Publications by authors named "Tomer Israely"

41 Publications

Human Kidney Spheroids and Monolayers Provide Insights into SARS-CoV-2 Renal Interactions.

J Am Soc Nephrol 2021 Jun 10. Epub 2021 Jun 10.

B Dekel, Pediatric Stem Cell Research Institute, Edmond and Lily Sara Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel

Although coronavirus disease 2019 (COVID-19) causes significant morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major components of the disease. Kidney disease, usually presenting as acute kidney injury (AKI), is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19's causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms. Using cell models, we sought to analyze SARS-Cov2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies and grown as proliferating monolayers) and more quiescent three-dimensional kidney spheroids. We demonstrated that viral entry molecules and high baseline levels of type 1 interferon-related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2-infected controls (Vero E6 cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-Cov-2 in actively proliferating monolayers, although the spheroid cultures exhibited higher levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules-including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)-as well as a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury. SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection.
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http://dx.doi.org/10.1681/ASN.2020111546DOI Listing
June 2021

Lipid Nanoparticle RBD-hFc mRNA Vaccine Protects hACE2 Transgenic Mice against a Lethal SARS-CoV-2 Infection.

Nano Lett 2021 06 25;21(11):4774-4779. Epub 2021 May 25.

Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona 76100, Israel.

The COVID-19 pandemic led to development of mRNA vaccines, which became a leading anti-SARS-CoV-2 immunization platform. Preclinical studies are limited to infection-prone animals such as hamsters and monkeys in which protective efficacy of vaccines cannot be fully appreciated. We recently reported a SARS-CoV-2 human Fc-conjugated receptor-binding domain (RBD-hFc) mRNA vaccine delivered via lipid nanoparticles (LNPs). BALB/c mice demonstrated specific immunologic responses following RBD-hFc mRNA vaccination. Now, we evaluated the protective effect of this RBD-hFc mRNA vaccine by employing the K18 human angiotensin-converting enzyme 2 (K18-hACE2) mouse model. Administration of an RBD-hFc mRNA vaccine to K18-hACE2 mice resulted in robust humoral responses comprising binding and neutralizing antibodies. In correlation with this response, 70% of vaccinated mice withstood a lethal SARS-CoV-2 dose, while all control animals succumbed to infection. To the best of our knowledge, this is the first nonreplicating mRNA vaccine study reporting protection of K18-hACE2 against a lethal SARS-CoV-2 infection.
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http://dx.doi.org/10.1021/acs.nanolett.1c01284DOI Listing
June 2021

Sensitive immunodetection of SARS-CoV-2 variants-of-concern 501Y.V2 and 501Y.V1.

J Infect Dis 2021 May 23. Epub 2021 May 23.

The Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona, 7410001, Israel.

Emerging SARS-CoV-2 variants potentially influence the effectiveness of existing laboratory diagnostics. In this study we determined whether the British (20I/501Y.V1) and South-African (20H/501Y.V2) SARS-CoV-2 variants-of-concern (VOC) are detected by an in-house S1-based antigen-detection assay. Analysis was performed in spiked pools of qRT-PCR negative nasopharyngeal swab specimens. The assay, composed of a combination of four monoclonal antibodies, allowed sensitive detection of both the wild-type and the analyzed VOCs, despite the accumulation of several mutations in the variants' S1 region. We suggest that the combination of four monoclonal antibodies, targeting distinct epitopes, maintained both the specificity and the universality of the assay.
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http://dx.doi.org/10.1093/infdis/jiab278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194863PMC
May 2021

SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis.

Nature 2021 06 12;594(7862):240-245. Epub 2021 May 12.

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-19. Coronaviruses have developed a variety of mechanisms to repress host mRNA translation to allow the translation of viral mRNA, and concomitantly block the cellular innate immune response. Although several different proteins of SARS-CoV-2 have previously been implicated in shutting off host expression, a comprehensive picture of the effects of SARS-CoV-2 infection on cellular gene expression is lacking. Here we combine RNA sequencing, ribosome profiling and metabolic labelling of newly synthesized RNA to comprehensively define the mechanisms that are used by SARS-CoV-2 to shut off cellular protein synthesis. We show that infection leads to a global reduction in translation, but that viral transcripts are not preferentially translated. Instead, we find that infection leads to the accelerated degradation of cytosolic cellular mRNAs, which facilitates viral takeover of the mRNA pool in infected cells. We reveal that the translation of transcripts that are induced in response to infection (including innate immune genes) is impaired. We demonstrate this impairment is probably mediated by inhibition of nuclear mRNA export, which prevents newly transcribed cellular mRNA from accessing ribosomes. Overall, our results uncover a multipronged strategy that is used by SARS-CoV-2 to take over the translation machinery and to suppress host defences.
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http://dx.doi.org/10.1038/s41586-021-03610-3DOI Listing
June 2021

Mice with induced pulmonary morbidities display severe lung inflammation and mortality following exposure to SARS-CoV-2.

JCI Insight 2021 May 11. Epub 2021 May 11.

Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.

Mice are normally unaffected by SARS-CoV-2 infection since the virus does not bind effectively to the murine version of the ACE2 receptor molecule. Here we report that induced mild pulmonary morbidities render SARS-CoV-2 refractive CD-1 mice to be susceptible to this virus. Specifically, SARS-CoV-2 infection after application of low-doses of the acute-lung-injury stimulants bleomycin or ricin caused a severe disease in CD-1 mice, manifested by sustained body weight loss and mortality rates of >50%. Further studies revealed markedly higher levels of viral RNA in the lungs, heart and serum of low-dose-ricin pretreated, as compared to non-pretreated mice. Furthermore, lung extracts prepared 2-3 days after viral infection contained subgenomic RNA and virus particles capable of replication, only when derived from the pretreated mice. The deleterious effects of SARS-CoV-2 infection were effectively alleviated by passive transfer of polyclonal or monoclonal antibodies generated against SARS-CoV-2 RBD. Thus, viral cell entry in the sensitized mice seems to depend on viral RBD binding, albeit by a mechanism other than the canonical ACE2-mediated uptake route. This unique mode of viral entry, observed over a mildly injured tissue background, may contribute to the exacerbation of COVID-19 pathologies in patients with preexisting morbidities.
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http://dx.doi.org/10.1172/jci.insight.145916DOI Listing
May 2021

Neutralizing Monoclonal Anti-SARS-CoV-2 Antibodies Isolated from Immunized Rabbits Define Novel Vulnerable Spike-Protein Epitope.

Viruses 2021 03 26;13(4). Epub 2021 Mar 26.

Israel Institute for Biological Research, Ness-Ziona 74100, Israel.

Monoclonal antibodies represent an important avenue for COVID-19 therapy and are routinely used for rapid and accessible diagnosis of SARS-CoV-2 infection. The recent emergence of SARS-CoV-2 genetic variants emphasized the need to enlarge the repertoire of antibodies that target diverse epitopes, the combination of which may improve immune-diagnostics, augment the efficiency of the immunotherapy and prevent selection of escape-mutants. Antigen-specific controlled immunization of experimental animals may elicit antibody repertoires that significantly differ from those generated in the context of the immune response mounted in the course of disease. Accordingly, rabbits were immunized by several recombinant antigens representing distinct domains of the viral spike protein and monoclonal antibodies were isolated from single cells obtained by cell sorting. Characterization of a panel of successfully isolated anti-receptor binding domain (RBD) and anti-N-terminal domain (NTD) antibodies demonstrated that they exhibit high specificity and affinity profiles. Anti-RBD antibodies revealing significant neutralizing potency against SARS-CoV-2 in vitro were found to target at least three distinct epitopes. Epitope mapping established that two of these antibodies recognized a novel epitope located on the surface of the RBD. We suggest that the antibodies isolated in this study are useful for designing SARS-CoV-2 diagnosis and therapy approaches.
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http://dx.doi.org/10.3390/v13040566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065470PMC
March 2021

Spike vs nucleocapsid SARS-CoV-2 antigen detection: application in nasopharyngeal swab specimens.

Anal Bioanal Chem 2021 May 25;413(13):3501-3510. Epub 2021 Mar 25.

The Department of Infectious Diseases, Israel Institute for Biological Research, 7410001, Ness-Ziona, Israel.

Public health experts emphasize the need for quick, point-of-care SARS-CoV-2 detection as an effective strategy for controlling virus spread. To this end, many "antigen" detection devices were developed and commercialized. These devices are mostly based on detecting SARS-CoV-2's nucleocapsid protein. Recently, alerts issued by both the FDA and the CDC raised concerns regarding the devices' tendency to exhibit false positive results. In this work, we developed a novel alternative spike-based antigen assay, comprising four high-affinity, specific monoclonal antibodies, directed against different epitopes on the spike's S1 subunit. The assay's performance was evaluated for COVID-19 detection from nasopharyngeal swabs, compared to an in-house nucleocapsid-based assay, composed of novel antibodies directed against the nucleocapsid. Detection of COVID-19 was carried out in a cohort of 284 qRT-PCR positive and negative nasopharyngeal swab samples. The time resolved fluorescence (TRF) ELISA spike assay displayed very high specificity (99%) accompanied with a somewhat lower sensitivity (66% for Ct < 25), compared to the nucleocapsid ELISA assay which was more sensitive (85% for Ct < 25) while less specific (87% specificity). Despite being outperformed by qRT-PCR, we suggest that there is room for such tests in the clinical setting, as cheap and rapid pre-screening tools. Our results further suggest that when applying antigen detection, one must consider its intended application (sensitivity vs specificity), taking into consideration that the nucleocapsid might not be the optimal target. In this regard, we propose that a combination of both antigens might contribute to the validity of the results. Schematic representation of sample collection and analysis. The figure was created using BioRender.com.
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http://dx.doi.org/10.1007/s00216-021-03298-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993413PMC
May 2021

Glucosylceramide synthase inhibitors prevent replication of SARS-CoV-2 and Influenza virus.

J Biol Chem 2021 Feb 24:100470. Epub 2021 Feb 24.

Departments of Infectious diseases, Israel institute for Biological Research, Ness-Ziona, 7410000, Israel.

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Vaccines are ideal solutions to prevent infection, but treatments are also needed for those who have contracted the virus to limit negative outcomes, when vaccines are not applicable. Viruses must cross host cell membranes during their lifecycle, creating a dependency on processes involving membrane dynamics. Thus, in this study we examined whether the synthetic machinery for glycosphingolipids, biologically active components of cell membranes, can serve as a therapeutic target to combat SARS-CoV-2. We examined the antiviral effect of two specific inhibitors of glucosylceramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, and (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit replication of SARS-CoV-2. Moreover, these inhibitors also disrupt replication of influenza virus A/PR/8/34 (H1N1). Our data imply that synthesis of glycosphingolipids is necessary to support viral life cycles, and suggest that GCS inhibitors should be further explored as antiviral therapies.
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http://dx.doi.org/10.1016/j.jbc.2021.100470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904475PMC
February 2021

Post-exposure protection of SARS-CoV-2 lethal infected K18-hACE2 transgenic mice by neutralizing human monoclonal antibody.

Nat Commun 2021 02 11;12(1):944. Epub 2021 Feb 11.

Israel Institute for Biological Research, Ness-Ziona, Israel.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits high levels of mortality and morbidity and has dramatic consequences on human life, sociality and global economy. Neutralizing antibodies constitute a highly promising approach for treating and preventing infection by this novel pathogen. In the present study, we characterize and further evaluate the recently identified human monoclonal MD65 antibody for its ability to provide protection against a lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice. Eighty percent of the untreated mice succumbed 6-9 days post-infection, while administration of the MD65 antibody as late as 3 days after exposure rescued all infected animals. In addition, the efficiency of the treatment is supported by prevention of morbidity and ablation of the load of infective virions in the lungs of treated animals. The data demonstrate the therapeutic value of human monoclonal antibodies as a life-saving treatment for severe COVID-19 infection.
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http://dx.doi.org/10.1038/s41467-021-21239-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878817PMC
February 2021

A single dose of recombinant VSV-∆G-spike vaccine provides protection against SARS-CoV-2 challenge.

Nat Commun 2020 12 16;11(1):6402. Epub 2020 Dec 16.

Israel Institute for Biological Research, Ness Ziona, Israel.

The COVID-19 pandemic caused by SARS-CoV-2 imposes an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we show the development of a replication competent recombinant VSV-∆G-spike vaccine, in which the glycoprotein of VSV is replaced by the spike protein of SARS-CoV-2. In-vitro characterization of this vaccine indicates the expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in-vivo model for COVID-19 is implemented. We show that a single-dose vaccination results in a rapid and potent induction of SARS-CoV-2 neutralizing antibodies. Importantly, vaccination protects hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss, and  alleviation of the extensive tissue damage and viral loads in lungs and nasal turbinates. Taken together, we suggest the recombinant VSV-∆G-spike as a safe, efficacious and protective vaccine against SARS-CoV-2.
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http://dx.doi.org/10.1038/s41467-020-20228-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745033PMC
December 2020

Characteristics of Clinically Asymptomatic Patients with SARS-CoV-2 Infections, Case Series.

Prehosp Disaster Med 2021 Feb 17;36(1):125-128. Epub 2020 Nov 17.

Infection Prevention & Control Unit, Sheba Medical Center, Ramat Gan, affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Up until now, there is much debate about the role of asymptomatic patients and pauci-symptomatic patients in severe acute respiratory syndrome novel coronavirus 2 (SARS-CoV-2) transmission, and little is known about the kinetics of viral ribonucleic acid (RNA) shedding in these populations. This article aims to describe key features and the nature of asymptomatic and pauci-symptomatic SARS-CoV-2 infected patients. The cohort consisted of six participants, three pairs, which were infected with SARS-CoV-2 during February 2020 on board the Diamond Princess. Of the six confirmed (reverse transcription polymerase chain reaction [RT-PCR]) cases, four were initially diagnosed in Japan and two upon their arrival to Israel. Duration of infection was between four days and up to 26 days. Of the six patients, three were completely asymptomatic and the others were pauci-symptomatic. All five patients in whom a computerized tomography (CT) scan was performed had lung pathology. In one patient, infectivity was tested using cell culture and a cytopathic effect was demonstrated. A serology test was performed in three of the patients and all three had a positive immunoglobulin G (IgG) four to eight weeks after disease onset. This case series demonstrates that asymptomatic and pauci-symptomatic patients may play a role in infection transmission by demonstrating probable transmission among asymptomatic spouses and by demonstrating a viable virus via a cell culture. Additionally, asymptomatic and pauci-symptomatic patients can have lung pathology and developing IgG antibodies.
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http://dx.doi.org/10.1017/S1049023X20001466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711496PMC
February 2021

Influenza virus infection augments susceptibility to respiratory Yersinia pestis exposure and impacts the efficacy of antiplague antibiotic treatments.

Sci Rep 2020 11 5;10(1):19116. Epub 2020 Nov 5.

Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.

Various respiratory viral infections in general and seasonal influenza in particular may increase the susceptibility to bacterial infections. Plague caused by Yersinia pestis endangers large populations during outbreaks or bioterrorism attacks. Recommended antibiotic countermeasures include well-established protocols based on animal studies and corroborated by effective treatment of human cases. Until now, prior exposure to viral respiratory infections was not taken into consideration when selecting the appropriate treatment for plague. Here, we show that as late as 25 days after exposure to influenza virus, convalescent mice still exhibited an increased susceptibility to sublethal doses of Y. pestis, presented with aberrant cytokine expression, and impaired neutrophil infiltration in the lungs. Increased levels of M2 alveolar macrophages and type II epithelial cells, as well as induction in metalloproteases expression and collagen and laminin degradation, suggested that the previous viral infection was under resolution, correlating with enhanced susceptibility to plague. Surprisingly, postexposure prophylaxis treatment with the recommended drugs revealed that ciprofloxacin was superior to doxycycline in mice recovering from influenza infection. These results suggest that after an influenza infection, the consequences, such as impaired immunity and lung tissue remodeling and damage, should be considered when treating subsequent Y. pestis exposure.
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http://dx.doi.org/10.1038/s41598-020-75840-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645720PMC
November 2020

A Cell-Based Capture Assay for Rapid Virus Detection.

Viruses 2020 10 15;12(10). Epub 2020 Oct 15.

The Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 74100, Israel.

Routine methods for virus detection in clinical specimens rely on a variety of sensitive methods, such as genetic, cell culture and immuno-based assays. It is imperative that the detection assays would be reliable, reproducible, sensitive and rapid. Isolation of viruses from clinical samples is crucial for deeper virus identification and analysis. Here we introduce a rapid cell-based assay for isolation and detection of viruses. As a proof of concept several model viruses including West Nile Virus (WNV), Modified Vaccinia Ankara (MVA) and Adenovirus were chosen. Suspended Vero cells were employed to capture the viruses following specific antibody labeling which enables their detection by flow cytometry and immuno-fluorescence microscopy assays. Using flow cytometry, a dose response analysis was performed in which 3.6e4 pfu/mL and 1e6 pfu/mL of MVA and WNV could be detected within two hours, respectively. When spiked to commercial pooled human serum, detection sensitivity was slightly reduced to 3e6 pfu/mL for WNV, but remained essentially the same for MVA. In conclusion, the study demonstrates a robust and rapid methodology for virus detection using flow cytometry and fluorescence microscopy. We propose that this proof of concept may prove useful in identifying future pathogens.
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http://dx.doi.org/10.3390/v12101165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602404PMC
October 2020

Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma.

EClinicalMedicine 2020 Sep 9;26:100525. Epub 2020 Sep 9.

Medical directorate, Ministry of Health, Jerusalem, Israel.

Background: We assessed outcome of patients with moderate and severe COVID-19 following treatment with convalescent plasma (CP) and the association with IgG levels in transfused CP.

Methods: A prospective cohort study. Primary outcome was improvement at day 14 defined as alive, not on mechanical ventilation, and moderate, mild, or recovered from COVID-19. Antibody levels in CP units were unknown at the time of treatment. IgG against the spike protein S1 was subsequently measured by ELISA. Neutralizing antibodies titers were determined in a subset. Outcome was assessed in relation to the mean antibody level transfused to the patients (≤4.0 versus >4.0).

Findings: Of 49 patients, 11 (22.4%) had moderate, 38 (77.6%) had severe disease, 28 were ventilated. At day 14, 24 (49.0%) patients improved, 9 (18.4%) died, and 13 (26.5%) were ventilated. In 14/98 (14.3%) CP units IgG was < 1.1 (cutoff calibration) and in 60 (61.2%) ≤4.0. IgG level and neutralizing antibody titer were correlated (0.85  < 0.001). In patients receiving ≤4.0 antibody levels, 11/30 improved (36.7%) versus 13/19 (68.4%) in patients receiving >4.0 odds ratio (OR) 0.267 [95% confidence interval (CI) 0.079-0.905],  = 0.030. In patients diagnosed >10 days prior to treatment, 4/14 (22.4%) improved in the ≤4.0 antibody group, versus 6/7 (85.7%) in the >4.0 antibody group, OR 0.048 (95% CI, 0.004-0.520),  = 0.007. No serious adverse events were reported.

Interpretation: Treatment with CP with higher levels of IgG against S1 may benefit patients with moderate and severe COVID-19. IgG against S1 level in CP predicts neutralization antibodies titers.
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http://dx.doi.org/10.1016/j.eclinm.2020.100525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480446PMC
September 2020

Detection and infectivity potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) environmental contamination in isolation units and quarantine facilities.

Clin Microbiol Infect 2020 Dec 10;26(12):1658-1662. Epub 2020 Sep 10.

Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel. Electronic address:

Objectives: Environmental surfaces have been suggested as likely contributors in the transmission of COVID-19. This study assessed the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contaminating surfaces and objects in two hospital isolation units and a quarantine hotel.

Methods: SARS-CoV-2 virus stability and infectivity on non-porous surfaces was tested under controlled laboratory conditions. Surface and air sampling were conducted at two COVID-19 isolation units and in a quarantine hotel. Viral RNA was detected by RT-PCR and infectivity was assessed by VERO E6 CPE test.

Results: In laboratory-controlled conditions, SARS-CoV-2 gradually lost its infectivity completely by day 4 at ambient temperature, and the decay rate of viral viability on surfaces directly correlated with increase in temperature. Viral RNA was detected in 29/55 surface samples (52.7%) and 16/42 surface samples (38%) from the surroundings of symptomatic COVID-19 patients in isolation units of two hospitals and in a quarantine hotel for asymptomatic and very mild COVID-19 patients. None of the surface and air samples from the three sites (0/97) were found to contain infectious titres of SARS-Cov-2 on tissue culture assay.

Conclusions: Despite prolonged viability of SARS-CoV-2 under laboratory-controlled conditions, uncultivable viral contamination of inanimate surfaces might suggest low feasibility for indirect fomite transmission.
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http://dx.doi.org/10.1016/j.cmi.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481174PMC
December 2020

The coding capacity of SARS-CoV-2.

Nature 2021 01 9;589(7840):125-130. Epub 2020 Sep 9.

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. To understand the pathogenicity and antigenic potential of SARS-CoV-2 and to develop therapeutic tools, it is essential to profile the full repertoire of its expressed proteins. The current map of SARS-CoV-2 coding capacity is based on computational predictions and relies on homology with other coronaviruses. As the protein complement varies among coronaviruses, especially in regard to the variety of accessory proteins, it is crucial to characterize the specific range of SARS-CoV-2 proteins in an unbiased and open-ended manner. Here, using a suite of ribosome-profiling techniques, we present a high-resolution map of coding regions in the SARS-CoV-2 genome, which enables us to accurately quantify the expression of canonical viral open reading frames (ORFs) and to identify 23 unannotated viral ORFs. These ORFs include upstream ORFs that are likely to have a regulatory role, several in-frame internal ORFs within existing ORFs, resulting in N-terminally truncated products, as well as internal out-of-frame ORFs, which generate novel polypeptides. We further show that viral mRNAs are not translated more efficiently than host mRNAs; instead, virus translation dominates host translation because of the high levels of viral transcripts. Our work provides a resource that will form the basis of future functional studies.
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http://dx.doi.org/10.1038/s41586-020-2739-1DOI Listing
January 2021

A panel of human neutralizing mAbs targeting SARS-CoV-2 spike at multiple epitopes.

Nat Commun 2020 08 27;11(1):4303. Epub 2020 Aug 27.

Israel Institute for Biological Research, Ness-Ziona, Israel.

The novel highly transmissible human coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Thus far, there is no approved therapeutic drug specifically targeting this emerging virus. Here we report the isolation and characterization of a panel of human neutralizing monoclonal antibodies targeting the SARS-CoV-2 receptor binding domain (RBD). These antibodies were selected from a phage display library constructed using peripheral circulatory lymphocytes collected from patients at the acute phase of the disease. These neutralizing antibodies are shown to recognize distinct epitopes on the viral spike RBD. A subset of the antibodies exert their inhibitory activity by abrogating binding of the RBD to the human ACE2 receptor. The human monoclonal antibodies described here represent a promising basis for the design of efficient combined post-exposure therapy for SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41467-020-18159-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452893PMC
August 2020

Innate immune response in neuronopathic forms of Gaucher disease confers resistance against viral-induced encephalitis.

Acta Neuropathol Commun 2020 08 24;8(1):144. Epub 2020 Aug 24.

Department of Infectious Diseases, Israel Institute for Biological Research, P.O. Box 19, 7410001, Ness-Ziona, Israel.

Both monogenic diseases and viral infections can manifest in a broad spectrum of clinical phenotypes that range from asymptomatic to lethal, suggesting that other factors modulate disease severity. Here, we examine the interplay between the genetic neuronopathic Gaucher's disease (nGD), and neuroinvasive Sindbis virus (SVNI) infection. Infection of nGD mice with SVNI had no influence on nGD severity. However, nGD mice were more resistant to SVNI infection. Significantly different inflammatory responses were seen in nGD brains when compared with SVNI brains: the inflammatory response in the nGD brains consisted of reactive astrocytes and microglia with no infiltrating macrophages, but the inflammatory response in the brains of SVNI-infected mice was characterized by infiltration of macrophages and altered activation of microglia and astrocytes. We suggest that the innate immune response activated in nGD confers resistance against viral infection of the CNS.
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http://dx.doi.org/10.1186/s40478-020-01020-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443817PMC
August 2020

CpG Oligonucleotides Protect Mice From Alphavirus Encephalitis: Role of NK Cells, Interferons, and TNF.

Front Immunol 2020 18;11:237. Epub 2020 Feb 18.

Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States.

Arboviruses including alphavirus are responsible for most emerging infectious diseases worldwide. Recent outbreaks of chikungunya virus serve as a stark reminder to their pathogenic potential. There are no vaccines or therapeutics currently available to contain alphavirus outbreaks. In this study we evaluated the effect of immunomodulatory CpG ODN on the clinical progression of neurotropic Sindbis virus infection. Neonatal C57Bl-6 mice challenged with Sindbis virus AR339 (25 PFU Subcutaneous) infect neurons in the CNS leading to the development of ataxia, seizures, paralysis, and death. We show that systemic administration of CpG ODN modulates the cytokine and chemokine gene expression levels in the CNS and ultimately protects neonatal mice from lethal neurotropic infection. The protection conferred by CpG ODN is controlled by innate immune response and T and B cells were dispensable. Further, protection required Type I, Type II interferons, and TNF as well as functional NK cells, but did not involve iNOS. This study confirms that administration of innate immune modulators can be used as a strategy to boost host innate immune responses and protect against neurotropic viruses reducing their pathogenic footprint.
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http://dx.doi.org/10.3389/fimmu.2020.00237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040238PMC
March 2021

Diagnosis of Imported Monkeypox, Israel, 2018.

Emerg Infect Dis 2019 05 17;25(5):980-983. Epub 2019 May 17.

We report a case of monkeypox in a man who returned from Nigeria to Israel in 2018. Virus was detected in pustule swabs by transmission electron microscopy and PCR and confirmed by immunofluorescence assay, tissue culture, and ELISA. The West Africa monkeypox outbreak calls for increased awareness by public health authorities worldwide.
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http://dx.doi.org/10.3201/eid2505.190076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478227PMC
May 2019

Differential Response Following Infection of Mouse CNS with Virulent and Attenuated Vaccinia Virus Strains.

Vaccines (Basel) 2019 Feb 12;7(1). Epub 2019 Feb 12.

Department of Infectious Diseases, Israel Institute of Biological Research (IIBR), Ness-Ziona, Israel.

Viral infections of the central nervous system (CNS) lead to a broad range of pathologies. CNS infections with Orthopox viruses have been mainly documented as an adverse reaction to smallpox vaccination with vaccinia virus. To date, there is insufficient data regarding the mechanisms underlying pathological viral replication or viral clearance. Therefore, informed risk assessment of vaccine adverse reactions or outcome prediction is limited. This work applied a model of viral infection of the CNS, comparing neurovirulent with attenuated strains. We followed various parameters along the disease and correlated viral load, morbidity, and mortality with tissue integrity, innate and adaptive immune response and functionality of the blood⁻brain barrier. Combining these data with whole brain RNA-seq analysis performed at different time points indicated that neurovirulence is associated with host immune silencing followed by induction of tissue damage-specific pathways. In contrast, brain infection with attenuated strains resulted in rapid and robust induction of innate and adaptive protective immunity, followed by viral clearance and recovery. This study significantly improves our understanding of the mechanisms and processes determining the consequence of viral CNS infection and highlights potential biomarkers associated with such outcomes.
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http://dx.doi.org/10.3390/vaccines7010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466266PMC
February 2019

High Endemicity and Distinct Phylogenetic Characteristics of Sindbis Virus in Israel.

J Infect Dis 2018 09;218(9):1500-1506

Central Virology Laboratory, Ministry of Health, Chaim Sheba Medical Center, Tel-Hashomer.

Sindbis virus (SINV) is a mosquito-borne Alphavirus responsible for outbreaks of SINV disease, mainly in north Europe. SINV has been isolated from mosquitoes in Israel since the 1980s but SINV disease outbreaks have never been recorded. To gain better understanding of the kinetics of SINV circulation in Israel, 3008 mosquito pools, collected 2004-2006 and 2013-2015, were tested for SINV and phylogenetic analysis was conducted on partially sequenced SINV-positive pools. Results indicate possible expansion of SINV circulation across Israel in 2013-2015 compared to 2004-2006 with 6.35% (191 pools) of total pools positive for SINV RNA. Phylogenetic analysis showed all sequenced Israeli SINV strains belong to genotype I and form, together with SINV sequences from Saudi Arabia, a distinct Middle Eastern cluster. With high endemicity of SINV and as a major crossroads for bird migration between Africa and Eurasia, Israel provides valuable information on SINV dynamics and pathogenicity.
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http://dx.doi.org/10.1093/infdis/jiy234DOI Listing
September 2018

Challenges and Achievements in Prevention and Treatment of Smallpox.

Vaccines (Basel) 2018 Jan 29;6(1). Epub 2018 Jan 29.

Department of Infectious Diseases, Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona 74100, Israel.

Declaration of smallpox eradication by the WHO in 1980 led to discontinuation of the worldwide vaccination campaign. The increasing percentage of unvaccinated individuals, the existence of its causative infectious agent variola virus (VARV), and the recent synthetic achievements increase the threat of intentional or accidental release and reemergence of smallpox. Control of smallpox would require an emergency vaccination campaign, as no other protective measure has been approved to achieve eradication and ensure worldwide protection. Experimental data in surrogate animal models support the assumption, based on anecdotal, uncontrolled historical data, that vaccination up to 4 days postexposure confers effective protection. The long incubation period, and the uncertainty of the exposure status in the surrounding population, call for the development and evaluation of safe and effective methods enabling extension of the therapeutic window, and to reduce the disease manifestations and vaccine adverse reactions. To achieve these goals, we need to evaluate the efficacy of novel and already licensed vaccines as a sole treatment, or in conjunction with immune modulators and antiviral drugs. In this review, we address the available data, recent achievements, and open questions.
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http://dx.doi.org/10.3390/vaccines6010008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874649PMC
January 2018

Cell based assay identifies TLR2 and TLR4 stimulating impurities in Interferon beta.

Sci Rep 2017 09 5;7(1):10490. Epub 2017 Sep 5.

Laboratory of Immunology, Division of Biotechnology Review and Research III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.

Immunogenicity can have devastating consequences on the safety and efficacy of therapeutic proteins. Therefore, evaluating and mitigating the risk of product immunogenicity is critical for the development these products. This study, showed that Betaseron and Extavia, which are reported to be more immunogenic among IFNβ products in clinical usage, contain residual innate immune response modulating impurities (IIRMIs) capable of activating NF-κB and induced expression of inflammatory mediators. These IIRMIs were undetectable in Rebif or Avonex. The stimulatory effect was attributed solely to IIRMIs because it was evident in murine cells lacking the interferon receptor (IFNAR). The IIRMIs in Betaseron and Extavia triggered NF-κB activation in HEK-293 cells bearing TLR2 and TLR4 in MyD88 dependent manner. Importantly, the IIRMIs in Betaseron induced up-regulation of IL-6, IL-1β, and ccl5 in the skin of IFNAR knock out mice following subcutaneous administration. This indicates that trace level IIRMIs in Betaseron could contribute to the higher immunogenicity rates seen in clinics. Together these data suggest that cell based assays can reveal subtle but clinically relevant differences in IIRMIs following manufacturing changes or between products with the same active ingredients but different manufacturing processes. Appreciating these differences may inform immunogenicity risk assessments.
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http://dx.doi.org/10.1038/s41598-017-09981-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585229PMC
September 2017

Induction, treatment and prevention of eczema vaccinatum in atopic dermatitis mouse models.

Vaccine 2017 07 20;35(33):4245-4254. Epub 2017 Jun 20.

Department of Infectious Diseases, Israel Institute for Biological Research (IIBR), Ness-Ziona, Israel. Electronic address:

Eczema vaccinatum is a severe and occasionally lethal complication of smallpox vaccine, characterized by systemic viral dissemination, distant from the initial inoculation site of the vaccine. A major risk factor for eczema vaccinatum is a background of atopic dermatitis, a chronic, common allergic, relapsing disorder, manifested by dry and inflamed skin, itchy rash, Th2 biased immune response and hypersensitivity to various antigens. Unlike the severe manifestations of eczema vaccinatum in humans, current models present only mild symptoms that limits examination of potential therapeutics for eczema vaccinatum. The atopic dermatitis and eczema vaccinatum models we present here, are the first to simulate the severity of the diseases in humans. Indeed, dermatitic mice display persistent severe dermatitis, characterized by dry and inflamed skin with barrier dysfunction, epidermal hyperplasia and significant elevation of serum IgE. By exposing atopic dermatitis mice to ectromelia virus, we generated eczema vaccinatum that mimic the human disease better than known eczema vaccinatum models. Similarly to humans, eczematous mice displayed enlarged and disseminated skin lesions, which correlated with elevated viral load. Cidofovir and antiviral antibodies conferred protection even when treatment started at a late eczematous stage. Moreover, we are the first to demonstrate that despite a severe background of atopic dermatitis, modified vaccinia Ankara virus (MVA) vaccination protects against lethal ectromelia virus exposure. We finally show that protection by MVA vaccination is dependent on CD4 T cells and is associated with significant activation of CD8 cytotoxic T cells and induction of humoral immunity.
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http://dx.doi.org/10.1016/j.vaccine.2017.06.014DOI Listing
July 2017

TLR3 and TLR9 agonists improve postexposure vaccination efficacy of live smallpox vaccines.

PLoS One 2014 28;9(10):e110545. Epub 2014 Oct 28.

Department of Infectious diseases, Israel Institute for Biological Research, Ness-Ziona, Israel.

Eradication of smallpox and discontinuation of the vaccination campaign resulted in an increase in the percentage of unvaccinated individuals, highlighting the need for postexposure efficient countermeasures in case of accidental or deliberate viral release. Intranasal infection of mice with ectromelia virus (ECTV), a model for human smallpox, is curable by vaccination with a high vaccine dose given up to 3 days postexposure. To further extend this protective window and to reduce morbidity, mice were vaccinated postexposure with Vaccinia-Lister, the conventional smallpox vaccine or Modified Vaccinia Ankara, a highly attenuated vaccine in conjunction with TLR3 or TLR9 agonists. We show that co-administration of the TLR3 agonist poly(I:C) even 5 days postexposure conferred protection, avoiding the need to increase the vaccination dose. Efficacious treatments prevented death, ameliorated disease symptoms, reduced viral load and maintained tissue integrity of target organs. Protection was associated with significant elevation of serum IFNα and anti-vaccinia IgM antibodies, modulation of IFNγ response, and balanced activation of NK and T cells. TLR9 agonists (CpG ODNs) were less protective than the TLR3 agonist poly(I:C). We show that activation of type 1 IFN by poly(I:C) and protection is achievable even without co-vaccination, requiring sufficient amount of the viral antigens of the infective agent or the vaccine. This study demonstrated the therapeutic potential of postexposure immune modulation by TLR activation, allowing to alleviate the disease symptoms and to further extend the protective window of postexposure vaccination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110545PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211728PMC
June 2015

Active vaccination with vaccinia virus A33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response.

Virol J 2013 Jul 10;10:229. Epub 2013 Jul 10.

Department of Infectious Diseases, Israel Institute for Biological Research, P.O. box 19, Ness-Ziona 74100, Israel.

Vaccinia virus protein A33 (A33VACV) plays an important role in protection against orthopoxviruses, and hence is included in experimental multi-subunit smallpox vaccines. In this study we show that single-dose vaccination with recombinant Sindbis virus expressing A33VACV, is sufficient to protect mice against lethal challenge with vaccinia virus WR (VACV-WR) and ectromelia virus (ECTV) but not against cowpox virus (CPXV), a closely related orthopoxvirus. Moreover, a subunit vaccine based on the cowpox virus A33 ortholog (A33CPXV) failed to protect against cowpox and only partially protected mice against VACV-WR challenge. We mapped regions of sequence variation between A33VACV and A33CPXVand analyzed the role of such variations in protection. We identified a single protective region located between residues 104-120 that harbors a putative H-2Kd T cell epitope as well as a B cell epitope - a target for the neutralizing antibody MAb-1G10 that blocks spreading of extracellular virions. Both epitopes in A33CPXV are mutated and predicted to be non-functional. Whereas vaccination with A33VACV did not induce in-vivo CTL activity to the predicted epitope, inhibition of virus spread in-vitro, and protection from lethal VACV challenge pointed to the B cell epitope highlighting the critical role of residue L118 and of adjacent compensatory residues in protection. This epitope's critical role in protection, as well as its modifications within the orthopoxvirus genus should be taken in context with the failure of A33 to protect against CPXV as demonstrated here. These findings should be considered when developing new subunit vaccines and monoclonal antibody based therapeutics against orthopoxviruses, especially variola virus, the etiologic agent of smallpox.
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http://dx.doi.org/10.1186/1743-422X-10-229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722049PMC
July 2013

A single cidofovir treatment rescues animals at progressive stages of lethal orthopoxvirus disease.

Virol J 2012 Jun 18;9:119. Epub 2012 Jun 18.

Israel Institute for Biological Research, Ness-ziona, Israel.

Background: In an event of a smallpox outbreak in humans, the window for efficacious treatment by vaccination with vaccinia viruses (VACV) is believed to be limited to the first few days post-exposure (p.e.). We recently demonstrated in a mouse model for human smallpox, that active immunization 2-3 days p.e. with either VACV-Lister or modified VACV Ankara (MVA) vaccines, can rescue animals from lethal challenge of ectromelia virus (ECTV), the causative agent of mousepox. The present study was carried out in order to determine whether a single dose of the anti-viral cidofovir (CDV), administered at different times and doses p.e. either alone or in conjunction with active vaccination, can rescue ECTV infected mice.

Methods: Animals were infected intranasally with ECTV, treated on different days with various single CDV doses and monitored for morbidity, mortality and humoral response. In addition, in order to determine the influence of CDV on the immune response following vaccination, both the "clinical take", IFN-gamma and IgG Ab levels in the serum were evaluated as well as the ability of the mice to withstand a lethal challenge of ECTV. Finally the efficacy of a combined treatment regime of CDV and vaccination p.e. was determined.

Results: A single p.e. CDV treatment is sufficient for protection depending on the initiation time and dose (2.5 - 100 mg/kg) of treatment. Solid protection was achieved by a low dose (5 mg/kg) CDV treatment even if given at day 6 p.e., approximately 4 days before death of the control infected untreated mice (mean time to death (MTTD) 10.2). At the same time point complete protection was achieved by single treatment with higher doses of CDV (25 or 100 mg/kg). Irrespective of treatment dose, all surviving animals developed a protective immune response even when the CDV treatment was initiated one day p.e.. After seven days post treatment with the highest dose (100 mg/kg), virus was still detected in some organs (e.g. lung and liver) yet all animals survived, suggesting that efficacious single CDV treatment requires a potent immune system. The combination of CDV and vaccination provided no additional protection over CDV alone. Yet, combining CDV and vaccination maintained vaccination efficacy.

Conclusions: Altogether, our data substantiate the feasibility of single post-exposure antiviral treatment to face orthopoxvirus infection.
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http://dx.doi.org/10.1186/1743-422X-9-119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409050PMC
June 2012

Induction of cell-cell fusion by ectromelia virus is not inhibited by its fusion inhibitory complex.

Virol J 2009 Sep 29;6:151. Epub 2009 Sep 29.

Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona, Israel.

Background: Ectromelia virus, a member of the Orthopox genus, is the causative agent of the highly infectious mousepox disease. Previous studies have shown that different poxviruses induce cell-cell fusion which is manifested by the formation of multinucleated-giant cells (polykaryocytes). This phenomenon has been widely studied with vaccinia virus in conditions which require artificial acidification of the medium.

Results: We show that Ectromelia virus induces cell-cell fusion under neutral pH conditions and requires the presence of a sufficient amount of viral particles on the plasma membrane of infected cells. This could be achieved by infection with a replicating virus and its propagation in infected cells (fusion "from within") or by infection with a high amount of virus particles per cell (fusion "from without"). Inhibition of virus maturation or inhibition of virus transport on microtubules towards the plasma membrane resulted in a complete inhibition of syncytia formation. We show that in contrast to vaccinia virus, Ectromelia virus induces cell-cell fusion irrespectively of its hemagglutination properties and cell-surface expression of the orthologs of the fusion inhibitory complex, A56 and K2. Additionally, cell-cell fusion was also detected in mice lungs following lethal respiratory infection.

Conclusion: Ectromelia virus induces spontaneous cell-cell fusion in-vitro and in-vivo although expressing an A56/K2 fusion inhibitory complex. This syncytia formation property cannot be attributed to the 37 amino acid deletion in ECTV A56.
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http://dx.doi.org/10.1186/1743-422X-6-151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760862PMC
September 2009

Effective post-exposure protection against lethal orthopoxviruses infection by vaccinia immune globulin involves induction of adaptive immune response.

Vaccine 2009 Mar 3;27(11):1691-9. Epub 2009 Feb 3.

Department of Infectious Diseases, Israel Institute for Biological Research, Israel.

The therapeutic potential of human vaccinia immunoglobulin (VIG) in orthopoxvirus infection was examined using two mouse models for human poxvirus, based on Ectromelia virus and Vaccinia Western Reserve (WR) respiratory infections. Despite the relatively fast clearance of human VIG from mice circulation, a single VIG injection protected immune-competent mice against both infections. Full protection against lethal Ectromelia virus infection was achieved by VIG injection up to one day post-exposure, and even injection of VIG two or three days post-infection conferred solid protection (60-80%). Nevertheless, VIG failed to protect VACV-WR challenged immune-deficient mice, even though repeated injections prolonged SCID mice survival. These results suggest the involvement of host immunity in protection. VIG provides the initial protective time-window allowing induction of the adaptive response required to achieve complete protection. Additionally, VIG can be administered in conjunction with active Vaccinia-Lister vaccination. Vaccine efficiency is not impaired, providing a non-prohibitive VIG dose is used. Thus, VIG can be used as a prophylactic measure against post-vaccinal complications but could also serve for post-exposure treatment against smallpox.
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http://dx.doi.org/10.1016/j.vaccine.2009.01.038DOI Listing
March 2009