The Ever-Changing Influenza Virus: From Seasonal Vaccines to Universal Protection

As the Influenza season is upon us, many individuals are receiving their annual influenza vaccine – the first line of defence against infection. Each year Influenza poses a substantial economic and clinical burden on the healthcare systems internationally, causing up to 650,000 estimated deaths annually and disproportionately affecting the vulnerable [1]. Current vaccines are administered annually and comprise of either inactivated influenza vaccines or live attenuated influenza vaccines. These vaccines typically consist of 3 or 4 strains, which are selected based on global surveillance data, indicating the strains which are most likely to be circulating in the season [2]. Despite the widespread use of these vaccines, maintaining effective immunity remains challenging due to the dynamic nature of the virus.

Continuous Virus Evolution (Antigenic Shift / Antigenic Drift)

The rapid evolution of the influenza virus is the predominant reason why lasting immunity against the virus is difficult to achieve and shows how important effective research is to the managing the virus. This evolution occurs through two distinct mechanisms: antigenic drift and antigenic shift.

Antigenic drift refers to the accumulation of point mutations in the viral RNA, a consequence of the high error rate of the influenza RNA-dependent RNA polymerase, which lacks proofreading activity. These mutations commonly occur in the genes which encode the surface proteins: hemagglutinin (HA) and neuraminidase (NA), leading to structural changes in their antigenic site [3]. As a result, antibodies from prior infection or vaccination no longer recognise the virus and therefore cannot protect from future infections. This process underpins the requirement for frequent updates to seasonal influenza vaccines [4].

In contrast, Antigenic Shift is a rarer and more pronounced event which is the result of the segmented nature of the Influenza genome. When a host (for example, pigs, which are susceptible to both avian and human influenza viruses) is co-infected with two distinct influenza strains, entire gene segments can reassort during viral replication. The resulting progeny may contain novel combinations of HA and/or NA, generating a new influenza strain [5]. Because the human population typically has little pre-existing immunity to this virus, antigenic shift can enable rapid global spread and has been the basis of several pandemics, including the 2009 H1N1 outbreak [6].

Figure 1: This figure shows the two primary mechanisms by which influenza viruses undergo antigenic change

Current influenza vaccines primarily target the immunodominant HA head domain, which undergoes continual antigenic drift. As these proteins evolve, vaccine-induced immunity wanes, necessitating the annual reformulation and administration of influenza vaccines to maintain protection against the most prevalent circulating strains [2].

Virus Surveillance and Strain Selection

To determine which strains to include the annual flu vaccine, global surveillance of the circulating strains is essential. This is coordinated through the World Health Organization (WHO)’s Global Influenza Surveillance and Response System, a network of more than 150 national influenza centres and collaborating laboratories worldwide. Clinical samples are collected from patients suffering from influenza symptoms and sent to a participating laboratory where the virus is isolated and sequenced before undergoing antigenic characterisation. The resulting data is uploaded to an online database. Twice annually the WHO meet to review the surveillance data and recommend the strains most likely to circulate in the upcoming Influenza season. Vaccine manufacturers adopt these recommendations and begin vaccine production using the antigens from the selected candidate viruses. This process ensures that vaccines are available ahead of the influenza season, providing protection against the most prevalent and clinically significant strains [7].

Limitations of Seasonal Vaccination

Seasonal influenza vaccines pose several significant challenges. Chief among them is antigenic mismatch, which occurs when strains selected by the WHO for the vaccine candidates do not match the viruses that circulate during the influenza season[8].This mismatch is often the result of the 6-month interval between strain selection and vaccine administration to facilitate the large scale manufacture of the vaccines. Typically, seasonal influenza vaccines are manufactured using embryonated chicken eggs or mammalian cell culture systems, which are laborious and time-consuming techniques [9]. This manufacture lag allows sufficient time for circulating viruses to undergo antigenic drift and in some rare cases, antigenic shift. Consequently, vaccine efficacy can vary considerably from year to year and typically ranges somewhere between 40-60% [10]. In some seasons, the efficacy is considerably lower, such as the 2014/2015 season where efficacy was as low as 9.2% [8].

Another limitation is the short duration of immunity which is conferred by these vaccines. As the viruses mutate, protection wanes, meaning these vaccines are usually only efficacious for a few months [11]. This necessitates annual revaccination. This places an economic burden on the healthcare systems, requiring the remobilisation of resources for the administration and awareness campaigns each year. In addition, the continual updating and large-scale production of vaccines represent a significant financial burden [12].

Advances in Universal Influenza Vaccine Development

To overcome the limitations of seasonal vaccination, researchers are pursuing next-generation universal influenza vaccines which aim to provide long lasting, strain independent immunity eliminating the need for yearly vaccination and offering protection against future pandemics [13]. Unlike, traditional vaccines which target the mutable HA head, researchers are focusing on conserved viral targets that are less susceptible to antigenic drift. Examples include the stalk region of the HA protein, which is structurally more stable and less prone to mutation than the HA head.[13]. Another promising target is the matrix 2 ectodomain of the M2 ion channel protein, which is essential for viral disassembly, assembly and budding [14].

Researchers are exploring a range techniques to aid in their selection of antigen sequences. One example is the use of the Computationally Designed Antigens (COBRA) approach. This approach employs bioinformatic algorithms to identify conserved regions across large data sets of antigen sequences from multiple strains of the virus, allowing the formation of a consensus sequence which incorporates the conserved residues. Ultimately, these antigens aim to elicit a broader immune response, which can neutralise many strains [15].

To address the limitations of the mammalian and egg culture vaccines, alternate vaccine platforms are being explored. Examples of these are: nanoparticles, virus-like particles, nucleic acids, and peptide-based vaccines, many of which are currently undergoing clinical trials [15]. In contrast to current seasonal vaccines, these platforms do not require viral propagation allowing for rapid production and easier updating. By combining antigen design approaches such as COBRA with adaptable vaccine technologies, researchers are paving the way to influenza vaccines capable of providing long-lasting protection against diverse and evolving strains [9].

In conclusion, seasonal influenza remains a persistent public health challenge, driven by the continual viral evolution, the limitations of current vaccine production and the strain-selection processes. While annual vaccines provide the public with some protection, issues such as antigenic mismatch, short-lived immunity, and lengthy manufacturing timelines underline the need for improved vaccines. Advances in computational antigen design, alongside emerging vaccine platforms are driving the development of vaccines which have the potential to induce broad and durable immunity. This showsthe impact research has in bettering our understanding of the influenza virus, these innovations offer a promising pathway to reduce the global burden of Influenza virus.

Abbexa is committed to accelerating influenza research by providing researchers with reliable tools that enable accurate results. Abbexa’s large range of biological tools featuring antibodies, ELISA kits, proteins and more will support your battle against the ever-changing influenza virus.

References:

[1] WHO.int (2025). Influenza (seasonal). [online] Who.int. Available at: https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal) [Accessed 14 Oct. 2025].

[2] Li, M., Guo, P., Song, H., Chen, C., Zhou, H. and Tao, P. (2025). Development of universal influenza vaccines: strategies for broadly cross-reactive influenza vaccine responses. Animal Diseases, [online] 5(1). doi:https://doi.org/10.1186/s44149-025-00187-6.

‌[3] Cheung PP, Watson SJ, Choy KT, Fun Sia S, Wong DD, Poon LL, Kellam P, Guan Y, Malik Peiris JS, Yen HL. Generation and characterization of influenza A viruses with altered polymerase fidelity. Nat Commun. 2014 Sep 3;5:4794. doi: 10.1038/ncomms5794. PMID: 25183443; PMCID: PMC4155405.

[4] Taubenberger, J.K. and Kash, J.C. (2010). Influenza Virus Evolution, Host Adaptation, and Pandemic Formation. Cell Host & Microbe, [online] 7(6), pp.440–451. doi:https://doi.org/10.1016/j.chom.2010.05.009.

‌[4]  Kim, H., Webster, R.G. and Webby, R.J. (2018). Influenza Virus: Dealing with a Drifting and Shifting Pathogen. Viral Immunology, [online] 31(2), pp.174–183. doi:https://doi.org/10.1089/vim.2017.0141.

[5] Jilani, T.N., Jamil, R.T., Nguyen, A.D. and Siddiqui, A.H. (2024). H1N1 Influenza. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK513241/ [Accessed 7 Oct. 2025].

‌ [6] Who.int. (2025). Global Influenza Surveillance and Response System (GISRS). [online] Available at: https://www.who.int/initiatives/global-influenza-surveillance-and-response-system [Accessed 22 Sep. 2025].

[7] Choi, Y.J., Song, J.Y., Wie, S.-H., Choi, W.S., Lee, J., Lee, J.-S., Kim, Y.K., Kim, S.W., Lee, S.H., Park, K.-H., Jeong, H.W., Yoon, J.G., Seong, H., Nham, E., Noh, J.Y., Cheong, H.J. and Kim, W.J. (2024). Real-world effectiveness of influenza vaccine over a decade during the 2011–2021 seasons—Implications of vaccine mismatch. Vaccine, [online] 42(26), pp.126381–126381. doi:https://doi.org/10.1016/j.vaccine.2024.126381.

[8] Nih.gov. (2019). Influenza Vaccine Production and Design. [online] Available at: https://www.niaid.nih.gov/diseases-conditions/influenza-vaccine-production-and-design [Accessed 14 Nov. 2025].

[9] Trombetta, C.M., Kistner, O., Emanuele Montomoli, Viviani, S. and Marchi, S. (2022). Influenza Viruses and Vaccines: The Role of Vaccine Effectiveness Studies for Evaluation of the Benefits of Influenza Vaccines. Vaccines, [online] 10(5), pp.714–714. doi:https://doi.org/10.3390/vaccines10050714.

[10] Patel, M.M., York, I.A., Monto, A.S., Thompson, M.G. and Fry, A.M. (2021). Immune-mediated attenuation of influenza illness after infection: opportunities and challenges. The Lancet Microbe, [online] 2(12), pp.e715–e725. doi:https://doi.org/10.1016/s2666-5247(21)00180-4.

‌[11] Waterlow, N.R., Procter, S.R., Leeuwen, E. van, Radhakrishnan, S., Jit, M. and Eggo, R.M. (2023). The potential cost-effectiveness of next generation influenza vaccines in England and Wales: A modelling analysis. Vaccine, [online] 41(41), pp.6017–6024. doi:https://doi.org/10.1016/j.vaccine.2023.08.031.

[12] Cnossen, V.M., Leao, P.C., Engelhardt, O.G., Jerzy Samolej, Groeneveld, G.H., Jochems, S.P., Huisman, W., Pedersen, G.K., Wørzner, K., Recek, L., Piccini, G., Trombetta, C.M., Aspelund, A., Hoag, A., Reiter, M., Wick, C., Muster, T. and Maria, I. (2025). Development of an intranasal, universal influenza vaccine in an EU-funded public-private partnership: the FLUniversal consortium. Frontiers in Immunology, [online] 16. doi:https://doi.org/10.3389/fimmu.2025.1568778.

[13] Saele 63. ns, X. (2019). The Role of Matrix Protein 2 Ectodomain in the Development of Universal Influenza Vaccines. The Journal of Infectious Diseases, [online] 219(Supplement_1), pp.S68–S74. doi:https://doi.org/10.1093/infdis/jiz003.

‌[15] Wang, L., Xie, Q., Yu, P., Zhang, J., He, C., Huang, W., Wang, Y. and Zhao, C. (2025). Research Progress of Universal Influenza Vaccine. Vaccines, [online] 13(8), pp.863–863. doi:https://doi.org/10.3390/vaccines130808