Concerns for efficacy of a 30-valent M-protein-based Streptococcus pyogenes vaccine in regions with high rates of rheumatic heart disease

The prevalence of rheumatic heart disease (RHD) in the Aboriginal population of the Australian Northern Territory is high, and Streptococcus pyogenes skin infections likely contribute to this. A promising candidate S. pyogenes 30mer vaccine is composed of 30 pharyngitis associated type-specific antigens from the S. pyogenes M protein. Cross opsonisation experiments suggest that 30mer vaccine protection may extend to non-cognate emm types. A new emm cluster scheme for classifying M protein is based on the full-length coding sequence, and correlates with functional and immunological properties, and anatomical tropism. Twenty-seven years of research in the Northern Territory has yielded 1810 S. pyogenes isolates with clinical and emm type data. The primary aim was to analyse these data with reference to the emm cluster scheme and cross opsonisation information, to inform estimation of 30mer vaccine efficacy in the Northern Territory. The isolates encompass 101 emm types. Variants of cluster A-C were enriched in throat isolates, and variants of emm cluster D enriched in skin isolates. Throat isolates were enriched for 30mer vaccine cognate emm types in comparison with skin isolates of which only 25% were vaccine emm types. While cross opsonisation data indicates potential for enhancing 30mer vaccine coverage, more than one third of skin isolates were within 38 emm types untested for cross opsonisation. Emm cluster D variants, in particular emm cluster D4, were not only all non-cognate with the vaccine, but were abundant and diverse, and less likely to be cross-opsonisation positive than other emm clusters. Long term persistence of many emm types in the study area was revealed. It was concluded that the 30mer vaccine efficacy in the Northern Territory will likely require both cross protection, and additional measures to elicit immunity against variants of emm cluster D. Author summary The bacterium Streptococcus pyogenes causes throat and skin infections. A danger from such infections is an immune response that attacks human heart tissue, leading to rheumatic heart disease, which is difficult to treat and potentially deadly. Disadvantaged populations such as the Indigenous people in remote tropical northern Australia have high burdens of S. pyogenes skin infection, and rheumatic heart disease. An effective vaccine would be a benefit, but none is approved for clinical use. We analysed data from 1810 S. pyogenes isolates from north Australia obtained over 28 years, to determine the potential of a previously described S. pyogenes vaccine candidate to be effective in this region. Only one quarter of the isolates from skin infections had a surface antigen corresponding to any one of the 30 antigen variants in the candidate vaccine. Previous work in animals indicates potential cross-protection from the vaccine against strains with mismatched antigens. However, even if this occurs in humans, protection against skin infection strains would likely remain compromised, unless there were additional components in the vaccine. Further studies on cross-protection are critical to defining the potential of this type of vaccine in populations burdened with S. pyogenes skin infections and rheumatic heart disease.