46 - Potential Impact of amino acid variation on purified protein vaccine efficacy against Streptococcus pneumoniae: an in-silico and whole-genome sequencing analysis

Poster Number: 46
Publication Number: 46.1509

Background: Invasive pneumococcal disease (IPD) remains a major cause of pneumonia morbidity and mortality globally despite the implementation of pneumococcal conjugate vaccines (PCVs) in childhood immunization programs due to the emergence of non-vaccine serotypes (NVTs). While PCVs are effective at reducing severe disease and prevent transmission, they cover a fraction (20/100) of serotypes capable of causing disease. Purified protein vaccines have the potential to overcome this issue as they utilize proteins that are present in all serotypes. While these proteins are consistently found in all serotypes, variations exist at the amino acid (AA) level. AA variation can have implications for vaccine efficacy because immune responses rely on recognizing specific segments of the protein, which can be impacted by AA variation.

Objective: This study aimed to describe AA variation of purified proteins that have been used in clinical trials such as pneumolysin.

Design/Methods: Whole genome sequencing data from IPD isolates in infants and children between 0-17 years old captured by the National Microbiology Lab during 2018-2020 were used; this includes isolates from IPD across Canada excluding Alberta. We phylogenetically described isolates using the core genome built with Roary where core genes were described as present in all isolates. Amino acid variation was assessed using the Standard Shannon entropy score. There were 449 sequences included in this analysis.

Results: The genome comprised of 2240 genes, 1735 of which were identified as core genes found in all isolates. AA variation was assessed for pneumolysin where the highest level of variation was observed in domain 4 at position 405 with an entropy score of 0.96. Domain 4 has been implicated in Toll-like receptor 4 activation and hemolysis. Highly conserved regions spanned domains 1-3 from amino acid positions 1-135, where domain 3 has been implicated to be involved in the initiation of transmembrane pore formation. Upcoming analyses will investigate the impact of AA variation on other pneumococcal vaccine candidates which have been used in clinical trials, including histidine triad protein D, choline binding protein A, and surface protein A.

Conclusion(s): The results of this study highlight the subtle differences at the AA level of proteins present in all serotypes. Thus, selecting highly conserved regions from multiple protein vaccine targets and incorporating them into a multi-valent vaccine formulation can mitigate potential challenges posed by AA variation or by including multiple variants of the same protein, thereby enhancing vaccine effectiveness.