key: cord-1054709-ltga2btq
authors: Chivese, T.; Matizanadzo, J.; Musa, O.; Hindy, G.; Furuya-Kanamori, L.; Islam, N.; Al-Shebly, R.; Shalaby, R.; Habibullah, M.; Al-Marwani, T.; Hourani, R. F.; Nawaz, A. D.; Haider, M.; Emara, M. M.; Cyprian, F.; Doi, S. A. R.
title: The prevalence of adaptive immunity to COVID-19 and reinfection after recovery, a comprehensive systematic review and meta-analysis of 12 011 447 individuals
date: 2021-09-07
journal: nan
DOI: 10.1101/2021.09.03.21263103
sha: 022bc1138e2004d2b085921c729ea3bfb6daaafc
doc_id: 1054709
cord_uid: ltga2btq

Abstract Objectives This study aims to estimate the prevalence and longevity of detectable SARS-CoV-2 antibodies as well as T and B memory cells during infection with SARS-CoV-2 and after recovery. In addition, prevalence of COVID-19 reinfection, and the preventive efficacy of previous infection with SARS-CoV-2 were investigated. Methods and analyses A synthesis of existing research was conducted. The Cochrane Library for COVID-19 resources, the China Academic Journals Full Text Database, PubMed, and Scopus as well as preprint servers were searched for studies conducted between 1 January 2020 to 1 April 2021. We included studies with the relevant outcomes of interest. All included studies were assessed for methodological quality and pooled estimates of relevant outcomes were obtained in a meta-analysis using a bias adjusted synthesis method. Proportions were synthesized with the Freeman-Tukey double arcsine transformation and binary outcomes using the odds ratio (OR). Heterogeneity between included studies was assessed using the I2 and Cochrans Q statistics and publication bias was assessed using Doi plots. Results Fifty-four studies, from 18 countries, with a total of 12 011 447 individuals, followed up to 8 months after recovery were included. At 6-8 months after recovery, the prevalence of SARS-CoV-2 specific immunological memory remained high; IgG 90.4% (95%CI 72.2 to 99.9, I2=89.0%, 5 studies), CD4+ 91.7% (95%CI 78.2 to 97.1, one study), and memory B cells 80.6% (95%CI 65.0 to 90.2, one study) and the pooled prevalence of reinfection was 0.2% (95%CI 0.0 to 0.7, I2 = 98.8, 9 studies). Individuals previously infected with SARS-CoV-2 had an 81% reduction in odds of a reinfection (OR 0.19, 95% CI 0.1 to 0.3, I2 = 90.5%, 5 studies). Conclusion Around 90% of people previously infected with SARS-CoV-2 had evidence of immunological memory to SARS-CoV-2, which was sustained for at least 6-8 months after recovery, and had a low risk of reinfection.

Despite the rapid development of several efficacious and safe vaccines against 2) , access to the vaccines is limited due to enormous demand in the context of limited supply chains and complicated logistics needed for vaccine distribution (3) . With the pandemic showing no signs of abating, a key question that . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ; https://doi.org/10.1101/2021.09.03.21263103 doi: medRxiv preprint remains unanswered is whether infection with COVID-19 confers immunity and how long that immunity lasts. Acquired immunity to COVID-19 may play a significant role in decisions to reopen economies in many countries as the world is faced with the need to vaccinate billions over a short period of time to reduce morbidity and mortality to COVID-19. If individuals with past COVID-19 infection have durable immunity, they may form a group that could be less prioritized for COVID-19 vaccination in resource-limited settings or subject to single-dose vaccination regimens (4-6). However, the protectiveness and duration of acquired immunity to COVID-19 is still not completely understood.

Several studies have shown that individuals infected with SARS-CoV-2 develop neutralizing antibodies (7, 8) , and that, up to 8 months later, most individuals who recover from COVID-19 have evidence of immunological memory (9) (10) (11) (12) (13) . However, many of these studies involve small numbers of participants and suffer from loss to follow up. Therefore, it is still not clear what percentage of people with COVID-19 do have detectable antibodies against SARS-CoV-2 after recovery.

Even though antibodies are necessary for sterilizing immunity against SARS-CoV-2, there is an increasing understanding of the role played by both cellular and humoral components of the adaptive immune response in fighting off infection by the SARS-CoV-2 virus (9, (14) (15) (16) (17) . Although the cellular immune response usually lags behind the humoral immune response by several days, there is evidence that even when there are no circulating antibodies, circulating memory T cells provide protection against clinical disease and death from infection by the hepatitis B virus (18) . This is likely to be true for SARS-CoV-2 which can progress relatively slowly to severe disease status, in a median of about 19 days (19) , as this gives the cellular immune response the time it requires to muster. Findings from the few small studies suggest that it is likely that most individuals develop immunological memory to SARS-CoV-2 in the form of CD4+ and CD8+ T cells (9, 17) , and it is not yet clear what proportion of people who recover from COVID- 19 have detectable SARS-CoV-2 specific CD4+ and CD8+ T cells and for how long.

Measuring the proportions of individuals with evidence of immunological memory of SARS-CoV-2 gives a relatively good idea of immunity against the virus after recovery.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) However, the best way of measuring immunity to COVID-19 after recovery is by measuring reinfection. Initial findings from earlier studies suggested that reinfection with SARS-CoV-2 was not rare (20) (21) (22) (23) , and this was worsened by sensational news reporting. However, a growing understanding of COVID-19 has allayed these initial fears as most of early cases were more likely to be due to either prolonged viral shedding or reactivation of an incompletely cleared virus, that may have been harbored in the nasal cavity, termed repositivity (24) (25) (26) . While repositive cases may not be as worrying as true reinfections, it is important to understand how prevalent these cases are, and whether they are infective or not. However, reinfection is still possible, and several case studies have reported confirmed reinfections (22, 23) . At a population level, establishing reinfection prevalence is a difficult process as this requires viral sequencing from both the primary and secondary infection during large longitudinal cohorts (27) , and not many studies can afford to do this on a large scale. Emerging data from a few large cohort studies (28) (29) (30) has shown that the prevalence of reinfection by SARS-CoV-2 lies anywhere between less than 1% and 5%.

It is still not clear what proportion of individuals with COVID-19 get re-infected by the virus and if the protective immunity from previous infection by SARS-CoV-2 wanes over time. Longitudinal studies of the main seasonal coronaviruses; HCoV-NL63, HCoV-229E, HCoV-OC43 and HCoV-HKU1, have shown that acquired immunity is short lived and reinfection occurs more frequently after six to 12 months of recovery (31) . This could be due to strain variation, which increases the risk of reinfection, a situation that may be similar to SARS-CoV-2 where divergent variants (32) (33) (34) have developed.

This research aims to estimate the prevalence of SARS-CoV-2 specific immunologic memory after recovery from COVID-19 and its efficacy in protecting against reinfection through synthesis of all existing research. Specifically, the research aims to estimate the prevalence of detectable SARS-CoV-2 specific IgM, IgG, IgA antibodies, CD4+, CD8+ and memory B cells after recovery, to estimate the prevalence of repositivity and reinfection after infection with SARS-CoV-2, and to estimate the protective efficacy of previous infection with SARS-CoV-2 against reinfection.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ; https://doi.org/10.1101/2021.09.03.21263103 doi: medRxiv preprint

The design and conduct of this systematic review and meta-analysis followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines (35) . The protocol for this study is registered online on PROSPERO, the International prospective register of systematic reviews (CRD42020201234), though it is unclear what benefit this lends to the research community.

We searched for studies, without language restrictions, from 1 January 2020 till 1 st of April 2021, the Web of Science Clarivate, the China Academic Journals Full Text Database, PubMed, Scopus, and the databases of preprints (https://www.medrxiv.org/ and https://www.biorxiv.org/). All references of retrieved articles were manually screened for further studies. The search strategy is shown in Supplementary Doc 1.

Articles retrieved from the search were exported to Endnote X7 where duplicates were removed and then uploaded for the initial screening using title and abstract on the Rayyan systematic review management website (https://www.rayyan.ai/). Due to the large number of records identified, records were subdivided into four groups and for each group, two investigators then screened titles, abstracts and if necessary full articles for inclusion. The full text of the records identified from screening using titles and abstracts were then screened for eligibility independently by the two investigators.

Disagreements were resolved by an independent third author from another group.

Criteria for considering studies for the review.

This synthesis included observational studies which reported the prevalence of SARS-CoV-2 specific IgG, IgM, IgA, CD4+, CD8+ and memory B cells during and after recovery from COVID-19, the prevalence of repositivity and reinfection with SARS-CoV-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ; https://doi.org/10.1101/2021.09.03.21263103 doi: medRxiv preprint COVID-19 reinfection is difficult to establish and is strictly defined as phylogenetically distinct genomic sequences in the first and second episodes (27) . It is becoming apparent that some recovered people may have a positive COVID-19 because of prolonged viral shedding. We defined repositivity as any positive PCR test within the first 3 months after a PCR negative tested recovery from COVID-19. Because very few population-based studies have been able to establish reinfection using genetic sequencing, and therefore distinguish reinfection from a chronic infection reservoir, we considered all participants who test positive on PCR for COVID-19 after being confirmed negative, or full clinical recovery with a negative COVID-19 test at least 3 months after recovery, according to the United States Centers for Disease Control criteria (27) . This definition could possibly result in an under-estimation of reinfection rates.

The effect of prior infection with SARS-CoV-2 in protection against future infection was defined similar to the vaccination effect, by calculation of the relative risk reduction.

However, the relative risk reduction was recomputed from the odds ratio (OR) using the Stata module logittorisk given that the synthesis needs to be done (36, 37) on the OR scale.

From each included study, two reviewers extracted data on study characteristics such as study authors, country of study, study setting, timepoints measured, length of followup, gender distribution, and mean or median age of participants. Because of the high number of studies included and the difficulties in locating the data that were required for this synthesis, the studies were grouped into four groups and a third author was required to double check extracted data from each pair of reviewers. To estimate the prevalence of adaptive immune responses, repositivity and reinfection, we extracted data on numbers of individuals, out of the total with confirmed COVID-19, with circulating SARS-CoV-2 specific IgG, IgM, IgA, CD4+, CD8+, memory B cells, and numbers of individuals who had a positive RT-PCR after confirmed recovery from COVID-19 at least 3 months post their initial diagnosis. If a study reported data on multiple timepoints, we extracted data from the latest timepoints. For each study we . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

We used tables to show descriptive data of included studies. For the prevalence objectives, we re-calculated prevalence estimates from each study using the number of cases with detectable SARS-CoV-2 specific IgG, IgM, CD4+, CD8+, memory B cells and cases with positive PCR (reinfection) after recovery from COVID-19 that was at or later than 3 months post initial diagnosis with COVID-19. We also carried out subgroup analysis of prevalence in the post-recovery period using three periods of 0 -2 months, 3 -5 months and at least 6 months. We used the quality effects model (40) to pool prevalence from studies, as it maintains a correct coverage probability and a less mean squared error when compared to the random effects model, when there is heterogeneity across studies (41) .

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ;

We used the Freeman-Tukey double arcsine transformation (42) to stabilize the variances in all prevalence data. To investigate the protective effect of prior COVID-19 on the risk of reinfection, we calculated unadjusted odds ratios from included studies Results of meta-analyses were presented in tables and forest plots.

Between study heterogeneity was investigated using the I2 statistic and Cochran's Q pvalues and exact p-values were presented. Heterogeneity was considered low (I2 below 50%), moderate (I2 between 50 -75%) and high (I2 above 75%). Doi plots (39) were used to visually assess small study effects in lieu of funnel plots as they are more reliable and easier to interpret. The LFK index was used to quantify Doi plot asymmetry.

We used the metan package in Stata IC version 15 software (43) for all analyses.

This study utilized published data and did not require ethical approval. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. Table 2 ). The included studies had deficiencies in items related to external validity (Supplementary Table 2 ). The exceptions were a few studies where some forms of total sampling were employed. These included one Chinese study where the whole City of CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. (Fig 3 and Supplementary Figs. 1-4) . There was no downward trend seen across these periods. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ;

Prevalence of SARS-CoV-2 specific CD4+ and CD8+ after recovery from

Data from four studies (9, 16, 17, 69) , three from the USA and one from the UK, with a total of 118 participants resulted in a synthesized prevalence of detectable CD4+ T cells after recovery of 100% (95%CI 83.9 -100.0) within one month (17) (Fig 3 and Supplementary Fig. 8 ).

Conversely, SARS-CoV-2 specific CD8+ T cells showed a steady decline after recovery from 70.0% (95%CI 48.1 -85.5) within one month (17) to 50% (95%CI 34.5 -65.5) at 6-8 months after recovery (7) (Fig 3 and Supplementary Fig. 9 ).

Two studies (9, 62) , both from the USA, reported data on the prevalence of SARS-CoV-2 specific memory B cells. In one study (62) , most participants (prevalence 92.9%, 95% CI 68.5 -98.7) had anti spike-RBD class switched memory B cells, between two to three months after recovery from COVID-19. The same pattern was observed in the other study (9) , with 80.6% (95%CI 65.0 -90.2) of the participants having RBD-specific memory B cells at 4-5 months. P  r  e  v  a  l  e  n  c  e  o  f  I  g  G  ,  I  g  M  ,  C  D  4  a  n  d  C  D  8   I  g  G  I  g  M  C  D  4  C  D  8 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ; https://doi.org/10.1101/2021.09.03.21263103 doi: medRxiv preprint

Nine studies, two from the UK (30, 46) , and the remaining studies each from the USA (70) , Austria (66) , Denmark (54) , Spain (52) , Iraq (29) , Qatar (28) and disputed territories (65) , with a total of 257 448 participants, reported data on the prevalence of reinfection ≥ 3 after recovery from COVID-19. The reported prevalence ranged from 0.0% in Spain (52) to 5.7% in the USA (70) (Fig. 5) . The pooled prevalence of reinfection was 0.2% (95% CI 0.0 -0.7) with high heterogeneity (I 2 = 98.8%, p<0.01) (Fig. 4) . There was gross study asymmetry with smaller studies favouring more reinfection ( Supplementary Fig. 12 ). In contrast to reinfection, the pooled prevalence of repositivity within one month was 0.9% (95%CI 0.0-8.0, I 2 = 99.8%, p<0.01, 17 studies, Supplementary Fig 10) . The . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ; https://doi.org/10.1101/2021.09.03.21263103 doi: medRxiv preprint pooled prevalence of COVID-19 repositivity at 2-3 months after recovery was 0.1% (95%CI 0.0 -0.7, 7 studies), with substantial heterogeneity (I 2 = 99.7%, p<0.01) and also gross study asymmetry with smaller studies favoring more repositivity ( Supplementary Fig. 11 ).

Five studies with a total of 11 459 882 individuals compared infection with SARS-CoV-2 between individuals with a previous confirmed COVID-19 diagnosis and those who had no prior infection. Two of the studies were from the UK (30, 46) , and one study each from Austria (66), Denmark (54) and the USA (70) , and all the studies followed up participants for at least seven months. The odds ratio of infection by SARS-CoV-2 in individuals with prior COVID-19 compared to those without prior infection ranged from 0.06 in a study (76) from the UK to 0.41 in a study (80) from the USA (Table 1) . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. .01) (Fig. 5) . The studies were asymmetrical with smaller studies favoring less reinfection ( Supplementary Fig. 13 ). Assuming a baseline risk of primary infection of 5%, this odds ratio translates (using logit to risk) to a relative risk reduction of 80.2%

(95%CI 66.9% -88.5%). We found that the prevalence of reinfection after recovery from COVID-19 was very low and that prior infection with SARS-CoV-2 conferred an 80% protective efficacy against reinfection (assuming baseline prevalence of 5%). The existing reviews (23, (85) (86) (87) (88) (89) (90) (91) (92) (93) (94) have not examined the question of prevalent immunity sufficiently (Supplementary Table 4 ).

The results of this study suggest that there is a sustained high prevalence of SARS-CoV-2 specific IgG antibodies, near 90%, up to 6-8 months after recovery from COVID-19, and, as expected, the prevalence of IgM antibodies decreased to just below 58%, 3-6 months after recovery. Although we assessed the prevalence of detectable IgG, and not the actual antibody titres, research in primates has shown that even low circulating neutralizing antibody tires had a protective effect against COVID-19 (95, 96) . This protective effect could be at the level of reducing severe COVID-19 and death from . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ; https://doi.org/10.1101/2021.09.03.21263103 doi: medRxiv preprint COVID-19, rather than stopping the infection in the upper respiratory tract. Sterilizing immunity that stops individuals from acquiring infection requires high antibody titres (9) , however the level of antibody titres that provides sterilizing immunity is still not known. Therefore, it is still theoretically possible that individuals with detectable IgG may be infected by and are able to spread SARS-CoV-2. Longitudinal studies are needed to investigate the relationship between antibody titres and the risk of reinfection. Notably, it appears that the SARS-CoV-2 antibody titres are stable after recovery with a half-life of almost 5 months for spike IgG and 7 months for spike IgA (9) . Further, several studies (5, 6, 97, 98) immunity is thought to be limited, they are highly associated with ensuring less severe COVID-19 (69, 99) . A diminished prevalence of cytotoxic CD8+ cells may imply that viral clearance is delayed in some individuals, in the event of reinfection. However, there is evidence of sustained high prevalence of T follicular helper cells (TFH) (9), a subset of CD4+ T cells that are the most important in helping memory B cells and in the production of neutralizing antibodies and long-term humoral immunity (99) . A high prevalence of memory B cells at ≥ 6 months also suggests that immunological memory may be long lasting, at least to the time points measured in the included studies.

This synthesis suggests that although repeat test-positives are likely to occur in about 2% of individuals within 1 month of recovery, the prevalence of reinfection with SARS-CoV-2 is low, with only 0.2% reinfected during a period of up to 8 months after recovery.

Further, prior infection with SARS-CoV-2 provides protection against reinfection with an efficacy of 80%, during the same period. While the presence of antibodies and memory . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ; https://doi.org/10.1101/2021.09.03.21263103 doi: medRxiv preprint T and B cells are evidence of immunological memory, prevalent reinfection is a stronger measure of clinical protection of prior infection (66) . It is likely that this protection may last longer than the period measured in the studies included in this synthesis because of the long lived humoral and cellular immune responses previously discussed (100), but more research is required. For example, in a letter to the editor published at the time of finalization of this review, the prevalence of reinfection in a period of up to 12 months was 0.3% in Italy (101) . Findings from this Italian study (101) seroprevalence data suggested that three-quarters of the population were previously infected with SARS-CoV-2 (104), suggesting that a large proportion of the population was still susceptible to infection by SARS-CoV-2 (105). While it is likely that the seroprevalence study overestimated the proportion infected with SARS-CoV-2, it is also equally likely that the resurgence in Manaus could have been driven by the emergence of the highly divergent and transmissible gamma (P1) variant which was first reported from Manaus (32, 105) . Divergent lineages of SARS-CoV-2 are more likely to be associated with antigenic escape (105) and therefore result in higher chances of reinfection. Estimates of reinfection with divergent variants such as delta are therefore unknown, and more research is required.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted September 7, 2021. ; https://doi.org/10.1101/2021.09.03.21263103 doi: medRxiv preprint Our research has several limitations, one of which is that these findings cannot be extended beyond the time of follow up of the included studies. Although, it is highly likely that protective immunity goes beyond this time period, data from longitudinal cohorts with longer follow up times are required. Another limitation is the heterogeneity in the studies that we included which was not reduced by subgroup analyses in measurements methods and follow up times. Many of the longitudinal studies in this meta-analysis suffered from loss to follow up and this may have affected their findings.

Further, although we included a comprehensive number of studies, studies on the cellular immune response are lacking and the ones we included had very small sample sizes, implying that our estimates of this aspect of the adaptive immune response may change with the accumulation of more data. Many of the included studies were small observational studies which are easily affected by confounding. Lastly, the review did not examine evidence for immunity against the new variants and did not include studies with longer follow up.

This synthesis shows around 90% of individuals have evidence of SARS-CoV-2 specific immunological memory. Further, the risk of reinfection is rare and previous infection with SARS-CoV-2 confers protective immunity against reinfection with an efficacy of 81% during a period up to 8 months after recovery from COVID-19. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet

Equitable distribution of COVID-19 vaccines. The Lancet Infectious Diseases

Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals

Antibody Response to the BNT162b2 mRNA COVID-19 Vaccine in Subjects with Prior SARS-CoV-2 Infection

Neutralizing Antibody and Soluble ACE2 Inhibition of a Replication-Competent VSV-SARS-CoV-2 and a Clinical Isolate of SARS-CoV-2

Neutralizing Antibody Production in Asymptomatic and Mild COVID-19 Patients, in Comparison with Pneumonic COVID-19 Patients

Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection

Post-lockdown SARS-CoV-2 nucleic acid screening in nearly ten million residents of Wuhan, China

CoV-2 induces a durable and antigen specific humoral immunity after asymptomatic to mild COVID-19 infection

Humoral Immune Response to SARS-CoV-2 in Iceland. The New England journal of medicine

Robust neutralizing antibodies to SARS-CoV-2 infection persist for months

Detection of SARS-CoV-2

Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals

Circulating cytokines and lymphocyte subsets in patients who have recovered from COVID-192020

Adaptive immunity to SARS-CoV-2 in cancer patients: The CAPTURE study

Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

A review of the long-term protection after hepatitis A and B vaccination

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical recurrences of COVID-19 symptoms after recovery: Viral relapse, reinfection or inflammatory rebound?

The first case of documented Covid-19

Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection After Recovery from Mild Coronavirus Disease

What reinfections mean for COVID-19

Post discharge positive re-tests in COVID-19: common but clinically non-significant

Clinical characteristics of recovered COVID-19 patients with re-detectable positive RNA test

Rates of recurrent positive SARS-CoV-2 swab results among patients attending primary care in Qatar

Centers for Disease Control. Common Investigation Protocol for Investigating Suspected SARS-CoV

SARS-CoV-2 reinfection in a cohort of 43,000 antibody-positive individuals followed for up to 35 weeks

Patients Negative for Immunoglobulin G Following Recovery from COVID-19

infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). The Lancet

Seasonal coronavirus protective immunity is short-lasting

Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings. 2021. 33. World Health Organization. Tracking SARS-CoV-2 variants 2021

Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa

PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews

Questionable utility of the relative risk in clinical research: a call for change to practice

The OR is "portable" but not the RR: time to do away with the log link in binomial regression

MASTER) scale demonstrated a unified framework for bias assessment

Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement

Advances in the meta-analysis of heterogeneous clinical trials I: the inverse variance heterogeneity model

Metan: fixed-and random-effects meta-analysis

Transformations related to the angular and the square root

Assessment of the risk of SARS-CoV-2 reinfection in an intense re-exposure setting

Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers

COVID-19 significantly reduces the risk of subsequent infection, but reinfections are seen after eight months

The clinical characteristic of eight patients of COVID-19

with positive RT-PCR test after discharge

Clinical course and risk factors for recurrence of positive SARS-CoV-2 RNA: a retrospective cohort study from Wuhan

SARS-CoV-2 RNA shedding in recovered COVID-19 cases and the presence of antibodies against SARS-CoV-2 in recovered COVID-19 cases and close contacts

SARS

CoV-2 Serology persistence over time in COVID-19 Convalescent Plasma Donors

Evidence of long-lasting humoral and cellular immunity against SARS-CoV-2 even in elderly COVID-19 convalescents showing a mild to moderate disease progression

Long-term clinical, virological and immunological outcomes in patients hospitalized for COVID-19: antibody response predicts long COVID

SARS-CoV-2 Antibody Responses Are Correlated to Disease Severity

Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study

Recurrence of SARS-CoV-2 PCR positivity in COVID-19 patients: a single center experience and potential implications

Characteristics of Anti-SARS-CoV-2 Antibodies in Recovered COVID-19 Subjects

CD4+ T Cell Response and Abundant Antibody Production in Children with COVID-19

Recurrent PCR positivity after hospital discharge of people with coronavirus disease 2019 (COVID-19)

Positive result of Sars-Cov-2 in faeces and sputum from discharged patients with COVID-19 in Yiwu

Recurrent positive SARS-CoV-2: Immune certificate may not be valid

Predictors of severe symptomatic laboratory-confirmed SARS-CoV-2 reinfection

Durable SARS-CoV-2 B cell immunity after mild or severe disease

Adaptive immune responses to SARS-CoV-2 in recovered severe COVID-19 patients

International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity

Changes in the humoral immunity response in SARS-CoV-2 convalescent patients over 8 months

CoV-2 reinfection proportion in members of a large healthcare provider in Israel: a preliminary report

SARS-CoV-2 re-infection risk in Austria

Cross-Sectional Evaluation of Humoral Responses against SARS-CoV-2 Spike

Re-positive Cases of Nucleic Acid Tests in Discharged Patients With COVID-19: A Follow-Up Study. Frontiers in medicine

Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity

Reinfection Rates Among Patients Who Previously Tested Positive for Coronavirus Disease 2019: A Retrospective Cohort Study

Dynamic Changes of

Antibodies to SARS-CoV-2 in COVID-19 Patients at Early Stage of Outbreak

Probable causes and risk factors for positive SARS-CoV-2 test in recovered patients: Evidence from Brunei Darussalam

Coronavirus Disease 2019 Test Results After Clinical Recovery and Hospital Discharge Among Patients in China

A follow-up study shows no new infections caused by patients with repeat positive of COVID-19 in Wuhan

International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity

Antibody Detection and Dynamic Characteristics in Patients With Coronavirus Disease

False negative of RT-PCR and prolonged nucleic acid conversion in COVID-19: Rather than recurrence

Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation

Recurrence of positive SARS-CoV-2 viral RNA in recovered COVID-19 patients during medical isolation observation

Polymerase Chain Reaction Assays Reverted to Positive in 25 Discharged Patients With COVID-19

Longitudinal Change of Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies in Patients with Coronavirus Disease

Antibody Responses to SARS

CoV-2 in Patients With Novel Coronavirus Disease

Follow-up study of the

Recurrent Viral RNA Positivity in Recovered COVID-19 Chinese Patients

convalescent patients with re-positive nucleic acid detection

Immunity and inflammatory biomarkers in COVID-19: A systematic review

T cell response to SARS-CoV-2 infection in humans: A systematic review

Differences of blood cells, lymphocyte subsets and cytokines in COVID-19 patients with different clinical stages: a network meta-analysis

Repeated SARS-CoV-2 Positivity: Analysis of 123 Cases

How strong is the evidence that it is possible to get SARS-CoV-2 twice? A systematic review

Current meta-analysis does not support the possibility of COVID-19 reinfections

A systematic review on the levels of antibodies in COVID-19 virus exposed but negative newborns: a possible vertical transmission of IgG/ IgM

A systematic review on the recurrence of SARS-CoV-2 virus: frequency, risk factors, and possible explanations

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Sequence Characteristics of Coronavirus Disease

Persistence and Reinfection. Clinical Infectious Diseases

Repeated SARS-CoV-2 Positivity: Analysis of 123 Cases

DNA vaccine protection against SARS-CoV-2 in rhesus macaques

Development of an inactivated vaccine candidate for SARS-CoV-2

Impact of age, ethnicity, sex and prior infection status on immunogenicity following a single dose of the BNT162b2 mRNA COVID-19 vaccine: real-world evidence from healthcare workers

Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine

Helper Cell Biology: A Decade of Discovery and Diseases

International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity

COVID-19 false dichotomies and a comprehensive review of the evidence regarding public health, COVID-19 symptomatology, SARS-CoV-2 transmission, mask wearing, and reinfection

Assessment of SARS-CoV-2 Reinfection 1 Year After Primary Infection in a Population in

Reinfection With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Patients Undergoing Serial Laboratory Testing

World Health Organization. COVID-19 Weekly Epidemiological Update

Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic

Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence

International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity

TC and SARD had full access to and verified the data