COVID-19: Does the infectious inoculum dose-response relationship contribute to understanding heterogeneity in disease severity and transmission dynamics?

Abstract

The variation in the speed and intensity of SARS-CoV-2 transmission and severity of the resulting COVID-19 disease are still imperfectly understood. We postulate a dose-response relationship in COVID-19, and that "the dose of virus in the initial inoculum" is an important missing link in understanding several incompletely explained observations in COVID-19 as a factor in transmission dynamics and severity of disease. We hypothesize that: (1) Viral dose in inoculum is related to severity of disease, (2) Severity of disease is related to transmission potential, and (3) In certain contexts, chains of severe cases can build up to severe local outbreaks, and large-scale intensive epidemics. Considerable evidence from other infectious diseases substantiates this hypothesis and recent evidence from COVID-19 points in the same direction. We suggest research avenues to validate the hypothesis. If proven, our hypothesis could strengthen the scientific basis for deciding priority containment measures in various contexts in particular the importance of avoiding super-spreading events and the benefits of mass masking.

Keywords: COVID-19; Initial infectious inoculum; Public health; SARS-CoV-2; Viral dose.

Fig. 1

The role of the dose of the initial viral inoculum on the immune system leading to mild/severe disease (based on immune responses observed in mild versus severe COVID-19) [Adapted from Ref. [42]]. Top panel: Low dose of the SARS-CoV-2 initial inoculum elicits an early innate immune response (INF pathway; elevated cytokines/chemokines; limited pro-inflammatory response) and normal adaptive/cellular response leading to early clearance of the virus with a limited spectrum of COVID-19 and mild disease. Bottom panel: High dose of the SARS-CoV-2 initial inoculum delays or blocks innate immune response (limited INF pathway; highly elevated cytokines/chemokines; elevated pro-inflammatory response leading to “cytokine storms”) and decreased or exhausted adaptive/cellular response leading to viral evasion of the immune system with increased spectrum of COVID-19 and severe disease.