Mount Sinai Wins $20.7 Million Deal to Build a Next-Generation Respiratory Vaccine Platform

Researchers at the Icahn School of Medicine at Mount Sinai have secured a five-year project agreement worth an estimated $20.7 million to develop a fundamentally rethought approach to vaccination against respiratory pathogens. The program, known as Vaccine Immunoengineering for Targeted Antigen Presentation and Layered Control, or VITAL, is supported by the Defense Threat Reduction Agency’s Joint Science and Technology Office through the Medical CBRN Defense Consortium, with funding provided incrementally over the period of performance. Rather than asking how to build a better vaccine against a single virus, the team aims to identify the underlying biological principles that could be incorporated into a single adaptable framework, one that could eventually be retooled for a wide range of respiratory threats.

VITAL was selected under Reimagining Available Vaccines and Envisioning Novelty, or RAVEN, a Joint Science and Technology Office program dedicated to advancing multivalent prophylactic biological countermeasures. RAVEN’s remit is deliberately broad: it seeks both incremental improvements to existing vaccine technologies and entirely new preventive platforms capable of addressing multiple biological threats simultaneously. That orientation marks a departure from the traditional one-pathogen, one-vaccine model that has dominated prophylactic development for decades. The Mount Sinai proposal was chosen because it promises a framework in which the delivery, presentation, and timing of antigen exposure can be systematically engineered rather than treated as fixed parameters of a given vaccine design.

The initial proof of concept will center on H5N1, a highly pathogenic avian influenza A virus that remains a persistent pandemic concern. The team will develop an unmodified mRNA-based vaccine prototype designed for intranasal delivery, with a distinctive twist: the construct is engineered to restrict expression of the immunogen primarily to macrophages, immune cells resident in the respiratory tract that participate in antigen presentation during natural infection. By confining antigen expression to these professional immune cells, the design seeks to avoid adverse events that can arise when vaccine-derived antigen is produced in other cell types that would never encounter the pathogen in the course of a real infection. The program will systematically evaluate how this targeting affects antigen presentation, immune stimulation, safety, and protection.

“VITAL is designed to directly support RAVEN’s objective by asking a broader question than whether we can make a vaccine against one virus,” said Gustavo Palacios, PhD, Professor of Microbiology at the Icahn School of Medicine and VITAL project lead. “Rather than focusing only on which antigens are delivered, we want to understand which biological principles can be incorporated into vaccination so that the same framework can eventually be adapted across different respiratory threats. H5N1 gives us a rigorous starting point to test those principles.”

The architecture of the program rests on five biological principles. The first is the exclusive targeting of immunogen expression to immune cells that help activate the body’s immune response, ensuring that antigen production occurs where it is immunologically useful. The second is the provision of appropriate stimulation to those cells, so that antigen presentation is paired with the right activation signals. The third involves engineering the antigens themselves to reduce toxicity and adverse responses without sacrificing expression or immunogenicity. The fourth principle matches antigen delivery to a pathogen’s natural route of entry, which in the case of respiratory viruses means delivering the vaccine intranasally rather than intramuscularly. The fifth is pulse immunization, a strategy intended to generate immune responses that mimic aspects of natural infection through controlled patterns of exposure over time.

Antigen detoxification occupies a central position in this design. Viral antigens can carry intrinsic toxic or inflammatory activities, and the VITAL team will engineer these molecules to reduce potential toxicity while preserving their ability to be expressed and to provoke a protective immune response. In parallel, the program will investigate different intranasal immunization schedules, including repeated low-dose regimens designed to reproduce aspects of the timing with which the immune system naturally encounters a respiratory virus. The underlying hypothesis is that the pattern of antigen exposure, not merely its identity, shapes the quality, breadth, and durability of the resulting immunity.

“One of the central challenges in influenza vaccination is achieving protection that is broad and durable rather than narrowly focused on a single circulating influenza virus variant,” said Adolfo García-Sastre, PhD, Irene and Dr. Arthur M. Fishberg Professor of Medicine and Director of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine. “VITAL gives us an opportunity to explore a different way of approaching that problem—by engineering not only the antigen, but also how, where, and over what time course the immune system encounters it.” García-Sastre’s long-standing work on influenza virus biology, virus-host interactions, and vaccine development anchors the program’s virological expertise.

To dissect the immune responses generated by this approach, VITAL will combine human immune tissue models and animal models with single-cell and spatial analysis, proteomics, and artificial intelligence and computational methods. The research will examine how targeted antigen-presenting cells, including macrophages and dendritic cells, respond to vaccination, how they interact with one another, and how those interactions drive downstream B cell and T cell responses. This systems-level view is intended to reveal which features of the engineered exposure correlate with durable, broad protection, providing the empirical basis for generalizing the framework beyond H5N1.

“A major strength of VITAL is the ability to study how vaccination shapes the immune response in physiologically relevant human systems,” said Ana Fernandez-Sesma, PhD, Chair of the Department of Microbiology at the Icahn School of Medicine. “By looking closely at macrophages, dendritic cells, and other immune populations using primary human tissues, we can predict whether a vaccine generates the appropriate immune response in humans as an alternative to animal models.” Her research on virus-host interactions and immune responses in human systems, including work with macrophages, dendritic cells, and human tonsil-based models, forms a core component of the program’s human immunology arm.

If the initial principles are successfully validated in the H5N1 prototype, VITAL is structured to scale toward a multivalent strategy encompassing at least 20 respiratory viruses, creating a framework that can be evaluated across a much broader spectrum of threats. Preclinical studies will assess the durability and breadth of immune responses across young and aged mice and ferrets, alongside the primary human systems, since animal models remain necessary under the current regulatory framework to characterize integrated immune responses, safety, and protection in vivo. These studies are positioned as a bridge toward a future in which validated human organoid systems may be accepted by regulatory agencies for defined aspects of preclinical evaluation. The program also incorporates regulatory planning and Investigational New Drug-enabling activities to support the potential clinical translation of selected vaccine candidates. The project agreement runs through August 28, 2031, giving the team a defined window to demonstrate whether engineering the where, when, and how of antigen presentation can yield a genuinely generalizable vaccine platform for respiratory disease.

Subject of Research: Development of a targeted mRNA vaccine platform for broad protection against respiratory pathogens, starting with H5N1 avian influenza

Article Title: Mount Sinai awarded five-year, $20.7 million vaccine development agreement to advance next-generation technologies against respiratory threats

Article References: Mount Sinai awarded five-year, $20.7 million vaccine development agreement to advance next-generation technologies against respiratory threats. (n.d.). Original publication

Image Credits: AI Generated

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Keywords: Mount Sinai, VITAL, RAVEN program, H5N1, mRNA vaccine, intranasal delivery, macrophages, antigen presentation, pulse immunization, respiratory viruses, Defense Threat Reduction Agency, influenza