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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 may vary, ranging from physical blockade to clearance via the recruitment of innate immunity. Here, we uncover striking functional diversity in vaccine-induced antibodies that is driven by immunization site and is associated with reduced risk of SIV infection in nonhuman primates. While equivalent levels of protection were observed following intramuscular (IM) and aerosol (AE) immunization with an otherwise identical DNA prime–Ad5 boost regimen, reduced risk of infection was associated with IgG-driven antibody-dependent monocyte-mediated phagocytosis in the IM vaccinees, but with vaccine-elicited IgA-driven neutrophil-mediated phagocytosis in AE-immunized animals. Thus, although 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. Moreover, the same correlates predicted protection from SHIV infection in a second nonhuman primate vaccine trial using a disparate IM canarypox prime–protein boost strategy, analogous to that used in the first moderately protective human HIV vaccine trial. These data identify orthogonal functional humoral mechanisms, initiated by distinct vaccination routes and immunization strategies, pointing to multiple, potentially complementary correlates of immunity that may support the rational design of a protective vaccine against HIV.

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We would like to thank W. E. Johnson (Boston University) for his help with statistical review. These studies were supported by the Bill and Melinda Gates Foundation (OPP1032817 and OPP1114729) and the National Institutes of Health (R37 AI080289, R01 AI102291, P01 AI120756, R01 AI131975, and R01 AI102660).

Author information

M.E.A., M.R. and G.A. conceived of and designed the study. M.E.A., G.D.T., B.F.H., D.A.L., C.B.-K., M.R. and G.A. supervised experimental and statistical analysis. J.D. and S.P. performed data analysis. T. Broge, C.L., E.P.B., T. Bradley, H.N., S.L., J.K.S., S.O.K., N.M., D.G., and M.S. performed assays. T.J.S. and J.A.W. aggregated data. M.E.A., J.D., S.P. and G.A. wrote the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Margaret E. Ackerman or Galit Alter.

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Fig. 1: There is equivalent protection from SIV acquisition in SIVmac239-immunized animals despite striking Fc-profile differences induced via distinct routes of immunization.
Fig. 2: Fc-biophysical antibody binding profiles accurately predict protection across immunogens and routes of administration.
Fig. 3: Phagocytic vaccine–specific functional antibodies predict protection from infection.
Fig. 4: Dissecting mechanisms of arm-specific protection.
Fig. 5: DNA–rAd5 minimal biomarkers of vaccine response also predict protection in ALVAC/protein-immunized NHPs.