Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review

Abstract

Background: A correlate of protection (CoP) is an immunological marker associated with protection against infection. A CoP can be used to determine whether an individual is protected from infection, evaluate candidate vaccines, guide vaccination dosing intervals and policy, and understand population-level immunity against a pathogen. Despite an urgent need, a CoP for SARS-CoV-2 is currently undefined, leaving an evidence gap for informing public health policy and adapting it appropriately as new variants of concern emerge. The objective of this study was to systematically review and assess the evidence for a humoral SARS-CoV-2 CoP. Methods and Findings: We searched OVID MEDLINE, EMBASE, Global Health, Biosis Previews and Scopus from inception to January 4, 2022 and pre-prints (using NIH iSearch COVID-19 portfolio) from inception to December 31, 2021, for studies describing SARS-CoV-2 re-infection or breakthrough infection with associated antibody measures. Two reviewers independently extracted study data and performed quality assessment. Twenty-five studies were included in our systematic review. Several studies reported re-infection or breakthrough cases that occurred in the presence of robust antibody levels. Studies that compared aggregate antibody concentrations from individuals who experienced re-infection or breakthrough compared to those who remained protected did not always find differences that were statistically significant. However, several studies found an inverse relationship between antibody levels and infection incidence, risk, or viral load, and a correlation between antibody levels and vaccine efficacy (VE). Estimates of the contribution of antibody levels to VE varied from 48.5% to 94.2%, suggesting that both humoral immunity and other immune components contribute to protection. Only two studies estimated a quantitative CoP. For Ancestral SARS-CoV-2, these included 154 (95% confidence interval (CI) 42, 559) anti-S binding antibody units/mL (BAU/mL), and 28.6% (95% CI 19.2, 29.2%) of the mean convalescent antibody level following infection. One study reported a CoP for the Alpha (B.1.1.7) variant of concern of 171 (95% CI 57, 519) BAU/mL. As of our search date, no studies reported an Omicron-specific CoP. Conclusions: The reviewed literature was limited by a wide variation in assay methodology and antibody targets. Few studies reported SARS-CoV-2 lineage. The studies included in our review suggest that if it exists, a SARS-CoV-2 CoP is likely relative, where higher antibody levels decrease the risk of infection, but do not eliminate it completely. More work is urgently needed in this area to establish a SARS-CoV-2 CoP and guide policy as the pandemic continues.

Immune response to SARS-CoV-2 after a booster of mRNA-1273: an open-label phase 2 trial

“…Although the optimal timing of a third dose has not been established, the data from this trial provide important information to address the potential need for a third booster dose in the event of waning vaccine effectiveness. Although nAb responses have been correlated to vaccine effectiveness, a correlate of protection has not been defined for Omicron or other variants [47][48][49][50] . Also, this study did not examine variant-specific booster vaccines or immune responses to variants of concern other than for Delta.…”

U.S. CDC support to international SARS-CoV-2 seroprevalence surveys, May 2020–February 2022

“…However, most serosurveys underway are using qualitative assays to assess circulating antibodies. Cellular immunity, which is generally more durable and likely to be integral to CoP, is generally not assessed in these surveys due to technical and cost challenges [35,41]. CDC technical assistance and financial support of SARS-CoV-2 international seroprevalence surveys contribute to strengthening local capacity to conduct epidemiologic surveillance and enhance the knowledge of the COVID-19 pandemic in almost three dozen LMI countries.…”

“…However, most serosurveys underway are using qualitative assays to assess circulating antibodies. Cellular immunity, which is generally more durable and likely to be integral to CoP, is generally not assessed in these surveys due to technical and cost challenges [35, 41].…”

“…Finally, the question of correlates of protection (CoP) for SARS-CoV2 is not resolved. Several studies have documented an inverse relationship between neutralizing antibody levels and incidence of infection, and a correlation between these antibody levels and vaccine efficacy suggests a possible relative CoP against infection that is likely defined by quantitative thresholds [35,[41][42][43][44]. However, most serosurveys underway are using qualitative assays to assess circulating antibodies.…”

Decline in antibody responses to SARS-CoV-2 post-vaccination poses a risk to health care workers

“…Similar trends in waning antibody levels have also been observed with other COVID-19 vaccines, with rapid decline in antibody levels reported in patients with obesity, autoimmune diseases, and other chronic inflammatory conditions [13] . While antibodies are not the only indication of protection against COVID-19, the presence of antibodies does decrease the risk of infection [14] .…”