Preprint Influence of Prior SARS-CoV-2 Infection on COVID-19 Severity: Evidence from the National COVID Cohort Collaborative, 2023, Hendrix et al

Influence of Prior SARS-CoV-2 Infection on COVID-19 Severity: Evidence from the National COVID Cohort Collaborative


Background As SARS-CoV-2 has transitioned from a pandemic to endemic disease, the majority of new infections have been among previously infected individuals. To manage the risks and benefits of ongoing COVID-19 policies, it is important to understand whether prior infection modifies the severity of subsequent infections.

Methods We used data from first and second COVID-19 episodes in the National COVID Cohort Collaborative (N3C), a collection of health systems who provide de-identified electronic health records for research purposes. Our analysis was a sequential series of nested trial emulations. In the first of two analytic stages, we created a month-specific model of the probability of prior infection for each individual. In the second stage, we used an ordinal logistic regression with inverse probability weights calculated in the first stage to simulate a series of monthly trials comparing severity between the cohorts of first and second infections. In addition to cohort-wide effect estimates, we also conducted analyses among race/ethnicity, sex, and age subgroups.

Results From an initial cohort of 7,446,481 combined first and second infections, we identified a cohort of 2,227,484 infections, among which 7.6% were second infections. Ninety-four percent of patients with two recorded infections experienced mild disease for both. The overall odds ratio (OR) for more severe disease with prior infection was 1.06 (95% confidence interval [CI]: 1.03 – 1.10). Monthly point estimates of the OR ranged from 0.56 (95% CI: 0.37 – 0.84) in October 2020 to 1.64 (95% CI: 1.33 – 2.00) in February 2023. In most subgroups, the effect of prior infection was significant. In 8 out of 10 subgroups, the maximum monthly OR occurred after the minimum monthly OR, suggesting that protection has waned throughout the pandemic.

Conclusion Overall, prior infection was associated with a significant slightly elevated risk of severe disease. This effect varied month to month. As the pandemic proceeded, the effect of prior infection tended to evolve from generally protective during the pre-Omicron era to unprotective during the Omicron era. This points to the need for continued strategies to avert and minimize the harms of COVID-19, rather than relying upon immunity acquired through previous infection.

Question Does prior infection with SARS-CoV-2 affect the severity of subsequent COVID-19 episodes?

Findings We observed a mild protective effect of prior infection during the early and mid-stages of the pandemic that waned after the rise of the Omicron variants, ultimately resulting in loss of protection or a tendency toward more severe second infections.

Meaning Prior infection alone is likely not enough to avert the worst public health harms of endemic SARS-CoV-2. Interventions to avoid infection and reduce the severity of COVID-19 will still be important in the post-pandemic era.

https://www.medrxiv.org/content/10.1101/2023.08.03.23293612v1