RT Journal Article SR Electronic T1 Antibody feedback limits the expansion of cognate memory B cells but drives the diversification of vaccine-induced antibody responses JF bioRxiv FD Cold Spring Harbor Laboratory SP 808543 DO 10.1101/808543 A1 Hayley A. McNamara A1 Azza H. Idris A1 Henry J. Sutton A1 Barbara J. Flynn A1 Yeping Cai A1 Kevin Wiehe A1 Kirsten E. Lyke A1 Deepyan Chatterjee A1 Natasha KC A1 Sumana Chakravarty A1 B. Kim Lee Sim A1 Stephen L. Hoffman A1 Mattia Bonsignori A1 Robert A. Seder A1 Ian A. Cockburn YR 2019 UL http://biorxiv.org/content/early/2019/10/18/808543.abstract 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.