Every year, the flu vaccine gets updated because its components are strain-specific. A universal vaccine would strengthen the efficacy of seasonal flu vaccines. In the case of an influenza pandemic, the universal vaccine could be used to help control a global outbreak until a variant-specific vaccine is developed.

Dr. Suresh Mittal
Distinguished Professor of Virology in the Purdue University College of Veterinary Medicine

Viruses are locked into a continuous battle with the human immune system. Many are able to mutate rapidly—the only constant is change. This means that even if you’ve been infected with a previous version of a certain virus, your immune system may not recognize an altered version the next time around. More than 20 types of flu viruses—each of which contain many different strains—circulate among people and animals, changing almost constantly (NIH, 2023).

To address this ongoing threat, the National Institute of Allergy and Infectious Diseases (NIAID) has unveiled a strategic plan for the development of a universal influenza vaccine. The goal is to provide durable protection for all age groups against multiple influenza strains, including those that might cause a pandemic (NIAID, 2024).

The strategic plan has developed criteria for defining a universal influenza vaccine, identified knowledge gaps, and delineated research strategies for addressing those gaps. According to the plan, a universal vaccine should (NIAID, 2024):

1. Be at least 75% effective.
2. Protect against group I and II influenza A viruses, with influenza B as a secondary target.
3. Have durable protection that lasts at least 1 year and preferably through multiple seasons.
4. Be suitable for all age groups, including the young and the old.

It is possible that a universal influenza vaccine may only need to be administered two to three times in a lifetime, costing significantly less than the existing standard of care. The reduced frequency would likely improve vaccine uptake and provide low- and middle-income countries with a less costly universal vaccine (Lim et al., 2024).

Seasonal Influenza Vaccine Limitations

Seasonal vaccines target specific viral strains well ahead of the flu season and vaccine/viral mismatches are common. They provide virtually no protection against novel pandemic strains—especially strains that may arise after the vaccines have been formulated.

Seasonal influenza vaccine effectiveness varies from year to year. In instances where mismatches occur between vaccine strains and circulating strains, effectiveness can drop to as low as 10%. Seasonal vaccines require updating and re-administration each flu season, annually costing billions of dollars (Lim et al., 2024).

In addition to the natural viral shifting and drifting, egg-based manufacturing is known to contribute to the development of viral mutations. Host factors such as immunization history, previous influenza exposure, age, and comorbidities can decrease a vaccine’s effectiveness (Lim et al., 2024).

How a Universal Vaccine Might Work

An ideal universal influenza vaccine should possess the ability to protect against all influenza A and B viruses while providing a long-lasting immune response. A universal vaccine should also protect antigens* from rapid degradation and diffusion, improving the ability of an antigen to induce an immune response within the body (Lim et al., 2024).

*Antigens: a toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies (Oxford English Dictionary). See also Chapter 6, Influenza Vaccines, for a short discussion of antigens and antibodies with an associated graphic.

Several scientific advances have made the development of a universal influenza vaccine more feasible than in the past. Gene-sequencing techniques allow for more-efficient characterization of viruses, enabling researchers to track genetic changes in flu viruses over time. Advances in structural biology have allowed researchers to understand how minor changes in the structure and conformation of the hemagglutinin protein affect function, antigenicity*, and immunogenicity** (Erbelding et al., 2018).

*Antigenicity: the ability of the antigen to combine with the antibody and also its ability to induce antibody formation.
**Immunogenicity: the ability for an object to stimulate an immune response if the immune system recognizes the substance as foreign.

One of the most important and most studied influenza viral proteins is hemagglutinin. Located on the surface of the flu virus, the bulb-like “head” of the hemagglutinin is a main target of seasonal flu vaccines. The head is the part of the viral protein that drifts and changes from season to season, making it difficult to develop a vaccine that is consistently effective. Underneath the head is a “stalk” that changes much less frequently than the head. Because the stalk is much less prone to genetic shifting and drifting, this “conserved” part of the flu virus is the focus of intense research. Conserved elements within the flu virus remain relatively unchanged over time.

Conserved elements can persist over time and have slower rates of mutation than the background mutation rate. However, viruses have the ability to hide these elements, making them less visible to the immune system.  A universal flu vaccine may be able to train the immune system by exposing it to conserved elements, allowing the immune system to recognize and fight off a wider range of flu strains.

To create the universal vaccine, researchers fused the hemagglutinin proteins from four different flu strains to building blocks that assemble into tiny nanoparticles. The researchers reasoned that this would encourage the immune system to respond to parts of the hemagglutinin protein that were more similar, or conserved, between influenza strains (NIH, 2023).

Immune response can also be enhanced through the use of complementary adjuvants* or agents added to vaccine formulations. Co-administration of appropriate adjuvants enhances the scale and breadth of the body's immune response and can reduce the amount of antigen needed. Various particulate adjuvants for injection and mucosal routes of administration have been evaluated (Lim et al., 2024).

*Adjuvant: any substance, agent, or strategy that enhances immune responses when delivered together with the antigen. They are an integral part of all modern vaccines.

Pandemic Preparedness

Although relatively rare, flu pandemics occurred four times during the last century (1918, 1957, 1968, and 2009) resulting in millions of deaths worldwide. Pandemics happen when novel influenza A viruses emerge that are able to infect people easily and spread from person to person in an efficient and sustained way. A global outbreak can occur when the new influenza A virus is very different from current and recently circulating human seasonal influenza A viruses.

A universal influenza vaccine would enhance pandemic preparedness. As the process of producing new matched vaccines to protect against pandemic strains takes approximately 6 months, people remain vulnerable during this long period of time. Regardless of vaccine coverage, the threat of any emerging pandemic strain can be completely eradicated (Lim et al., 2024).