A composite CoR: A brief summary of extrinsic viral and
intrinsic host elements that should be
considered
Variation in exposure dose and transmission
route
Viral load varies widely between infected individuals and over time
(22), with viral emissions independent of symptom severity (23).
Exposure to SARS-CoV-2 is tempered by the use of personal protective
measures and, at the population level, adherence to public health
measures that reduce exposure has been variable (24,25), making
assessment of exposure dose complex.
Controlled human infections to directly study the impact of viral
inoculum and disease severity are controversial (26), and only one human
challenge trial of SARS-CoV-2 using a single low inoculum dose has been
reported to date (27). However, the initial infective dose of SARS-CoV-2
is thought to be associated with disease severity (28-30), since
relationships between dose and severity exist for many other viral
infections (30). Evidence from SARS-CoV-2 animal models suggests that
the route of transmission similarly affects disease severity (30,31).
Viral genetic variation
Risk reduction depends on the dominant variant in circulation. Continued
evolution of SARS-CoV-2 can lead to significant changes in viral
transmission and impact reinfection rates (32). Mechanistically, the
receptor binding domain (RBD) within the viral spike (S) glycoprotein
engages in initiation of infection via interaction with the angiotensin
converting enzyme-2 (ACE2) receptor (33). The RBD is a target for many
nAbs (33) and mutations are frequently located at the RBD–ACE2
interface (34). It is therefore not surprising that changes to the viral
epitope can reduce antibody binding (34), helping to drive immune escape
from anti-RBD nAbs (35), decreasing previously generated protective
immunity (36-38), and leading to variant-specific risks of severe
illness (39,40).
Patient factors
Patient differences impact susceptibility to reinfection and disease
severity. The immune response declines with increasing age (41,42), and
age is the strongest predictor of SARS-CoV-2 infection–fatality ratio
(43). Older individuals have been shown to exhibit reduced binding
antibody titers and neutralization following vaccination (44-46).
Pregnant women are also at high risk of severe outcomes (47). Similarly,
immunocompromised or immunosuppressed individuals exhibit reduced immune
responses to infection or an increased risk of hospitalization (48-51).
Other co-morbidities are frequently observed in those with severe
COVID-19 (52).
Vaccination status
COVID-19 vaccines include recombinant subunit, nucleic acid, viral
vector and whole virus vaccines, amongst others, and some vaccines have
been adapted for Omicron variants (53). The use of different vaccines,
combinations, the number of boosters received, the occurrence of natural
infection, and combinations thereof, trigger the immune system to
varying degrees in depth, breadth or duration of response (21,54-66).
Following primary infection, severely ill patients exhibit higher
binding and neutralizing antibody titers or activity compared with
individuals with mild disease (67-72). Persistence of nAbs has also been
associated with disease severity (73). In the event of reinfection,
there is an implicit assumption that nAb titers ameliorate severe
COVID-19 (74,75). In brief, in infection-naïve individuals,
post-vaccination antibody titers (anti-S IgG and nAbs) correlate with
higher vaccine efficacy (55), and post-vaccination anti-RBD IgG and nAbs
levels associate with protection against infection and symptomatic
disease even during the Omicron era (76) or inversely correlate with
risk of death (anti-S IgG below 20th percentile) (77).
Generally, individuals with higher nAbs (levels or capacity) are
considered increasingly protected from infection (78-80), symptomatic
reinfection (80-82), severe disease (81), or death (83) compared with
individuals with lower nAbs. There is evidence that neutralization
capacity can be strain specific (84).
Summary
In summary, viral and host elements modify the risk of reinfection or
development of severe COVID-19. Although not described above, other
relevant factors include whether an individual previously received
monoclonal antibodies (85) (but potentially not antiviral medication
(86)), genetic predisposition (87-91), and socioeconomic, air pollution,
co-infection, microbiota, and frailty factors (reviewed in detail (31)).