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

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.

Detection of the Lassa Virus in a Group of Odontogenic Bone Tumor Tissues

“…Very recently, the identification of LASV genotypes capable of spillover from rodents to humans in Sierra Leone was reported through a comparison of human-derived viral samples, with samples collected from animal reservoirs [31,32]. We are therefore convinced that the genotyping of the kind of LASV identified in OT tissues could also be of significant interest to shed light on the involvement of LASV in tumor onset and recurrence.…”

The Adaptive Immune Response against Bunyavirales

“…LASV GPC immunization using various formulations induces potent protective humoral responses in animals, also confirmed by passive transfer experiments [ 253 ]. Even though these immunization strategies mostly induce binding but non-neutralizing Abs, they still provide protection, likely facilitated by cellular immune responses or antibody-dependent cellular cytotoxicity [ 253 , 254 , 255 ]. LCMV induces Abs against N and GP2 soon after infection, reaching higher titers, whereas nAbs exclusively target GP1 and remain undetectable for the first two months after infection in mice [ 256 , 257 , 258 , 259 ].…”

“…For the Nairoviridae family, CCHFV glycoprotein vaccines primarily promote protection through CD8+ T cell-,mediated mechanisms, with neutralization not proven necessary for protection, as GP38 vaccines achieve protection though non-neutralizing Abs [ 122 , 123 , 233 ]. Similarly, glycoprotein-based vaccines provide protection primarily via cellular immunity against LASV infection [ 254 , 255 ]. Furthermore, vaccines targeting the N protein have faced challenges in inducing full protection for certain bunyaviruses in animals, while N mRNA vaccines induced protection against CCHFV infection mostly through cell-mediated responses [ 35 , 79 , 123 ].…”

Deep mutational scanning reveals functional constraints and antigenic variability of Lassa virus glycoprotein complex

“…29–32 In addition, vaccines that elicit antibodies against GPC are also being developed. 33–37 However, the high variability of GPC (up to ∼8% amino-acid divergence among lineages) raises the specter of antibody and vaccine escape, a problem that has been observed for other viruses—including most recently SARS-CoV-2. 38–41…”