# Prototype strategies for antibodies and vaccines for respiroviruses

> **NIH NIH U19** · WASHINGTON UNIVERSITY · 2024 · $5,035,895

## Abstract

Human parainfluenza virus type 3 (HPIV3) is the P1-Respiroviruses prototype for advancement of vaccines
and therapeutic antibodies against respiroviruses due to the advanced state of knowledge of structure and
function of the viral surface proteins: HN (receptor-binding protein; hemagglutinin-neuraminidase) and F (fusion
protein). Respirovirus HN and F form a functional complex on the virus surface and mediate entry by fusing the
viral envelope directly with the cell membrane. Structural transitions in the HN/F complex during sequential
steps of entry will be characterized using cryo-electron microscopy (cryo-EM) and tomography (cryo-ET) to
identify optimal antigenic targets for respirovirus vaccines and antibodies. HPIV3 and human parainfluenza
virus type 1 (HPIV1) bracket the diversity of known respiroviruses making HPIV1 ideal for testing strategies
established with HPIV3. We will determine the utility of each surface glycoprotein as a target for immunity and
how best to present the antigen(s) by evaluating three vaccine platforms (subunit, mRNA, rVSV).
Aim 1: Define structure-function relationships of HN and F and extend the findings from prototype
HPIV3 to HPIV1. Structures of HN, F, and HN/F complexes and their intermediates for the prototype
respirovirus HPIV3 will be obtained to address gaps in basic understanding of the functions of the envelope
proteins in viral entry and assembly, reveal essential functional interactions between the proteins, and inform
immunogen design for vaccines and antibodies. Immunogenicity of proteins will be assessed in mice and
iterated back to antigen design. Results will be extended to HPIV1 to assess generalizability.
Aim 2: Identify monoclonal antibodies to prototype respirovirus HPIV3 HN and F with a high genetic
barrier to resistance and assess the generalizability of strategies using HPIV1. We will produce HPIV3-
binding mAbs from human B cells, compare their binding affinity, epitopes, and neutralization potencies;
identify neutralization mechanisms, leveraging mAbs that bind one or both proteins, different domains, and
different intermediate states of HN/F during entry; and evaluate mechanisms of escape. Abs that block critical
entry functions of HN/F, are protective, and have a high genetic barrier to resistance will be assessed for in
vivo protective/therapeutic capacity. Antigens that elicit such desirable antibodies will iteratively aid vaccine
antigen design. HPIV3-based approaches will be generalized and tested against HPIV1.
Aim 3: Comparison of vaccine platforms expressing HPIV3 HN, F, or HN/F complex. Immunogenicity of
mRNA- and VSV-expressed vaccine candidates will be evaluated in mice and compared to subunit antigens.
All three vaccine platforms (subunit, mRNA, rVSV) will be assessed for efficacy in cotton rats (HPIV3 model),
with iteration back to Aims 1 and 2. Generalizability of each platform design will be determined with HPIV1.
The results will define optimal immunogens and vaccine pla...

## Key facts

- **NIH application ID:** 10863697
- **Project number:** 1U19AI181984-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Anne Moscona
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $5,035,895
- **Award type:** 1
- **Project period:** 2024-09-11 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863697

## Citation

> US National Institutes of Health, RePORTER application 10863697, Prototype strategies for antibodies and vaccines for respiroviruses (1U19AI181984-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10863697. Licensed CC0.

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