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Immune response following infection with SARS‐CoV‐2 and other coronaviruses: A rapid review

Summary In this review, we systematically searched and summarized the evidence on the immune response and reinfection rate following SARS‐CoV‐2 infection. We also retrieved studies on SARS‐CoV and MERS‐CoV to assess the long‐term duration of antibody responses. A protocol based on Cochrane rapid review methodology was adhered to and databases were searched from 1/1/2000 until 26/5/2020. Of 4744 citations retrieved, 102 studies met our inclusion criteria. Seventy‐four studies were retrieved on SARS‐CoV‐2. While the rate and timing of IgM and IgG seroconversion were inconsistent across studies, most seroconverted for IgG within 2 weeks and 100% (N = 62) within 4 weeks. IgG was still detected at the end of follow‐up (49‐65 days) in all patients (N = 24). Neutralizing antibodies were detected in 92%‐100% of patients (up to 53 days). It is not clear if reinfection with SARS‐CoV‐2 is possible, with studies more suggestive of intermittent detection of residual RNA. Twenty‐five studies were retrieved on SARS‐CoV. In general, SARS‐CoV‐specific IgG was maintained for 1‐2 years post‐infection and declined thereafter, although one study detected IgG up to 12 years post‐infection. Neutralizing antibodies were detected up to 17 years in another study. Three studies on MERS‐CoV reported that IgG may be detected up to 2 years. In conclusion, limited early data suggest that most patients seroconvert for SARS‐CoV‐2‐specific IgG within 2 weeks. While the long‐term duration of antibody responses is unknown, evidence from SARS‐CoV studies suggest SARS‐CoV‐specific IgG is sustained for 1‐2 years and declines thereafter.

In conclusion, limited early data suggest that most patients seroconvert for SARS-CoV-2-specific IgG within 2 weeks. While the long-term duration of antibody responses is unknown, evidence from SARS-CoV studies suggest SARS-CoV-specific IgG is sustained for 1-2 years and declines thereafter.

| METHODS
A standardized protocol was adhered to 1 based on Cochrane rapid review methodology guidance. 2 Electronic databases (PubMed, EMBASE and EuropePMC) and pre-print servers (medRxiv, bioRxiv and Health Research Board [HRB] Open) were searched for the period 1 January 2000 until 26 May 2020. All potentially eligible papers, including non-peerreviewed pre-prints, were exported to Endnote X8.2 and screened for relevance.
For each included study, data on the study design, participant demographics and clinically relevant data (such as the severity of initial infection) were extracted by two reviewers. As no universally accepted quality appraisal tool exists for many study designs included in this review, including for case series, a de-novo quality appraisal tool was developed, adapted from existing tools (such as the Newcastle-Ottowa scale 3 and the ROBINS-I tool 4 ). Supplementary Material 1 in Data S1 provides the full search strategy, inclusion criteria for the selection of studies and details of the quality appraisal tool used. The findings of the research question were synthesized narratively due to the heterogeneity of study designs and outcome data.

| Duration of immune response
As SARS-CoV-2 was first identified in December 2019, there is a lack of evidence on the long-term duration of antibody responses following infection. Therefore, studies were also retrieved that investigated the long-term duration of immune responses to SARS-CoV and MERS-CoV.

| Duration of immune response: SARS-CoV-2
Eleven studies were identified that examined the duration of the By the end of follow-up, 92%-100% of patients had detectable neutralizing antibody levels.

| Duration of immune response: SARS-CoV
The duration of the immune response to SARS-CoV was investigated in 25 studies. 8

| Duration of immune response: MERS-CoV
Three studies were identified that investigated the immune response associated with MERS-CoV infection, with the longest follow-up 24 months. One study (n = 9) reported a rigorous antibody response in all survivors who had severe disease, but not in survivors of mild disease. 6 Similar findings were reported in another study of 11 patients (five with severe disease and six with mild disease) who were followed up for 1 year. 19 5,20,35,64,68,106 The association between lymphocyte counts (CD4 + and CD8 + subsets) and the severity of infection was investigated in two studies (N = 243 patients). 35,57 In both, authors reported that CD4 + T cell and CD8 + T cell counts were significantly inversely associated with disease severity; the more serious the disease was, the lower were the T cell, CD4 + T cell and CD8 + T cell counts on admission. One study also measured the CD4 +/CD8 + ratio; all analyses indicated that the ratio was not significantly different between different conditions and outcomes. 57 The association between re-detection positive and severity of initial disease was investigated in two studies (N = 679 patients). 7,41 Both studies found that mild or moderate cases were significantly more likely to re-present with detectable RNA by RT-PCR post-discharge compared with severe cases. Eleven studies provided a rate of re-detection via RT-PCR of respiratory samples in a cohort of recovered patients (defined as at least two RNA not detected samples for SARS-CoV-2 collected at ≥24-hour intervals). 17,22,33,41,71,75,76,79,81,84 In these studies, the redetection rate ranged from 3% (2/62 cases) 79 to 31% (4/13 cases), 111 with the largest cohort reporting a re-detection rate of 17% (95% CI:

| Reinfection rate following SARS-CoV-2 infection
13%-20%; n = 69/414 cases). 41 Patients in whom SARS-CoV-2 RNA was re-detected were asymptomatic at the time of the positive re-detection test in all but two of the 19 studies. 17,41 The first study reported that the majority of those in whom RNA was re-detected still had respiratory symptoms, including cough and increased sputum production on readmission. 41  3.9 | Methodological quality An agreed definition for reinfection (as opposed to re-detection) with SARS-CoV-2 was not identified, possibly due to the limited number of such events described in the literature.

| Quality of evidence
The overall quality of evidence was low due to the inherent bias associated with study designs. Concerns exist regarding the small sample size in many studies and the methodological quality of preprint studies that have not undergone a formal peer review process.

| Limitations of included studies
While studies consistently demonstrated anti-SARS-CoV-2 IgG and neutralizing antibody detection beyond 2 weeks, limitations of this The levels of detection for SARS-CoV-2-specific antibodies were not uniform across studies, and frequently not reported. Differences This review was also limited by small sample size in a number of studies, although more recent studies typically included a larger number of participants with longer follow-up periods. Differences in the rate and timing of seroconversion, in particular, may become more consistent when studies that use validated tests on larger sample sizes are conducted. The evidence available to answer these research questions is evolving. While studies consistently found that all patients tested positive for IgG (and nearly all tested positive for neutralizing antibodies) beyond 4 weeks post-symptom onset, larger studies are necessary to validate these findings.

| Conclusion
While the role or duration of the antibody response following SARS-CoV-2 infection is unknown, all patients in reviewed studies maintained an IgG response at the longest follow-up (8 weeks post-infection). We hypothesize that this response may last much longer, as evidence from studies of SARS-CoV has shown that SARS-CoV-specific IgG is sustained for one to 2 years post-infection, with detection up to 12 years post-infection in one study. It is unclear if reinfection can occur following recovery from SARS-CoV-2, and the limited data to date are more suggestive of intermittent detection of inconsistently shed residual viral RNA. Limited evidence suggests that these individuals are not infectious to others. In the coming months, as the pandemic progresses, more evidence will emerge on the duration of immunity, pre-existing immunity due to crossprotection from seasonal coronaviruses, potential for re-infection and recurrent infectivity.