TY - JOUR
T1 - Bivalent Junin & Machupo experimental vaccine based on alphavirus RNA replicon vector
AU - Johnson, Dylan M.
AU - Jokinen, Jenny D.
AU - Wang, Min
AU - Pfeffer, Tia
AU - Tretyakova, Irina
AU - Carrion, Ricardo
AU - Griffiths, Anthony
AU - Pushko, Peter
AU - Lukashevich, Igor S.
N1 - Funding Information:
The authors sincerely thank Dr. Slobodan Paessler (University of Texas Medical Branch, Galveston, TX) for providing Candid #1 and challenge stock of Machupo (Carvallo) virus. These studies were supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01 AI093450. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Funding Information:
The authors sincerely thank Dr. Slobodan Paessler (University of Texas Medical Branch, Galveston, TX) for providing Candid #1 and challenge stock of Machupo (Carvallo) virus. These studies were supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01 AI093450 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/3/23
Y1 - 2020/3/23
N2 - 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).
AB - 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).
KW - Alphavirus RNA replicons
KW - Bivalent vaccine
KW - Junin and Machupo arenaviruses
KW - South American Hemorrhagic Fevers
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U2 - 10.1016/j.vaccine.2020.02.053
DO - 10.1016/j.vaccine.2020.02.053
M3 - Article
C2 - 32111526
AN - SCOPUS:85080099545
SN - 0264-410X
VL - 38
SP - 2949
EP - 2959
JO - Vaccine
JF - Vaccine
IS - 14
ER -