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

TitleSustained antigen availability during germinal center initiation enhances antibody responses to vaccination
Publication TypeJournal Article
Year of Publication2016
AuthorsTam, HHei, 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
JournalProceedings of the National Academy of Sciences of the United States of America
PaginationE6639 - E6648
Date Published2016/10/25/
ISBN Number0027-8424
Keywordsadjuvant, affinity maturation, antigen retention, center b-cells, computational immunology, follicular helper-cell, germinal center formation, hiv-1 envelope trimer, humoral response, immune-responses, infection, malaria antigen, release, vaccination kinetics, vaccines

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.

Short TitleProc. Natl. Acad. Sci. U. S. A.