Immunological characteristics govern the transition of COVID-19 to endemicity

Abstract

We are currently faced with the question of how the severity of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may change in the years ahead. Our analysis of immunological and epidemiological data on endemic human coronaviruses (HCoVs) shows that infection-blocking immunity wanes rapidly but that disease-reducing immunity is long-lived. Our model, incorporating these components of immunity, recapitulates both the current severity of SARS-CoV-2 infection and the benign nature of HCoVs, suggesting that once the endemic phase is reached and primary exposure is in childhood, SARS-CoV-2 may be no more virulent than the common cold. We predict a different outcome for an emergent coronavirus that causes severe disease in children. These results reinforce the importance of behavioral containment during pandemic vaccine rollout, while prompting us to evaluate scenarios for continuing vaccination in the endemic phase.

Fig. 1. A low mean age of primary infection suggests that partially transmissible reinfections are common.

(A) Mean proportion seropositive for IgG (green, top lines) and IgM (purple, bottom lines) against the four endemic HCoV strains [dots connected by dashed lines; vertical lines represent the 95% confidence interval (CI); data from (10)]. The mean age of primary infection (MAPI) based on IgM data with 95% CI is shown in the inset of each panel (see SM for details). (B) MAPI as a function of waning of sterilizing immunity ω (y axis) and transmissibility of reinfections ρ (x axis). The MAPI was calculated from the equilibrium dynamics of the model shown in fig. S1 and supplementary equations 3 to 9 with a plausible basic reproductive number (R₀ = 5), 0 < ω < 2, and 0 < ρ < 1. See SM section 2.1 for details. The inset shows the plausible combinations of values of ρ and ω consistent with the MAPI for HCoVs estimated in (A). F.O.I., force of infection; I₂, reinfection. [See fig. S1 for parallel figures calculated at extreme plausible values for R₀ (i.e., R₀ = 2 and 10).]

Fig. 2. The time scale of the transition from epidemic to endemic dynamics for emerging coronaviruses depends on R₀ and the rate of immune waning.

Transition from epidemic to endemic dynamics for emerging HCoVs, simulated from an extension of the model presented in fig. S1 that includes age structure. Demographic characteristics (age distribution, birth, and age-specific death rates) are taken from the United States, and seasonality is incorporated via a sinusoidal forcing function (see SM section 2.2). Weak social distancing is approximated by R₀ = 2. (See figs. S9 to S11 for strong social distancing results, R₀ < 1.5.) (A) Daily number of new infections (black line; calculations in SM section 2.3). An initial peak is followed by a low-incidence endemic state (years 5 to 10 shown in the inset). A higher R₀ results in a larger and faster initial epidemic and a more rapid transition to endemic dynamics. The proportion of primary cases in different age groups changes over time (plotted in different colors), and the transition from epidemic to endemic dynamics results in primary cases being restricted to younger age groups. Parameters for simulations: ω = 1 and ρ = 0.7. (B) Time for the average IFR (6-month moving average) to fall to 0.001, which is the IFR associated with seasonal influenza. Gray areas represent simulations where the IFR did not reach 0.001 within 30 years. The time to IFR = 0.001 decreases as the transmissibility (R₀) increases and the duration of sterilizing immunity becomes shorter. Results are shown for ρ = 0.7. See SM section 2.3 and figs. S4 to S7 for sensitivity analyses and model specifications.

Fig. 3. The overall infection fatality ratio (IFR) of emerging coronaviruses once they reach endemicity is strongly influenced by the IFR of young children in the initial epidemic.

The age dependence of the IFR determines how the overall IFR changes during the transition from epidemic to endemic dynamics for emerging HCoVs. (A) Age dependence of the IFRs for the three emerging HCoVs. Primary infections with MERS-CoV and SARS-CoV-1 are consistently symptomatic, and the IFR and CFR are therefore assumed to be the same. SARS-CoV-1 and SARS-CoV-2 have J-shaped profiles, with a monotonic increase in IFR with age. The age-specific IFR for MERS-CoV is U-shaped, with high mortality in both the young and old age groups. Details of the statistical smoothing are described in SM section 6. (B) The overall IFR changes during the transition to endemic dynamics. These calculations assume that deaths due to reinfections are negligible. We relax this assumption to allow for a slower buildup of immunity and possible death due to secondary infection in figs. S5 to S9 and show that the qualitative results do not change.