More progress toward a potential universal flu shot

Intranasal EV vaccine protected mice from H5N1, H7N9

by Georgia State University

edited by Alexander Pol

A novel vaccine platform has been developed to induce broad, protective immunity against numerous influenza virus infections, showing promise as an effective mucosal vaccine strategy, according to a study published by researchers in the Institute for Biomedical Sciences at Georgia State University.

The study published in the journal ACS Nano used cell-derived extracellular vesicles (EVs) as a vaccine platform to display various human and avian influenza hemagglutinins (HAs) in an upside-down manner on the EV surfaces. The inverted HA tends to present the conserved HA stalk to the immune system to induce cross-protective influenza immunity while hiding the highly variable HA head to avoid strain-specific immunity.

The investigators used mice to evaluate cellular and mucosal immune responses induced by the multiple HA EV vaccines. HA is a major influenza surface glycoprotein. EVs are natural nanoparticles that facilitate cell-to-cell communications.

The researchers found that EV-based inverted HA vaccines hold great promise for developing universal influenza vaccines that target a mucosal route.

Developing innovative vaccine platforms and delivery strategies to induce protective immunity against diverse influenza virus strains in the respiratory tract is crucial for preventing influenza infection and transmission in potential epidemics and pandemics.

Mucosal vaccination effectively induces local immune responses, protecting against respiratory virus infections at the site of invasion. Although various mucosal vaccines have been studied for intranasal administration against respiratory virus infections in clinical trials, FluMist (MedImmune and AstraZeneca) remains the only FDA-approved mucosal influenza vaccine. Creating an effective mucosal vaccination strategy that elicits robust mucosal immune responses while minimizing safety concerns is still urgently needed.

"The influenza virus is smart. They have evolved to evade the immune system by hiding their critical conserved structures, rendering these elements poorly immunogenic," said Bao-Zhong Wang, senior author of the study and a Distinguished University Professor in the Institute for Biomedical Sciences at Georgia State. "These results highlight that the inverted HA is a smarter strategy for inducing protective immunity to the conserved HA stalk. Meanwhile, cell-origin EVs are a biocompatible platform for mucosal vaccine delivery. Using EVs simultaneously displaying multiple inverted HAs is a powerful approach for developing universal influenza vaccines."

The investigators determined that immunization with the multiple HA-EV vaccine elicited cross-reactive antibodies against influenza HA stalks and viruses, robust virus-specific cellular immune responses and a balanced Th1/Th2 immune profile.

"Intranasal immunization with multiple inverted HA-EV vaccines conferred complete protection against lethal heterosubtypic challenges with H7N9 and H5N1 reassortants," said Wandi Zhu, first author of the study and a research assistant professor in the Institute for Biomedical Sciences at Georgia State.

Publication details

Wandi Zhu et al, Mosaic Inverted Hemagglutinin Extracellular Vesicle Vaccines Elicit Protective Systemic and Mucosal Immunity against Heterosubtypic Influenza Infection, ACS Nano (2026). DOI: 10.1021/acsnano.5c13363

Journal information: ACS Nano