Impact of Human STING Variants on Pneumococcal Vaccine Effectiveness

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Abstract The goal of this proposal is to determine the effectiveness of pneumococcal vaccines influenced by the common human STING (stimulator of interferon genes) variant R71H-G230A-R293Q (HAQ). Pneumococcal diseases kill more people than all other vaccine-preventable diseases combined. Pneumovax® 23 and Prevnar 13® are polysaccharide vaccines providing serotype-specific protection. Since its approval in 1983, Pneumovax 23® results in only ~57% of overall disease reduction. Recently, Dr. Bruce Beutler’s group showed that polysaccharide Ag generates a cyclic dinucleotide (CDN) called 2’5’-3’5’-cyclic GMP-AMP (2’3’-cGAMP) in B cells leading to the activation of STING-Type I IFN pathway. STING is a receptor for CDN. STING-/- mice have decreased Ab production to Pneumovax® 23. Our own data showed that STING-/- mice also have decreased Ab production to Prevnar® 13. We previously identified a human STING variant HAQ that is common in non-Africans. ~3% of Caucasians and ~16% of East Asians are HAQ/HAQ. In fact, R232(wt)/HAQ, not the R232(wt)/R232(wt), is the most common STING genotype in East Asians. Examining B cells derived from human HAQ/HAQ individuals, we found that HAQ B cells have dramatically decreased STING expression. We hypothesize that Pneumovax ® 23 and Prevnar 13® vaccine effectiveness is influenced by HAQ STING variant. To test this hypothesis and uncover the in vivo mechanism, we generated the HAQ, AQ and Q293 STING knock-in mice. In Aim 1, we will determine (a) the impact of HAQ STING on the effectiveness of Pneumovax® 23 and Prevnar13® vaccines in vivo (Aim 1.1); (b) the in vivo mechanism by which HAQ STING influences Pneumovax® 23 and Prevnar13® effectiveness (Aim 1.2). Pneumovax® 23 and Prevnar 13® do not elicit strong mucosal immunity. A mucosal pneumococcal vaccine consists of a common protein Ag and a potent mucosal adjuvant can provide serotype-independent mucosal protection. Recently, a synthetic CDN, RpRp-c-di-AMPss, was reported to activate all human STING variants in HEK293T cells. Our preliminary data demonstrated that RpRp-c-di-AMPss has mucosal vaccine adjuvant activity eliciting strong Ab production and balanced Th1/Th2/Th17 response that depends on STING. In Aim 2, we will determine (a) the impact of HAQ STING on the mucosal adjuvant activity of RpRp-c-di-AMPss in vivo (Aim 2.1); (b) the in vivo mechanism by which HAQ STING influences RpRp-c-di-AMPss mucosal adjuvant activity (Aim 2.2). We will evaluate RpRp-c-di-AMPss adjuvanted pneumococcal surface protein A (PspA) vaccine induced humoral, cellular immune responses, and the protective immunity against S. pneumoniae infection in our knock-in mice. Achieving these Aims will pave the way for the development of STING-targeting precision medicine in humans.