The Importance and Challenges of Identifying SARS-CoV-2 Reinfections

Abstract

Reports of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection have raised important questions about the strength and durability of the immune response to primary infection, which are key factors in predicting the course of the pandemic. Identifying reinfection requires detecting the virus at two different time points and using viral genomic data to distinguish reinfection from persistent viral carriage. This process is hindered by challenges of logistics and capacity, such as banking samples from primary infection and performing viral genome sequencing. These challenges may help to explain why very few cases have been described to date. In addition, reinfection may be a rare phenomenon, but detailed prospective studies are needed to rigorously assess its frequency. To provide context for future investigations of SARS-CoV-2 reinfection, we review 16 cases that have been published to date or are available in preprint. Reinfection occurred across demographic spectra and in patients whose initial infections were both asymptomatic/mild and moderate/severe. For cases in which severity could be compared between episodes, half of reinfections were less severe, raising the possibility of partial immune protection. Although many patients had a positive total immunoglobulin or IgG result at the time of reinfection, very little examination of their immune response was performed. Further work is needed to elucidate the frequency, determinants, and consequences of SARS-CoV-2 reinfection. Establishing the necessary frameworks for surveillance and investigation will rely heavily on clinical laboratories and clinical investigators, and we propose several considerations to guide the medical community in identifying and characterizing SARS-CoV-2 reinfections.

Keywords: COVID-19; SARS-CoV-2; reinfection; viral immunity.

FIG 1

Centers for Diseases Control and Prevention investigation protocol for investigating suspected SARS-CoV-2 reinfection (10). Figure created using BioRender. * CDC also defined poor evidence but possible category as ≤2 nucleotide differences per month in consensus between sequences that meet quality metrics or >2 nucleotide differences per month in consensus between sequences that do not meet the quality metrics, ideally coupled with other evidence of actual infection (e.g., high viral titers in each sample or positive for subgenomic mRNA [sgmRNA] and culture). COVID-19, coronavirus disease 2019.