Humoral correlate of protection for SARS-CoV-2 may reduce COVID-19 infection risk

In a recent study posted to the medRxiv* pre-print server, a team of researchers reviewed the published literature to find evidence for humoral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlate of protection (CoP).

Study: Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review. Image Credit: CROCOTHERY/ShutterstockStudy: Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review. Image Credit: CROCOTHERY/Shutterstock

A CoP of SARS-CoV-2, an immunological marker, could help determine the extent of protection against breakthrough or re-infection after a prior SARS-CoV-2 infection or vaccination.

Further, it could help in evaluating vaccine candidates, guide vaccination policies, and dosage intervals, and understand population-level immunity against SARS-CoV-2. 

CoPs could be classified as mechanistic CoPs (directly conferring protection), surrogate, absolute (guaranteeing definite immune protection only above a threshold CoP value), or relative (where higher levels of a biomarker correspond to more protection). A CoP may vary by endpoints, such as symptomatic infection or severe disease, or remain applicable to a specific endpoint. 

If measurable using a diagnostic test, CoPs could enable the determination of individual-level immunity and may serve several functions, such as providing vaccine trial endpoints, thereby leading to a pathway to licensure for new vaccines. At the population level, a CoP may enhance the utility of serosurveys by enabling the assessment of the level of protection within a community.

Although currently, it is uncertain whether a CoP for SARS-CoV-2 exists, in its absence, serological testing can confirm previous infection or vaccination, but not immunity. 

To date, most of the defined CoPs are humoral and used in a surrogate manner because it is easier to detect antibodies in clinical laboratory settings than as components of cellular immunity.

Despite the challenges, more SARS-CoV-2 CoPs must be searched and discovered to inform public health policy, especially as there is a possibility that variants of concern (VOC)-specific CoP also exist. 

About the study

In the present study, the researchers extensively searched OVID MEDLINE, EMBASE, Global Health, Biosis Previews, and Scopus and pre-prints from inception to January 4, 2022, and December 31, 2021, respectively.

The present study included 25 studies, written either in English or French, describing SARS-CoV-2 re-infection or breakthrough infections with the presence of robust antibody levels to evaluate humoral immune protection. As the immune responses following natural SARS-CoV-2 infection and vaccination may differ, the researchers analyzed studies examining each of these phenomena separately.

The authors extracted study data, curated and synthesized it, stratifying the included studies by whether they described re-infection or breakthrough infection, and explored the possibility of meta-analysis. 

For quality assessment of each study, they used study quality assessment tools and used the cohort and cross-sectional tool to evaluate studies correlating vaccine effectiveness (VE) to antibody levels.

Study findings

The study utilized diverse data, including data of several vaccines, a multitude of assays, VE endpoints, and populations. The observed robust correlations between antibody levels and VE despite data heterogeneity supported the concept of an anti-spike (S) antibody or neutralizing antibody CoP. 

Several included studies explored differences in geometric mean titers (GMTs) between cases and non-cases or associations between antibody levels and viral load with infection incidence or risk, found significant differences and associations further supporting an antibody target as a potential correlate.

A substantial proportion of VE was not explained by antibody levels, suggesting that anti-S or neutralizing antibodies are only one component of immune protection, and cellular immunity or non-neutralizing antibodies may also play a role in immune protection. 

Similar observations have been reported from SARS-CoV-2 vaccine trial data, where vaccinated individuals who have received only one dose are well-protected despite having low levels of neutralizing antibodies.

Overall, the analyses indicated that while a humoral SARS-CoV-2 CoP may exist, it may be relative, thereby reducing the risk of infection but not eliminating it. 

The study findings were also consistent with real-world observations where SARS-CoV-2 breakthrough cases are often mild or asymptomatic, suggesting that while this immunity may not be adequate to prevent infection, it was enough to avert COVID-19 severity.

Furthermore, the analysis showed that the CoP following vaccination may differ by vaccine product as mRNA vaccines produce high antibody levels while viral vector vaccines confer robust cellular immunity. 


To summarize, these findings emphasize that further research into the role of humoral immunity, including non-neutralizing antibody, Fc effector functions, and cellular and mucosal immunity is a priority, especially in the context of immune-evading variants like Omicron. 

The effect of SARS-CoV-2 lineage, vaccine product, and the endpoint being measured (i.e. infection, symptomatic disease, severe disease) on the CoP also appear to play a critical role in the context of CoP. 

Currently, 40.5% of the global population is unvaccinated against SARS-CoV-2, and the need to approve more COVID-19 vaccines is urgent to raise global vaccine coverage. Placebo-controlled clinical trials have become difficult to perform, and even a temporary and less effective CoP would allow to break through this bottleneck and start non-inferiority studies to license new COVID-19 vaccine products.

Although these findings suggest that humoral immunity is an integral part of protection against SARS-CoV-2 and that an antibody target is the most likely immune marker for a SARS-CoV-2 CoP, tools to interpret serology with regards to immune protection is currently unavailable. 

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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