Bivalent Junin & Machupo experimental vaccine based on alphavirus RNA replicon vector
| Autor: | Igor S. Lukashevich, Dylan M. Johnson, Jenny D. Jokinen, Min Wang, Anthony Griffiths, Irina Tretyakova, Tia L. Pfeffer, Peter Pushko, Ricardo Carrion |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
030231 tropical medicine
Guinea Pigs Transferrin receptor Alphavirus Antibodies Viral Neutralization Bivalent (genetics) Article Hemorrhagic Fever American 03 medical and health sciences 0302 clinical medicine Animals 030212 general & internal medicine Replicon Vaccines Combined Neutralizing antibody Arenaviruses New World chemistry.chemical_classification Junin virus General Veterinary General Immunology and Microbiology biology Public Health Environmental and Occupational Health Viral Vaccines Virology Antibodies Neutralizing Immunity Humoral Vaccination Hemorrhagic Fevers Infectious Diseases chemistry biology.protein Molecular Medicine RNA Glycoprotein |
| Zdroj: | Vaccine |
| Popis: | Junin (JUNV) and Machupo (MACV), two mammalian arenaviruses placed on the 2018 WHO watch list, are prevalent in South America causing Argentine and Bolivian hemorrhagic fevers (AHF and BHF), respectively. The live attenuated JUNV vaccine, Candid #1, significantly reduced the incidence of AHF. Vaccination induces neutralizing antibody (nAb) responses which effectively target GP1 (the viral attachment glycoprotein) pocket which accepts the tyrosine residue of the cellular receptor, human transferrin receptor 1 (TfR1). In spite of close genetic relationships between JUNV and MACV, variability in the GP1 receptor binding site (e.g., MACV GP1 loop 10) results in poor MACV neutralization by Candid #1-induced nAbs. Candid #1 is not recommended for vaccination of children younger than 15 years old (a growing “at risk” group), pregnant women, or other immunocompromised individuals. Candid #1’s primary reliance on limited missense mutations for attenuation, genetic heterogeneity, and potential stability concerns complicate approval of this vaccine in the US. To address these issues, we applied alphavirus RNA replicon vector technology based on the human Venezuelan equine encephalitis vaccine (VEEV) TC-83 to generate replication restricted virus-like-particles vectors (VLPVs) simultaneously expressing cellular glycoprotein precursors (GPC) of both viruses, JUNV and MACV. Resulting JV&MV VLPVs were found safe and immunogenic in guinea pigs. Immunization with VLPVs induced humoral responses which correlated with complete protection against lethal disease after challenge with pathogenic strains of JUNV (Romero) and MACV (Carvallo). |
| Databáze: | OpenAIRE |
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