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Analysis of Memory B-Cell Responses Reveals Suboptimal Dosing Schedule of a Licensed Vaccine. Current guidance recommends that adolescents receive a 2-dose human papillomavirus (HPV) vaccine, whereas young adults and immunocompromised persons receive 3 doses. We examined secondary responses of vaccine-elicited memory B cells (Bmem) in naive women receiving 3 doses of the quadrivalent HPV vaccine to understand the quality of B-cell memory generated by this highly effective vaccine. Unexpectedly, we observed a lower Bmem response rate and magnitude of Bmem responses to the third dose than to a booster dose administered at month 24. Moreover, high titers of antigen-specific serum antibody at vaccination inversely correlated with Bmem responses. As the purpose of additional doses/boosters is to stimulate Bmem to rapidly boost antibody levels, these results indicate the timing of the third dose is suboptimal and lend support to a 2-dose HPV vaccine for young adults. Our findings also indicate more broadly that multidose vaccine schedules should be rationally determined on the basis of Bmem responses.