Abstract
New World arenaviruses are rodent-transmitted viruses and include a number of pathogens that are responsible for causing severe human disease. This includes Junín virus (JUNV), which is the causative agent of Argentine hemorrhagic fever. The wild nature and mobility of the rodent reservoir host makes it difficult to control the disease, and currently passive immunization with high-titer neutralizing antibody-containing plasma from convalescent patients is the only specific therapy. However, dwindling supplies of naturally available convalescent plasma, and challenges in developing similar resources for other closely related viruses, have made the development of alternative antibody-based therapeutic approaches of critical importance. In this study, we sought to induce a neutralizing antibody response in rabbits against the receptor-binding subunit of the viral glycoprotein, GP1, and the specific peptide sequences in GP1 involved in cellular receptor contacts. While these specific receptor-interacting peptides did not efficiently induce the production of neutralizing antibodies when delivered as a particulate antigen (as part of hepatitis B virus core-like particles), we showed that recombinant JUNV GP1 purified from transfected mammalian cells induced virus-neutralizing antibodies at high titers in rabbits. Further, neutralization was observed across a range of unrelated JUNV strains, a feature that is critical for effectiveness in the field. These results underscore the potential of GP1 alone to induce a potent neutralizing antibody response and highlight the importance of epitope presentation. In addition, effective virus neutralization by rabbit antibodies supports the potential applicability of this species for the future development of immunotherapeutics (e.g., based on humanized monoclonal antibodies). Such information can be applied in the design of vaccines and immunogens for both prevention and specific therapies against this and likely also other closely related pathogenic New World arenaviruses.
Highlights
Arenaviruses include a number of rodent-borne pathogens that can infect mammals
Based on the available structural information for Junín virus (JUNV) GP1, including the GP1–TfR1 interface, we considered whether this could be used to support a structure-assisted approach to optimizing the humoral immune response to the glycoprotein by focusing it towards structural determinants that are crucial for receptor recognition
Since the goal of this study was to induce a strong neutralizing antibody response that impairs the interaction of JUNV with its receptor, the receptor-binding JUNV GP1 subunit was chosen as the basis for the generated immunogens
Summary
Arenaviruses include a number of rodent-borne pathogens that can infect mammals. They are divided into those found in Eurasia and Africa (i.e., Old World (OW) arenaviruses) [1] and the Americas (i.e., New World (NW) arenaviruses) [2]. The latter include several important agents of human disease, including Guanarito virus, Sabiá virus, Chapare virus, Machupo virus (MACV), and Junín virus (JUNV), all of which cause hemorrhagic fever [3,4]. Disease is characterized by early non-specific febrile symptoms that develop in 20–30% of cases to include hemorrhages and/or neurological symptoms, which are indicative of a poor prognosis [6] and contribute to the 15% to 20% case fatality rate associated with untreated AHF
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