Publications by authors named "Jessica Bassi"

11 Publications

  • Page 1 of 1

SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape.

Nature 2021 Jul 14. Epub 2021 Jul 14.

Humabs BioMed SA, a subsidiary of Vir Biotechnology, 6500, Bellinzona, Switzerland.

An ideal anti-SARS-CoV-2 antibody would resist viral escape, have activity against diverse SARS-related coronaviruses (sarbecoviruses), and be highly protective through viral neutralization and effector functions. Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a tradeoff between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a previously undescribed cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we characterize one potent RBM antibody (S2E12) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth, and potency among antibodies targeting the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.
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http://dx.doi.org/10.1038/s41586-021-03807-6DOI Listing
July 2021

SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern.

Science 2021 Jul 1. Epub 2021 Jul 1.

Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.

A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429), originally detected in California, carries spike glycoprotein mutations S13I in the signal peptide, W152C in the N-terminal domain (NTD), and L452R in the receptor-binding domain (RBD). Plasma from individuals vaccinated with a Wuhan-1 isolate-based mRNA vaccine or convalescent individuals exhibited neutralizing titers, which were reduced 2-3.5 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The L452R mutation reduced neutralizing activity of 14 out of 34 RBD-specific monoclonal antibodies (mAbs). The S13I and W152C mutations resulted in total loss of neutralization for 10 out of 10 NTD-specific mAbs since the NTD antigenic supersite was remodeled by a shift of the signal peptide cleavage site and formation of a new disulphide bond, as revealed by mass spectrometry and structural studies.
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http://dx.doi.org/10.1126/science.abi7994DOI Listing
July 2021

SARS-CoV-2 immune evasion by variant B.1.427/B.1.429.

bioRxiv 2021 Apr 1. Epub 2021 Apr 1.

SARS-CoV-2 entry is mediated by the spike (S) glycoprotein which contains the receptor-binding domain (RBD) and the N-terminal domain (NTD) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.
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http://dx.doi.org/10.1101/2021.03.31.437925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020983PMC
April 2021

Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.

Nature 2021 05 11;593(7857):136-141. Epub 2021 Mar 11.

Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, UK.

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b2. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.
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http://dx.doi.org/10.1038/s41586-021-03412-7DOI Listing
May 2021

Chylopericardium Effusion in a Lac Alaotra Bamboo Lemur ().

Animals (Basel) 2021 Feb 19;11(2). Epub 2021 Feb 19.

Department of Veterinary Medicine, University Veterinary Teaching Hospital, University of Milan, 26900 Lodi, Italy.

An 11-year-old female was evaluated following a history of dyspnea of 15 days' duration. Thoracic radiography performed by the referring veterinarian revealed a large cardiac silhouette and dorsal deviation of the trachea. Heart sounds were muffled. Echocardiographic findings were indicative of severe pericardial effusion without cardiac tamponade. No pleural effusion was identified. A computed tomography (CT) exam confirmed the presence of severe pericardial effusion and allowed identification of a parenchymatous mediastinal lesion sited at the level of the left hemithorax. To delineate the thoracic duct, lymphoCT was also performed by injection of iodinated contrast medium in the perianal subcutaneous tissue. Pericardiocentesis yielded a considerable amount of effusion with chylous biochemical and cytological properties. A diagnosis of chylopericardium with absence of pleural effusion was made. Initially, the chylopericardium was managed conservatively with two centesis and oral treatment with prednisolone. Medical treatment did not result in complete resolution of effusion and clinical signs; therefore, subtotal pericardiectomy and thoracic duct ligation were recommended. After the second pericardiocentesis, the subject died and the pericardiectomy could not be performed. To the authors' knowledge, this is the first report of the development of chylopericardium in a .
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http://dx.doi.org/10.3390/ani11020536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922474PMC
February 2021

Prostatic leiomyosarcoma in a dog treated using a multimodal approach.

J Vet Intern Med 2021 Mar 24;35(2):1105-1110. Epub 2021 Feb 24.

Department of Veterinary Medicine, Università degli Studi di Milano, Lodi, Italy.

Prostatic leiomyosarcoma is an uncommon tumor encountered in male dogs, with only 2 cases reported in the veterinary literature with no follow-up described. A 12-year-old male intact German Wirehaired Pointer presented for evaluation of straining to defecate and urinate. Whole body computed tomography (CT) examination identified a spherical multicavitary expansile mass arising from the prostate gland and severely obliterating the pelvic canal. Partial subcapsular prostatectomy was performed, and histological and immunohistochemical results were consistent with prostatic leiomyosarcoma. Metronomic cyclophosphamide and nonsteroidal anti-inflammatory drugs were administered as adjuvant chemotherapy. Follow-up CT 10 months later indicated no signs of recurrence or metastasis. To the best of our knowledge, this patient represents the first report of successful multidisciplinary treatment consisting of partial subcapsular prostatectomy and adjuvant chemotherapy for prostatic leiomyosarcoma in a dog. After 15 months of follow-up, the patient remained recurrence-free without metastasis.
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http://dx.doi.org/10.1111/jvim.16081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995369PMC
March 2021

Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity.

Cell 2021 03 28;184(5):1171-1187.e20. Epub 2021 Jan 28.

MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK.

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.
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http://dx.doi.org/10.1016/j.cell.2021.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843029PMC
March 2021

SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies.

medRxiv 2021 Feb 15. Epub 2021 Feb 15.

Department of Clinical Biochemistry and Immunology, Addenbrookes Hospital, UK.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.
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http://dx.doi.org/10.1101/2021.01.19.21249840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899479PMC
February 2021

Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology.

Cell 2020 11 16;183(4):1024-1042.e21. Epub 2020 Sep 16.

III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy.

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.
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http://dx.doi.org/10.1016/j.cell.2020.09.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494283PMC
November 2020

Angiostrongylus vasorum in a Red Panda (Ailurus fulgens): Clinical Diagnostic Trial and Treatment Protocol.

Acta Parasitol 2021 Mar 25;66(1):282-286. Epub 2020 Aug 25.

Department of Veterinary Medicine, Lodi University Veterinary Hospital, University of Milan, Via dell'Università n. 6, 26900, Lodi, Lombardy, Italy.

Purpose: The literature refers that Angiostrongylus vasorum should always be considered in the differential diagnosis of respiratory diseases in captive red panda (Ailurus fulgens) from endemic areas, and the importance of undertaking a careful diagnostic process and timely medical treatment are crucial when the disease is suspected. The authors think that the description of this clinical case can help other colleagues in the deworming, clinical and anesthesiologic management of infected subjects.

Methods: A red panda was referred to the Veterinary Teaching Hospital of the University of Milan in Lodi, due to a diagnosis of A. vasorum formulated in May 2015. The diagnosis was made after the detection of both first-stage larvae by Baermann technique and antigens by serological rapid in-clinic assay. In addition, haemochromocytometric and blood chemistry tests, echocardiography and a CT examination were carried out.

Results: The subject was successfully treated by oral administration of milbemycin oxime and praziquantel (Milbemax, Novartis, Italy), respectively, at the weekly dose of 12.5 mg/subject and 125 mg/subject for three consecutive weeks, alternated with 20 days of suspension. Treatment continued with the same scheme until clinical examination carried out in Lodi in December 2018.

Conclusion: The follow-up of the described clinical case demonstrates how appropriate management of the infection and the subsequent prophylaxis can correctly eliminate the parasite, thus avoiding the spread of the nematode and the onset of severe and lethal lung forms as described in the literature.
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http://dx.doi.org/10.1007/s11686-020-00271-6DOI Listing
March 2021

Dynamic tomographic studies of interscapular feline injection-site sarcoma: essential or useless practice?

J Feline Med Surg 2018 06 30;20(6):502-508. Epub 2017 Jun 30.

2 Department of Veterinary Medicine, University of Milan, Milan, Italy.

Objectives Feline injection-site sarcomas (FISSs) are soft tissue tumours typically characterised by an interscapular location and highly infiltrative behaviour. CT is considered the modality of choice for FISS staging and double positioning (dynamic approach) was reported to successfully detect the exact extent of infiltration into the muscles. The aim of the present study was to investigate the utility of the dynamic approach in feline patients referred for preoperative staging of interscapular FISS. Methods Tumour volume estimates were compared between the ellipsoid and the semi-automated segmentation methods. Two radiologists blinded to the patient coding used images from each position to assess the extent of muscular infiltration. The distance between the neoplasm and the adjacent skeletal structures (scapulae, spinous processes) was recorded in both positions by a single radiologist. Results Fifty-nine of 84 neoplasms invaded the adjacent muscular structures, with up to 15 muscles infiltrated. Between the extended and flexed position the average estimated numbers of muscles infiltrated were 1.9 (extended) and 1.84 (flexed) for observer A and 1.89 (extended) and 1.85 (flexed) for observer B. Good agreement between observers was established, with higher tumour volumes detected via the ellipsoid method. Moreover, tumours with smaller volumes showed slightly decreased muscular infiltration. Marked difference in the recorded distance between the skeletal structures and the neoplasm in the two different positions was established (mean ± SD difference spinous processes: 9.74 ± 9.57 mm; mean ± SD difference scapulae: 15.15 ± 11.76 mm). Conclusions and relevance A dynamic approach should be used for a complete evaluation of the invasiveness of FISS along with appropriate methodology for tumour volume measurement, which could potentially alter the tomographic estimation of the real dimension of the neoplasms.
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http://dx.doi.org/10.1177/1098612X17717176DOI Listing
June 2018