Current research for a vaccine against Lassa hemorrhagic fever virus

Warner, Bryce M; Safronetz, David; Stein, Derek R

Despite the considerable list of preclinical candidates for LASV prevention, none have yet shown combined efficacy and safety in humans. In 2013, an unprecedented Ebola outbreak in West Africa resulted in over 30,000 documented cases of infection and .10,000 deaths. As an emergency measure, several vaccines were accelerated into Phase III clinical trials for testing during the outbreak. One of the most successful vaccines to show 100% efficacy in a ring vaccination trial was recombinant vesicular stomatitis virus expressing Ebola virus GPC (VSV-EBOV-GPC). 56 Antibodies have been implicated as the main correlate of protection for EBOV infection 57 with respect to VSV-EBOV-GPC vaccination, and has been shown to be long lasting for up to 14 months in the NHP model. 58 However, multiple lines of evidence suggest that the main correlate of protection for LASV involves cell-mediated immunity despite recent studies indicating that monoclonal antibody therapy is sufficient for protection. 37,38 The recombinant VSV system is able to tolerate the replacement of the VSV glycoprotein with foreign virus glycoproteins. The resulting recombinant viruses are attenuated, safe, and highly immunogenic, making this vaccine a strong candidate for LASV prevention. In 2004, the first description of VSV expressing LASV GPC was published and was shown to be apathogenic in mice. 59 A follow-up study by the same group characterized the VSV-LASV-GPC vaccine in NHPs. 28 Cynomolgus macaques were vaccinated with a single dose of VSV-LASV-GPC (2×10 7 PFU) and challenged 28 days later with a lethal dose of Josiah. All vaccinated animals survived the challenge with no overt signs of disease or changes in blood chemistry or hematology. There is considerable genetic variability between strains of LASV, which cluster into at least five clades. Clades I-III are generally localized to Nigeria, while clade IV and V viruses were isolated from Sierra Leonne, Guinea, Liberia, and Mali. Renewed studies almost 10 years after the initial characterization of the VSV-LASV-GPC vaccine sought to test whether it could act as a universal vaccine against genetically distinct LASV isolates. Geographically distinct isolates have been shown to have drastically altered disease manifestations and thus may not be covered by the VSV-LASV-GPC vaccine originally constructed with Josiah GPC. 60 Safronetz et al discovered that the single Josiah-based VSV vaccine could provide 100% protection against several isolates including Sierra Leone (Josiah; clade IV), Liberia (Z-132; clade IV), Mali (Soromba-R; clade V), and Nigeria (Pinneo; clade I) in strain 13 guinea pigs, identifying VSV-LASV-GPC as a universal vaccine candidate. Additionally, cynomolgus macaques vaccinated with VSV-LASV-GPC showed no overt signs of disease when challenged with the Liberian isolate. 61 The current Nigerian outbreak strain of LASV is thought to be a clade III isolate and has yet to be tested for efficacy against the VSV-LASV-GPC vaccine. These data lend strong support to the possibility of a universal LASV vaccine capable of being effective against all lineages in the region.