key: cord-0901881-djxwuubm authors: Morris, Stephen; Anjan, Shweta; Pallikkuth, Suresh; Frattaroli, Paola; Courel, Steve; Fernandez, Anmary; Natori, Akina; Abbo, Lilian; Pahwa, Savita; Guerra, Giselle; Natori, Yoichiro title: Reinfection with SARS‐CoV‐2 in solid‐organ transplant recipients: Incidence density and convalescent immunity prior to reinfection date: 2022-04-06 journal: Transpl Infect Dis DOI: 10.1111/tid.13827 sha: 2bee088497887207b75cb6e9b97c920ed82f81cf doc_id: 901881 cord_uid: djxwuubm BACKGROUND: Long‐term protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains poorly characterized, particularly in solid organ transplant (SOT) patients. METHOD: We determined the incidence density of SARS‐CoV‐2 reinfection in a cohort of adult SOT recipients initially infected between March 1st, 2020 and March 30th, 2021 and included those with initial infection before or after transplantation. Incidence density was the total cases divided by total days after initial diagnosis with active graft. RESULTS: Of 210 infected recipients, five (2.4%) developed reinfection, including two who had received full mRNA vaccination, but none developed hypoxia. The incidence density for reinfection was 9.4 (95% confidence interval [CI] 3.9‐22.6) and for primary infection the density was 9.1 (95% CI 7.9–10.5) cases/100,000 patient days. Two recipients had immunity evaluated in the weeks prior to reinfection, by measuring immunoglobulin‐G (IgG) antibody titer to the SARS‐CoV‐2 receptor binding domain and virus‐specific CD4+ and CD8+ T‐cell reactivity following stimulation with SARS‐CoV‐2 peptide pools. Both mounted virus specific CD4 T‐cell responses prior to reinfection (1.19% and 0.28% of total CD4 T cells) and both had reactive IgG testing (1.30 and 4.99 signal/cut off ratio). CONCLUSIONS: This suggests that SOT recipients infected with SARS‐CoV‐2 remain at high risk for reinfection even after generating cellular and humoral immune responses. have been observed. Immunity after vaccination is also suboptimal in SOT recipients and breakthrough infection have occurred despite full mRNA vaccination. 8 Here, we describe a case series of reinfection in SOT recipients, along with the incidence density of reinfection of a large SOT center in United States. Also, we report convalescent virusspecific humoral and T-cell immunity from two of the patients approximately 6 months after initial infection and prior to SARS-CoV-2 reinfection. We performed a retrospective cohort study of SARS-CoV-2 reinfec- On March 1st, 2020, when the first case of SARS-CoV-2 infection was identified in the state of Florida, our center followed 5919 recipients with active graft. During the study, we identified 14 SOT recipients diagnosed with initial SARS-CoV-2 infection prior to transplant and 196 diagnosed after SOT, with the latter having incidence density of 9.1 (95% CI 7.9-10.5) cases/100,000 patient days. Of note, 210 recipients included 150 kidney, 18 liver, 16 heart, six lung, and 20 combined transplants. Out of those 210 recipients, 5 (2.4%) developed PCR confirmed reinfection with the incidence density of 9.4 (95% CI 3.9-22.6) cases/100,000 patient days. When analysis for subjects with initial infection after transplantation, the incidence density was 6.0 (95% CI 1.9-18.6) cases/100,000 patient days. The five reinfection cases are summarized in the Table 1 and Table S1 , which includes two cases of mRNA vaccine breakthrough. Two and three cases developed their first infection prior and after transplant, respectively. The median time to reinfection was 308 (range: 287-349) days. Of note, Patient 1 had the third infection and two of the other four patients had the second infection after the Delta (B.1.617.2) variant had been detected in the Miami metropolitan area. 13 All patients had sufficiently low Ct values (< 33) per CDC investigative criteria 8 except for one case (Patient 2) in whom Ct value could not be obtained but the patient had symptoms consistent with COVID- 19 . For the primary infections, all five recipients developed acute viral symptoms, but one recipient's testing was conducted as a part of routine admission testing. For reinfection, four of five recipients had viral symptoms including respiratory symptoms and the other was diagnosed on testing during admission for hyperkalemia. Details on illness characteristics are described in Table S1 . Four were hospitalized for the first infection and two for the latter. None of the patients had documented hypoxia during either hospitalization. As shown in Table S1 , four patients had clinical serology available before the second infection: two had unreactive IgG testing performed several weeks after the first infection and other two had reactive IgG testing within about 1 month of reinfection, although one of these recipients (Patient 3) only had reactive IgG testing following subsequent vaccination and not primary infection. Two SOT recipients participated in the prospective immunity study ( Patient 2 participated in the study at day 208 since initial diagnosis and 79 days prior to reinfection. IgG titer and total SARS-CoV-2-specific activated CD4+ were 4.99 SCR and 0.28%, respectively, but no total SARS-CoV-2-specific activated CD8+ T-cell responses were identified ( Figure 1 ). This study identified the incidence density of SARS-CoV-2 reinfection confirmed by quantitative PCR in one of the largest SOT centers, located in a COVID-19 high incidence area. Also, we report detailed information of the five cases of reinfection and describe the convalescent humoral and cellular immunity to SARS-CoV-2 in two of the cases just prior to the reinfection. This is the first study reporting the incidence density of SARS-CoV-2 reinfection in SOT recipients. Compared to prior studies of reinfec-tion in the general population, the incidence density in SOT recipients was higher than another retrospective study in Italy 3 using proactive case finding and was comparable to a prospective study with bimonthly sampling. 4 The higher reinfection rate among SOT recipients may suggest a potential impact of immunosuppression, consistent with a recent study reporting immunosuppression as a significant risk factor for SARS-CoV-2 vaccine breakthrough infection. 14 However, the impact of immunosuppression on reinfection should be confirmed with further studies comparing subjects from similar geographic locations and from comparable intervals of the pandemic to account for regional differences in circulating virus and adherence to public health measures. Of five subjects who had IgG serology available within approximately 3 months of reinfection, three had reactive testing in either clinical or research studies. Both subjects in the immunity study experienced mild disease in both infections and mounted virus-specific CD4+ T-cell responses comparable to data from the general population. 11, 12 This is consistent with robust CD4+ T-cell responses reported in SOT recipients 3 months after SARS-CoV-2 infection. 15 Taken together, these data are hypothesis-generating and further studies should evaluate immune correlates in SOT recipients at least 6 months after natural infection 16, 17 -timing which corresponds to long-term immunity 18 and increased risk of reinfection. 1 It is unclear what led to the discordance between immune correlates and protection from infection in our study. One possibility is that IgG-RBD titers and T-cell reactivity correlate with protection from infection, but the magnitudes we observed do not correspond to a level above the threshold of protection-which has not been well defined. 16, 17 Another possibility is that serum markers are correlates of protection from severe disease but are weaker sur- The strengths of this study are the large size of the cohort with proactive systems for case finding of positive tests, as well as the fortuitous timing of the mechanistic immunity study in two of the cases; close to reinfection but with negative PCR testing before and after this blood draw: a true convalescent sample. Such data are quite limited 25 and there are no published studies of cellular immunity during or especially just before reinfection. 16, 17 Our report has some limitations to be considered. A limitation of the incidence density study is that diagnosis with a second SARS-CoV- Antibody status and incidence of SARS-CoV-2 infection in health care workers Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection Assessment of SARS-CoV-2 reinfection 1 year after primary infection in a population in Lombardy, Italy SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN) Longterm shedding of viable SARS-CoV-2 in kidney transplant recipients with COVID-19 SARS-CoV-2 reinfection in a liver transplant recipient Centers for Disease Control and Prevention. Investigative criteria for suspected cases of SARS-CoV-2 reinfection (ICR) Risk of breakthrough SARS-CoV-2 infections in adult transplant recipients A simple method to calculate the confidence interval of a standardized mortality ratio (SMR) Preanalytical issues and cycle threshold values in SARS-CoV-2 real-time rt-pcr testing: should test results include these Differential T-cell reactivity to endemic coronaviruses and SARS-CoV-2 in community and health care workers Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals SARS-CoV-2 gene variant trends from patient and student samples in Association between immune dysfunction and COVID-19 breakthrough infection after SARS-CoV-2 vaccination in the US SARS-CoV-2 infection induces greater T-cell responses compared to vaccination in solid organ transplant recipients The immunology of SARS-CoV-2 infection and vaccines in solid organ transplant recipients SARS-CoV-2 Infection-induced and vaccine-induced immunity Adaptive immunity to SARS-CoV-2 and COVID-19 IgA dominates the early neutralizing antibody response to SARS-CoV-2 SARS-CoV-2 mucosal antibody development and persistence and their relation to viral load and COVID-19 symptoms Distinct features and functions of systemic and mucosal humoral immunity among SARS-CoV-2 convalescent individuals Mucosal immunity in COVID-19: a neglected but critical aspect of SARS-CoV-2 infection Exploiting mucosal immunity for antiviral vaccines The importance and challenges of identifying SARS-CoV-2 reinfections A multicenter cohort study of indian centers on reoccurring SARS-CoV-2 infections in kidney transplant recipients Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. December1, 2021. Accessed Effectiveness of 2-dose vaccination with mRNA COVID-19 vaccines against COVID-19-associated hospitalizations among immunocompromised adultsnine states REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19 Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals