Rational design of a safe recombinant Candid#1 vaccine

Information

  • Research Project
  • 10117686
  • ApplicationId
    10117686
  • Core Project Number
    R01AI150950
  • Full Project Number
    1R01AI150950-01A1
  • Serial Number
    150950
  • FOA Number
    PA-18-873
  • Sub Project Id
  • Project Start Date
    4/1/2021 - 3 years ago
  • Project End Date
    3/31/2025 - 3 months from now
  • Program Officer Name
    DUPUY, LESLEY CONRAD
  • Budget Start Date
    4/1/2021 - 3 years ago
  • Budget End Date
    3/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    3/31/2021 - 3 years ago
Organizations

Rational design of a safe recombinant Candid#1 vaccine

Arenaviruses are endemic in rodent populations and can be transmitted to humans to cause severe life- threatening hemorrhagic fevers. Relevant US agencies (DHHS, DHS and DoD) and the WHO recognize these viruses as high priority pathogens that pose a serious threat to public health and national security. The live- attenuated Candid#1 strain of Junín virus (JUNV) is currently used in Argentina to protect against Argentine hemorrhagic fever, but this virus carries the distinct liability that attenuation is solely dependent on a single phenylalanine-to-isoleucine substitution at position 427 (F427I) in the GP2 fusion subunit of the JUNV envelope glycoprotein (GPC). Indeed, reversion at the attenuating position occurs readily in cell culture and in laboratory animals. The current proposal seeks to capitalize on our understanding of GPC structure and function to design recombinant Candid#1 (rCan) viruses that stably maintain attenuation without compromising protective efficacy. We have discovered an epistatic interaction between the attenuating F427I mutation in GP2 and a lysine-to-serine mutation at position 33 (K33S) in the stable signal peptide (SSP) subunit of GPC that provides an evolutionary barrier against reversion to the pathognomonic F427. Pilot studies indicate that K33S rCan is indeed attenuated in guinea pigs and capable of eliciting protective immunity against lethal challenge with JUNV. We hypothesize further that safety in a K33S rCan vaccine can be additionally enhanced by incorporating well-characterized and genetically stable GPC deletions. By characterizing rCan viruses that embody these strategies, we aim to enhance safety in a second-generation rCan vaccine. Towards this goal, we will pursue the following specific aims: Aim 1. Determine the degree of attenuation and genetic stability of K33S rCan in mice. We will utilize well-established mouse models to determine the degree of attenuation in rCan variants and confirm the genetic stability of the attenuating F427I mutation. Aim 2. Assess the balance of attenuation, immunogenicity and protective immunity of K33S rCan in the guinea pig model of lethal JUNV infection. Guinea pigs serve as the gold-standard model for assessing Candid#1 attenuation and protective efficacy. We will expand upon our pilot findings to optimize the balance between attenuation and protective efficacy. We will evaluate production of virus-neutralizing antibodies, an accepted surrogate of protection, and the ability of the vaccine to elicit virus-specific CD8+ T cells. Aim 3. Design and characterize rCan variants bearing redundant and genetically stable mutations that promote attenuation. We have identified two deletions in GPC that support rCan infectivity. We will characterize rCan variants bearing these deletions to integrate additional layers of attenuation. Taken together, our efforts will establish an optimal balance of attenuation, genetic stability and efficacy in a second-generation rCan vaccine, and elucidate the molecular basis for attenuation and the immunologic correlates of protection. These strategies may also be applicable towards the development of an urgently needed live-attenuated Lassa virus vaccine.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    1
  • Direct Cost Amount
    288254
  • Indirect Cost Amount
    90721
  • Total Cost
    378975
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
    ORGANIZED RESEARCH UNITS
  • Funding ICs
    NIAID:378975\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    VMD
  • Study Section Name
    Vaccines Against Microbial Diseases Study Section
  • Organization Name
    UNIVERSITY OF MONTANA
  • Organization Department
    NONE
  • Organization DUNS
    010379790
  • Organization City
    MISSOULA
  • Organization State
    MT
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    598124104
  • Organization District
    UNITED STATES