Vaccines inducing immunity to Lassa virus glycoprotein and nucleoprotein protect macaques after a single shot

Abstract

Lassa fever is a major threat in Western Africa. The large number of people living at risk for this disease calls for the development of a vaccine against Lassa virus (LASV). We generated live-attenuated LASV vaccines based on measles virus and Mopeia virus platforms and expressing different LASV antigens, with the aim to develop a vaccine able to protect after a single shot. We compared the efficacy of these vaccines against LASV in cynomolgus monkeys. The vaccines were well tolerated and protected the animals from LASV infection and disease after a single immunization but with varying efficacy. Analysis of the immune responses showed that complete protection was associated with robust secondary T cell and antibody responses against LASV. Transcriptomic and proteomic analyses showed an early activation of innate immunity and T cell priming after immunization with the most effective vaccines, with changes detectable as early as 2 days after immunization. The most efficacious vaccine candidate, a measles vector simultaneously expressing LASV glycoprotein and nucleoprotein, has been selected for further clinical evaluation.

Inter-Lineage Variation of Lassa Virus Glycoprotein Epitopes: A Challenge to Lassa Virus Vaccine Development

“…In vivo protection was not extensively tested in this study in which few cross-reactive GP2 mAbs were raised, and the lack of protection conflicts with a prior report by Ruo et al demonstrating the neutralizing property of GP2 specific mAbs that bind conserved epitopes on GP2 subunit of Old World and New World arenaviruses. Furthermore, recent vaccine studies have also shown that non-NAbs may contribute to protection against clinical disease in guinea pig and NHP models [50,51,62]. However, the GP binding site of the vaccine-induced non-NAbs were not mapped in these studies.…”

“…Another approach is to present whole LASV GP complex on vaccine constructs (e.g., viral vectors, virus-like particles (VLP), and replicons), as practiced in most of the successful LASV vaccine candidates [23,46,50,51,69]. This presents both variable and conserved GP subunit epitopes, as well as quaternary GP epitopes, to induce B-cell and T-cell mediated protection.…”

“…The expression of both LASV GP and NP has been shown to be required for efficient protection with near sterilizing immunity in NHPs [21,47,51,70]. Additional LASV NP expression in the ML29 vaccine is suggested to be critical for extending cross-protection from LCMV which has a 50% NP sequence homology with LASV [27].…”

“…Evidence from human survivor, vaccine, and therapeutic monoclonal antibody (mAb) studies have shown that adaptive immune protection in LASV infection is probably conferred mainly by a cell-mediated immune response that is dependent on the early activation of innate immune and inflammatory pathways, especially for Type I IFN response [43][44][45][46][47][48][49]. While it is speculated that non-neutralizing antibody (non-NAb) dependent ADCC/ADCP functions is the likely purveyor of humoral immune protection, as seen in LASV vaccine studies in animal models [50,51]. There is no evidence for this role in human LF cases.…”

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

“…This vaccine mediates expression of CHIKV virus-like particles. Using a similar approach, a measles-based Lassa virus vaccine has been developed and was shown to protect cynomolgus monkeys from a Lassa virus challenge [11].…”