Influenza Vaccine Technologies: What’s New to Fight the Flu

As the world continues to navigate the ups and downs of the COVID-19 pandemic, one thing remains certain—influenza is still a threat. Although influenza cases were at record lows during the 2020-2021 season when pandemic precautions and stay-at-home orders were in place, the numbers crept back up during the 2021-2022 season as these measures were lifted.^1,2 Preliminary estimates from the CDC indicate that there were 82,000
to 170,000 hospitalizations and 5000 to 14,000 deaths associated with influenza between October 1, 2021, and June 11, 2022.² Influenza surveillance does not capture all cases of flu that occur; therefore, the CDC produces this estimated range of cases to better reflect the greater burden of influenza in the United States.²

Influenza A (H3N2) has accounted for nearly all specimens tested during the 2021-2022 season.³ On March 3, 2022, the FDA endorsed the World Health Organization (WHO) recommendations for the 2022- 2023 influenza vaccine composition, which applies to egg-, cell culture–, and recombinant-based vaccines.^4,5 As has been the case for many years, the WHO recommended that quadrivalent vaccines target 2 influenza A strains (H1N1 and H3N2) and 2 B strains.^6-8 The recommended strains are based on global surveillance data and are not always a good match for the strains that ultimately circulate during the impending season. This mismatch and, consequently, low vaccine effectiveness may be due to antigenic drift in circulating viruses and/or egg-adaptive mutations that occur during the manufacturing of egg-based vaccines.^9,10 Investigators are determined to find influenza vaccines that circumvent these challenges and demonstrate greater vaccine effectiveness. New manufacturing technologies and the development of a universal influenza vaccine have been at the forefront of this research.

Status of a Universal Influenza Vaccine

The National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health has outlined a strategic plan for the development of a universal influenza vaccine.¹¹ Making this one of its highest priorities, the NIAID budgets $220 million annually in the hopes of identifying a vaccine that is^11-13:

• highly effective (≥ 75%);
• long-lasting (≥ 1 year of protection);
• suitable for all age groups; and
• able to cover multiple influenza strains, including those that could lead to a pandemic.

To meet these criteria, the NIAID has called for a vaccine that provides protection against groups 1 and 2 influenza A viruses, which account for 18 subtypes (H1- H18).^11,14 Type A viruses have been solely responsible for influenza pandemics. H1 (H1N1) and H3 (H3N2) have been co-circulating for years and, along with the influenza B/Victoria lineage and influenza B/Yamagata lineage viruses, are responsible for seasonal influenza infections.¹⁵ However, H2, H5, H6, H7, H9, and H10 also have caused human infections and deaths, and they are considered potential threats. A universal influenza vaccine ideally should target all of these subtypes.¹⁶

In addition, the NIAID suggests that a universal influenza vaccine induce antibodies that target other components of the virus, such as the stalk of the hemagglutinin (HA) protein. This protein on the outer surface of the influenza virus allows it to attach to a human cell (Figure).¹⁵ It has a head and a stalk. The head is considered to be the immunodominant domain; it is responsible for most of the escape mutations seen with the virus.¹⁴ The stalk is more stable, and it remains relatively unchanged; however, its immune response is less robust. The seasonal influenza vaccines currently in use induce antibodies that target the head domain and, as a result, the strains in the vaccine often need to be changed each year to account for antigenic drift. A universal influenza vaccine that targets the stalk while still eliciting a robust immune response has been the focus of recent research.¹⁷ Other studies have begun exploring either neuraminidase or the bottom of the stalk (ie, the anchor) as targets.¹⁸ Chimeric HA technology has been proposed to induce stalk-specific antibodies; however, underwhelming results from phase 1 clinical trials prompted GlaxoSmithKline to halt development of its chimeric HA universal influenza vaccine.^19,20

The NIAID has several exploratory and phase 1 clinical trials underway.^21-23 Most recently publicized is the phase 1 trial of FluMos-v1, a nanoparticle influenza vaccine designed to stimulate antibodies against multiple strains.²¹ In addition to eliciting antibodies against the 4 strains targeted in seasonal vaccines, FluMos-v1 displays multiple copies of the HA types. The results of animal studies demonstrated additional protection against H5 and H7, which are not in the seasonal vaccine.²⁴

BiondVax is also making strides towards a universal vaccine. Its investigators have been researching a universal vaccine for more than 10 years.²⁵ BiondVax’s “multimeric” vaccine is a recombinant protein containing 9 conserved, common linear influenza epitopes that activate both cellular and humoral immunity against a wide variety of influenza A and B strains. Studies have been conducted in Eastern Europe; the research currently is in various phases, including phase 3 trials.^26-28

Challenges With Universal Influenza Vaccine Research

Large-scale efficacy studies for a universal vaccine have been challenging to conduct.^17,25 A person’s age may contribute to their preexisting immunity to different influenza strains. Prior exposures may impact the ability to generate protective antibodies that target the HA stalk.²⁸ Clinical trials would need to include a range of age groups; manufacturers may then need to develop age-specific vaccines. Comparing such a universal vaccine to those currently licensed for seasonal influenza has its shortcomings; it’s akin to comparing apples to oranges. To be approved, the vaccine will likely need to demonstrate in clinical studies its impact on clinical infection, hospitalizations, and death. Such research takes time and money. Additionally, manufacturers will need to stay ahead of drifted and shifted strains as the product advances through the trial phases. More advanced manufacturing platforms (eg, nanoparticle messenger RNA [mRNA], adenovirus-vector, cell-based, and recombinant technologies) will likely be key for targeting different components of the virus and eliciting more robust T-cell immunity.

mRNA-Based Influenza Vaccines

When people encounter the term mRNA vaccines, they may think of COVID-19 vaccines. However, mRNA technology for vaccine development predates the emergence of SARS-CoV-2 by at least a decade.^29,30 This initial research provided the knowledge and framework needed to rapidly develop COVID-19 vaccines. Safety, efficacy, and rapid scalability have been the focal points of mRNA vaccine research. These 3 factors are critical when developing new influenza vaccines, especially if an influenza pandemic unexpectedly emerges. Several companies, including Moderna, GlaxoSmithKline, Sanofi Pasteur, CureVac AG, and Pfizer, have been conducting clinical trials in healthy adults to assess the safety and efficacy of seasonal influenza mRNA vaccines, which include monovalent, bivalent, and quadrivalent formulations.^30-33

Moderna has several mRNA influenza vaccines in development, and interim phase 1 data have been released for its quadrivalent seasonal vaccine.³⁴ Immunogenicity data for the 4 strains were promising, but there is concern that the increase in antibody titers was comparable to that of currently available vaccines.³⁵ Phase 2 trials aim to assess dosing and provide a head-to-head comparison with an approved vaccine. To get ahead of the next influenza pandemic, Moderna has also explored vaccines that target the avian strains H10N8 and H7N9; these were evaluated for safety and efficacy in phase 1 trials and found to be well-tolerated and to offer robust humoral immunity.³⁶

One of the benefits of mRNA technology is that it does not rely on cell cultures or chicken eggs for vaccine production. Other potential benefits afforded by mRNA influenza vaccines include high fidelity, meaning that they can provide an exact antigen match to the influenza strains recommended for the vaccine, the ability to target different components of the virus, induction of T-cell immunity, and faster production time, which allows companies to wait to begin manufacture to ensure a better match to circulating strains. The mRNA influenza vaccines may have disadvantages similar to those of COVID-19 mRNA vaccines; these include short-term protection and a higher incidence of local and systemic effects (due in part to the lipid nanoparticle component necessary to provide vaccine stability and delivery into cells).^31,37

Research on the mRNA vaccine has been expanded to assess the impact of encoding for the HA stalk, neuraminidase, matrix-2 ion channel, and nucleoprotein (Figure).^15,31 This may also pave the way for potential universal influenza vaccines.

Cell-Based and Recombiant Vaccine Updates

Cell-based and recombinant influenza vaccines were first licensed in the United States in 2012 and 2013, respectively. Cell-based vaccines do not rely on chicken eggs.³⁸ Rather, the manufacturer inoculates mammalian cells using the candidate vaccine viruses (CVVs) that were grown in cells. After the CVVs replicate, they are extracted from the cells to make the vaccine. Recombinant vaccines are synthetic and do not use CVVs. The gene for making HA is combined with a baculovirus, resulting in a recombinant baculovirus that is introduced to a host cell line. The cells are instructed to produce the HA antigen, which is used to make the vaccine.³⁸ Recombinant protein vaccines, like mRNA vaccines, can provide an exact match to the antigens in the strains recommended for the respective season’s influenza vaccine. However, the manufacturing process for recombinant protein vaccines is more complex than it is for mRNA vaccines.³¹

Flucelvax Quadrivalent (Seqirus, Inc) is the only cell-based influenza vaccine licensed for use in the United States. It is a quadrivalent vaccine, and its approval was recently expanded for use in individuals aged 6 months and older.³⁹ FluBlok Quadrivalent (Protein Sciences Corporation, a Sanofi company) is currently the only quadrivalent recombinant influenza vaccine available in the United States; it is approved for use in adults (age ≥ 18 years).⁴⁰

Another recombinant vaccine is currently in development. Made by Novavax, Inc., NanoFlu is being tested in phase 3 trials.⁴¹ In an attempt to induce a T-cell response, which would give this quadrivalent vaccine a potential advantage over FluBlok Quadrivalent, a novel adjuvant (Matrix-M) has been added.⁴² NanoFlu contains 60 μg of recombinant HA per each of the 4 strains. This is more than in FluBlok Quadrivalent, which contains 45 μg of HA per strain, and in a standard-dose inactivated influenza vaccine, which contains 15 μg of HA per strain.⁴³ When compared with the standard-dose quadrivalent inactivated influenza vaccine, NanoFlu demonstrated enhanced humoral and cellular immune response in adults aged at least 65 years. Its safety profile was comparable overall. Injection site pain was reported more frequently in the NanoFlu group than in individuals given standard-dose inactivated influenza vaccine (25.6% vs 16.1%); this is consistent with the higher incidence of local reactions often reported for adjuvanted vaccines.⁴⁴

It is not yet known how NanoFlu compares with other quadrivalent influenza vaccines that are specifically marketed for use in older patients (adjuvanted influenza vaccine, Fluad Quadrivalent [Seqirus]; high-dose influenza vaccine, Fluzone-HD Quadrivalent [Sanofi]). As they noted in an editorial, investigators comparing the trivalent formulation (tNIV) with the trivalent high-dose influenza vaccine in adults aged 60 years and older found that the tNIV induced substantially greater antibody responses against 4 H3N2 strains while maintaining a similar safety profile.⁴⁴ Next steps for Novavax include clinical efficacy studies for NanoFlu.

Influenza and COVID-19 Vaccine Combination

Considering the anticipated emergence of new SARS-CoV-2 variants and the waning immunity of the COVID-19 vaccines, FDA and CDC officials along with vaccine manufacturers have speculated that recurring COVID-19 vaccine boosters will be needed.⁴⁵ Combining such boosters with seasonal influenza vaccination has become a strategy that some vaccine manufacturers, most notably Moderna and Novavax, have set in motion. Moderna announced to its investors plans to develop 2 respiratory combination vaccines: 1 that encodes for the SARS-CoV-2 spike protein and influenza HA glycoproteins, and 1 that targets the SARS-CoV-2, influenza, and respiratory syncytial viruses.^34,46 Novavax is conducting a phase 1/2 study to assess NanoFlu combined with its recombinant nanoparticle COVID-19 vaccine coformulated with the Matrix-M adjuvant (NVX-CoV2373). NVX-CoV2373 was granted the WHO’s emergency use listing under the brand names Covovax and Nuvaxovid; however, emergency use authorization for use of the vaccine in the United States is pending.^47,48

With so many new technologies and approaches being explored to prevent influenza, it is likely that the market will see an increase in the number and type of influenza vaccines available over the next 1 or 2 years. Whether these technologies lead to a universal vaccine that meets the NIAID criteria or simply an enhanced seasonal vaccine remains to be determined.

About The Author

Lauren B. Angelo, PharmD, MBA, is an associate dean of Academic Affairs and associate professor of Pharmacy Practice at Rosalind Franklin University of Medicine and Science in North Chicago, Illinois.

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