PT - JOURNAL ARTICLE AU - Hayley A. McNamara AU - Azza H. Idris AU - Henry J. Sutton AU - Barbara J. Flynn AU - Yeping Cai AU - Kevin Wiehe AU - Kirsten E. Lyke AU - Deepyan Chatterjee AU - Natasha KC AU - Sumana Chakravarty AU - B. Kim Lee Sim AU - Stephen L. Hoffman AU - Mattia Bonsignori AU - Robert A. Seder AU - Ian A. Cockburn TI - Antibody feedback limits the expansion of cognate memory B cells but drives the diversification of vaccine-induced antibody responses AID - 10.1101/808543 DP - 2019 Jan 01 TA - bioRxiv PG - 808543 4099 - http://biorxiv.org/content/early/2019/10/18/808543.short 4100 - http://biorxiv.org/content/early/2019/10/18/808543.full AB - Generating sufficient antibody to block infection is a key challenge for vaccines against malaria. Here we show that antibody titres to a key target, the repeat region of the Plasmodium falciparum circumsporozoite protein (PfCSP), plateaued after two immunizations in a clinical trial of the radiation-attenuated sporozoite vaccine. To understand the mechanisms limiting vaccine responsiveness, we developed Ig-knockin mice with elevated numbers of PfCSP-binding B cells. We determined that recall responses were inhibited by antibody feedback via epitope masking of the immunodominant PfCSP repeat region. Importantly, the amount of antibody that prevents boosting is below the amount of antibody required for protection. Finally, while antibody feedback limited responses to the PfCSP-repeat region in vaccinated volunteers, potentially protective subdominant responses to C-terminal regions did expand with subsequent boosts. These data suggest that antibody feedback drives the diversification of immune responses and that vaccination for malaria will require the targeting of multiple antigens.