On the impact of Masking and Blocking Hypotheses for measuring efficacy of new tuberculosis vaccines

TL;DR

This study introduces models to distinguish masking and blocking effects influencing TB vaccine efficacy, finding high blocking effects and negligible masking, which is crucial for evaluating new TB vaccines in previously exposed populations.

Contribution

The paper develops models to differentiate masking and blocking mechanisms and applies them to interpret clinical trial data, providing insights into their relative impacts on vaccine efficacy.

Findings

High levels of blocking effect observed in trials

No significant evidence for masking effect

Implications for future TB vaccine development

Abstract

Over the past 60 years, the Mycobacterium bovis bacille Calmette-Gu\'erin (BCG) has been used worldwide to prevent tuberculosis (TB). However, BCG has shown a very variable efficacy in different trials, showing a wide range of protection in adults against pulmonary TB. Previous studies indicate that this failure is related to pre-existing immune response to antigens that are common to environmental sources of mycobacterial antigens and Mycobacterium tuberculosis. Specifically, two different mechanisms have been hypothesized: the masking, (previous sensitization confers some level of protection against TB), and the blocking (previous immune response prevent vaccine taking of a new TB vaccine), effects. In this work we introduce a series of models to discriminate between masking and blocking mechanisms and address their relative likelihood. The application of our models to interpret the results coming from the BCG-REVAC clinical trials, specifically designed for the study of sources of efficacy variability yields estimates that are consistent with high levels of blocking (41% in Manaus -95% C.I. [14%-68%]- and 96% in Salvador -95% C.I. [52%-100%]-), and no support for masking to play any relevant role in modifying vaccine efficacy either alone or aside blocking. The quantification of these effects around a plausible model constitutes a relevant step towards impact evaluation of novel anti-tuberculosis vaccines, which are susceptible of being affected by similar effects if applied on individuals previously exposed to mycobacterial antigens.