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

Nat Med. 2018 Oct;24(10):1590-1598. doi: 10.1038/s41591-018-0161-0. Epub 2018 Sep 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / immunology*
  • AIDS Vaccines / therapeutic use
  • Administration, Inhalation
  • Animals
  • Antibodies / immunology*
  • Disease Models, Animal
  • Drug Administration Routes
  • Humans
  • Immunity, Innate / genetics*
  • Immunization
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / immunology
  • Immunoglobulin G / immunology
  • Injections, Intramuscular
  • Phagocytosis / immunology
  • Primates / immunology
  • Primates / virology
  • Simian Acquired Immunodeficiency Syndrome / immunology
  • Simian Acquired Immunodeficiency Syndrome / prevention & control*
  • Simian Immunodeficiency Virus / drug effects
  • Simian Immunodeficiency Virus / immunology
  • Simian Immunodeficiency Virus / pathogenicity
  • Vaccines / administration & dosage*
  • Vaccines / adverse effects


  • AIDS Vaccines
  • Antibodies
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Vaccines