Rotavirus mucosal immunology: insights and research priorities from an international convening in Liverpool, March 2024

Rotavirus remains a major cause of acute diarrhoea among children under five years of age 1 , 2 , 3 , 4 . Four oral rotavirus vaccines (ORVs), RotaTeq (Merck & Co, Inc., Whiteriver, PA, USA), Rotavac (Bharat Biotech International Ltd., Hyderabad, India), Rotarix (GSK, Rixensart, Belgium) and Rotasiil (Serum Institute of India, Pune, India), are currently prequalified by the World Health Organization (WHO). These vaccines are safe, and offer protection against severe disease after a two- or three-dose schedule 5 , 6 , 7 ORVs have significantly reduced rotavirus disease morbidity and mortality, yet their efficacy and effectiveness is markedly lower in low-and middle-income countries (LMICs) compared to high-income countries, which has been comprehensively observed in clinical trials 8 , 9 , 10 , 11 , 12 , observed post rotavirus vaccine roll-out 13 , 14 and modelled from real-world usage 15 , 16 . The reasons for this reduced effectiveness in LMICs are poorly understood, multi-factorial and likely include chronic malnutrition, concurrent infections, gut dysbiosis, environmental enteric dysfunction (EDD), altered gut microbiota, and maternal antibody interference 17 , 18 , 19 . Viral VP4-histo-blood group antigen (HBGA) interactions confer genotype-dependent resistance, with Lewis-negative and non-secretor phenotypes offering protection against common strains 20 . Maternal secretor status affects breast milk antibody levels, with secretor-positive mothers often reducing vaccine take 21 . These are some of the key determinants of ORV underperformance in LMICs 18 , 22 , 23 , 24 . Serum IgA remains a commonly used marker of oral vaccine performance; however, it does not represent a mechanistic correlate of protection (CoP) 17 . Measurement of total anti-RV IgA titres does not identify specific rotavirus protein target or the mechanisms underlying heterotypic protection 25 , 26 . Consequently, serum IgA may have limited applicability for evaluating non-replicating or parenteral vaccine platforms. Some studies have also assessed type-specific neutralizing antibodies, although these too provided an incomplete picture of protective immunity. Emerging insights from mucosal immunology highlights important roles of B and T cell responses, non-neutralizing antibodies (nNAbs), and tissue-resident memory (TRM) cells. For example, VP6-specific nNAbs can mediate intracellular neutralisation via TRIM21 27 , while T cell responses, although often transient and functionally limited, may contribute to longer-term protection through TRM populations 28 .