# Immunological characterization of rationally-designed vaccines against plague in mice and non-human primate models

> **NIH NIH R56** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $224,539

## Abstract

Yersinia pestis (Yp) is the causative agent of bubonic and pneumonic plague. The increasing number of plague
cases globally (2010-2017), including the U.S., with a ~18% case fatality rate may reflect climate changes and
a rodent carrier range shift. An outbreak of 2017 in Madagascar with ~2400 cases (>75% pneumonic) and ~9%
causalities has led WHO (April 2018) to intensify the need for developing new generation subunit and live-
attenuated plague vaccines. Yp’s ability to persist in dead hosts, and then resurge after years of silence, is
alarming. Also, antibiotic-resistant Yp strains occur naturally or have been intentionally developed and currently
no FDA-approved plague vaccine is available. Finally, two-component subunit vaccines composed of capsular
antigen F1 and a T3SS component and effector LcrV (low calcium response V antigen), which only generate a
humoral immune response, provide variable protection in African green monkeys (AGM) and generate poor T
cell-mediate immune responses in humans. Since the cellular immunity is also critical for protection, we focused
first on identifying new virulence genes of Yp and then to delete such genes in combination to develop novel
live-attenuated vaccine strains. Our data indicated that two such vaccine candidates were 100% attenuated in
inducing bubonic/pneumonic plague in mice/rats and generated long-term robust humoral and cellular immune
responses to provide 100% protection to rodents against developing pneumonic plague. No clinical symptoms
of the disease or histopathological lesions were noted either during immunization or when the vaccinated animals
were subsequently exposed to wild-type Yp CO92 in a pneumonic plague model. We hypothesize that further
immunological characterization of these mutants and their testing in higher animals, such as cynomolgus
macaques (CM) and AGM, will provide a rationale for future preclinical and clinical studies. There is a precedent
for using a live-attenuated vaccine against plague, as EV76 strain is used in humans in some parts of the world
where plague is endemic. However, the vaccine is reactogenic, represents a spontaneous mutant, and causes
disease in patients with over iron load. Three Aims have been proposed: Aim 1, to demonstrate efficacy and
immune responses of two vaccine candidates generated from Yp CO92 (biovar Orientalis) against other Yp
biovars (Antiqua and Medievalis), and the F1-minus mutant of CO92 in bubonic and pneumonic mouse models.
Our data with the mutants indicated a potential role of IL-17 (a Th17 cytokine), Th1-IFN-γ, and antibodies in
protection. In Aim 2, we will study the mechanistic basis of this protection (one chosen mutant) by using RORt-
/- mice, which lack Th17 cells, as well as IFN-γ, and IgA k/o mice and to discern their links to neutrophil
recruitment and mucosal immunity, to combat Yp infection in bubonic/pneumonic plague models. In Aim 3, CM
and AGM will be used with one mutant to demonstrate its short- and long-term ...

## Key facts

- **NIH application ID:** 10213974
- **Project number:** 1R56AI153524-01
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** ASHOK K CHOPRA
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $224,539
- **Award type:** 1
- **Project period:** 2020-08-05 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213974

## Citation

> US National Institutes of Health, RePORTER application 10213974, Immunological characterization of rationally-designed vaccines against plague in mice and non-human primate models (1R56AI153524-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213974. Licensed CC0.

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