# Immunotherapeutic approach for the prevention of secondary infection with drug-resistant TB

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2024 · $978,338

## Abstract

Pulmonary infections with Mycobacterium tuberculosis (M.tb) account for a staggering amount of morbidity and
mortality worldwide. A highly effective vaccine able to prevent (i) active disease, (ii) relapse after chemotherapy,
and (iii) reinfection, remains elusive even in the face of concerted global efforts. One obstacle hindering the
comparison of vaccine candidates and their progression in the pipeline is a lack of consensus in the field on
important immunological endpoints to include in preclinical studies and clinical trials. The research proposed
here aims to leverage core models with a suboptimal drug treatment regimen to resolve differences in relapse
rates with or without concurrent vaccine candidate immunizations. Relapse and reinfection are clearly defined
outcomes for TB patients, and we aim to develop not only an effective therapeutic vaccine but also better
screening methods for understanding efficacy endpoints in preclinical models. To achieve these goals, we will
screen sixteen vaccine candidates consisting of four subunit antigens (including clinically proven M72 and ID93
antigens, a promising therapeutic candidate ID91, and a novel TB subunit (TBSU) candidate) formulated with
four adjuvant candidates that differ in their modes of action, which will be screened using innovative therapeutic
animal models (in mice and guinea pigs). M72 with an AS01E-like adjuvant, co-developed by our team, will be
included as a comparator in these studies, which will add scientific rigor as this is the first defined vaccine to
show protection in previously M.tb infected individuals.
We hypothesize that combined with a drug treatment regimen, an optimized therapeutic vaccine
candidate protein + adjuvant can reduce relapse and reinfection by eliciting a multifaceted antigen-
specific immune response. In Aim 1 16 vaccine candidates will be assessed using safety and efficacy
endpoints both in vitro and in vivo. We will also choose an antigen dose that is effective and safe for use in Aim
2. Aim 2 will be devoted to evaluating the full complement of 16 candidates (4 antigens x 4 adjuvants) for
therapeutic protection from relapse in the mouse model. Following a mouse relapse screen, vaccine candidates
will be further downselected. Finally, 2 lead vaccine combinations that show efficacy (survival, relapse, and
protection from drug-resistant M.tb) in both sexes will be advanced into the guinea pig therapy model where they
will be assessed for durable treatment success as measured by a reduction in bacterial counts (in the lung and
spleen), reduction in lung pathology, prevention of disease RNA signatures, clinical scoring (including weights),
and enhanced survival over drug treatment alone, to select the final candidate for advancement to Aim 3. In Aim
3, we will examine the lead candidate for therapeutic efficacy of protection from reinfection following primary TB
infection. We will also investigate the mechanisms of therapeutic efficacy by systematically...

## Key facts

- **NIH application ID:** 10979381
- **Project number:** 1R01AI181218-01A1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Susan Louise Baldwin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $978,338
- **Award type:** 1
- **Project period:** 2024-06-13 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979381

## Citation

> US National Institutes of Health, RePORTER application 10979381, Immunotherapeutic approach for the prevention of secondary infection with drug-resistant TB (1R01AI181218-01A1). Retrieved via MORVS 2026-10-26 from https://api.morvs.ai/grant/nih/10979381. Licensed CC0.

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