TY - JOUR
T1 - A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection
AU - Ronk, Adam J.
AU - Lloyd, Nicole M.
AU - Zhang, Min
AU - Atyeo, Caroline
AU - Perrett, Hailee R.
AU - Mire, Chad E.
AU - Hastie, Kathryn M.
AU - Sanders, Rogier W.
AU - Brouwer, Philip J. M.
AU - Saphire, Erica Olmann
AU - Ward, Andrew B.
AU - Ksiazek, Thomas G.
AU - Alvarez Moreno, Juan Carlos
AU - Thaker, Harshwardhan M.
AU - Alter, Galit
AU - Himansu, Sunny
AU - Carfi, Andrea
AU - Bukreyev, Alexander
N1 - Funding Information: We thank Dr. Erin Lee and the staff of the UTMB Animal Resource Center for performing procedures and daily checks in ABSL-4, Dr. Geisbert (UTMB) for providing guinea pig adapted LASV Josiah, Dr. Freiberg (UTMB) for providing Vero NY cells, and Dr. Luis Branco and Zalgen labs for providing the human mAbs 37.7H, 3.3D, and 22.5D. We would also like to thank Dr. Meyer (UTMB) for her guidance and assistance with the biolayer interferometry studies and data analysis. The project was funded by the Department of Defense grant PR0180486 (to A.B.). Work on prefusion-stabilized LASV GPC was supported by NIH grant R01 AI171438 (to A.B.W.). H.R.P. was supported by a David C. Fairchild Endowed Fellowship, Achievement Rewards for College Scientists Foundation and NIH F31 Ruth L. Kirschstein Predoctoral Award 1F31Al172358. P.J.M.B. was supported by a Rubicon fellowship from the Netherlands Organisation for Scientific Research (NWO). Publisher Copyright: © 2023, Springer Nature Limited.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85170701537&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-41376-6
DO - https://doi.org/10.1038/s41467-023-41376-6
M3 - Article
C2 - 37699929
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5603
ER -