Defining the determinants of protection against SARS-CoV-2 infection and viral control in a dose-down Ad26.CoV2.S vaccine study in nonhuman primates

Abstract

Despite the rapid creation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines, the precise correlates of immunity against severe Coronavirus Disease 2019 (COVID-19) are still unknown. Neutralizing antibodies represent a robust surrogate of protection in early Phase III studies, but vaccines provide protection prior to the evolution of neutralization, vaccines provide protection against variants that evade neutralization, and vaccines continue to provide protection against disease severity in the setting of waning neutralizing titers. Thus, in this study, using an Ad26.CoV2.S dose-down approach in nonhuman primates (NHPs), the role of neutralization, Fc effector function, and T-cell immunity were collectively probed against infection as well as against viral control. While dosing-down minimally impacted neutralizing and binding antibody titers, Fc receptor binding and functional antibody levels were induced in a highly dose-dependent manner. Neutralizing antibody and Fc receptor binding titers, but minimally T cells, were linked to the prevention of transmission. Conversely, Fc receptor binding/function and T cells were linked to antiviral control, with a minimal role for neutralization. These data point to dichotomous roles of neutralization and T-cell function in protection against transmission and disease severity and a continuous role for Fc effector function as a correlate of immunity key to halting and controlling SARS-CoV-2 and emerging variants.

SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines

“…The identification of the RBD as the sole target of vaccine-elicited polyclonal antibodies broadly neutralizing SARS-CoV-2 variants is reminiscent of recent reports describing broadly neutralizing sarbecovirus monoclonal antibodies isolated from infected individuals (14 -16, 18, 20, 76-78, 93) and the rapid accumulations of mutations in the NTD (25,66,67,73,75). Although cross-variant plasma neutralization is determined by RBD-directed antibodies, we note that Fc-mediated effector functions, including antibody-dependent phagocytosis, cellular cytotoxicity, and complement activation, can play key roles for in vivo protection in addition to direct viral neutralization (94)(95)(96)(97)(98)(99). These findings motivate the clinical development of RBD-based vaccines against SARS-CoV-2 (37,(100)(101)(102)(103)(104) and sarbecoviruses (105)(106)(107)(108) for future pandemic preparedness.…”

Class switch toward noninflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination

“…Once infection is established, Fc-mediated effector functions become more relevant to clear viral infections. Systemic serology approaches have even revealed that different antibody functions can contribute to various degrees to protection dependent on the viral pathogen, as shown for influenza viruses, RSV, or SARS-CoV-2 (36)(37)(38)(39). Passive immunization studies in animal models have further demonstrated that the degree of protection achieved by the application of mAbs depends on their IgG subclass (40)(41)(42)(43).…”

Fcγ receptor-dependent antibody effector functions are required for vaccine protection against infection by antigenic variants of SARS-CoV-2

“…Although neutralizing activity of antibodies is a correlate of vaccine-mediated protection 4 , the ability of monovalent COVID-19 vaccines to protect against Omicron disease in the setting of waning serum antibody neutralization suggests additional protective immune mechanisms. These include anamnestic B cell responses that rapidly generate cross-reactive neutralizing antibodies, cross-reactive T cells responses, and/or non-neutralizing, cross-reactive antibodies that promote Fc mediated effector activities 6,16,18,38,39 . In our experiments, we focused on evaluating Fc mediated effector functions as a possible mechanism of vaccine-mediated protection against antigenic variants.…”

“…Despite the loss in serum neutralizing activity against variants such as those in Omicron lineage, most individuals remain protected against severe disease and death. The basis for this protection has not been fully determined but could be due to beneficial effects of non-neutralizing antibodies, cross-reactive T cell responses, or anamnestic memory B cell responses 6,[15][16][17][18] .…”