Antibodies from Sierra Leonean and Nigerian Lassa fever survivors cross-react with recombinant proteins representing Lassa viruses of divergent lineages

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.

Experimental Morogoro Virus Infection in Its Natural Host, Mastomys natalensis

“…No correlation between antibody presence and virus clearance could be observed, indicating that the developed antibodies do not play a major role in virus clearance [27]. This finding resembles observation from human Lassa Fever cases, where the presence of antibodies does not appear to be correlated with virus clearance [36]. Neutralizing antibodies, if at all, only appear several months post-infection [37].…”

Space-Time Trends in Lassa Fever in Sierra Leone by ELISA Serostatus, 2012–2019

“…The highest incidence rates for LF have historically been observed in the Eastern Province of Sierra Leone [ 14 ]. Sierra Leone is primarily associated with the Lineage IV Josiah strain of LASV [ 27 ], which is the target of most vaccines [ 28 ]. The first LF studies in Sierra Leone were carried out from 1973 to 1992 but were halted from 1993–2001 during the Blood Diamonds War [ 29 ].…”

Construction and Immunological Evaluation of an Adenoviral Vector-Based Vaccine Candidate for Lassa Fever

“…According to our experimental design ( Figure 3 a), mice were immunized once on day 0, or twice, on days 0 and 28, with either 1 × 10 6 /10 7 /10 8 PFU of the Ad5-GPC LASV ( n = 10). To determine the antibody levels after vaccination, sera collected on day 42 post first immunization were evaluated using enzyme-linked immunosorbent assay (ELISA) using a linked Expi293 cell-produced recombinant GPC lacking the transmembrane and intracytoplasmic domains (rGPe) [ 27 , 29 ] as the capture antigen ( Figure 3 b,c). The ELISA titers of sera from mice vaccinated once or twice with LASV GPC were 400–4000 and 1000–8000, respectively ( Figure 3 d,e).…”

“…The recombinant linked ectodomain (residues 1–424) of LASV GPC (rGPe) [ 27 , 29 ] was generated by mutating the putative S1P cleavage site 256-RRLL-259 to 256--LLLL-259. rGPe was fused to an enterokinase cleavage site followed by a dual strep II tag and cloned into the pcDNA3.1 vector for transient expression in Expi293 cells (Thermo Fisher Scientific).…”