The Holy Grail: A ‘Universal’ Flu Vaccine

By Henry I. Miller, MS, MD — Oct 19, 2023
The inconvenience of yearly flu shots prevents many people from getting them, while flu kills thousands of Americans annually. We need vaccines that will provide durable immunity and work against new variants. There is progress.

Flu and COVID-19 are examples of respiratory diseases that require repeated vaccine boosters to prevent illness. They are a reminder that we need better vaccines that offer improved durability and enhanced breadth of protection against new variants.  This article will discuss progress in developing “universal” flu vaccines, and Part 2 (to follow) will focus on COVID-19 vaccines with similar properties.          

Although annual seasonal flu vaccines are invaluable tools for controlling the spread and severity of influenza, they do not provide immunity against every strain of the virus, which constantly mutates, sometimes radically. Numerous attempts over many years to develop flu vaccines that would not require yearly shots to protect against new variants have not succeeded. They would, however, be an important public health advance.  Many Americans fail to get flu shots, and the CDC estimates that from 2010 to 2020, between 12,000 and 52,000 people died of flu in the United States annually.

There are two ways that flu viruses commonly evolve. One is called "antigenic drift," which is caused by changes in the surface proteins of the virus, hemagglutinin (HA) and neuraminidase (NA). Those mutations usually produce viruses closely related to one another, which means that antibodies elicited by exposure to one flu virus will likely recognize other viruses that arose from antigenic drift.

Another, more drastic type of change is called "antigenic shift," a major genetic change that gives rise to new, significantly different HA and/or NA proteins in flu viruses that enable them to infect humans. This is more likely to occur when there is co-infection by different viruses — for example, human and avian flu viruses simultaneously infecting an animal host — giving rise to reassortment of viral RNAs, the formation of a new hybrid virus containing parts from the genomes of two distinct viruses in a mixed infection. The new viruses may be sufficiently different that most people do not have immunity to them.

Such a "shift" occurred in the spring of 2009, when an H1N1 flu virus with genes from viruses originating from North American swine, Eurasian swine, humans, and birds emerged, infecting people, spreading quickly, and causing a pandemic.

Antigenic drift (the two circular genomes at the top) and shift (the reassortment of RNA segments, below), respectively, are illustrated here:



Figure legend: (A) Antigenic Drift (the two circular genomes at the top): Gradual accumulation of mutations in the genome of viruses leads to emergence of new virus variants. Mutations in the HA (blue) and NA (red) can affect the antigenic epitopes leading to antigenically new variants. (B) Antigenic Shift (the four figures below (A)): The exchange/reassortment of genetic segments between two or more infecting viruses in a host cell can lead to emergence of antigenically distinct, new subtypes. Courtesy: Wikimedia Commons.

Therefore, every spring, a group of scientific experts gets together to try to predict which strains are likely to be prevalent during the following flu season (which begins in the fall), and they select three or four of these strains to include in the next seasonal vaccine. Using a variety of platforms, drug companies then produce their versions of the vaccine in preparation for distribution in late summer or early fall.

However, sometimes their predictions are inaccurate, and unexpected changes in the dominant strains of the virus cause “immune escape” and decreased vaccine efficacy. An effective universal flu vaccine could address these problems by protecting vaccinees against a wide variety of strains and ideally providing durable long-term immunity.

Such a vaccine would have two advantages: It would stop the guessing game about which flu strains will become dominant, and people would not need to be vaccinated yearly.  Several clinical research trials to develop universal vaccines are underway; two of the more promising ones are described below.

The results of a small clinical trial of a candidate were published in July in the journal Lancet Infectious Diseases.  The active, immunogenic moiety of the OVX836 vaccine, which is made by a French company called Osivax, is a recombinant H1N1 nucleoprotein, a protein in viral particles that is not very prone to the mutations that change surface antigens and characterize new strains. Therefore, used as a vaccine, it should be better able to elicit immunity to new virus strains that have arisen by antigenic drift or shift.

In the single-center trial conducted in Belgium, three doses of the OVX836 vaccine induced dose-dependent cell-mediated immune responses.  There were four cases of influenza A in the 33-patient placebo group and two in the 104 patients who received the vaccine. The vaccine had a favorable safety profile.  But vaccines are typically tested in tens of thousands of subjects before regulatory approval, so it’s still in its early days.

Another clinical trial of an experimental universal flu vaccine, developed by researchers at the NIH’s National Institute of Allergy and Infectious Diseases, began enrolling volunteers earlier this year.  This very small Phase 1 trial will test the vaccine, designated H1ssF-3928 mRNA-LNP and consisting of messenger RNA (mRNA) encapsulated in lipid nanoparticles (LNP), for safety and its ability to induce an immune response.

The trial will enroll up to 50 healthy subjects aged 18 through 49.  Three groups of study participants will receive various doses of the vaccine, and another group will receive a current quadrivalent seasonal influenza vaccine. That will allow a direct comparison between the immunogenicity and safety of the candidate vaccine and available seasonal flu vaccines.

Another complementary approach is to enhance vaccines with adjuvants, chemicals that boost the immune response, making it more rapid and stronger and making possible smaller doses of the immunogen.

The bottom line is that there are several lines of research underway to develop flu vaccines that would be effective against new viral variants that arise.  Given the health and economic burdens of flu and Americans’ resistance to getting yearly shots, the availability of “universal” vaccines would be an important advance.


Henry I. Miller, MS, MD

Henry I. Miller, MS, MD, is the Glenn Swogger Distinguished Fellow at the American Council on Science and Health. His research focuses on public policy toward science, technology, and medicine, encompassing a number of areas, including pharmaceutical development, genetic engineering, models for regulatory reform, precision medicine, and the emergence of new viral diseases. Dr. Miller served for fifteen years at the US Food and Drug Administration (FDA) in a number of posts, including as the founding director of the Office of Biotechnology.

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