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.