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

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.

Listeria-Vectored Multiantigenic Tuberculosis Vaccine Enhances Protective Immunity against Aerosol Challenge with Virulent Mycobacterium tuberculosis in BCG-Immunized C57BL/6 and BALB/c Mice

“…To further expand the M. tuberculosis antigen repertoire, we selected 15 M. tuberculosis proteins (including r30) as potential vaccine candidates for further investigation ( Table 2 ), including (i) secreted proteins r30 ( 4 ), Mpt64 ( 24 – 26 ), TB8.4 ( 27 ), and Apa ( 28 ); (ii) ESAT6 and associated proteins secreted by the Esx/type VII secretion system, ESAT6 ( 24 , 29 ), CFP10 ( 30 ), TB10.4 ( 31 , 32 ), EspA ( 24 ), EspC ( 24 ), and EsxN; (iii) antigenic PE/PPE proteins PE25 ( 33 ) and PPE68 ( 24 , 34 ); and (iv) latency-associated proteins α-crystallin/hspX ( 35 , 36 ), Hrp1 ( 37 ), and VapB47 ( 37 , 38 ). Among the 15 selected proteins, all but two (EsxN and PE25) have been shown by us or others to be immunoprotective antigens when incorporated into various vaccines, including protein/adjuvant, DNA, Listeria -vectored, or virus-vectored vaccines, and 4 proteins, Mpt64, PPE68, CFP-10, and ESAT-6, are absent either from all BCG strains or the modern BCG strain (Mpt64) ( 39 , 40 ) ( Table 2 ).…”

Progressive Host-Directed Strategies to Potentiate BCG Vaccination Against Tuberculosis

“…On the account of immense attempts, several groups have developed vaccines by employing diverse approaches to control TB. Some classic examples include the attenuated M.tb bacilli strains ( 101 ) with high immunogenicity ( 102 ), the generation of genetically modified BCG strains for better immune responses ( 70 ), sub-unit vaccines incorporating immunogens absent in BCG ( 103 ), and adjuvants with enhanced potency. Major TB vaccine candidates in advanced clinial trials are tabulated in Table 2 .…”

Host genetic background is a barrier to broadly effective vaccine protection: Relevance to BCG andMycobacterium tuberculosisInfection

“…Importantly, it is among the most resistant of all inbred strains to Mtb infection (9), which makes it difficult to identify conditions that increase its resistance to disease. Investigators have addressed these limitations by using F1 hybrids and susceptible strains to increase MHC and genetic diversity and to identify strategies to increase host resistance (10)(11)(12)(13). However, even among a range of classical inbred strains, the genetic diversity is limited (14).…”