaccination: Effect on the Infant Immune Response, Unrelated Pathogens and Other EPI Vaccines. MPhil thesis The Open University.



Tuberculosis (TB) is one of the leading causes of mortality in developing countries and infants are at particular risk. Currently, the only licensed vaccine is Bacillus Calmette-Guerin (BCG), which has variable efficacy. BCG has been shown to provide heterologous protection against unrelated pathogens and enhance immunity to other Expanded Programme on Immunization (EPI) vaccines when given at birth. However, only one recently published study has shown an enhanced pro-inflammatory effect of BCG among vaccinated neonates and the immunological mechanisms of this effect in infants are not known. Further studies are required if this BCG effect is to be understood.

This thesis describes the differences in soluble and cellular responses to vaccine specific and non-specific heterologous antigens and EPI antibody levels between infants vaccinated with BCG at 6 weeks and those delayed until 18 weeks of age using flow cytometry, multiplex cytokine arrays and vaccine antibody assays.

We found low plasma cytokine levels and little cytokine production to PPD (the BCG-recall antigen) regardless of vaccination status. However, the BCG vaccinated group had lower production of IL-10 with both Toll like receptor (TLR) agonists and unrelated pathogen stimulation when compared to their unvaccinated counterparts, and this was more prominent in females than males. This contrasts with previous studies showing enhanced pro-inflammatory responses to TLR agonists and killed pathogens following BCG vaccination. The infants received BCG Denmark in these latter studies, whereas BCG Russia was used in our study, therefore strain differences in heterologous effects of BCG may be one explanation for the discrepancy.

When cellular responses were analyzed by flow cytometry low cellular responses were observed in both groups. However, we observed a significantly higher proportion of IFNγ+ CD8+ cells 1 week after vaccination compared to the unvaccinated group in response to PPD and Candida albicans stimulation.

Despite their different vaccine schedules, protective antibody levels to polio, tetanus and hepatitis B vaccines were obtained by all subjects; although no boosting effect of BCG was seen in contrast to previous studies when BCG was given at birth. A tuberculin skin test (TST) was performed at 18 weeks of age as a functional measure of delayed type hypersensitivity to Mtb. Due to the influence of BCG vaccination on TST induration, the vaccinated infants had significantly higher indurations than the unvaccinated infants and this was more pronounced in males.

Our findings are in contrast to a study in South Africa, but support findings from a study in Uganda, where delayed BCG vaccination significantly reduced responses to BCG compared to infants vaccinated at birth, suggesting an impact of environment (including exposure to non-tuberculous mycobacteria) in masking the immune response to BCG, differences in vaccine strains might be a major reason for differences observed in our study and the other South African studies However, two major limitations of our study are the lack of a vaccine group at birth as per the current vaccine schedule, and a postvaccination follow up for the infants vaccinated at 18 weeks to determine differences in immunity to BCG with a further delay in vaccination.

In conclusion, BCG vaccination given at 6 weeks of age showed no difference in Th1 responses, but decreased IL-10 responses after TLR agonist and unrelated pathogen stimulation compared to unvaccinated infants. These effects, together with TST induration, were influenced by sex. Importantly, however, delaying vaccination did not have an effect on other EPI vaccine antibody levels, with all infants reaching protective levels by 18 weeks of age. This study provides further insight into BCG effects in infants in a West African setting.

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