Reinfection Rates Among Patients Previously Infected by SARS-CoV-2: Systematic Review and Meta-Analysis
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has had profound global implications. Beyond its impact on human health, the pandemic has significantly affected mental health, economies, and social structures worldwide. As of June 2021, SARS-CoV-2 had caused over 174 million cases of COVID-19, leading to more than 3.7 million deaths globally. One critical aspect of the pandemic that has garnered significant attention is the possibility of reinfection with SARS-CoV-2. Understanding the incidence of reinfection and the protection conferred by prior infection is essential for guiding public health measures and vaccination strategies.
This systematic review and meta-analysis aimed to assess the incidence of SARS-CoV-2 reinfection and the protective effect of prior infection against reinfection. The study analyzed data from 19 studies involving 1096 reinfection patients, providing a comprehensive overview of reinfection rates and the factors influencing them.
Background and Significance
Reinfection with SARS-CoV-2 has been a topic of concern since the first confirmed case was reported in August 2020. This case involved a patient who exhibited 24 nucleotide differences between the viruses identified in the two infections, suggesting that reinfection could occur with a genetically distinct strain. Subsequent reports of reinfection cases worldwide have raised questions about the durability of natural immunity and the potential for viral mutations to evade immune responses.
Understanding the incidence of reinfection is crucial for several reasons. First, it helps determine the degree of protection conferred by prior infection, which is essential for guiding vaccination strategies. Second, it provides insights into the factors that may increase the risk of reinfection, such as viral mutations, waning immunity, and individual susceptibility. Finally, it informs public health measures aimed at controlling the spread of the virus, particularly in high-risk populations.
Methods
The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was conducted across multiple databases, including PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov, up to May 1, 2021. The search strategy included terms such as “coronavirus,” “COVID-19,” “reinfection,” “SARS-CoV-2,” and “severe acute respiratory.”
Inclusion criteria focused on studies reporting the number of COVID-19 reinfections that met the US Centers for Disease Control and Prevention (CDC) criteria for reinfection. These criteria defined reinfection as occurring at least 90 days after the initial positive test or at least 45 days with supporting evidence of contact with confirmed cases or the reappearance of COVID-19-like symptoms. Studies that included patients with Middle East respiratory syndrome coronavirus (MERS-CoV) or other serotypes of SARS-CoV were excluded, as were reviews, commentaries, case reports, case series, and non-human studies.
Data extraction and quality assessment were performed independently by two reviewers, with disagreements resolved through consensus involving a third reviewer. The extracted data included study characteristics, patient demographics, reinfection rates, and clinical outcomes. The quality of the included studies was assessed using the Newcastle-Ottawa Scale for cohort studies and the Joanna Briggs Institute critical appraisal tool for cross-sectional and ecological studies.
Results
The analysis included 19 studies with a total of 325,225 COVID-19 patients who had initially tested positive for the virus. The studies were published between 2020 and 2021 and included 17 cohort studies (3 prospective and 14 retrospective), 1 ecological study, and 1 cross-sectional study. Reinfection cases were reported across three continents, with patients ranging in age from less than 1 year to 99 years old.
The pooled reinfection rate across all studies was 0.65%, with a 95% confidence interval (CI) of 0.39% to 0.98%. The symptomatic reinfection rate was slightly lower at 0.37% (95% CI 0.11% to 0.78%). In high-risk populations, such as healthcare workers and residents of care homes, the reinfection rate was significantly higher at 1.59% (95% CI 0.30% to 3.88%).
The protection against reinfection provided by prior infection was estimated to be 87.02% (95% CI 83.22% to 89.96%), while the protection against symptomatic reinfection was 87.17% (95% CI 83.09% to 90.26%). These findings suggest that natural infection confers a level of protection comparable to that of vaccines, which have reported efficacies ranging from 62% to 95%.
Subgroup Analyses
Subgroup analyses were conducted to explore the factors influencing reinfection rates. Among the studies reporting reinfection rates by sex, the rate was 0.38% in females and 1.77% in males. The reinfection rate varied by study design, with cross-sectional studies reporting the highest rate at 4.46%. Geographically, North America had a higher reinfection rate (0.73%) compared to Europe (0.54%) and Asia (0.63%). Additionally, the reinfection rate was higher in studies with an infection interval of at least 90 days (0.74%) compared to those with an interval of at least 45 days (0.14%).
Cumulative and Sensitivity Analyses
Cumulative meta-analyses indicated that the point estimate of the reinfection rate stabilized as the sample size increased, suggesting greater accuracy with larger studies. Sensitivity analyses, which involved excluding each study one by one, confirmed the robustness of the results, with reinfection rates ranging from 0.51% to 0.73%.
Discussion
The findings of this meta-analysis indicate that the reinfection rate of SARS-CoV-2 is relatively low in the general population but significantly higher in high-risk populations. The protection against reinfection provided by prior infection is substantial, with an estimated efficacy of 87%, which is comparable to that of vaccines. These results have important implications for public health measures and vaccination strategies.
Several factors may contribute to the observed reinfection rates. First, the decline in immunity over time or the failure of naturally acquired immunity could lead to reinfection with the same virus strain. Second, viral mutations may enable the virus to evade immune responses, resulting in reinfection with a different strain. Additionally, the accuracy of reinfection identification may be influenced by false-positive test results or protracted first infections, which could lead to an overestimation of reinfection rates.
The study also highlights the importance of preventive measures, such as social distancing, mask-wearing, and hand hygiene, particularly for individuals in high-risk populations. Vaccination remains a critical tool for controlling the spread of SARS-CoV-2, and the findings suggest that in areas with limited vaccine availability, individuals who have previously been infected may be prioritized for vaccination after high-risk populations.
Limitations
Several limitations should be considered when interpreting the results of this meta-analysis. First, the incidence of reinfection may have been overestimated due to the lack of genetic lineage or clade confirmation in most studies. Second, the lack of detailed clinical features in many studies limits the ability to examine reinfection cases in detail, particularly with respect to immune responses and viral escape mechanisms. Finally, subgroup analyses based on disease severity, age, and comorbidities could not be performed due to insufficient data, which may affect the generalizability of the findings.
Conclusion
The reinfection rate of SARS-CoV-2 is relatively low, with natural infection providing a level of protection comparable to that of vaccines. These findings have important implications for public health measures and vaccination strategies in response to the COVID-19 pandemic. Future studies should focus on identifying the factors that influence reinfection incidence, such as viral strains, patient immune status, and other individual characteristics, to develop more effective strategies for controlling and preventing reinfections.
doi.org/10.1097/CM9.0000000000001892
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