A Mycobacterium tuberculosis-specific subunit vaccine that provides synergistic immunity upon co-administration with Bacillus Calmette-Gu\xe9rin

Joshua S Woodworth,Rasmus Mortensen,Helena Strand Clemmensen,Thomas Lindenstrøm,Hannah Battey,Karin Dijkman,Randy Taplitz,Peter Andersen,Jeffrey Morgan,Cecilia S Lindestam Arlehamn,Raquel Salvador Laureano,Ida Rosenkrands,Claus Aagaard

doi:10.1038/s41467-021-26934-0

Abstract

Given the encouraging clinical results of both candidate subunit vaccines and revaccination with Bacillus Calmette-Guérin (BCG) against tuberculosis (TB), there is support for combining BCG and subunit vaccination for increased efficacy. BCG and Mycobacterium tuberculosis (Mtb) share ~98% of their genome and current subunit vaccines are almost exclusively designed as BCG boosters. The goal of this study is to design a TB subunit vaccine composed of antigens not shared with BCG and explore the advantages of this design in a BCG + subunit co-administration vaccine strategy. Eight protective antigens are selected to create an Mtb-specific subunit vaccine, named H107. Whereas traditional vaccines containing BCG-shared antigens exhibit in vivo cross-reactivity to BCG, H107 shows no cross-reactivity and does not inhibit BCG colonization. Instead, co-administering H107 with BCG leads to increased adaptive responses against both H107 and BCG. Importantly, rather than expanding BCG-primed T cells, H107 broadens the overall vaccine repertoire with new T cell clones and introduces ‘adjuvant-imprinted’ qualities including Th17 responses and less-differentiated Th1 cells. Collectively, these features of H107 are associated with a substantial increase in long-term protection.

Highlights

Given the encouraging clinical results of both candidate subunit vaccines and revaccination with Bacillus Calmette-Guérin (BCG) against tuberculosis (TB), there is support for combining BCG and subunit vaccination for increased efficacy
To design an Mtbspecific TB vaccine with multiple antigens that do not cross-react with BCG, we identified three criteria for the selection of vaccine antigens: i) non-immunogenic in the context of BCG vaccination, ii) previously reported immunogenicity in Mycobacterium tuberculosis (Mtb)-infected humans, and iii) induction of protective immune response in animal models
We have previously shown that boosting pre-existing BCG-induced immunity by immunizing with Mtb-specific antigens to complement BCG has a greater impact on the CD4 T cell phenotype than traditional BCG boosting, wherein the immunizing subunit antigens are shared with BCG39

Summary

Introduction

Given the encouraging clinical results of both candidate subunit vaccines and revaccination with Bacillus Calmette-Guérin (BCG) against tuberculosis (TB), there is support for combining BCG and subunit vaccination for increased efficacy. Rather than expanding BCG-primed T cells, H107 broadens the overall vaccine repertoire with new T cell clones and introduces ‘adjuvant-imprinted’ qualities including Th17 responses and lessdifferentiated Th1 cells These features of H107 are associated with a substantial increase in long-term protection. Two subunit vaccines have recently demonstrated the first signals of VE in clinical trials: H4:IC31® against sustained Quantiferon (QFT) conversion (VE 30.5%; 95% confidence interval [CI], −15.8 to 58.3)[12] and, more convincingly, M72/AS01E against TB disease (VE 49.7%; 95% CI, 2.1–74.2)[13] Despite these promising results, vaccines with improved efficacy of >50% are considered necessary to reach the target of the World Health Organization (WHO) End TB strategy[14] and there has been a call for new vaccine candidates that broaden the antigen repertoire toward this endeavor[15,16,17]

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