Route of immunization defines multiple mechanisms of vaccine-mediated protection against SIV

Antibodies are the primary correlate of protection for most licensed vaccines; however, their mechanisms of protection vary, ranging from physical blockade to clearance via the recruitment of innate immunity. Here, we uncover striking functional diversity in vaccine-induced antibodies associated with reduced risk of SIV infection in nonhuman primates. While equivalent levels of protection were observed following intramuscular (IM) and aerosol (AE) immunization, reduced risk of infection was associated IgG-driven antibody-dependent monocyte-mediated phagocytosis in the IM vaccinees, and via vaccine-elicited IgA-driven neutrophil-mediated phagocytosis in AE immunized animals. Thus while route independent correlates indicate a critical role for phagocytic Fc-effector activity in protection from SIV, the site of immunization may drive this Fc-activity via distinct innate effector cells and antibody isotypes. These data identify orthogonal functional humoral mechanisms, initiated by distinct vaccination routes, pointing to critical correlates of immunity that may support the rational design of a protective vaccine against HIV.Bill & Melinda Gates Foundation (OPP1032817)Bill & Melinda Gates Foundation (OPP1114729)National Institutes of Health (U.S.) (R37 AI080289)National Institutes of Health (U.S.) (R01 AI102291)National Institutes of Health (U.S.) (P01 AI120756)National Institutes of Health (U.S.) (R01 AI131975)National Institutes of Health (U.S.) (R01 AI102660