Discussion

A composite CoR would be helpful particularly for high-risk groups, such as solid organ transplant recipients (136), and those in occupations with high risk of exposure to SARS-CoV-2. However, whether a composite CoR would operate at the individual or population level is yet uncertain.
For health policymakers, a composite CoR could be useful for: 1) predicting the durability of protection, supporting serosurveys to determine the protection levels of individuals and populations; 2) aiding decision-making with regard to monitoring vaccination efficacy and identifying individuals who would benefit from booster vaccinations; 3) evaluating the need for extra protection of vulnerable communities in the face of new variants with low cross protection and less efficacious vaccines; 4) licensing new vaccines; and 5) developing clear immunologic vaccine trial endpoints.
A previous systematic review by Perry and colleagues found mixed evidence for a serologic CoP, with the lack of standardization between laboratory methodology, differing assay targets and sampling time points, and the lack of information on the SARS-CoV-2 variant confounding interpretation (137). We have highlighted various parameters that should be controlled for in any measure of risk, some of which will be challenging to obtain (such as host genetics). Comparing different protection studies is also difficult as infectious pressure in the observation time period is often uncertain as, in reality, community data are incomplete and the number of oligosymptomatic infections is unclear. Of course, individual responses to infection and vaccination with regards to antibody production will make long-term assessment difficult, intrinsic risk will vary by age and protection will not be linear (122,138). All the variables previously described need to be thought of in the general context of laboratory diagnostics, paying attention to sensitivity, specificity, reliability, precision, dilution, linearity, robustness, stability, preanalytics, scalability (automation), cost-efficiency, In Vitro Diagnostic Regulation certification, and the use of qualified standard and control materials. Laboratory quality is essential for meaningful follow-up of quantitative antibody levels.
Whilst the development of a composite CoR is a sizeable task, steps can be taken to address this need. Studies need to adapt to the requirements of new variants, controlling for patient settings (vaccination types, earlier infections), and levels of disease severity. The emergence of VOCs means that a CoR will undoubtedly be variant-specific and the timing of infections and vaccination, how variants impact disease severity, antibody kinetics, and assay reactivity, must be respected. Frequently revisiting the data would be helpful as overall epidemiology changes; since almost all epidemiologic population-based studies have ended, background data is increasingly difficult to acquire, and this must be reversed. Whilst serologic testing has retreated from the political agenda and public interest, there is still an obligation to broaden the scientific knowledge base, and collect data to inform public health authorities, given that COVID-19 still causes a significant number of deaths and there is a considerable population of those with post-acute sequelae of SARS-CoV-2 infection (long COVID; (139)).
A composite CoR will differ depending on the clinical endpoint (12). Definitions of symptomatic or severe disease are often not consistent across studies (81). Clinical outcomes must be precisely defined: an evaluation of the primary endpoints of 19 clinical trials for severe COVID-19 revealed the complexity of this task, reporting 12 different primary endpoints (140). In addition, the ideal timeframe for predictive ability is yet to be determined.
Whilst we support the development of a composite CoR and serologic testing by high- quality controlled assays, viruses such as influenza have significant strain variation and similar disease severity, so the importance of a composite CoR for SARS-CoV-2 should be judged against other pathogens of interest. Assessment of cost-effectiveness will likely inform upon the need for a composite CoR.