A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection

Adam J. Ronk, Nicole M. Lloyd, Min Zhang, Caroline Atyeo, Hailee R. Perrett, Chad E. Mire, Kathryn M. Hastie, Rogier W. Sanders, Philip J. M. Brouwer, Erica Olmann Saphire, Andrew B. Ward, Thomas G. Ksiazek, Juan Carlos Alvarez Moreno, Harshwardhan M. Thaker, Galit Alter, Sunny Himansu, Andrea Carfi () and Alexander Bukreyev ()
Additional contact information
Adam J. Ronk: University of Texas Medical Branch
Nicole M. Lloyd: University of Texas Medical Branch
Min Zhang: University of Texas Medical Branch
Caroline Atyeo: Harvard T.H. Chan School of Public Health
Hailee R. Perrett: Department of Integrative Structural and Computational Biology California Campus, Scripps Research
Chad E. Mire: University of Texas Medical Branch
Kathryn M. Hastie: La Jolla Institute for Immunology
Rogier W. Sanders: Academic Medical Center
Philip J. M. Brouwer: Academic Medical Center
Erica Olmann Saphire: La Jolla Institute for Immunology
Andrew B. Ward: Department of Integrative Structural and Computational Biology California Campus, Scripps Research
Thomas G. Ksiazek: University of Texas Medical Branch
Juan Carlos Alvarez Moreno: University of Texas Medical Branch
Harshwardhan M. Thaker: University of Texas Medical Branch
Galit Alter: Harvard T.H. Chan School of Public Health
Sunny Himansu: Moderna, Inc
Andrea Carfi: Moderna, Inc
Alexander Bukreyev: University of Texas Medical Branch

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate. We have designed and generated lipid nanoparticle encapsulated, modified mRNA vaccines that encode for the wild-type Lassa virus strain Josiah glycoprotein complex or the prefusion stabilized conformation of the Lassa virus glycoprotein complex. Hartley guinea pigs were vaccinated with two 10 µg doses, 28 days apart, of either construct. Vaccination induced strong binding antibody responses, specific to the prefusion conformation of glycoprotein complex, which were significantly higher in the prefusion stabilized glycoprotein complex construct group and displayed strong Fc-mediated effects. However, Lassa virus-neutralizing antibody activity was detected in some but not all animals. Following the challenge with a lethal dose of the Lassa virus, all vaccinated animals were protected from death and severe disease. Although the definitive mechanism of protection is still unknown, and assessment of the cell-mediated immune response was not investigated in this study, these data demonstrate the promise of mRNA as a vaccine platform against the Lassa virus and that protection against Lassa virus can be achieved in the absence of virus-neutralizing antibodies.

Date: 2023
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DOI: 10.1038/s41467-023-41376-6

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