BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA– Indian adults

Abstract

BACKGROUND. Bacille Calmette-Guérin (BCG) vaccine is protective against Tuberculosis (TB) in children, but its efficacy wanes with age. Consequently, determining if BCG revaccination augments anti-TB immunity in young adults in TB endemic regions is vital. METHODS. Two hundred healthy adults, BCG vaccinated at birth, were tested for their IFN-γ release assay (IGRA) status. Of these, 28 IGRA + and 30 IGRAwere BCG revaccinated, and 24 IGRA + and 23 IGRAsubjects served as unvaccinated controls. T and innate cell responses to mycobacterial antigens were analyzed by 14-color flow cytometry over 34 weeks. RESULTS. IFN-γ and/or IL-2 Ag85A-and BCG-specific CD4 + and CD8 + T cell responses were boosted by revacciantion at 4 and 34 weeks, respectively, and were > 2-fold higher in IGRA + compared with IGRAvaccinees. Polyfunctional Ag85A, BCG, and mycobacterium tuberculosis (Mtb) latency Agspecific (LTAg-specific) CD4 + T cells expressing up to 8 cytokines were also significantly enhanced in both IGRA + and IGRAvaccinees relative to unvaccinated controls, most markedly in IGRA + vaccinees. A focused analysis of Th17 responses revealed expansion of Ag85A-, BCG-, and LTAgspecific total IL-17A + ,IL-17F + ,IL-22 + , and IL-10 + CD4 + T cell effectors in both IGRA + and IGRAsubjects. Also, innate IFN-γ + NK/γδ/NKT cell responses were higher in both IGRA + and IGRAvaccinees compared with controls. This is the first evidence to our knowledge that BCG revaccination significantly boosts antimycobacterial Th1/Th17 responses in IGRA + and IGRAsubjects. CONCLUSION. These data show that BCG revaccination is immunogenic in IGRAand IGRA + subjects, implying that Mtb preinfection in IGRA + subjects does not impact immunogenicity. This has implications for public health and vaccine development strategies.

‘Trained immunity’ from Mycobacterium spp. exposure or BCG vaccination and COVID-19 outcomes

“…Bacille Calmette-Guérin or BCG vaccination policy implementation by countries and its coverage had been proposed to lower the COVID-19 cases and mortality [REFs in [1][2][3][4]. The BCG vaccination given to children and adults has been known to protect them from many unrelated pathogens and diseases [REFs in 1,3, 5-10 ] supposedly through the generation of 'trained immunity' and heterologous cell-mediated immunity (e.g., Th1 and Th17) that last for a variable period [1,5,[9][10][11][12]. However, the confounding variables among the countries for COVID-19 such as the stage of the outbreak, population age distribution, health infrastructure, management practices, the testing/screening, and reporting guidelines, etc.…”

“Trained immunity” from Mycobacterium spp. exposure or BCG vaccination and COVID-19 outcomes

“…(environmental or BCG) could help reduce COVID-19 infections or mortality in a population, the estimated prevalence of the tuberculin immunoreactivity or the so-called “% LTBI” [ 21 ] of resident populations would closely correlate with COVID-19 infection and mortality rates regardless of the BCG vaccination policy, BCG coverage, or its implementation among countries [ 22 ]. The European countries that have quite a mix of diverse BCG vaccination policies—ranging from none ever to current universal vaccination [ 22 ], relatively comparable medical infrastructure, mobility, exposure to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and other confounding variables and more importantly currently at a similar stage of epidemic curve, i.e., postinfections peak, but could have differential “trained immunity” and cell-mediated immunity status as may be supposed from % LTBI prevalence [ 5 , 6 , 7 , 12 ], offer an excellent opportunity to evaluate such an assertion.…”

“…It must be remembered that BCG vaccination does not necessarily elicit a cell-mediated immune response in all, at the same rate, and there is also reported loss with age, absence of rechallenge, and immune suppression. In the view of the observation presented, it may be suggested that ongoing trials/studies evaluating the effect of BCG vaccination on COVID-19 infections [ 1 , 13 ], including the one recently concluded in Israel and reported in JAMA [ 14 ], could provide more objective conclusions on inclusion of the estimates about the “trained immunity” and heterologous cell-mediated immune response of study participants/ populations [ 5 , 12 ].…”

Expanding the role of bacterial vaccines into life-course vaccination strategies and prevention of antimicrobial-resistant infections

“…In mice, wP and adjuvanted intranasal pertussis vaccines induced Th17 responses and showed higher efficacy against nasal infection than an aluminium-adjuvanted aP vaccine 63,64 . BCG revaccination of adults in India was also shown to boost antimycobacterial Th1/Th17 responses 65 . This, in combination with evidence that BCG revaccination prevented sustained seroconversion by IFN-γ release assay infection in a South African study 66 , may suggest an association between successful induction of Th1/ Th17 and prevention of Mtb infection.…”

“…The protective adaptive response is thought to be mediated mainly by CD4+ Th1 cells with contributions from Th17 and CD8+ T-cells, but as yet no solid explanation how bacterial killing is finally achieved is forthcoming 116,117 . Recent findings from India using BCG revaccination in IGRA+ (IFN-y release assay linked to presence of Mycobacteria) subjects demonstrated boosting of Th1/Th17 CD4+ T-cell responses including polyfunctional T-cells 65 . BCG prevented sustained seroconversion (by IFN-γ release assay) in South African adolescents when given as a booster 66 .…”