PT  - JOURNAL ARTICLE
AU  - Liang, Frank
AU  - Lindgren, Gustaf
AU  - Sandgren, Kerrie J.
AU  - Thompson, Elizabeth A.
AU  - Francica, Joseph R.
AU  - Seubert, Anja
AU  - De Gregorio, Ennio
AU  - Barnett, Susan
AU  - O’Hagan, Derek T.
AU  - Sullivan, Nancy J.
AU  - Koup, Richard A.
AU  - Seder, Robert A.
AU  - Loré, Karin
TI  - Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake
AID  - 10.1126/scitranslmed.aal2094
DP  - 2017 Jun 07
TA  - Science Translational Medicine
PG  - eaal2094
VI  - 9
IP  - 393
4099  - http://stm.sciencemag.org/content/9/393/eaal2094.short
4100  - http://stm.sciencemag.org/content/9/393/eaal2094.full
AB  - Vaccine enhancement by adjuvants has been known for decades, but the mechanistic differences in how specific adjuvants influence the immune response are just beginning to be elucidated. Liang et al. sought a model that closely mimics humans, so they intramuscularly immunized nonhuman primates with a prototypical HIV antigen in combination with various adjuvants. They then inspected the muscles and lymph nodes to characterize antigen-presenting cells and resulting adaptive immune responses. Their findings should provide valuable information on adjuvant selection for vaccine development in humans.The innate immune mechanisms by which adjuvants enhance the potency and protection of vaccine-induced adaptive immunity are largely unknown. We introduce a model to delineate the steps of how adjuvant-driven innate immune activation leads to priming of vaccine responses using rhesus macaques. Fluorescently labeled HIV-1 envelope glycoprotein (Env) was administered together with the conventional aluminum salt (alum) adjuvant. This was compared to Env given with alum with preabsorbed Toll-like receptor 7 (TLR7) ligand (alum-TLR7) or the emulsion MF59 because they show superiority over alum for qualitatively and quantitatively improved vaccine responses. All adjuvants induced rapid and robust immune cell infiltration to the injection site in the muscle. This resulted in substantial uptake of Env by neutrophils, monocytes, and myeloid and plasmacytoid dendritic cells (DCs) and migration exclusively to the vaccine-draining lymph nodes (LNs). Although less proficient than monocytes and DCs, neutrophils were capable of presenting Env to memory CD4+ T cells. MF59 and alum-TLR7 showed more pronounced cell activation and overall higher numbers of Env+ cells compared to alum. This resulted in priming of higher numbers of Env-specific CD4+ T cells in the vaccine-draining LNs, which directly correlated with increased T follicular helper cell differentiation and germinal center formation. Thus, strong innate immune activation promoting efficient vaccine antigen delivery to infiltrating antigen-presenting cells in draining LNs is an important mechanism by which superior adjuvants enhance vaccine responses.