Differential effects of BCG vaccine on immune responses induced by vi polysaccharide typhoid fever vaccination: an explorative randomized trial

Bastiaan A Blok,Peter Aaby,Mihai G Netea,Leo A.B Joosten,Rob J.W Arts,Christine S Benn,Reinout Van Crevel

doi:10.1007/s10096-020-03813-y

Abstract

The Vi polysaccharide typhoid fever vaccine (TFV) provides incomplete protection against typhoid fever. BCG, the vaccine against tuberculosis, can potentiate immune responses to other vaccines through induction of trained innate immunity and heterologous adaptive immunity. We performed an explorative, randomized, noncontrolled open trial to investigate whether BCG vaccination increases humoral and cellular response to TFV and whether BCG and TFV modulate nonspecific immune responses. Thirty volunteers were randomized to receive either TFV alone or BCG followed by TFV after 2 weeks. Ex vivo leukocyte responses and anti-Vi IgG antibody titers were measured 2 weeks and 3 months after TFV. BCG administration prior to TFV vaccination did not increase specific humoral or cellular immune responses to Salmonella typhi. TFV vaccination decreased pro-inflammatory responses to non-related stimuli. This effect was counteracted by prior BCG administration, which also led to decreased IL-10 and increased IL-22 responses to non-related stimuli. In an in vitro model of trained immunity TFV led to immunotolerance, which was partially reversed by BCG-induced trained immunity. BCG does not modulate adaptive immune responses to TFV but partially prevents inhibition of innate immune responses induced by TFV. Nonspecific effects of vaccines to unrelated microbial stimuli must be considered in the evaluation of their biological effects (ClinicalTrials.gov NCT02175420).

Highlights

Typhoid fever is a significant health problem in low-income countries and in returning travelers in high-income countries [1,2,3]
We investigated whether Bacille Calmette-Guérin (BCG) vaccination increases the humoral and cellular response to typhoid fever vaccine (TFV) and whether BCG and TFV modulate the immune response to non-related antigens
BCG vaccination prior to TFV did not affect absolute S. typhi antibody titers, and seroconversion was more common in the BCG group, this failed to reach statistical significance

Summary

Introduction

Typhoid fever is a significant health problem in low-income countries and in returning travelers in high-income countries [1,2,3]. Whereas the oral Ty21a vaccine confers protection by inducing both antibody formation and cell mediated immune responses, protection against infection with S. typhi after Vi. Eur J Clin Microbiol Infect Dis (2020) 39:1177–1184 polysaccharide vaccination is thought to be generated mainly by formation of anti-Vi specific IgG antibodies [5, 6]. Apart from its protective effect against tuberculosis, BCG has been shown to confer protection against mortality and morbidity due to all-cause mortality in low-birth weight children [7]. The mechanism behind this nonspecific effect of BCG vaccination is hypothesized to involve the induction of memory properties of the innate immune system, known as trained immunity and induction of heterologous lymphocyte responses [8, 9]. BCG has been shown to increase adaptive antibody response to concurrent or subsequent vaccinations, such as hepatitis B vaccine, pneumococcal vaccine, and influenza vaccine [12,13,14]

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