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)).