A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity

Abstract

Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV, MERS-CoV and endemic human coronaviruses (HCoVs). We reviewed 2,452 abstracts and identified 491 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While further studies of SARS-CoV-2 are necessary to determine immune responses, evidence from other coronaviruses can provide clues and guide future research.

Fig. 1. Aspects of antibody response included in this review.

This figure shows the areas of focus of our review within our conceptualization of the stages of exposure and infection at which we believe that antibody-mediated immunity may play a role in the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the individual level (a), antibody response following the first infection/exposure increases and then declines (antibody kinetics). Sometime later, individuals may be exposed to SARS-CoV-2 again. They may be protected from infection by their acquired immunity (correlates of protection). Their acquired immunity may also moderate the severity of infection with some possibility that pre-existing immunity may lead to immunopathogenesis (relevant to both first and second exposure). These individual-level dynamics aggregate to form the population-level seroprevalence. b Measures of seroprevalence may imperfectly measure past exposure to infection due to antigenic diversity of future SARS-CoV-2 viruses and cross-reactivity of endemic human coronaviruses (HCoVs) with SARS-CoV-2. c Measures of seroprevalence may also be inconsistent across times, as antibody levels within individuals wane.

Fig. 2. Distributions of times from symptom onset to detection of antibodies.

Times between symptom onset and the detection of IgM (left column), IgG (middle column), and neutralizing antibodies (right column), for MERS-CoV (upper row), SARS-CoV (middle row), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (bottom row). Dots and lines below each histogram indicate the median values and interquartile range (IQR) across all severity ratings (black), mild symptoms (blue), severe symptoms (red), and no reported severity (gray). Data were digitized from 17 studies^{,,,,–,,,,,,–}.

Fig. 3. MERS-CoV antibody kinetics.

The top row shows the data for studies reporting IgG concentration in units of optical density, while the bottom row shows the data for studies reporting neutralizing antibodies in units of titers. The columns correspond to different severity categories. Each line corresponds to time series for an individual patient. Some studies reported titers that were lower than or greater than some threshold value; those are here plotted at those values (e.g., for ≥320, the value is assumed to be 320). Some studies may report the kinetics of different antibodies or using different assays (and different units) for the same patient. Note that while these are plotted on the same axis, values may not necessarily be comparable across studies within each panel, as each lab may have different assay conditions resulting in different scales. See Supplementary Figs. 3 and 4 for (more limited) the data on SARS-CoV and IgA. Colors reflect the severity categories: not reported (gray), mild (blue), and severe (red).

Fig. 4. Antigenic and phylogenetic relationships among HCoVs.

Ordinal qualitative summary of the reactivity of antisera (rows) provided by individuals with confirmed infections with each human coronavirus against the panel of human coronaviruses (columns), shown in relation to their phylogeny. Cell color indicates the magnitude of change in the antibody response (measured by neutralization assay, IFA, and/or enzyme-linked immunosorbent assays (ELISA) or western blot to N or S proteins) between acute and convalescent samples with dark green indicating strong, homologous response, light green indicating strong, heterologous response, yellow indicating weak response, and gray indicating no response. White boxes indicate that no data are available. The black grid indicates relationships between viruses of the same genera. Note that in some cases, cross-reactivity may be due to stimulation of immunity to previous infections (e.g., SARS-CoV serological responses toward HCoV-OC43), and in other cases, to relatedness of the viruses (SARS-CoV serological responses toward MERS-CoV).

Fig. 5. Evidence supporting/contradicting SARS-CoV antibody-related pathogenesis. Supporting evidence given in red and contradicting evidence in blue.

Weaker evidence (speculation in discussions) shown in gray, evidence from in vitro studies in thin lines, and evidence observed in humans in thick lines. Anti-S1 antibodies triggered upon infection may facilitate entry into immune cells at later stages of the infection if concentration is low. Replication happens but no virus is released. Consequential induction of cytokines is inconclusive, but if they occur, they are associated with severe disease. Roles of anti-S2 and anti-N antibodies are supported by binding observations.

Fig. 6. Age-seroprevalence curves on endemic HCoV.

The color denotes the study, and the point type denotes the assay and antibody measured. The data from 134 are averaged over two serosurveys conducted in 1975 and 1976. Points are the observed proportion seropositive in each age group, while lines are predicted age-seroprevalence curves from catalytic models fit to each study and strain separately.

Fig. 7. Age-seroincidence curves under four models of coronavirus immunity.

Each curve displays the age seroincidence for a single endemic strain. The four hypothetical models of coronavirus immunity are (1) infection grants lifelong, complete homologous immunity (red), (2) infection grants complete homologous immunity for 5 years, then reversion to complete susceptibility (green), (3) infection grants lifelong homologous immunity at 50% efficacy (cyan), and (4) the strain consists of four antigenically diverse genotypes, each granting complete homologous immunity within genotype, but no cross-protection between genotypes (blue). Confidence bands represent uncertainty in the force of infection as estimated from the seroprevalence data.