There are more than 2.5 million severe cases of influenza every year, and the virus is responsible for 250,000 to 500,000 deaths annually. The influenza virus mutates regularly, which means that vaccines need to be reformulated and administered annually to provide immunity. This results in costly vaccine administration that is largely impractical and inaccessible for low- and middle-income countries (LMICs). Moreover, the strain to which vaccines provide immunity is predicted based on virus surveillance. This can create a mismatch between the vaccine strain and the circulating strain, which will result in low efficacy.
Universal Influenza Vaccines (UIVs) could reduce the cost of administration and the number of doses, while providing more robust immunity. Ultimately, UIVs have the potential to provide better and more widespread immunity and protect against novel pandemic flu strains, such as the flu that is estimated to have killed more than 50 million in 1918.
However, despite the urgent need for a UIV, there continues to be scientific and ethical challenges in its development.
Expandable List
The Influenza Virus
• The influenza virus changes every year. There are two primary ways the virus can change: antigenic drift and antigenic shift.
• Antigenic drift refers to individual mutations of either of the two glycoproteins that make up the influenza virus’s membrane: hemagglutinin (HA) and neuraminidase (NA).1
• HA is the glycoprotein that allows the influenza virus’s attachment and entry into our cells in our upper respiratory tract. NA is the glycoprotein that facilitates the spread of the virus into these cells.
• Antigenic shift only occurs in influenza A and refers to the mutation of novel subtypes of HA or NA (primarily HA) — this leads to vastly different strains of influenza to which many people have no pre-existing immunity and increases the potential for pandemic influenza viruses (e.g., the shift from H1 to H2 in 1957 and H2 to H3 in 1968).2
• This yearly antigenic drift and/or antigenic shift in the influenza strain is what necessitates an annual vaccine that responds to the year’s specific virus.
Challenges of Annual Influenza Vaccines3
• Scientists determine which strains are selected for seasonal influenza vaccines based on global surveillance of influenza. They try to predict which strain will arrive in “flu season” months before it arrives to ensure vaccine production is completed in time. Mismatches between vaccine strains and circulating strains occur frequently and decrease vaccine efficacy.
• Seasonal influenza is estimated to cause 2.5 million severe cases and 250,000 to 500,000 deaths per year globally. Low- and middle-income countries (LMICs) carry a disproportionate share of the burden of influenza disease and death, but they lack the infrastructure and resources to surveil circulating strains and to administer annual revaccinations.
• Even in High-Income Countries (HICs), it is expensive to develop and administer annual influenza vaccines.
• Annual vaccines would have limited efficacy against newly emergent pandemic-influenced variants.
Promise of a Universal Influenza Vaccine (UIV)
• The need for a Universal Influenza Vaccine (UIV) is clear. As stated above, seasonal influenza is estimated to cause 2.5 million severe cases and 250,000 to 500,000 deaths per year globally.3 Additionally, a UIV could eliminate future pandemics, such as the H1N1 pandemic in 1918 which is estimated to have killed more than 50 million people. Some experts believe another pandemic flu event is inevitable.4
• In addition to saving lives, the UIV could greatly reduce the monetary and human resource cost of influenza protection. Annual influenza vaccination in the United States is estimated to cost more than $3500 per person per lifetime (this cost excludes fees from medical personnel to administer the vaccine). Extrapolated to encompass the population of the United States, billions of dollars are spent vaccinating people every year. A two- or three-dose UIV would significantly reduce this cost.3
Research Gaps What Constitutes a “Universal” Vaccine?
There is debate regarding what should be considered a “universal” influenza vaccine. Ideally, this vaccine should “induce lifelong protection against all drift and shift variants, including seasonal influenza A and B, pandemic, and zoonotic strains.”3 In this definition, vaccines that protect from select subsets of influenza viruses should be considered only broadly protective.
However, the National Institute of Allergy and Infectious Diseases (NIAID) defines a UIV with the following necessary characteristics:
• Be at least 75% effective;
• Protect against groups 1 and 2 influenza A viruses;
• Have durable protection that lasts at least 1 year; and
• Be suitable for all age groups.5
Others define UIV even more broadly as an influenza vaccine that attempts to induce better cross-protection than seasonal influenza vaccines.3
The Impact of COVID-19 on the Development of UIV
With the COVID-19 pandemic, there are new questions and concerns regarding the development of a UIV. For example: Have resources been redirected away from UIV and towards COVID-19? Has the fast development of COVID-19 vaccines skewed our expectations about our ability to respond to a pandemic virus? Can some of the recent progress in vaccine technology be applied to the development of a UIV?
Resurrection of Old Influenza Vaccines
An ethical concern for studies that use multiple influenza strains, such as those aimed at creating a UIV, is the resurrection of strains that are currently not in circulation. Not all UIV studies would require this process. However, to create a true UIV (understood as protecting all strains, past, present, and future), it is likely that old influenza strains will have to be resurrected. There is currently no guidance in the field of UIV ethics research as to whether such a practice is ethical.
NIAID’s Strategic Plan for Investments in the Development of UIVs
- Erbelding, Emily J., Diane J. Post, Erik J. Stemmy, Paul C. Roberts, Alison Deckhut Augustine, Stacy Ferguson, Catharine I. Paules, Barney S. Graham, and Anthony S. Fauci. “A Universal Influenza Vaccine: The Strategic Plan for the National Institute of Allergy and Infectious Diseases.” The Journal of Infectious Diseases 218, no. 3 (July 2, 2018): 347–54. https://doi.org/10.1093/infdis/jiy103.
This article provides a summary of all the UIV clinical trials in the 2010s decade:
- Corder, Brigette N., Brianna L. Bullard, Gregory A. Poland, and Eric A. Weaver 2020. “A Decade in Review: A Systematic Review of Universal Influenza Vaccines in Clinical Trials during the 2010 Decade.” Viruses12, no. 10: 1186. https://doi.org/10.3390/v12101186.
This review discusses advances in the development of UIVs:
Kumar, Arun, Trine Sundebo Meldgaard, and Sylvie Bertholet. “Novel Platforms for the Development of a Universal Influenza Vaccine.” Frontiers in Immunology 9 (2018): 600. https://doi.org/10.3389/fimmu.2018.00600.
- Gamblin SJ, Skehel JJ. Influenza Hemagglutinin and Neuraminidase Membrane Glycoproteins. J Biol Chem. 2010 Sep 10;285(37):28403–9
- Berlanda Scorza F, Tsvetnitsky V, Donnelly JJ. Universal influenza vaccines: Shifting to better vaccines. Vaccine. 2016 Jun 3;34(26):2926–33.
- Krammer F, García-Sastre A, Palese P. Is It Possible to Develop a “Universal” Influenza Virus Vaccine? Toward a Universal Influenza Virus Vaccine: Potential Target Antigens and Critical Aspects for Vaccine Development. Cold Spring Harb Perspect Biol. 2017 Jun 29;a028845.
- Cohen J. Universal flu vaccine is ‘an alchemist’s dream.’ Science. 2018 Dec 7;362(6419):1094–1094.
- NIH/NIAID. Universal Influenza Vaccine Research [Internet]. 2018 [cited 2019 Feb 25]. Available from: https://www.niaid.nih.gov/diseases-conditions/universal-influenza-vaccine-research
December 2021