Abstract
Machupo virus (MACV) is a New World (NW) arenavirus and causative agent of Bolivian hemorrhagic fever (HF). Here, we identified a variant of MACV strain Carvallo termed Car91 that was attenuated in guinea pigs. Infection of guinea pigs with an earlier passage of Carvallo, termed Car68, resulted in a lethal disease with a 63% mortality rate. Sequencing analysis revealed that compared to Car68, Car91 had a 35 nucleotide (nt) deletion and a point mutation within the L-segment intergenic region (IGR), and three silent changes in the polymerase gene that did not impact amino acid coding. No changes were found on the S-segment. Because it was apathogenic, we determined if Car91 could protect guinea pigs against Guanarito virus (GTOV), a distantly related NW arenavirus. While naïve animals succumbed to GTOV infection, 88% of the Car91-exposed guinea pigs were protected. These findings indicate that attenuated MACV vaccines can provide heterologous protection against NW arenaviruses. The disruption in the L-segment IGR, including a single point mutant and 35 nt partial deletion, were the only major variance detected between virulent and avirulent isolates, implicating its role in attenuation. Overall, our data support the development of live-attenuated arenaviruses as broadly protective pan-arenavirus vaccines.
Highlights
Members of the Arenaviridae are enveloped ambisense single-stranded RNA viruses with two segments, small (S) and large (L), encoding a 10.7 Kb genome expressing five distinct proteins[1,2,3]
Some evidence based on studies in guinea pigs and non-human primates (NHPs) suggest that Candid#1 can cross-protect against MACV24; these findings have not been validated in humans
Other New World (NW) arenavirus vaccine strategies have included the use of Tacaribe virus (TACV), an arenavirus serologically related to Junin virus (JUNV) and Machupo virus (MACV) believed to be apathogenic in humans
Summary
Members of the Arenaviridae are enveloped ambisense single-stranded RNA viruses with two segments, small (S) and large (L), encoding a 10.7 Kb genome expressing five distinct proteins[1,2,3]. An attenuated live-virus vaccine, termed Candid#1, is currently used in populations at high risk to JUNV infection in Argentina[20,21,22,23]. Candid#1 was produced by passage of the virulent XJ strain twice in guinea pigs, 44 times in mouse brains and several passages in fetal rhesus lung diploid cells (FRhL-2)[23, 25,26,27] This process produced a strain attenuated in humans, non-human primates, guinea pigs, and mice that lacked neurotropism in animal models. Glycoprotein-targeting subunit vaccines based on modified vaccine Ankara or Venezuelan equine encephalitis replicon vectored systems protect against lethal infection by JUNV in guinea pig models[30, 31]. Because Car[91] was apathogenic in guinea pigs, but produced detectable humoral immune responses, we investigated if it could function as a live-attenuated vaccine and protect against more distantly related NW arenaviruses
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