Epidemiological and clinical characteristics of hospitalized human metapneumovirus patients in Israel, 2015-2021: A retrospective cohort study.

This study evaluated the epidemiological and clinical characteristics of human metapneumovirus (hMPV) infection among hospitalized patients with acute respiratory infections during 2015-2021 and assessed the impact of the coronavirus disease 2019 pandemic on hMPV infection. A single-center, retrospective cohort study was performed, including pediatric and adult patients with laboratory-confirmed hMPV. Of a total of 990 patients, 253 (25.6%), 105 (10.6%), 121 (12.2%), and 511 (51.6%) belonged to age groups 0-2, 3-17, 18-59, and ≥60 years, respectively. The highest percentage (23.0%) of patients were hospitalized during 2019 and the lowest (4.7%) during 2020. Patients < 18 years experienced high rates of comorbidities (immunodeficiencies: 14.4% and malignancies: 29.9%). Here, 37/39 (94.9%) of all bronchiolitis cases were diagnosed in patients < 2 years, whereas more patients in older age groups were diagnosed with pneumonia. A greater proportion of hMPV patients diagnosed with viral coinfection (mostly respiratory syncytial virus and adenovirus) were <18 years. The highest percentages of intensive care unit admissions were recorded among patients < 18 years. Our findings demonstrate that hMPV is an important cause of morbidity in young children and a possibly underestimated cause of morbidity among older adults.

The Outbreak of Unexplained Acute Hepatitis in Children: The Role of Viral Infections in View of the COVID-19 Pandemic.

BACKGROUND AND AIMS: An increase in the number of cases of acute hepatitis of unknown origin (HUO) in children was observed in 2021. Adenovirus and adeno-associated virus 2 (AAV2) infections have been suggested as possible triggers. However, the potential etiology is still unclear. We aimed to characterize a cohort of children with HUO in Israel in view of the COVID-19 pandemic. METHOD: Demographics, clinical data, and laboratory results on the children compatible with the CDC criteria for HUO were collected by the established registry of the Ministry of Health. Available specimens were sent to the Central Virology Laboratory. RESULTS: A total of 39 children were included in the registry. A total of 20 were enrolled prospectively, in which human herpes virus 6 (HHV6) infection or reactivation was identified in 11/19, adenovirus was found in 4/19 of the cases, and AAV2 was detected in 2/16. Past COVID-19 exposure was recorded for 24/39 of the children. A total of 10 children underwent liver biopsy, and 8 were successfully treated with steroids and 2 underwent liver transplantation. CONCLUSIONS: The COVID-19 pandemic and the related containment measures combined with reactivation or active infection with other viruses could have been a trigger for the HUO outbreak. In our cohort, HHV6 was the most abundant finding.

Highly sensitive extraction-free saliva-based molecular assay for rapid diagnosis of SARS-CoV-2.

The COVID-19 pandemic highlighted the necessity of fast, sensitive, and efficient methods to test large populations for respiratory viruses. The "gold standard" molecular assays for detecting respiratory viruses, such as quantitative polymerase chain reaction (qPCR) and reverse transcription qPCR (RT-qPCR), rely on invasive swab samples and require time-consuming and labor-intensive extraction processes. Moreover, the turnaround time for RT-qPCR-based assays is too lengthy for rapid screening. Extraction-free saliva-based methods provide a non-invasive sampling process with a fast turnaround time and are suitable for high-throughput applications. However, when used with a standard RT-qPCR system, the absence of extraction significantly reduces the assays' sensitivity. Here, using a novel optical modulation biosensing (OMB) platform, we developed a rapid and highly sensitive extraction-free saliva-based molecular assay. We blindly tested 364 paired nasopharyngeal swabs and saliva samples from suspected SARS-CoV-2 cases in Israel. Compared with the gold standard swab-based RT-qPCR assay, the sensitivity of the extraction-free saliva-based OMB assay is 90.7%, much higher than the sensitivity of extraction-free saliva-based RT-qPCR assay (77.8%) with similar specificity (95.3% and 97.6%, respectively). Moreover, out of 12 samples identified by the OMB-based assay as positive, 8 samples were collected from hospitalized patients in a COVID-19 ward and were verified to be SARS-CoV-2-positive upon admission, indicating that the actual clinical sensitivity and specificity of the OMB assay are higher. Considering its user-friendly saliva-based protocol, short and cost-effective extraction-free process, and high clinical accuracy, the OMB-based molecular assay is very suitable for high-throughput testing of large populations for respiratory viruses. IMPORTANCE: Three years after the SARS-CoV-2 outbreak, there are no molecular tests that combine low-cost and straightforward sample preparation, effective sample handling, minimal reagent and disposable requirements, high sensitivity, and high throughput required for mass screening. Existing rapid molecular techniques typically sacrifice certain requirements to meet others. Yet, localized outbreaks of novel viral diseases happen daily in different parts of the world. In this context, respiratory diseases are of specific importance, as they are frequently airborne and highly contagious, with the potential for a rapid global spread. The widely accepted opinion is that another pandemic is just a question of time. To ensure that the containment efforts for the upcoming "disease X" are successful, introducing rapid, high-throughput, and highly sensitive diagnostic methods for detecting and identifying pathogens is critical. A few months into the pandemic, saliva was suggested as a diagnostic matrix for SARS-CoV-2 detection. The collection of saliva does not require swabs and is minimally invasive. In particular, extraction-free saliva-based assays require fewer reagents and disposables, and therefore are faster and cheaper, offering an appealing alternative for low-income countries. Unfortunately, current extraction-free saliva-based detection methods, such as direct RT-qPCR or isothermal amplification, have either low sensitivity or low throughput. Therefore, we believe that the presented highly sensitive ht-OMBi platform and the extraction-free saliva-based molecular assay can become an essential tool in the infectious disease monitoring toolbox.

Incursion of SARS-CoV-2 BA.2.86.1 variant into Israel: National-scale wastewater surveillance using a novel quantitative real-time PCR assay.

The emergence of the SARS-CoV-2 variant BA.2.86.1 raised a considerable concern, due to the large number of potentially virulent mutations. In this study, we developed a novel assay that specifically detects variant BA.2.86.1, and used it to screen environmental samples from wastewater treatment sites across Israel. By using a multiplex assay that included a general SARS-CoV-2 reaction, together with the BA.2.86.1-specific reaction and a control reaction, we quantified the absolute number of viral copies in each sample and its relative abundance, compared with the total copy number of circulating SARS-CoV-2. Evaluation of the new reactions showed that they are both sensitive and specific, detecting down to four copies per reaction, and maintain specificity in the presence of Omicron variants BA.1, 2 and 4 RNA. Examination of 279 samples from 30 wastewater collection sites during August-September 2023 showed that 35 samples (12.5 %) were positive, from 18 sites. Quantitative analysis of the samples showed that the relative abundance of variant BA.2.86.1 with respect to the total viral load of SARS-CoV-2 was very low and consisted between 0.01 % and 0.6 % of the total SARS-CoV-2 circulation. This study demonstrates the importance of combining wastewater surveillance with the development of specialized diagnostic assays, when clinical testing is insufficient. This approach may be useful for timely response by public health authorities in future outbreaks.

SARS-CoV-2 IgG Levels as Predictors of XBB Variant Neutralization, Israel, 2022- and 2023.

Although a vaccine against SARS-CoV-2 Omicron-XBB.1.5 variant is available worldwide and recent infection is protective, the lack of recorded infection data highlights the need to assess variant-specific antibody neutralization levels. We analyzed IgG levels against receptor-binding domain-specific SARS-CoV-2 ancestral strain as a correlate for high neutralizing titers against XBB variants.

The host transcriptional response to superinfection by influenza A virus and Streptococcus pneumoniae.

Secondary bacterial challenges during influenza virus infection "superinfection") cause excessive mortality and hospitalization. Here, we present a longitudinal study of bulk gene expression changes in murine lungs during superinfection, with an initial influenza A virus infection and a subsequent Streptococcus pneumoniae infection. In addition to the well-characterized impairment of the host response, we identified superinfection-specific alterations in the global transcriptional program that are linked to the host's ability to resist the pathogens. Particularly, whereas superinfected mice manifested an excessive rapid induction of the resistance-to-infection program, there was a substantial tissue-level rewiring of this program: upon superinfection, interferon-regulated genes were switched from positive to negative correlations with the host's resistance state, whereas genes of fatty acid metabolism switched from negative to positive correlations with resistance states. Thus, the transcriptional resistance state in superinfection is reprogrammed toward repressed interferon signaling and induced fatty acid metabolism. Our findings suggest new insights into a tissue-level remodeling of the host defense upon superinfection, providing promising targets for future therapeutic interventions. IMPORTANCE: Secondary bacterial infections are the most frequent complications during influenza A virus (IAV) pandemic outbreaks, contributing to excessive morbidity and mortality in the human population. Most IAV-related deaths are attributed to Streptococcus pneumoniae (SP) infections, which usually begin within the first week of IAV infection in the respiratory tracts. Here, we focused on longitudinal transcriptional responses during a superinfection model consisting of an SP infection that follows an initial IAV infection, comparing superinfection to an IAV-only infection, an SP-only infection, and control treatments. Our longitudinal data allowed a fine analysis of gene expression changes during superinfection. For instance, we found that superinfected mice exhibited rapid gene expression induction or reduction within the first 12 h after encountering the second pathogen. Cell proliferation and immune response activation processes were upregulated, while endothelial processes, vasculogenesis, and angiogenesis were downregulated, providing promising targets for future therapeutic interventions. We further analyzed the longitudinal transcriptional responses in the context of a previously defined spectrum of the host's resistance state, revealing superinfection-specific reprogramming of resistance states, such as reprogramming of fatty acid metabolism and interferon signaling. The reprogrammed functions are compelling new targets for switching the pathogenic superinfection state into a single-infection state.

Sixth monovalent XBB.1.5 vaccine elicits robust immune response against emerging SARS-CoV-2 variants in heart transplant recipients.

Continued circulation of severe acute respiratory syndrome coronavirus 2 has driven the selection of variants with improved ability to escape preexisting vaccine-induced responses, posing a persistent threat to heart transplant recipients (HTRs). The immunogenicity and safety of the updated XBB.1.5-containing monovalent vaccines are unknown. We prospectively enrolled 52 HTRs who had previously received a 5-dose ancestral-derived monovalent and bivalent messenger RNA (mRNA) vaccination schedule to receive the monovalent XBB.1.5 vaccine. Immunogenicity was evaluated using live virus microneutralization assays. The XBB.1.5 monovalent vaccine elicited potent and diverse neutralizing responses and broadened the reactivity spectrum to encompass newer strains, with the highest increase in neutralization activity being more pronounced against XBB.1.5 (15.8-fold) and JN.1 (13.3-fold) than against BA.5 (6.7-fold) and wild-type (4-fold). Notably, XBB.1.5 and JN.1 were resistant to neutralization by prevaccination sera. There were no safety concerns. Our findings support the updating of coronavirus disease 2019 vaccines to match antigenically divergent variants and exclude ancestral spike-antigen to protect HTRs.

Efficacy of preexposure prophylaxis with monoclonal-antibody tixagevimab-cilgavimab against emerging SARS-CoV-2 resistant variants in patients with chronic lymphocytic leukemia.

Introduction Pre exposure prophylaxis with monoclonal antibodies (mAbs) were developed in addition to COVID19 vaccine for immunocompromised and those with insufficient immune response, among them patients with CLL. Omicron variant and its sublineages evolved mutations that escape mAbs neutralizing effect, yet the extent of which was not studied. Methods We evaluated anti-spike titters and neutralization activity of COVID-19 wild type (WT) , Delta , Omicron, BA2, BA4 and BA5 before and after tixagevimab-cilgavimab (TGM/CGM) dose of 150/150mg or 300/300mg in patients with CLL. Results 70 patients were tested 2 weeks before and 4 weeks after receiving TGM/CGM mAbs. After TGM/CGM anti-spike ab level increased 170 folds from 13.6 BAU/ml (IQR, 0.4-288) to 2328 BAU/ml (IQR, 1681-3500). Neutralization activity increased in all variants, and was 176 folds higher in WT and 55 folds higher in Delta compared to 10 folds higher in Omicron and its sublineages (BA2 x11, BA4 x4 , BA5 x18). Over follow-up period of 3 months, 20 patients (29%) with CLL acquired COVID-19 infection, all recovered uneventfully. In a multivariate analysis anti-spike antibody titer was found a significant predictor for post TGM/CGM COVID19 infection. Conclusion Efficacy of preexposure prophylaxis with TGM/CGM in patients with CLL is significantly reduced in era of Omicron and its sublineages BA2, BA4 and BA5.

A Systematic Review and Clinical Presentation of Central Nervous System Complications of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospitalized Pediatric Patients During the Coronavirus Disease 2019 Pandemic in Israel.

BACKGROUND: Coronavirus disease-associated central nervous system complications (CNS-C) in hospitalized children, especially during the Omicron wave, and in comparison with influenza associated CNS-C, are not well understood. METHODS: The study population included 755 children aged <18 years hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at Sheba Medical Center, during March 2020 to July 2022. A comparative cohort consisted of 314 pediatric patients with influenza during the 2018-2019 and 2019-2020 influenza seasons. RESULTS: Overall, 5.8% (n = 44) of patients exhibited CNS-C. Seizures at presentation occurred in 33 patients with COVID-19 (4.4%), with 2.6% (n = 20) experiencing nonfebrile seizures, 1.1% (n = 8) febrile seizures, and 0.7% (n = 5) status epilepticus. More patients with CNS-C experienced seizures during the Omicron wave versus the pre-Omicron period (77.8% vs 41.2%, P = 0.03). Fewer patients were admitted to the intensive care unit in the Omicron wave (7.4%) versus prior waves (7.4% vs 41.2%, P = 0.02). Fewer patients with SARS-CoV-2 experienced CNS-C (5.8%) versus patients with influenza (9.9%), P = 0.03. More patients with SARS-CoV-2 experienced nonfebrile seizures (2.6% vs 0.6%, P = 0.06), whereas more patients with influenza experienced febrile seizures (7.3% vs 1.1%, P < 0.01). CONCLUSIONS: The Omicron wave was characterized by more seizures and fewer intensive-care-unit admissions than previous waves. Pediatric patients with SARS-CoV-2 experienced fewer CNS-C and more nonfebrile seizures compared with patients with influenza.

Tumor Treating Fields (TTFields) demonstrate antiviral functions in vitro, and safety for application to COVID-19 patients in a pilot clinical study.

Coronaviruses are the causative agents of several recent outbreaks, including the COVID-19 pandemic. One therapeutic approach is blocking viral binding to the host receptor. As binding largely depends on electrostatic interactions, we hypothesized possible inhibition of viral infection through application of electric fields, and tested the effectiveness of Tumor Treating Fields (TTFields), a clinically approved cancer treatment based on delivery of electric fields. In preclinical models, TTFields were found to inhibit coronavirus infection and replication, leading to lower viral secretion and higher cell survival, and to formation of progeny virions with lower infectivity, overall demonstrating antiviral activity. In a pilot clinical study (NCT04953234), TTFields therapy was safe for patients with severe COVID-19, also demonstrating preliminary effectiveness data, that correlated with higher device usage.

Immunogenicity of Co-Administered Omicron BA.4/BA.5 Bivalent COVID-19 and Quadrivalent Seasonal Influenza Vaccines in Israel during the 2022-2023 Winter Season.

Vaccination against COVID-19 and influenza provides the best defense against morbidity and mortality. Administering both vaccines concurrently may increase vaccination rates and reduce the burden on the healthcare system. This study evaluated the immunogenicity of healthcare workers in Israel who were co-administered with the Omicron BA.4/BA.5 bivalent COVID-19 vaccine and the 2022-2023 quadrivalent influenza vaccine. SARS-CoV-2 neutralizing antibody titers were measured via microneutralization while influenza antibody titers were measured via hemagglutination inhibition. No immunogenic interference was observed by either vaccine when co-administered. Antibody titers against SARS-CoV-2 variants increased significantly in the cohort receiving the COVID-19 vaccine alone and in combination with the influenza vaccine. Antibody titers against the A/H1N1 influenza strain increased significantly in the cohort receiving the influenza vaccine alone and in combination with the COVID-19 vaccine. Antibody titers against B/Victoria increased significantly in the cohort that received both vaccines. This study has important public health implications for the 2023-2024 winter season, and supports co-administration of both vaccines as a viable immunization strategy.

Persistent Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia in Patients Treated With Anti-CD20 Monoclonal Antibodies.

We report 8 cases of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia in patients previously treated with anti-CD20 monoclonal antibodies. Polymerase chain reaction of nasopharyngeal swabs for SARS-CoV-2 was negative in most cases; viral cell cultures confirmed that viable SARS-Co-2 virus was present. Four patients were treated with anti-SARS-CoV-2 hyperimmune globulins with rapid resolution of disease.

BNT162b2-vaccine-induced neutralization responses are immune correlates of clinical protection against SARS-CoV-2 in heart transplant recipients.

BACKGROUND: Defining immune correlates of protection against COVID-19 is pivotal for optimizing the use of COVID-19 vaccines, predicting the impact of novel variants on clinical outcomes, and advancing the development of immunotherapies and next-generation vaccines. We aimed to identify vaccine-induced immune correlates of protection against COVID-19-related hospitalizations in a highly vaccinated heart transplant (HT) cohort. METHODS: In a case-control study of HT recipients vaccinated with the BNT162b2 vaccine, patients were prospectively assessed for vaccine-induced neutralization of the wild-type virus, and the Delta and Omicron BA.1, BA.2, BA.4, and BA.5 variants. Comparative analyses with controls were conducted to identify correlates of protection against COVID-19 hospitalization. ROC analyses were performed. Primary outcomes were COVID-19 hospitalizations and severity of SARS-CoV-2 breakthrough infection. RESULTS: The study cohort comprised 59 HT recipients aged 58 (49,65) years with breakthrough infections after three or four monovalent BNT162b2 doses; 41 (69.5%) were men. Thirty-six (61%) patients with COVID-19 were hospitalized; most cases were non-severe (58, 98%). For hospitalized (vs. non-hospitalized) COVID-19 patients, vaccine-induced neutralization titers were significantly lower against all SARS-CoV-2 variants (p < .005). Vaccine-induced neutralization of the wild-type virus and delta and omicron BA.1, BA.2, BA.4, and BA.5 variants was associated with a reduced risk for COVID-19-related hospitalization. The optimal neutralization titer thresholds that were predictive of COVID-19 hospitalizations were 96 (wild-type), 48 (delta), 12 (BA.1), 96 (BA.2), 96 (BA.4), and 48 (BA.5). CONCLUSIONS: BNT162b2-vaccine-induced neutralization responses are immune correlates of protection and confer clinical protection against COVID-19 hospitalizations.

VSV-ΔG-Spike Candidate Vaccine Induces Protective Immunity and Protects K18-hACE2 Mice against SARS-CoV-2 Variants.

Since the emergence of the original SARS-CoV-2, several variants were described, raising questions as to the ability of recently developed vaccine platforms to induce immunity and provide protection against these variants. Here, we utilized the K18-hACE2 mouse model to show that VSV-ΔG-spike vaccination provides protection against several SARS-CoV-2 variants: alpha, beta, gamma, and delta. We show an overall robust immune response, regardless of variant identity, leading to reduction in viral load in target organs, prevention of morbidity and mortality, as well as prevention of severe brain immune response, which follows infection with various variants. Additionally, we provide a comprehensive comparison of the brain transcriptomic profile in response to infection with different variants of SARS-CoV-2 and show how vaccination prevents these disease manifestations. Taken together, these results highlight the robust VSV-ΔG-spike protective response against diverse SARS-CoV-2 variants, as well as its promising potential against newly arising variants.

Changes within the P681 residue of spike dictate cell fusion and syncytia formation of Delta and Omicron variants of SARS-CoV-2 with no effects on neutralization or infectivity.

The rapid spread and dominance of the Omicron SARS-CoV-2 lineages have posed severe health challenges worldwide. While extensive research on the role of the Receptor Binding Domain (RBD) in promoting viral infectivity and vaccine sensitivity has been well documented, the functional significance of the 681PRRAR/SV687 polybasic motif of the viral spike is less clear. In this work, we monitored the infectivity levels and neutralization potential of the wild-type human coronavirus 2019 (hCoV-19), Delta, and Omicron SARS-CoV-2 pseudoviruses against sera samples drawn four months post administration of a third dose of the BNT162b2 mRNA vaccine. Our findings show that in comparison to hCoV-19 and Delta SARS-CoV-2, Omicron lineages BA.1 and BA.2 exhibit enhanced infectivity and a sharp decline in their sensitivity to vaccine-induced neutralizing antibodies. Interestingly, P681 mutations within the viral spike do not play a role in the neutralization potential or infectivity of SARS Cov-2 pseudoviruses carrying mutations in this position. The P681 residue however, dictates the ability of the spike protein to promote fusion and syncytia formation between infected cells. While spike from hCoV-19 (P681) and Omicron (H681) promote only modest cell fusion and formation of syncytia between cells that express the spike-protein, Delta spike (R681) displays enhanced fusogenic activity and promotes syncytia formation. Additional analysis shows that a single P681R mutation within the hCoV-19 spike, or H681R within the Omicron spike, restores fusion potential to similar levels observed for the Delta R681 spike. Conversely, R681P point mutation within the spike of Delta pseudovirus abolishes efficient fusion and syncytia formation. Our investigation also demonstrates that spike proteins from hCoV-19 and Delta SARS-CoV-2 are efficiently incorporated into viral particles relative to the spike of Omicron lineages. We conclude that the third dose of the Pfizer-BNT162b2 provides appreciable protection against the newly emerged Omicron sub-lineages. However, the neutralization sensitivity of these new variants is diminished relative to that of the hCoV-19 or Delta SARS-CoV-2. We further show that the P681 residue within spike dictates cell fusion and syncytia formation with no effects on the infectivity of the specific viral variant and on its sensitivity to vaccine-mediated neutralization.

Proof-of-concept for effective antiviral activity of an in silico designed decoy synthetic mRNA against SARS-CoV-2 in the Vero E6 cell-based infection model.

The positive-sense single-stranded (ss) RNA viruses of the Betacoronavirus (beta-CoV) genus can spillover from mammals to humans and are an ongoing threat to global health and commerce, as demonstrated by the current zoonotic pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current anti-viral strategies focus on vaccination or targeting key viral proteins with antibodies and drugs. However, the ongoing evolution of new variants that evade vaccination or may become drug-resistant is a major challenge. Thus, antiviral compounds that circumvent these obstacles are needed. Here we describe an innovative antiviral modality based on in silico designed fully synthetic mRNA that is replication incompetent in uninfected cells (termed herein PSCT: parasitic anti-SARS-CoV-2 transcript). The PSCT sequence was engineered to include key untranslated cis-acting regulatory RNA elements of the SARS-CoV-2 genome, so as to effectively compete for replication and packaging with the standard viral genome. Using the Vero E6 cell-culture based SARS-CoV-2 infection model, we determined that the intracellular delivery of liposome-encapsulated PSCT at 1 hour post infection significantly reduced intercellular SARS-CoV-2 replication and release into the extracellular milieu as compared to mock treatment. In summary, our findings are a proof-of-concept for the therapeutic feasibility of in silico designed mRNA compounds formulated to hinder the replication and packaging of ssRNA viruses sharing a comparable genomic-structure with beta-CoVs.

Disinfection of SARS-CoV-2 by UV-LED 267 nm: comparing different variants.

UV irradiation is an efficient tool for the disinfection of viruses in general and coronavirus specifically. This study explores the disinfection kinetics of SARS-CoV-2 variants wild type (similar to the Wuhan strain) and three variants (Alpha, Delta, and Omicron) by 267 nm UV-LED. All variants showed more than 5 logs average reduction in copy number at 5 mJ/cm2 but inconsistency was evident, especially for the Alpha variant. Increasing the dose to 7 mJ/cm2 did not increase average inactivation but did result in a dramatic decrease in the inactivation inconsistency making this dose the recommended minimum. Sequence analysis suggests that the difference between the variants is likely due to small differences in the frequency of specific UV extra-sensitive nucleotide sequence motifs although this hypothesis requires further experimental testing. In summary, the use of UV-LED with their simple electricity need (can be operated from a battery or photovoltaic panel) and geometrical flexibility could offer many advantages in the prevention of SARS-CoV-2 spread, but minimal UV dose should be carefully considered.

Predictors of reinfection with pre-Omicron and Omicron variants of concern among individuals who recovered from COVID-19 in the first year of the pandemic.

OBJECTIVES: The predictors of SARS-CoV-2 reinfection are unclear. We examined predictors of reinfection with pre-Omicron and Omicron variants among COVID-19-recovered individuals. METHODS: Randomly selected COVID-19-recovered patients (N = 1004) who donated convalescent plasma during 2020 were interviewed between August 2021 and March 2022 regarding COVID-19 vaccination and laboratory-proven reinfection. The sera from 224 (22.3%) participants were tested for antispike (anti-S) immunoglobulin G and neutralizing antibodies. RESULTS: The participants' median age was 31.1 years (78.6% males). The overall reinfection incidence rate was 12.8%; 2.7% versus 21.6% for the pre-Omicron (mostly Delta) versus Omicron variants. Negative associations were found between fever during the first illness and pre-Omicron reinfection: relative risk 0.29 (95% confidence interval 0.09-0.94), high anti-N level at first illness and Omicron reinfection: 0.53 (0.33-0.85), and overall reinfection: 0.56 (0.37-0.84), as well as between subsequent COVID-19 vaccination with the BNT162b2 vaccine and pre-Omicron 0.15 (0.07-0.32), Omicron 0.48 (0.25-0.45), and overall reinfections 0.38 (0.25-0.58). These variables significantly correlated with immunoglobulin G anti-S follow-up levels. High pre-existing anti-S binding and neutralizing antibody levels against the SARS-CoV-2 Wuhan and Alpha strains predicted protection against Omicron reinfections. CONCLUSION: Strong immune responses after the first COVID-19 infection and subsequent vaccination with the BNT162b2 vaccine provided cross-protection against reinfections with the Delta and Omicron variants.