"Extended dosing" immunization to enhance humoral immunity to next-generation vaccines

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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.