Antibody Feedback Limits the Expansion of B Cell Responses to Malaria Vaccination but Drives Diversification of the Humoral Response

McNamara HA, Idris AH, Sutton HJ, Vistein R, Flynn BJ, Cai Y, Wiehe K, Lyke KE, Chatterjee D, Kc N, Chakravarty S, Lee Sim BK, Hoffman SL, Bonsignori M, Seder RA, Cockburn IA.

Cell Host Microbe. 2020, doi: 10.1016/j.chom.2020.07.001. Epub 2020 Jul 21.

Highlights:

• Human antibody and B cell responses to a malaria vaccine plateau after 2 immunizations
• Anti-CSP Ig-knockin mice developed to probe regulatory mechanisms
• Antibody feedback via likely epitope masking limits immunodominant B cell responses
• Repeated boosting diversifies the immune response as subdominant responses expand

Abstract: 

Generating sufficient antibody to block infection is a key challenge for vaccines against malaria. Here, we show that antibody titers 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 immunoglobulin (Ig)-knockin mice with elevated numbers of PfCSP-binding B cells. We determined that recall responses were inhibited by antibody feedback, potentially 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 PfCSP C-terminal regions expanded with subsequent boosts. These data suggest that antibody feedback drives the diversification of immune responses and that vaccination for malaria will require targeting multiple antigens.

Graphical Abstract: