Alessandro Ceschi

Prof. Dr. Alessandro Ceschi

orcid

Research Focus & Metrics

Academic Career Length

18Years (2009-Present)

(Calculated once Scilit publication data is synced: current year − year of first publication + 1)

Representative Publications

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23 December 2021 in Nature
Verified
Journal Article
Closed access
ECElisabetta Cameroni
Elisabetta Cameroni
JBJohn E. Bowen
John E. Bowen
LRLaura E. Rosen
Laura E. Rosen
CSChristian Saliba
Christian Saliba
SZSamantha K. Zepeda
Samantha K. Zepeda
DCDavide Corti
Davide Corti

1 March 2021 in Cell
Verified
Journal Article
Open access
ETEmma Thomson
Emma Thomson
LRLaura E. Rosen
Laura E. Rosen
JSJames G. Shepherd
James G. Shepherd
RSRoberto Spreafico
Roberto Spreafico
AFAna da Silva Filipe
Ana da Silva Filipe
GSGyorgy Snell
Gyorgy Snell
SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Herein 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 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.

3 September 2021 in Science
Verified
Journal Article
Open access
DPDora Pinto
Dora Pinto
MSMaximilian M. Sauer
Maximilian M. Sauer
NCNadine Czudnochowski
Nadine Czudnochowski
JLJun Siong Low
Jun Siong Low
MTM. Alejandra Tortorici
M. Alejandra Tortorici
DVDavid Veesler
David Veesler
Targeting a range of betacoranaviruses: In the past 20 years, three highly pathogenic β-coronaviruses have crossed from animals to humans, including the most recent: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A spike protein that decorates these viruses has an S1 domain that binds host cell receptors and an S2 domain that fuses the viral and cell membranes to allow cell entry. The S1 domain is the target of many neutralizing antibodies but is more genetically variable than S2, and antibodies can exert selective pressure, leading to resistant variants. Pinto et al . identified five monoclonal antibodies that interact with a helix in the S2 domain. The most broadly neutralizing antibody inhibited all β-coronavirus subgenera and reduced viral burden in hamsters infected with SARS-CoV-2. —VV

11 November 2022 in Science
Verified
Journal Article
Open access
YPYoung-Jun Park
Young-Jun Park
DPDora Pinto
Dora Pinto
AWAlexandra C. Walls
Alexandra C. Walls
ZLZhuoming Liu
Zhuoming Liu
AMAnna De Marco
Anna De Marco
DVDavid Veesler
David Veesler
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant–neutralizing antibody that is a strong candidate for clinical development.

12 August 2022 in Science
Verified
Journal Article
Open access
JLJun Siong Low
Jun Siong Low
JJJosipa Jerak
Josipa Jerak
MTM. Alejandra Tortorici
M. Alejandra Tortorici
MMMatthew McCallum
Matthew McCallum
DPDora Pinto
Dora Pinto
FSFederica Sallusto
Federica Sallusto
The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus spike proteins from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and betacoronaviruses, including animal coronaviruses WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses showed that the fusion peptide–specific mAbs bound with different modalities to a cryptic epitope hidden in prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs.

30 August 2023 in Nature
Verified
Journal Article
Open access
PDF file
AAAmin Addetia
Amin Addetia
LPLuca Piccoli
Luca Piccoli
JCJames Brett Case
James Brett Case
YPYoung-Jun Park
Young-Jun Park
MBMartina Beltramello
Martina Beltramello
DVDavid Veesler
David Veesler
Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.