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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.

IntroductionFollowing the significant decrease in SARS-CoV-2 cases worldwide, Israel, as well as other countries, have again been faced with a rise in seasonal influenza. This study compared circulating influenza A and B in hospitalized patients in Israel with the influenza strains in the vaccine following the 2021–2022 winter season which was dominated by the omicron variant.MethodsNasopharyngeal samples of 16,325 patients were examined for the detection of influenza A(H1N1)pdm09, influenza A(H1N1)pdm09 and influenza B. Phylogenetic trees of hemagglutinin were then prepared using sanger sequencing. Vaccine immunogenicity was also performed using the hemagglutination inhibition test.ResultsOf the 16,325 nasopharyngeal samples collected from hospitalized patients between September 2021 (Week 40) and April 2023 (Week 15), 7.5% were found to be positive for influenza. Phylogenetic analyses show that in the 2021–2022 winter season, the leading virus subtype was influenza A(H3N2), belonging to clade 3C.2a1b.2a.2. However, the following winter season was dominated by influenza A(H1N1)pdm09, which belongs to clade 6B.aA.5a.2. The circulating influenza A(H1N1)pdm09 strain showed a shift from the vaccine strain, while the co-circulating influenza A(H3N2) and influenza B strains were similar to those of the vaccine. Antigenic analysis coincided with the sequence analysis.DiscussionInfluenza prevalence during 2022–2023 returned to typical levels as seen prior to the emergence of SARS-CoV-2, which may suggest a gradual viral adaptation to SARS-CoV-2 variants. Domination of influenza A(H1N1)pdm09 was observed uniquely in Israel compared to Europe and USA and phylogenetic and antigenic analysis showed lower recognition of the vaccine with the circulating influenza A(H1N1)pdm09 in Israel compared to the vaccine.

Objectives: Ivermectin, an antiparasitic agent, also has antiviral properties. In this study, we aimed to assess whether ivermectin has anti-SARS-CoV-2 activity. Methods: In this double-blinded trial, we compared patients receiving ivermectin for 3 days versus placebo in nonhospitalized adult patients with COVID-19. A reverse transcriptase-polymerase chain reaction from a nasopharyngeal swab was obtained at recruitment and every 2 days for at least 6 days. The primary endpoint was a reduction of viral load on the sixth day as reflected by cycle threshold level >30 (noninfectious level). The primary outcome was supported by the determination of viral-culture viability. Results: Of 867 patients screened, 89 were ultimately evaluated per-protocol (47 ivermectin and 42 placeboes). On day 6, the odds ratio (OR) was 2.62 (95% confidence interval [CI]: 1.09-6.31) in the ivermectin arm, reaching the endpoint. In a multivariable logistic regression model, the odds of a negative test on day 6 were 2.28 times higher in the ivermectin group but reached significance only on day 8 (OR 3.70; 95% CI: 1.19-11.49, P = 0.02). Culture viability on days 2 to 6 was positive in 13.0% (3/23) of ivermectin samples versus 48.2% (14/29) in the placebo group (P = 0.008). Conclusion: There were lower viral loads and less viable cultures in the ivermectin group, which shows its anti-SARS-CoV-2 activity. It could reduce transmission in these patients and encourage further studies with this drug.

ABSTRACT: Objectives: To compare infection rates and circulating subtypes of human metapneumovirus (hMPV) before (2019-2020) and after the emergence of coronavirus disease 2019 (COVID-19) (2021) in Israel. Methods: In total, 12,718 respiratory samples were collected from hospitalized patients of all ages during the years 2019 to 2021 at the Sheba Medical Center in Israel and subjected to reverse transcription-polymerase chain reaction analysis. In addition, whole-genome sequencing was performed to characterize the subtypes of hMPV circulating in Israel between 2019 and 2021. Results: A total of 481 samples were found positive for hMPV. Before the emergence of COVID-19, hMPV peaked in winter months and declined thereafter. In sharp contrast, during the COVID-19 pandemic, we observed a delayed peak in hMPV infection cases and higher infection of young children. Viral sequencing showed a shift in the most prevalent circulating hMPV strain from A2b to B1 during the years 2019, 2020, and 2021. Conclusion: Compared with the years before the COVID-19 pandemic, in 2021, hMPV mostly affected young children, and the most prevalent circulating subtype shifted from A2b in 2019 to B1.

Here, Israeli and Finkel et al. perform genome-wide CRISPR knockout screens to identify host factors required for the infection with SARS-CoV-2 and two additionally variants of concern, Alpha and Beta, unveiling shared and differential host pathways required by the variants, and demonstrate GATA6 is critical for SARS-CoV-2 viral entry through modulation of ACE2 expression.

Objective: : This study aimed to describe the distribution of respiratory pathogens and the occurrence of co-pathogens during the first year of the COVID-19 pandemic. Methods: We used a multiplex polymerase chain reaction (PCR) panel targeting 23 microorganisms to analyze the oro-pharyngeal samples of patients admitted to our hospital with acute respiratory infection (ARI) between March 1, 2020, and February 28, 2021. We matched 40 to 50 patients who were SARS-CoV-2 positive and SARS-CoV-2 negative per month for age and sex. Results: A total of 939 patients with multiplex PCR test results were included in the study. Respiratory pathogens where detected in only 8/476 (1.6%) patients with COVID-19 versus 87/463 (18.7%) patients with non–COVID-19 ARI patients. Diversity and rates of pathogens vastly differed from previous years but showed seasonal variance. Conclusion: Patients with SARS-CoV-2 infection presenting with ARI during the first year of the COVID-19 pandemic demonstrated paucity of respiratory co-pathogens.

Background: Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran’s Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both alpha and delta variants. Analysis of 3233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930.

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.

Summary: The global pandemic caused by SARS-CoV-2 is a major public health problem. Virus entry occurs via binding to ACE2. Five SARS-CoV-2 variants of concern (VOCs) were reported so far, all having immune escape characteristics. Infection with the current VOC Omicron was noticed in immunized and recovered individuals; therefore, the development of new treatments against VOC infections is urgently needed. Most approved mAbs treatments against SARS-CoV-2 are directed against the spike protein of the original virus and are therefore inefficient against Omicron. Here, we report on the generation of hACE2.16, an anti-ACE2 antibody that recognizes and blocks ACE2-RBD binding without affecting ACE2 enzymatic activity. We demonstrate that hACE2.16 binding to ACE2 does not affect its surface expression and that hACE2.16 blocks infection and virus production of various VOCs including Omicron BA.1 and BA.2. hACE2.16 might, therefore, be an efficient treatment against all VOCs, the current and probably also future ones.

Influenza A and other respiratory viruses, circulate each winter and cause respiratory illness that can lead to severe complications in hospitalized patients. During the COVID-19 pandemic, only a few cases of respiratory viruses were detected in Israel. Our study applied RT-PCR to examine 13,674 samples collected from patients hospitalized with respiratory symptoms in 2019, 2020, and 2021 and the first half of the 2022 winter. A sharp increase in influenza A(H3N2) cases was observed in winter 2021-2022 as compared to 2020, followed by a sudden decrease in influenza cases after the detection of the SARS-CoV-2 omicron variant in Israel. Comparison of the area under the curve (AUC) of influenza infection rates during 7 consecutive winter seasons found that the minimal AUC between 2015 and 2020 was 281.1, while in 2021-2022, it was significantly lower (162.6 AUC; p = 0.0017), although the percentage of positive influenza cases was similar to those of previous years. The presented findings show how the dominance of influenza A(H3N2) abruptly ended upon circulation of the SARS-CoV-2 omicron variant. However, a post-COVID-19 influenza outbreak is possible, hence the planning of the next influenza vaccine is critical to ensure lower influenza-related hospitalization rates.

The immune responses of liver transplant (LT) recipients after the third boost of the BNT162b2mRNA vaccine improved. This study evaluates the durability of the immune response of LT recipients after the third boost, its predictors, and the impact of emerging variants. The receptor-binding domain IgG was determined at median times of 22 (first test) and 133 days (second test) after the administration of the third boost. IgG antibody titers > 21.4 BAU/mL were defined as a positive response. The neutralization efficacies of the vaccine against the wild-type, Omicron, and Delta variants were compared in the first test. The 59 LT recipients were of a median age of 61 years (range 25–82); 53.5% were male. Following administration of the third dose, the positive immune response decreased from 81.4% to 76.3% between the first and second tests, respectively, (p < 0.0001). The multivariate analysis identified CNI monotherapy (p = 0.02) and hemoglobin > 12 g/dL (p = 0.02) as independent predictors of a maintained positive immune response 133 days after the third dose. The geometric mean titers of Omicron neutralization were significantly lower than the wild-type and Delta virus (21, 137, 128, respectively; p < 0.0001). The immune response after the third BNT162b2mRNA vaccine dose decreased significantly in LT recipients. Further studies are required to evaluate the efficacy of the fourth vaccine dose and the durability of the immune response.

The immune response of liver transplant (LT) recipients to a third dose of the BNT162b2 mRNA vaccine significantly waned after four months. We aimed to evaluate the immune response and breakthrough infection rates of a fourth dose against the Omicron variants among LT recipients. LT recipients who had no past or active SARS-CoV-2 infection and received three doses of the BNT162b2mRNA vaccine were included. Of the 73 LT recipients, 50 (68.5%) received a fourth dose. The fourth dose was associated with a significantly higher positive immune response than the third dose. Receptor-binding domain (RBD) IgG and Omicron BA.1 and BA.2 neutralizing antibodies were determined at a median of 132 and 29 days after the third and fourth vaccines. They were 345 binding antibody units per milliliter (BAU/mL) vs. 2118 BAU/mL (p < 0.0001), 10 vs. 87 (p < 0.0001), and 15 vs. 149 (p = 0.001), respectively. Breakthrough infections were documented among nine (18%) LT recipients after the fourth dose and among seven (30.4%) patients following the third dose (p = 0.2); 93.5% of breakthrough infections were mild. The infection rate after the fourth dose was higher among diabetic vs. nondiabetic recipients (33.3% vs. 6.9%, respectively; p = 0.02). Further studies are needed to evaluate additional factors influencing the breakthrough infection rate among LT recipients.

Emerging SARS-CoV-2 variants may threaten global vaccination efforts and the awaited reduction in outbreak burden. In this study, we report a novel variant carrying the L452R mutation that emerged from a local B.1.362 lineage, B.1.362+L452R. The L452R mutation is associated with the Delta and Epsilon variants and was shown to cause increased infection and reduction in neutralization in pseudoviruses. Indeed, the B.1.362+L452R variant demonstrated a X4-fold reduction in neutralization capacity of sera from BNT162b2-vaccinated individuals compared to a wild-type strain. The variant infected 270 individuals in Israel between December 2020 and March 2021, until diminishing due to the gain in dominance of the Alpha variant in February 2021. This study demonstrates an independent, local emergence of a variant carrying a critical mutation, L452R, which may have the potential of becoming a variant of concern and emphasizes the importance of routine surveillance and detection of novel variants among efforts undertaken to prevent further disease spread.