Abstract
Lassa virus (LASV) is the causative agent of Lassa fever, an often-fatal hemorrhagic disease that is endemic in West Africa. Seven genetically distinct LASV lineages have been identified. As part of CEPI’s (Coalition for Epidemic Preparedness Innovations) Lassa vaccine development program, we assessed the potential of the human immune system to mount cross-reactive and cross-protective humoral immune responses to antigens from the most prevalent LASV lineages, which are lineages II and III in Nigeria and lineage IV in Sierra Leone. IgG and IgM present in the blood of Lassa fever survivors from Nigeria or Sierra Leone exhibited substantial cross-reactivity for binding to LASV nucleoprotein and two engineered (linked and prefusion) versions of the glycoproteins (GP) of lineages II–IV. There was less cross-reactivity for the Zinc protein. Serum or plasma from Nigerian Lassa fever survivors neutralized LASV pseudoviruses expressing lineage II GP better than they neutralized lineage III or IV GP expressing pseudoviruses. Sierra Leonean survivors did not exhibit a lineage bias. Neutralization titres determined using LASV pseudovirus assays showed significant correlation with titres determined by plaque reduction with infectious LASV. These studies provide guidance for comparison of humoral immunity to LASV of distinct lineages following natural infection or immunization.
Highlights
Assessed the potential of the human immune system to mount cross-reactive and cross-protective humoral immune responses to antigens from the most prevalent Lassa virus (LASV) lineages, which are lineages II and III in Nigeria and lineage IV in Sierra Leone
As a component of Coalition for Epidemic Preparedness Innovations (CEPI)’s efforts to facilitate and accelerate Lassa vaccine development, serum or plasma from Lassa fever survivors living in different geographical areas and representing different lineages has been collected through a contractual arrangement between CEPI and the Viral Hemorrhagic Fever Consortium (VHFC)
We assess the ability of antibodies from Nigerian Lassa fever survivors exposed to LASV lineages II and III and Sierra Leonean Lassa fever survivors exposed to LASV lineage IV to cross-react with recombinant NP, GP and Z proteins representing LASV of these divergent lineages and to crossneutralize pseudoviruses expressing LASV GPC of these divergent lineages
Summary
Assessed the potential of the human immune system to mount cross-reactive and cross-protective humoral immune responses to antigens from the most prevalent LASV lineages, which are lineages II and III in Nigeria and lineage IV in Sierra Leone. A suite of Lassa fever diagnostic immunoassays has been developed based on LASV recombinant proteins, including antigen- IgG- and IgM-capture ELISA and rapid diagnostic tests (RDTs)[39,40,41,42,43]. The antibody-capture ELISA has demonstrated the capability to detect IgM seropositivity and subsequent class-switching to IgG seropositivity in Lassa fever c ases[41] and has proven useful in surveillance and vaccine s tudies[30,44,45,46,47] These prior assays were configured with recombinant antigens based on the lineage IV LASV Josiah strain[39]. To quantify seroreactivity to genetically diverse LASV strains recombinant NP, GP and Z proteins representing additional prominent West African lineages, Nigerian lineages II and III, have been cloned and molecularly characterized. We assess the ability of antibodies from Nigerian Lassa fever survivors exposed to LASV lineages II and III and Sierra Leonean Lassa fever survivors exposed to LASV lineage IV to cross-react with recombinant NP, GP and Z proteins representing LASV of these divergent lineages and to crossneutralize pseudoviruses expressing LASV GPC of these divergent lineages
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