Correlates of protection against SARS-CoV-2 infection and COVID-19 disease

Abstract

Antibodies against epitopes in S1 give the most accurate CoP against infection by the SARS-CoV-2 coronavirus. Measurement of those antibodies by neutralization or binding assays both have predictive value, with binding antibody titers giving the highest statistical correlation. However, the protective functions of antibodies are multiple. Antibodies with multiple functions other than neutralization influence efficacy. The role of cellular responses can be discerned with respect to CD4⁺ T cells and their augmentation of antibodies, and with respect to CD8⁺ cells with regard to control of viral replication, particularly in the presence of insufficient antibody. More information is needed on mucosal responses.

Keywords: T cells; antibodies; correlates; fc effector; neutralization.

FIGURE 1

Correlation between antibody responses and efficacy rate for 7 COVID‐19 vaccines. Panels A and B display correlations of antibody responses for neutralization and ELISA assay ratios, respectively, normalized to HCS panel titers from the same assay. Dot size corresponds to the number of cases reported for Phase III efficacy analyses. The y‐axis is estimated log risk ratio reported on the vaccine efficacy scale. The x‐axis is ratio of the peak geometric mean neutralization titer or ELISA titer at 7‐28 days post‐vaccination, relative to HCS. Error bars indicate 95% confidence Intervals (except for Oxford/AZ antibody responses, which represent ratios of median titers with interquartile ranges) with dashed line showing non‐parametric LOESS fit. A rank correlation value was calculated with R2 in a linear model utilized for variance explanation. Reprinted from Vaccine Volume 39, Earle KA, Ambrosino DM, Fiore‐Gartland A, et al. Evidence for Antibody as a protective correlate for COVID‐19 vaccines, 4423‐4428, 2021

FIGURE 2

Correlation of spike IgG binding antibody measured on the same platform with vaccine efficacy for wild‐type, alpha and delta variants. Vaccine efficacy/effectiveness (VE) and SARS‐CoV‐2 spike binding IgG GMC, against original (WT), alpha and delta variants. Superscript 1 or 2 indicates the number of doses for the vaccine regimen. The y‐axis is estimated log risk‐ratio reported on the vaccine efficacy scale. The x‐axis is the geometric mean concentration (GMC) of spike‐specific IgG antibody binding measured by MSD and calibrated to the WHO standard (binding antibody units per mL). Error bars indicate 95% confidence intervals for either the GMC IgG level (x‐axis) or VE (y‐axis). Weighted least‐squares linear regression fit using inverse variance weighting on VE estimates (dashed line black for WT, dashed line blue for alpha variant). Rank correlation coefficient, variance explained by the model, and mean squared error (MSE) are indicated for the WT, and alpha variant models. Reprinted from Vaccine Volume 40, Goldblatt D, Fiore‐Gartland A, Johnson M, et al., Towards A Population‐Based Threshold of Protection for COVID‐19 Vaccines, 306‐315, 2022

FIGURE 3

Layered defenses against SARS‐CoV‐2, or the “Swiss cheese” model of immunity. Multiple types of adaptive immunity with diverse mechanisms and locations likely provide layers of defense against COVID‐19. Conceptually, layered defenses are like a “Swiss cheese model”: even though each layer is imperfect, all together they make it highly unlikely that the pathogen breaches all of the layers of defense. Graphic inspired by the masking and public health layered defenses Swiss cheese model of Ian M. Mackay

FIGURE 4

Gradations of protective immunity. “Protection” can be defined many ways and can be categorized based on COVID‐19 disease severity. Sterilizing immunity can only be provided by antibodies at the portal of entry. Prevention of detectable infection (e.g., a positive test) can be accomplishing by neutralizing antibodies and possibly tissue‐resident T cells. Prevention of hospitalization‐level COVID‐19 or fatal COVID‐19 can likely be accomplished by multiple branches of adaptive immunity acting together over time

FIGURE 5

Antibody anatomy. Antibody molecules can be divided into 2 functional domains: Domain #1—composed of 2 antigen‐binding domains that contribute to antigen specificity and drive neutralization and Domain #2—consisting of a single constant domain that provides instructions to the immune system for elimination of antibody‐opsonized material

FIGURE 6

Antibody mechanisms of action. The cartoon depicts that potential contribution of Fab versus Fc mediated antibody functions at different antibody titers. Where neutralization alone may be sufficient to block transmission at peak titers (left). However, as titers wane, or variants evade large fractions of antibodies, the ability of antibodies to leverage immune effector functions may be vital to protection from disease

FIGURE 7

Relevance of antibody effector functions throughout the SARS‐CoV‐2 viral life cycle. The cartoon depicts the interactions of the virus with the host cell, and the moments when the spike antigen may be visible to circulating antibodies. As the virus roles across the cell surface and may be targetable by many effector mechanisms including those driven by phagocytic cells and natural killer (NK) cells (left). However, once binding to ACE2 has occurred, the virus is rapidly endocytosed, leaving limited to no spike on the surface of cells. Moreover, new viruses assemble and release from the Golgi, leaving little to no spike on the surface at the time of egress (right). Thus, functional spike‐specific antibodies likely confer the bulk of their protective functions via the recognition and elimination of free particles prior to infection or soon after egress, providing a critical bottleneck for the virus

FIGURE 8

Impact of viral mutation on antibody recognition. The cartoon on the left depicts the restricted binding sites for neutralizing antibodies (purple), that either interfere directly with binding or fusion machinery, or may allosterically interfere with binding/fusion. Conversely, non‐neutralizing Fc‐functional antibodies (yellow) may bind to the entire surface of the spike. Yet, with the incorporation of mutations, in Variations of Concern, changes that may impede neutralizing antibody binding may disrupt a few, but only a fraction of non‐neutralizing antibodies

FIGURE 9

T cell mechanisms of action in protection against disease. CD4 T cells and CD8 T cells possess multiple mechanisms of action that are valuable in protection against viral infections