# Rational design of a safe recombinant Candid#1 vaccine

> **NIH NIH R01** · UNIVERSITY OF MONTANA · 2021 · $378,975

## Abstract

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 e...

## Key facts

- **NIH application ID:** 10117686
- **Project number:** 1R01AI150950-01A1
- **Recipient organization:** UNIVERSITY OF MONTANA
- **Principal Investigator:** Jack H Nunberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,975
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117686

## Citation

> US National Institutes of Health, RePORTER application 10117686, Rational design of a safe recombinant Candid#1 vaccine (1R01AI150950-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10117686. Licensed CC0.

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