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Winter 2022 - Critical Care

Universal Flu Vaccines Advance from Concept to Clinical Trials

“Scientists have identified components of the influenza virus that do not really change much at all. The critical challenge is getting a vaccine to induce a response to those components.” — Anthony Fauci, MD, Director, National Institute of Allergy and Infectious Diseases

YEAR AFTER YEAR, the extra-ordinary mutability of influenza (flu) viruses that enables their progeny to escape immune detection to reinfect us translates into more than 450,000 hospitalizations and more than 40,000 flu-related deaths annually.1 If this were not enough, the ongoing COVID-19 pandemic serves as a harsh reminder that we may someday face an influenza pandemic to rival the catastrophic 1918 pandemic that claimed more than 650,000 U.S. lives — at a time when our population was less than one-third the size it is today. This ability of influenza viruses to continually reinvent themselves has another important ramification. Those spontaneous RNA mutations in the large mushroom-like head region of the hemagglutinin protein that decorates the viral membrane surface necessitates a complex, costly global effort each year to isolate and produce new vaccines against emergent influenza strains believed most likely to circulate in the upcoming flu season.

Adding to the fact that selecting the eventual epidemic strains is an imperfect art, ongoing genetic drift of the selected A and B strains over the months that elapse before availability of mass-produced vaccines can enable them to evade antibody-mediated immunity induced by the inactivated whole-virus or synthetic antigen vaccine. As a consequence, the effectiveness of seasonal flu vaccines can differ widely from one year to the next; over the last decade, it has ranged from about 50 percent to as low as 20 percent.2 This in turn partly accounts for why more than one-half of U.S. adults don’t elect to get the annual flu shot.3

For decades, virologists and public health experts have touted the concept of “universal” flu vaccines capable of inducing broad immune protection against both seasonal and pandemic influenza outbreaks. Ideally, such vaccines would eliminate the need for annual vaccination, and provide at least some degree of herd immunity to help reduce infection risk in those who fail to get immunized. The National Institute of Allergy and Infectious Diseases (NIAID) has defined several criteria for any universal influenza vaccine, including the ability to:

• Be at least 75 percent effective;

• Protect against both group I and II influenza A viruses;

• Provide durable protection that lasts at least one year; and

• Be suitable for all age groups.

Advances over the last decade in virology and molecular genetics have enabled academic, government and industry scientists to design, produce and test a diverse spectrum of universal flu vaccine candidates. Today, more than 100 university and private sector-based laboratories are working on novel universal flu vaccines of one type or another, at least 16 of which are currently in clinical-stage development (Table).4

The strategy behind all of these candidate vaccines essentially amounts to eliciting a robust host immune response to one or more viral proteins — the hemagglutinin (HA) stem domain, matrix proteins M1 and M2, nucleoprotein (NP) and neuraminidase (NM) — that are highly conserved across different influenza strains and subtypes. But the vaccines themselves and the technology platforms used to produce them broadly fall into six distinct categories (Table):

• Nucleic acid-based vaccines

• Recombinant influenza virus-based vaccines

• Recombinant protein vaccines

• Virus-vectored vaccines

• Virus-like particle (VLP) vaccines

• Non-VLP nanoparticle vaccines

Several vaccine candidates in each of these categories have currently advanced to human trials, and numerous others are being tested in animal models to characterize their safety, immunogenicity and tolerability.

Table with candidate flu vaccines in development

Nucleic Acid-Based Vaccines

Population-based experience over this last year of the COVID-19 pandemic has proven that messenger RNA (mRNA) vaccines are safe and highly protective against multiple strains of SARS-CoV-2. mRNA vaccines can direct expression of virtually any membrane-bound or soluble target antigen, thus mimicking antigen expression that occurs in a natural infection. The ability to be rapidly formulated and manufactured on a large scale can additionally help avert antigenic drift over the multiple months required for egg-based vaccine production.

mRNA lipid nanoparticle vaccines (Moderna). In essence, mRNA is a temporary set of instructions that directs cells to make a protein. This may include virtually any membrane-bound or soluble viral antigen, mimicking the antigen expression that occurs in a natural infection. A particularly strong appeal of mRNA influenza vaccines is the ability to rapidly formulate and manufacture them on a large scale, helping to avert the problem of antigenic drift that occurs over the roughly six months between early identification of anticipated circulating strains and large-scale production of whole-virus influenza vaccines in chicken eggs or mammalian cells.

Over the five years prior to the COVID-19 pandemic, Moderna had already been developing mRNA vaccines targeting a number of viral infections, including seasonal and pandemic influenza. The company recently completed a pair of Phase I dose-ranging studies evaluating lipid nanoparticle-encapsulated mRNA vaccines directed against potentially pandemic avian H10N8 and H7N9 influenza viruses.5 Both vaccines were well-tolerated and elicited robust humoral immune responses in healthy adult volunteers, as measured both by hemagglutinin inhibition (HAI) and microneutralization assays.

Modified mRNA vaccines (Pfizer/ BioNTech). In September 2021, Pfizer announced the first study participants had received a single dose of monovalent or bivalent investigational quadrivalent mRNA influenza vaccines.6 This Phase I trial in more than 600 healthy adults aged 65 years to 85 years will assess the safety, tolerability and immunogenicity against an FDA-approved standard quadrivalent influenza vaccine used as a control. While it is a seasonal mRNA flu vaccine, its performance in this and later efficacy studies is an important first step toward gauging the potential utility of a pandemic mRNA flu vaccine.

Numerous other novel mRNA and DNA-based vaccine candidates are currently in preclinical development. For example, collaborators at the University of Pennsylvania and the Icahn School of Medicine have shown that a single intradermal dose of their modified mRNA-lipid nanoparticle vaccine targeting a combination of conserved influenza virus antigens (HA stem, NM, NP) induced a strong immune response and was provided protection from challenge with pandemic H1N1 virus at 500 times the lethal dose in a murine model.7 Strong immunogenicity and broad protection against pandemic viruses was also shown in ferrets immunized with Denmark-based Statens Serum Institute’s polyvalent influenza A DNA vaccine, which encodes HA and NA proteins derived from the pandemic 2009 H1N1 and 1968 H3N2 virus strains, as well as matrix proteins from the pandemic 1918 strain.8

Recombinant Influenza Virus- Based Vaccines

Two of four recombinant virus-based universal flu vaccines currently in clinical development have advanced to Phase II testing: live attenuated influenza virus (LAIV) vaccines developed by FluGen in Madison, Wis., and Austria-based Vivaldi Biosciences.

Single-replication (SR) recombinant live influenza vaccine (FluGen). Licensed from the University of Wisconsin, FluGen’s novel M2SR vaccine contains genetically engineered influenza viruses in which a portion of the M2 gene has been deleted. Delivered intranasally like another licensed LAIV, FluMist, M2SR can infect cells and express the entire spectrum of influenza RNA and proteins, but cannot produce any infectious virus particles or cause any pathological signs of infection. Further, the M2SR vaccine can be engineered to express HA and neuraminidase antigens common to different influenza virus strains.

Healthy adults enrolled in a Phase II human challenge study received a single low intranasal dose of the “supra-seasonal” M2SR vaccine constructed with the H3N2 virus Bris2007, then were challenged with an H3N2 influenza strain seven years drifted from the vaccine. Despite the mismatch of vaccine and challenge strains, the subset of subjects with a neutralizing antibody response had significantly reduced rates of infection after challenge and reduced illness.9 A dose-escalation study has shown that up to 10-fold higher doses of M2SR induce protective immune response in a higher proportion of recipients. In May 2021 with support from NIAID, FluGen initiated the first placebo-controlled study of M2SR in older adults aged 65 years to 85 years who are most vulnerable to serious complications and death from the flu.

Replication-deficient LAIV vaccine (Vivaldi Biosciences). Austria-based Vivaldi recently completed Phase I and II clinical testing of DeltaFLU, another intranasally administered LAIV universal influenza vaccine missing a specific viral protein that prevents viral replication. According to the company, findings indicate that DeltaFLU “shows potential for universal protection against all influenza A and B virus strains, including drifted seasonal influenza strains and emerging pandemic strains.”10

Vivaldi has also announced positive preclinical data that supports further development of a novel intranasal combination vaccine called Delta-19, which is designed to confer protection against both COVID-19 and all influenza strains.

Chimeric hemagglutinin (cHA)-based LAIV vaccine (Icahn/Mount Sinai). This research team has developed a sequential chimeric HA vaccination strategy that combines the highly conserved stem domain with immunodominant head domains from avian influenza virus subtypes. Boosting with a cHA construct that contains the same stem but a different head induces a stronger recall response against the stem than the initial low-level “immune priming” response.

A Phase I study in healthy 18- to 39-year old subjects documented a strong, durable and functional immune response targeting the conserved HA stem domain, suggesting that “chimeric hemagglutinins have the potential to be developed as universal vaccines that protect broadly against influenza viruses.”11

Recombinant Protein Vaccines

A number of laboratories have developed recombinant peptide vaccines that match conserved antigens present in specific internal or external viral proteins. Among the leading efforts is a collaboration between UK-based Imutex and NIAID to conduct Phase IIb clinical studies of FLU-v, a mixture of four recombinant peptides that originate from highly conserved internal proteins (M1, M2 and NP) common to all influenza A and B viruses.

A pair of recently completed Phase II studies found healthy adults who received a single dose of an adjuvanted version of FLU-v mounted a protective T cell-mediated response and were significantly less likely than control subjects to develop mild-to-moderate flu following intranasal challenge with a single H1N1 strain.12,13

In addition to the potential for FLU-v to confer protective immunity against any influenza strain, the selective cellular immune response could be of particular benefit for the 10 percent to 20 percent in the general population who fail to mount a good antibody response against the exposed HA region of the virus.

Numerous other laboratories across the globe are currently in preclinical development with their own universal recombinant protein vaccines to try to induce T cell and humoral immunity directed against conserved epitopes on the viral HA stem, M1, M2 and NP proteins. But several of the most advanced candidate vaccines have failed in clinical testing, most disappointingly BiondVax Pharmaceuticals’ M-001 vaccine comprising nine highly conserved HA head domain epitopes common to some 40,000 isolated influenza virus strains. After 15 years of largely encouraging preclinical and clinical findings, the company announced in late 2020 that data from a pivotal Phase III trial of M-001 failed to show a significant difference in flu illness or severity in more than 12,000 adult subjects (half of whom were age 65 and older) over the 2018- 2019 flu season.14

Virus-Vectored Vaccines

Similar to how gene therapy uses viral vectors to carry genetic instructions to host cells to express key missing functional proteins, novel vaccines are being developed to induce our cells toillustration of virus express influenza virus proteins that are largely conserved across strains and subtypes.

Of more than a dozen initiatives in progress, Vaccitech’s modified vaccinia Ankara (MVA)-vectored construct expressing influenza A-derived NP and M1 protein has completed a Phase IIb safety and immunogenicity study in 846 adults aged 65 years and older. While this VMA-NP+M1 vaccine induced a substantial M1-specific T cell response,15 the study sample was too small to draw any conclusions about potential efficacy endpoints such as incidence and duration of influenza-like illness (ILI) or number of days with moderate or severe symptoms during an ILI episode.16

Other promising virus-vectored influenza vaccines have reached Phase II clinical development. In particular, a single dose of Altimmune’s intranasally delivered replication-deficient adenovirus-based vaccine, NasoVax, mediates expression of the HA protein found on a targeted flu virus strain, and elicits robust mucosal and systemic immune responses. However, it is strain-specific and therefore is not designed to confer broad protection against other flu strains and subtypes.17

Virus-Like Particle Vaccines

Comprising one or more viral structural proteins, virus-like particles (VLPs) are molecules that closely resemble their live virus counterparts, but are noninfectious because they contain no viral generic material. More than a decade ago, intranasal immunization of mice with recombinant VLPs generated from structural proteins of the pandemic 1918 H1N1 virus were first shown to be protective against a lethal challenge with both the 1918 virus and a highly pathogenic avian H5N1 virus.18

Furthest along among nearly 20 influenza VLP development programs is Medicago, a privately held Canadian firm whose investigational HA-bearing quadrivalent VLP (QVLP) vaccine is produced in a relative of the tobacco plant. In a large-scale multinational study in elderly participants covering two influenza seasons between 2017 and 2019, the QVLP vaccine met its primary noninferiority endpoint relative to standard quadrivalent influenza vaccine for the prevention of ILI caused by any strain.19

Non-VLP Nanoparticle Vaccines

Perhaps most exotic of all are the nanoparticle vaccines, which are novel constructs of conserved viral antigens displayed on a nonviral nanoparticle. A prime example is a stabilized leadless HA stem nanoparticle vaccine being co-developed by Sanofi Pasteur and NIAID. Numerous HA stem portion “spikes” are presented on the surface of a microscopic nonhuman ferritin nanoparticle, mimicking the natural organization of HA on the influenza virus.

While HA stem antigens were derived from an H1N1 flu virus, this candidate vaccine protected both mice and ferrets against a lethal H5N1 flu virus, despite the fact that H5N1 is an entirely different viral subtype.20 This vaccine has also elicited broadly neutralizing antibody responses to diverse H1 and H3 viruses in nonhuman primates. NIAID completed a safety, tolerability and immunogenicity study earlier this year, and findings are currently being analyzed.

Another non-VLP nanoparticle vaccine showing promise is NIAID’s “mosaic” quadrivalent flu vaccine that displays 20 HA antigens arranged in repeated patterns, sending a strong “danger” signal to the immune system that prompts a vigorous antibody response.21 Dubbed FluMos-v1, this universal flu vaccine candidate began Phase I clinical testing in May 2021.

Many Candidate Vaccines Boost Prospects

“Our ultimate aspirational goal is to have vaccines that you can give relatively infrequently — maybe every five or 10 years — that provide protection against the broad array of influenza viruses that we encounter,” NIAID Director Anthony Fauci, MD, recently noted.22 But he cautioned that effective universal flu vaccines could arrive in a stepwise fashion, with successive iterations providing protection against increasing portions of the numerous influenza subtypes and groups.

Time will tell, but the many novel universal flu vaccine candidates entering the pipeline and advancing from preclinical development to human testing offer new hope that the realization of a decades-old dream is not far off.


1. Sah P, Alfaro-Murillo JA, Fitzpatrick MC, et al. Future epidemiological and economic impacts of universal influenza vaccine. Proc Natl Acad Sci USA 2019 Oct 8;116(41):20786-92.

2. U.S. Centers for Disease Control and Prevention. Effectiveness of Seasonal Flu Vaccines from the 2009-2021 Flu Seasons. Accessed at

3. U.S. Centers for Disease Control and Prevention. Flu vaccination coverage, United States, 2018-2019 influenza season. Accessed at

4. Center for Infectious Disease Research and Policy. University of Minnesota. Universal Influenza Vaccine Technology Landscape. Accessed at

5. Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 2019 May 31;37(21):3326-34.

6. Pfizer. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Modified RNA Vaccine Against Influenza. Accessed at

7. Freyn AW, da Silva JR, Rosado VC, et al. A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice. Molec Therapy 2020 July;28(7):1569-84.

8. Guikfoyle K, Major D, Skeldon S, et al. Protective efficacy of a polyvalent influenza A DNA vaccine against both homologous and heterologous challenge in the ferret model. Vaccine 2021 Aug 9;39(34):4903-13.

9. Eiden J, Volckaert B, Rudenko O, et al. M2-deficient single-replication influenza vaccine-induced immune responses associated with protection against human challenge with highly drifted H3N2 influenza strain. J Infect Dis 2021 July 29; online ahead of print.

10. Vivaldi Biosciences. Oct. 6, 2021 press release. Accessed at vivaldi

11. Nachbagauer R, Feser J, Naficy A, et al. A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial. Nature Med 2020 Dec;27:106-14.

12. PLeguezuelos O, Dille J, de Groen S, et al. Immunogenicity, safety and efficacy of a standalone universal influenza vaccine, FLU-v, in healthy adults: A randomized clinical trial. Ann Intern Med 2020 Apr 7;172(7):453-62.

13. Pleguezuelos O, James E, Fernandez A, et al. Efficacy of FLU-v, a broad-spectrum influenza vaccine, in a randomized Phase IIb human influenza challenge study. NPJ Vaccines 2020 Mar 13;5:22.

14. BiondVax announces topline results from Phase 3 clinical trial of the M-001 universal influenza vaccine candidate, Oct. 23, 2020. Accessed at biondvax-announces-topline-results-from-phase-3-clinical-trial-of-the-m-001-universal-influenza-vaccine-candidate.

15. Puksuriwong S, Ahmed MS, Sharma R, et al. Modified vaccinia Ankara-vectored vaccine expressing NP and M1 activates mucosal M1-specific T-cell immunity. J Infect Dis 2020 Sept 1;222(5):807-19.

16. Butler C, Ellis C, Folegatti PM, et al. Efficacy and safety of a modified vaccine combined with QIV in people aged 65 and older: a randomised controlled clinical trial (INVICTUS). Vaccines 2021, 9(8), 851.

17. Tasker S, O’Rourke AW, Suyundikov A, et al. Safety and immunogenicity of a novel intranasal influenza vaccine (NasoVAX): a phase 2 randomized, controlled trial. Vaccines (Basel) 2021 Mar 5;9(3):224

18. Perrone JA, Ahmad A, Veguilla V, et al. Intranasal vaccination with 1918 influenza virus-like particles protects mice and ferrets from lethal 1918 and H5N1 influenza viral challenge. J Virol 2009 Jun;83(11):5726-34.

19. Ward BJ, Kakarkov A, Séguin A, et al. Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18-64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials. Lancet 2020 Nov 7;396(10261):1491-1503.

20. Yassine HM, Boyington JC, McTamney PM, et al. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat Med 2015 Sep;21(9):1065-70.

21. National Institute of Allergy and Infectious Diseases (NIAID). Tiny nanoparticles could be a big jump for flu vaccines. Accessed at 22. C-Span. Dr. Anthony Fauci and Rick Bright on a Universal Flu Vaccine. Accessed at

Keith Berman, MPH, MBA
Keith Berman, MPH, MBA, is the founder of Health Research Associates, providing reimbursement consulting, business development and market research services to biopharmaceutical, blood product and medical device manufacturers and suppliers. He also serves as editor of International Blood/Plasma News, a blood products industry newsletter.