A Randomized Controlled Clinical Trial of Nasal Immunization with Live Virulence Attenuated Streptococcus pneumoniae Strains Using Human Infection Challenge

作者：Helen Hill, Elena Mitsi, Elissavet Nikolaou, Annie Blizard, Sherin Pojar, Ashleigh Howard, Angela Hyder-Wright, Jack Devin, Jesús Reiné, Ryan Robinson, Carla Solórzano, Simon P. Jochems, Tinashe Kenny-Nyazika, Elisa Ramos‐Sevillano, Caroline M. Weight, Chris Myerscough, Daniella McLenaghan, Ben Morton, Emily Gibbons, Madlen Farrar, Victoria Randles, Hassan Burhan, Tao Chen, Adam D. Shandling, Joe J. Campo, Robert S. Heyderman, Stephen B. Gordon, Jeremy Brown, Andrea M. Collins, Daniela M. Ferreira · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2023 · DOI：10.1164/rccm.202302-0222oc · 被引用次数：16 · 研究领域：Pneumonia and Respiratory Infections、Respiratory viral infections research、Bacterial Infections and Vaccines

Abstract Rationale Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods Healthy adults aged 18–50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given Spn...