Project Summary/Abstract
The majority of licensed vaccines are thought to elicit protection mediated by humoral immunity. A key
determinant of the specificity and affinity of the antibody response is the germinal center (GC) response elicited
by immunization, wherein B cells enter GCs to undergo cyclic rounds of proliferation and somatic hypermutation
to evolve higher-affinity antibodies, followed by exit from the GC to become long-lived plasma cells or memory
B cells. Effective GC responses are thought to be critical for difficult pathogens such as HIV, and even for easily-
neutralized viruses such as SARS-CoV-2, effective and long-lived GC responses are associated with more
effective cross-neutralization of viral variants. Hence, optimizing GC responses is fundamental to vaccines
broadly. In recent work, we have studied how vaccine kinetics– the temporal pattern of antigen and adjuvant
exposure during immunization– impact humoral immunity and GC reaction in particular. Our preliminary studies
have revealed that prolonged delivery of antigen to draining lymph nodes over a period of 2-3 weeks substantially
alters the immune response. One particularly effective immunization approach, which we term “extended
dosing” (ext-dosing) immunization, involves administering a given total dose of vaccine antigen and adjuvant
as a half-dozen injections over two weeks in an escalating-dose pattern. Ext-dosing enhances the magnitude
of the GC response in both small and large animal models and increases the clonality (number of distinct B cell
clones participating in the GC), leading to enhanced neutralizing antibody production. These dramatic effects of
ext-dosing vaccination warrant close study to understand how and why this strategy is so effective. As ext-dosing
through repeat injections is not practical for human immunization, we are also highly motivated to develop
alternate strategies to achieve the same immunologic effects without the need for 6 or more injections. To
address these goals, our specific aims are (1) define how antigen exposure kinetics govern the immune
response elicited by ext-dosing immunization, (2) determine how adjuvant exposure kinetics impact the immune
response in ext-dosing, (3) test strategies to achieve “extended-dosing” effects using bolus subunit vaccine
administration, and (4) to evaluate the potential for ext-dosing-like effects in mRNA vaccines. Altogether, these
studies will both clarify fundamental concepts underlying effective primary immune responses and develop new
translationally-relevant approaches to enhance immune responses elicited by subunit and mRNA vaccines. We
test-bed these concepts using clinically-relevant antigens and adjuvants, and aim to pursue strategies we expect
to be broadly applicable to vaccines independent of disease target.