The tetravalent live attenuated dengue vaccine candidate TV003 induces neutralizing antibodies against all four dengue virus serotypes (DENV1-4), and protects against experimental DENV2 challenge in humans. Protection occurred with or without a secondary post-challenge rise in DENV2-specific neutralizing antibodies. Here we combined high resolution temporal sampling and analysis of antigen-specific responses after vaccination and challenge to determine the cellular underpinnings of the B cell response in relation to vaccine viremia and serum antibodies. TV003 vaccine-related viremia was associated with an acute plasmablast response that correlated with the development of serum neutralizing antibodies. At six-months following immunization, subjects had developed DENV2-specific memory B cells including serotype-specific and multi-valent responders. DENV2 challenge of vaccinees did not induce a post-challenge plasmablast response, though stronger and earlier post-vaccine plasmablast responses were associated with sterile humoral protection from DENV2 challenge (i.e. a lack of DENV2 antibody boosting). Our findings demonstrate that TV003 vaccine triggers a durable B cell response containing plasmablasts and memory B cells which functionally link early vaccine viremia and the serum antibody responses.
