# Enhancing protective immunity against RSV by inhibitors of sphingolipid synthesis

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $269,375

## Abstract

PROJECT SUMMARY
Infections with respiratory syncytial virus (RSV) are a considerable global health threat with high
morbidity and mortality in populations at risk, especially young children. Despite decades of
intense efforts, a safe and effective vaccine against RSV is not available. The development of
an active immunization strategy has been hampered by the risk for severe lung disease. Severe
RSV lung disease first occurred in small children who had been vaccinated with a formalin-
inactivated vaccine upon infection with RSV. Lessons learned from studying severe RSV
disease, and responses to RSV antigens point to the need for a successful vaccine to induce
robust Th1-biased immune response and potent neutralizing antibodies. We found that
simultaneous inhibition of sphingolipid de novo synthesis and mucosal administration RSV
induces a robust, Th1 biased and protective immune responses. We hypothesize that inhibitors
of serine-palmitoyl CoA transferase (SPT), the rate-limiting step of sphingolipid synthesis, can
function as potent adjuvants to enhance and favorably shape the immunogenicity of an RSV
vaccine. Further, the mechanism of this novel adjuvant strategy might differ substantially from
the pro-inflammatory and TLR-activating properties of other adjuvants. The aims of this
exploratory proposal are two-fold: First, to confirm the adjuvant effect of SPT-inhibitors for a
variety or biological relevant variables and targets for a RSV vaccine, most importantly the
capacity to enhance Th1 immunity and to lower the risk for vaccine-enhanced disease. Second,
to elucidate the innate immune mechanisms that trigger the increased adaptive immune
responses. Given the early stage of this project, we will focus mostly on lung dendritic cells and
potential alterations in immune cell trafficking induced by changes in pulmonary mucosal
sphingolipid synthesis. These results could then inform further detailed immune characterization
of other potentially affected cells, such as T follicular helper and regulatory cells and further
development of SPT-inhibitors as potential adjuvants for vaccines against other respiratory
pathogens.

## Key facts

- **NIH application ID:** 10354486
- **Project number:** 1R21AI166469-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Stefan Worgall
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $269,375
- **Award type:** 1
- **Project period:** 2022-05-09 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354486

## Citation

> US National Institutes of Health, RePORTER application 10354486, Enhancing protective immunity against RSV by inhibitors of sphingolipid synthesis (1R21AI166469-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10354486. Licensed CC0.

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