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Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination.

Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination.
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Tam HH, Melo MB, Kang M, Pelet JM, Ruda VM, Foley MH, Hu JK, Kumari S, Crampton J, Baldeon AD, Sanders RW, Moore JP, Crotty S, Langer R, Anderson DG, Chakraborty AK, Irvine DJ,


Tam HH, Melo MB, Kang M, Pelet JM, Ruda VM, Foley MH, Hu JK, Kumari S, Crampton J, Baldeon AD, Sanders RW, Moore JP, Crotty S, Langer R, Anderson DG, Chakraborty AK, Irvine DJ, (click to view)

Tam HH, Melo MB, Kang M, Pelet JM, Ruda VM, Foley MH, Hu JK, Kumari S, Crampton J, Baldeon AD, Sanders RW, Moore JP, Crotty S, Langer R, Anderson DG, Chakraborty AK, Irvine DJ,

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Proceedings of the National Academy of Sciences of the United States of America 2016 Oct 4() pii

Abstract

Natural infections expose the immune system to escalating antigen and inflammation over days to weeks, whereas nonlive vaccines are single bolus events. We explored whether the immune system responds optimally to antigen kinetics most similar to replicating infections, rather than a bolus dose. Using HIV antigens, we found that administering a given total dose of antigen and adjuvant over 1-2 wk through repeated injections or osmotic pumps enhanced humoral responses, with exponentially increasing (exp-inc) dosing profiles eliciting >10-fold increases in antibody production relative to bolus vaccination post prime. Computational modeling of the germinal center response suggested that antigen availability as higher-affinity antibodies evolve enhances antigen capture in lymph nodes. Consistent with these predictions, we found that exp-inc dosing led to prolonged antigen retention in lymph nodes and increased Tfh cell and germinal center B-cell numbers. Thus, regulating the antigen and adjuvant kinetics may enable increased vaccine potency.

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