ChAdOx1-vectored Lassa fever vaccine elicits a robust cellular and humoral immune response and protects guinea pigs against lethal Lassa virus challenge

Abstract

Lassa virus (LASV) infects hundreds of thousands of individuals each year, highlighting the need for the accelerated development of preventive, diagnostic, and therapeutic interventions. To date, no vaccine has been licensed for LASV. ChAdOx1-Lassa-GPC is a chimpanzee adenovirus-vectored vaccine encoding the Josiah strain LASV glycoprotein precursor (GPC) gene. In the following study, we show that ChAdOx1-Lassa-GPC is immunogenic, inducing robust T-cell and antibody responses in mice. Furthermore, a single dose of ChAdOx1-Lassa-GPC fully protects Hartley guinea pigs against morbidity and mortality following lethal challenge with a guinea pig-adapted LASV (strain Josiah). By contrast, control vaccinated animals reached euthanasia criteria 10–12 days after infection. Limited amounts of LASV RNA were detected in the tissues of vaccinated animals. Viable LASV was detected in only one animal receiving a single dose of the vaccine. A prime-boost regimen of ChAdOx1-Lassa-GPC in guinea pigs significantly increased antigen-specific antibody titers and cleared viable LASV from the tissues. These data support further development of ChAdOx1-Lassa-GPC and testing in non-human primate models of infection.

The Combined Expression of the Nonstructural Protein NS1 and the N-Terminal Half of NS2 (NS2 1-180 ) by ChAdOx1 and MVA Confers Protection against Clinical Disease in Sheep upon Bluetongue Virus Challenge

“…ChAdOx1 is a chimpanzee adenovirus vector platform that has been employed in the development of vaccine candidates for several pathogens. A single dose of ChAdOx1-vectored vaccine fully protects against Rift Valley fever virus, Middle East respiratory syndrome coronavirus, Lassa virus, or Zika virus in animal models of infection ( 35 , 48 – 51 ). In the same vein, we also observed the efficacy of a single dose of the recombinant ChAdOx1 as IFNAR(-/-) mice immunized with a single dose of ChAdOx1-NS1-NS2-Nt were fully protected against BTV-4M, showing an aviremic status throughout the experiment.…”

Lassa virus glycoprotein nanoparticles elicit a neutralizing antibody that defines a new site of vulnerability

“…The relevance of NAbs as a protective endpoint for LASV vaccines has only recently been made clear through the success of several passive immunization studies with monoclonal bNAbs in animal models (Cross et al, 2016(Cross et al, , 2019Mire et al, 2017). Yet, various studies have also shown protection to LASV challenge in the absence of measurable (pseudovirus) NAb responses, suggesting a role for cellular immunity or non-neutralizing Ab effector functions in vaccine-induced protection (Abreu-Mota et al, 2018;Fischer et al, 2021;Mateo et al, 2021). Our guinea pig study provides additional evidence that NAb responses may not be the sole determinant for protection.…”

Pathogenicity and virulence mechanisms of Lassa virus and its animal modeling, diagnostic, prophylactic, and therapeutic developments

“…Additionally, a single vaccinated dose of the ChAdOx1 vector-based vaccine expressing the Josiah LASV GPC has been shown to induce robust T-cell and antibody responses in mice and can protect guinea pigs against morbidity and mortality following lethal challenge of the vaccinated animal with a guinea pig-adapted Josiah LASV strain. A prime-and-boost vaccination of this vaccine has also been shown to significantly enhance LASV antigen-specific antibody titers and clear LASV from the tissues of the virus-challenged animals [ 177 ]. Therefore, adenovirus vectored LASV vaccines have shown some encouraging results in guinea pig models that warrant additional testing in the gold-standard non-human primate LF model.…”