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

Abstract

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.

Antibody Fab‐Fc properties outperform titer in predictive models of SIV vaccine‐induced protection

“…We next sought to evaluate the generality of the observation that humoral response quality, beyond magnitude alone, is important in analyzing protection. Recently, Fc Array and functional measurements were collected for animals in a distinct SIV vaccine study (employing a DNA prime‐Ad5 boost vaccine regimen), and the analysis pointed to strikingly different antibody properties and correlates of protection associated with different routes of vaccination (Ackerman et al , ). In that study, animals vaccinated with a SIVmac239 Env immunogen (administered either intramuscularly or mucosally) exhibited significantly better protection against infection compared to those vaccinated with a mosaic Env immunogen.…”

“…Here, protection was modeled with a multi‐dimensional, multi‐group CoxPH survival model, combining animals from all adjuvant groups and employing aggressive feature filtering, to incorporate only a small number of features. The use of a Cox modeling approach follows that used in recent studies (Bradley et al , ; Ackerman et al , ), so as to avoid having to discretize protection levels (Chung et al , ; Vaccari et al , ). We found that to avoid overfitting, it was necessary to perform feature pre‐filtering and employ greedy feature elimination methods to narrow down the number of features used by the Cox model (Frejno et al , ); regularization techniques (Simon et al , ) displayed substantially poorer performance, resulting in empty models (i.e., with no features selected), likely due to the semi‐parametric formulation of the Cox PH model and the small sample size of the study.…”

“…Similarly, a study of three different Ebola vaccines revealed that while they induced similar levels of anti‐Ebola antibodies, only one yielded a substantially better response providing total protection (Blaney et al , ). Additionally, a recent SIV vaccine study identified a number of specific antibody qualities that were associated with protection whereas IgG response magnitudes were not (Ackerman et al , ). Antibody quality has been frequently characterized in terms of neutralization potency and breadth (Mascola & Haynes, ; Hraber et al , ), as well as specificity to particular epitopes (Wrammert et al , ; Klein et al , ; Zolla‐Pazner et al , ; Frei et al , ; Ha et al , ).…”

“…In order to enable “systems serology” studies (Chung et al , ; Ackerman et al , ), we have recently developed a platform, the “Fc Array”, to comprehensively dissect antibody profiles of serum samples (Brown et al , , ). By characterizing antibodies in terms of simultaneous Fab and Fc properties (i.e., both antigen specificity as well as subclass and ability to bind complement and different FcγR receptors), the Fc Array has provided a refined characterization of immune responses in a variety of vaccination and natural infection studies (Lai et al , ; Choi et al , ; Ackerman et al , , ; Vaccari et al , ; Bradley et al , ).…”

Optimized Mucosal MVA Prime/ Soluble gp120 Boost Vaccination Regimen Induces Similar Antibody Responses as an Intramuscular Regimen

“…For example, passive transfer of the combination of a systemically administered anti-HIV IgG1 and a mucosally administered anti-HIV dimeric IgA2 provided complete protection against a high-dose rectal SHIV challenge while transfer of the anti-HIV IgG1 alone was not protective (5), suggesting that the combination of systemic and mucosal anti-HIV IgG and IgA, respectively, may be required for maximum protection. Another recent study demonstrated that systemic (intramuscular) and mucosal (aerosol) immunization with the same vaccine induced equivalent levels of protection against SIV challenge(6). However, evaluation of vaccine-induced immune responses determined that protection induced by intramuscular immunization was associated with serum IgG-mediated immune responses while protection induced by aerosol immunization was associated with serum IgA-mediated immune responses(6) Therefore, optimizing both systemic and mucosal immunization regimens may be required to provide consistent protection against mucosal HIV transmission(7).…”