Improved cross-protection and immunity against influenza A virus in mice using a novel mRNA vaccine with optimized design of RNA sequence

Sep 29, 2026

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Improved cross-protection and immunity against influenza A virus in mice using a novel mRNA vaccine was investigated through a multi-antigen, lipopolyplex-delivered construct (LPP-HNH) encoding headless hemagglutinin stem and neuraminidase in three optimized RNA sequences. In mouse models, all three single-chain mRNA vaccines elicited sustained, robust antibody and cellular immune responses against H1N1, H3N2, and H5N1. Optimized variants (HNH-E1, HNH-E2) enhanced protein expression and CD4+ and CD8+ T cell responses, yielding stronger protection linked to lower minimum free energy and higher codon adaptation index.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

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Introduction

Influenza vaccine limitations

Conserved antigen targets for universal vaccines

mRNA vaccine platforms and LPP delivery

Original Article Improved cross-protection and immunity against influenza A virus in mice using a novel mRNA vaccine with optimized design of RNA sequence Tangqi Wang,1,2 Ruiwen Han,1,2 Zhanyihao Hao,3 Xueting Cheng,2 Jia Li,1,2 Chengcheng Zhai,2 Junjia Guo, 1 Donghong Wang,2 Yao Deng,2 Liang Zhang,3 and Wenjie Tan 1,2 1Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; 2National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Key Laboratory of Biosafety, National Health Commissions, National Institute for Viral Disease Control and Prevention, China CDC, 155 Changbai Road, Beijing 102206, China; 3Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China Conventional influenza vaccines provide strain-specific immunity, and their production can be affected by egg-cultureadapted mutations. A universal influenza vaccine with conserved antigens and novel vaccine platforms is urgently required. To induce the immune responses toward more conserved epitopes, we generated a multi-antigen influenza mRNA vaccine, lipopolyplex (LPP)-HNH mRNA, coding headless hemagglutinin stem and neuraminidase with three different sequences (HNH-ORI, HNH-E1, or HNH-E2) and delivered by LPP. The immunogenicity and protective efficacy of these single-chain mRNA vaccines against influenza A viruses were evaluated in mice models. Mice exhibited sustained and robust antibody and cellular immune responses against all three LPP-HNH mRNA vaccines, indicating that these vaccines provided mice with broad protection against H1N1, H3N2, or H5N1 influenza viruses. HNH-E1 and HNH-E2 with optimized sequence showed higher protein expression, stronger specific CD4+ and CD8+ T cell responses, and more effective protection than those of HNH-ORI, owing to their lower minimum free energy and higher codon adaptation index. These results reveal that theLPP-HNH mRNA vaccine encoding conserved antigens with optimized sequences is a promising strategy for the development of universal influenza vaccines. INTRODUCTION The influenza virus currently circulates in humans, and vaccination is an efficient way to contain influenza epidemics. 1 However, most licensed seasonal influenza vaccines recognize the globular head domain of hemagglutinins (HAs), which are highly plastic and variable.2–5 The effectiveness of vaccines is greatly reduced when they do not match the circulating strains due to antigenic drift.6,7 In addition, conventional influenza vaccines have a lengthy production cycle, which makes it challenging to keep up with the continuous mutation in influenza viruses.8 Therefore, a universal influenza vaccine that targets conserved antigens and is convenient for rapid production to provide broad-spectrum protection is urgently needed. HA and neuraminidase (NA) are the major glycoproteins on the surface of influenza viruses.9 The HA stem, which is conserved, contains extensive neutralizing epitopes, which can induce cross-protective antibodies that restrict viral entry by locking HA in a pre-fusion state.10–12 The antigenic drift of NA is independent of HA and has a slower mutation rate, allowing it to be used as a complementary antigen for vaccines. 13, 14 Recently, the antibodies targeting NA have been found to provide protection within a single subtype. 15, 16 The HA stem and NA have emerged as promising conserved targets fora universal influenza vaccine. mRNA vaccines have the advantages of flexible design and a short production period, which make mRNA a promising platform for a universal influenza vaccine.17 A core-shell structured lipopolyplex (LPP) is a novel delivery system for mRNA vaccines with superior colloidal stability, encapsulation, and delivery efficiency. Compared with traditional lipid nanoparticles (LNPs), LPP expresses mRNA primarily at the injection site after intramuscul

FAQs

What vaccine design was used in the study?

The study generated a multi-antigen influenza mRNA vaccine (LPP-HNH) delivered by lipopolyplex, encoding headless hemagglutinin stem and neuraminidase with three different RNA sequences.

How did the three mRNA vaccine variants perform in mice?

All three LPP-HNH mRNA vaccines induced sustained, robust antibody and cellular immune responses and provided broad protection against H1N1, H3N2, or H5N1 in mice.

Why did the optimized sequences (HNH-E1 and HNH-E2) show stronger protection?

HNH-E1 and HNH-E2 produced higher protein expression, stronger CD4+ and CD8+ T cell responses, and more effective protection, associated with lower minimum free energy and higher codon adaptation index.

Sep 29, 2026

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