Universal Flu Vaccine: mRNA Approaches Advance in Clinical Trials

Why Do We Need a Universal Flu Vaccine?

Influenza viruses mutate rapidly through two primary mechanisms: antigenic drift (gradual point mutations in surface proteins) and antigenic shift (major reassortment events creating novel subtypes). Current seasonal vaccines target the head region of the hemagglutinin (HA) protein, which is the most immunogenic but also the most variable part of the virus. The WHO Global Influenza Surveillance and Response System monitors circulating strains and recommends vaccine compositions approximately 6 months before each flu season, but mismatches between predicted and actual circulating strains can reduce vaccine effectiveness to as low as 10-20%.

The consequences of this approach are significant. Even in moderately effective seasons, influenza causes 9 to 41 million illnesses, 140,000 to 710,000 hospitalizations, and 12,000 to 52,000 deaths annually in the United States alone, according to CDC estimates. Globally, the WHO estimates 290,000 to 650,000 respiratory deaths per year. Pandemic influenza strains, such as the 2009 H1N1 pandemic and the persistent threat of H5N1 avian influenza, pose additional catastrophic risks that seasonal vaccines cannot address.

A universal flu vaccine would target conserved regions of the influenza virus that remain stable across subtypes and over time, providing broad and durable protection without annual reformulation. Such a vaccine could also provide baseline immunity against novel pandemic strains, dramatically reducing the lead time needed for pandemic response. The National Institute of Allergy and Infectious Diseases (NIAID) has identified development of a universal influenza vaccine as a top strategic priority, allocating substantial research funding to this goal.

How Are mRNA Vaccines Being Used to Create a Universal Flu Vaccine?

The success of mRNA COVID-19 vaccines has accelerated application of this platform to influenza. Moderna's mRNA-1010 is a quadrivalent seasonal influenza vaccine that has completed Phase 3 clinical trials, demonstrating non-inferior immunogenicity to standard egg-based vaccines with the potential for faster manufacturing and better strain matching. More ambitiously, mRNA-1020 is a next-generation candidate designed to elicit broader cross-reactive immunity by encoding multiple hemagglutinin antigens, including those from less common subtypes.

A landmark study published in Science by researchers at the University of Pennsylvania and collaborators demonstrated that a single mRNA vaccine encoding hemagglutinin proteins from all 20 known influenza A and B subtypes (H1 through H18 and two influenza B lineages) elicited broad antibody responses in animal models. Vaccinated mice and ferrets were protected against matched and mismatched influenza challenges, suggesting the approach could provide truly universal protection. This multivalent mRNA approach exploits the platform's unique ability to encode multiple antigens in a single formulation without the manufacturing complexity of traditional protein-based vaccines.

NIH-funded researchers are also pursuing mRNA vaccines targeting the conserved stalk domain of hemagglutinin rather than the variable head domain. The HA stalk is far less prone to mutation and is shared across multiple influenza subtypes. Phase 1 trials of stalk-targeted vaccines, including both mRNA and nanoparticle-based approaches developed by NIAID's Vaccine Research Center, have shown the ability to generate stalk-directed antibodies with broadly neutralizing activity. Combining stalk-targeting with neuraminidase-based immunity and T-cell responses represents a multi-pronged strategy for durable universal protection.

What Are the Challenges in Developing a Universal Flu Vaccine?

One of the greatest scientific challenges is immune imprinting, also known as original antigenic sin. An individual's first exposure to influenza, whether through infection or vaccination, shapes their immune response to all subsequent encounters. The immune system preferentially recalls and boosts antibodies against the original strain rather than generating new responses to novel epitopes. This phenomenon can limit the ability of universal vaccine candidates to redirect immunity toward conserved targets, as the immune system defaults to familiar but strain-specific responses. Researchers are developing strategies to overcome imprinting, including prime-boost regimens with different antigen presentations.

Durability of protection is another critical concern. While seasonal vaccines provide reasonable short-term immunity, a universal vaccine would ideally confer protection lasting years or even decades. Achieving this requires robust engagement of memory B cells and long-lived plasma cells that produce broadly neutralizing antibodies over time. Current candidates have shown encouraging early immunogenicity data, but long-term follow-up is essential to assess whether initial immune responses translate into lasting protection. Additionally, the correlates of protection for universal flu vaccines are not yet fully defined, making it difficult to predict clinical efficacy from immunogenicity data alone.

Regulatory pathways for universal flu vaccines also present challenges. Traditional influenza vaccine licensure relies on hemagglutination inhibition (HAI) titers as surrogate endpoints, but these correlates are specific to strain-matched head antibodies and may not capture the stalk-directed, T-cell-mediated, or broadly neutralizing responses that universal vaccines aim to elicit. The FDA and EMA are working with developers to define appropriate endpoints and trial designs for these novel approaches, but the lack of established regulatory precedent adds uncertainty to development timelines.

When Could a Universal Flu Vaccine Become Available?

As of 2025, at least seven universal or broadly protective influenza vaccine candidates are in clinical trials, spanning mRNA, nanoparticle, and chimeric protein platforms. Moderna's seasonal mRNA flu vaccine (mRNA-1010) could receive regulatory approval as early as 2026, establishing the mRNA platform for influenza and paving the way for more broadly protective next-generation formulations. The NIH's Vaccine Research Center is conducting Phase 1 trials of nanoparticle vaccines displaying the HA stalk domain, with results expected to inform Phase 2 designs by 2026.

The NIAID strategic plan for universal influenza vaccine development envisions a phased approach: first improving seasonal vaccines with broader coverage (achievable near-term), then developing vaccines protective against all subtypes within a single influenza group (intermediate goal), and ultimately creating a vaccine effective against all influenza A and B viruses with durable multiyear protection (long-term goal). BARDA (Biomedical Advanced Research and Development Authority) has also invested in advanced development of promising candidates through Project NextGen-style initiatives.

Industry analysts and vaccine experts suggest that a truly universal vaccine providing broad, durable protection against all influenza subtypes is likely 5-10 years from widespread availability, accounting for the time needed for large-scale Phase 3 efficacy trials, regulatory review, and manufacturing scale-up. However, improved broadly protective vaccines offering better cross-reactivity than current seasonal formulations could arrive sooner. The convergence of mRNA technology, structural biology insights, and computational antigen design has created unprecedented momentum in this field, making many researchers cautiously optimistic that the long-sought goal of a universal flu vaccine is within reach.