Introduction
The COVID-19 pandemic, caused by severe acute respiratory coronavirus 2
(SARS-CoV-2) led to unprecedented, accelerated vaccine development (1)
and expansive roll-out programs (2,3). Much of the global population now
has some level of adaptive immunity to SARS-CoV-2 induced by exposure to
the virus (natural infection), vaccination, or a combination of both
(hybrid immunity).
Natural infection induced by, and/or vaccination against, SARS-CoV-2
leads to the development of both binding and neutralizing antibodies
(nAbs) (4,5), and the induction of T-cell responses during active immune
reaction and clearance of infection (6). Key questions that subsequently
arise relate to the duration and the level of protection an individual
might expect based on their infection and vaccination history. Studies
of those infected early in the pandemic documented that natural
SARS-CoV-2 infection afforded some level of protection against
reinfection in most individuals, and that subsequent reinfections were
typically less severe than the primary episode (Table 1 ).
However, SARS-CoV-2 has high rates of mutation and heavily mutated
variants have emerged (7). Most significant are the ‘variants of
concern’ (VOCs) (8), and there is now ample evidence that protection
against reinfection with the B.1.1.529/21K (Omicron) variant (9,10) is
dramatically reduced compared with previous variants (Table 1 ).
Any descriptor of immunity based on patient history will encompass a
population of individuals with vastly variable exposure to vaccines and
viral variants with differing orders of immune challenge intensity.
Unrecognised ‘silent infections’, especially in Omicron-positive
subjects with underlying immunity, further complicate the assessment.
Therefore derivation of potential immunity based on patient history
requires assistance from a surrogate composite score to inform about
protection and to aid decision making.
Correlates of protection or
risk
In vaccinology, a correlate of protection (CoP) reflects a statistical
non-causal relationship between an immune marker and protection after
vaccination (11). Most accepted CoPs are based on antibody measurements
(12) and vary depending on the clinical endpoint, for example protection
from (symptomatic) infection or severe disease. In contrast, a correlate
of risk (CoR) can be used as a measurement of an immunologic parameter
that is correlated with a study endpoint (13) and can predict a clinical
endpoint in a specified population with a defined future timeframe.
Notably, antibody markers have been used as correlates of immune
function in clinical trials of SARS-CoV-2 vaccine efficacy (14-19), and
for identifying the risk of symptomatic infection by VOCs (20,21).
A CoR would likely comprise a measure of the immune component plus
determinants that act to modify such a measure (a multi-component
composite CoR). In general, the immune component of a composite CoR
should be easily measured by widely available technologies that are
amenable to automation, are scalable, cost-efficient, and have a rapid
turn-around time. Given the relative complexity, cost and pre-analytic
requirements for cellular immune response testing, the preferred
candidate for the immune component of a CoR would be detection of
humoral immune response(s) (i.e. antibody). This perspective evaluates
the various elements that need to be accommodated in the development of
an antibody-based composite CoR for reinfection with SARS-CoV-2 or
severe COVID-19.