Pneumococcal vaccine efficacy for mucosal pneumococcal infections depends on Fcγ receptor IIa polymorphism

IgG2 antibodies are the main antibody subclass produced after pneumococcal polysaccharide vaccination. For these antibodies to be effective, interaction with FcγIIa receptors on phagocytic cells is necessary. FcγRIIa displays a functional polymorphism with either a histidine (H) or arginine (R) at position 131. Interaction of IgG2 antibodies depends on the H131 allele, whereas this interaction is low to absent with the R131 allele.We tested the clinical efficacy of combined pneumococcal conjugate and pneumococcal polysaccharide vaccination according to FcγIIa-H/R131 genotype in a randomized double blind placebo controlled vaccination trial in children with a history of acute otitis media.We found a decisive role for the FcγIIa-H/R131 polymorphism on the clinical vaccine efficacy of combined pneumococcal conjugate and polysaccharide vaccinations. RR homozygotes showed a significant increase in recurrence of acute otitis media after pneumococcal vaccinations. This cannot be explained by differences in the pneumococcal specific antibody response or differences in nasopharyngeal pneumococcal carriage, but may be explained by less efficient interaction of FcγRIIa with polysaccharide-induced IgG2 anti-pneumococcal antibodies in RR homozygotes. Our data show that the genetic make-up of individuals or populations under study should be considered while evaluating vaccine efficacy trials.