Treatment-Emergent Cilgavimab Resistance Was Uncommon in Vaccinated Omicron BA.4/5 Outpatients
Cesare Ernesto Maria Gruber,
Fabio Giovanni Tucci,
Martina Rueca,
Valentina Mazzotta,
Giulia Gramigna,
Alessandra Vergori,
Lavinia Fabeni,
Giulia Berno,
Emanuela Giombini,
Ornella Butera,
Daniele Focosi,
Ingrid Guarnetti Prandi,
Giovanni Chillemi,
Emanuele Nicastri,
Francesco Vaia,
Enrico Girardi,
Andrea Antinori,
Fabrizio Maggi
Affiliations
Cesare Ernesto Maria Gruber
Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Fabio Giovanni Tucci
Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Martina Rueca
Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Valentina Mazzotta
Clinical and Research Infectious Diseases Department, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Giulia Gramigna
Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Alessandra Vergori
Clinical and Research Infectious Diseases Department, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Lavinia Fabeni
Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Giulia Berno
Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Emanuela Giombini
Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Ornella Butera
Laboratory of Microbiology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Daniele Focosi
North-Western Tuscany Blood Bank, Pisa University Hospital, 56124 Pisa, Italy
Ingrid Guarnetti Prandi
Department for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), University of Tuscia, Via S. Camillo de Lellis s.n.c, 01100 Viterbo, Italy
Giovanni Chillemi
Department for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), University of Tuscia, Via S. Camillo de Lellis s.n.c, 01100 Viterbo, Italy
Emanuele Nicastri
Clinical and Research Infectious Diseases Department, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Francesco Vaia
General Direction, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Enrico Girardi
Scientific Direction, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Andrea Antinori
Clinical and Research Infectious Diseases Department, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Fabrizio Maggi
Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy
Mutations in the SARS-CoV-2 Spike glycoprotein can affect monoclonal antibody efficacy. Recent findings report the occurrence of resistant mutations in immunocompromised patients after tixagevimab/cilgavimab treatment. More recently, the Food and Drug Agency revoked the authorization for tixagevimab/cilgavimab, while this monoclonal antibody cocktail is currently recommended by the European Medical Agency. We retrospectively reviewed 22 immunocompetent patients at high risk for disease progression who received intramuscular tixagevimab/cilgavimab as early COVID-19 treatment and presented a prolonged high viral load. Complete SARS-CoV-2 genome sequences were obtained for a deep investigation of mutation frequencies in Spike protein before and during treatment. At seven days, only one patient showed evidence of treatment-emergent cilgavimab resistance. Quasispecies analysis revealed two different deletions on the Spike protein (S:del138–144 or S:del141–145) in combination with the resistance S:K444N mutation. The structural and dynamic impact of the two quasispecies was characterized by using molecular dynamics simulations, showing the conservation of the principal functional movements in the mutated systems and their capabilities to alter the structure and dynamics of the RBD, responsible for the interaction with the ACE2 human receptor. Our study underlines the importance of prompting an early virological investigation to prevent drug resistance or clinical failures in immunocompetent patients.
