Background
Influenza, also known as flu, is a contagious respiratory illness caused by the influenza viruses. It primarily affects the nose, throat, and lungs, causing symptoms such as cough, fever, headache, and sore throat. Influenza spreads through airborne droplets and contact with contaminated surfaces, which means people can easily get infected during flu season. As one of the most widespread illnesses globally, influenza has a high infection rate, with up to 10% of the global population infected each year. (Alshahrani et al. 2025)
(A) TEM image of influenza virus mainly in spherical shapes with particle sizes around 100–150 nm; (B) Schematic diagram of an influenza A virus, representing the virus components, including surface glycoproteins HA and NA, M1, and M2 protein, nonstructural proteins, and nucleoproteins. (Nuwarda, R. F. et al. 2021)
Although influenza is very common in life, its severity is often underestimated by the public. That being said, people need to be cautious not to get infected by influenza due to its complications. Some of the serious complications are myocarditis, encephalitis, and sepsis. High-risk groups such as children and the elderly getting those complications often lead to severe health damage or even death. (CDC 2025) Globally, as many as 500,000 people die from complications related to influenza every year. Therefore, treating and preventing influenza is necessary and exigent.
Comparing and Contrasting Symptoms of Influenza, COVID-19, Common Cold, and Seasonal Allergies (Javanian, M. et al. 2021)
In modern medicine, receiving a flu vaccine is the most effective way to prevent influenza and its complications. However, people need to receive the flu vaccine annually to be fully immunized, as influenza viruses are constantly changing. Influenza viruses (of the family Orthomyx-oviridae) are enveloped negative-strand RNA viruses that can be categorized into four types based on their differences in gene segments: eight segments for influenza A and B and seven segments for influenza C and D. Among these, only types A, B, and C infect humans, with influenza A being the primary cause of seasonal epidemics. (Taubenberger and Morens 2008) Influenza viruses are covered with glycoproteins that are coded by its eight gene segments. Antigenic domains on these glycoproteins serve as critical targets for host immune recognition. However, due to the error-prone nature of viral RNA polymerases lacking proofreading activity, mutations accumulate during replication. (Webster et al. 1992) Those mutations cause variations in the glycoproteins of influenza viruses. Specifically, hemagglutinin (HA), which binds to sialic acid receptors on host cells and initialize infection, is the main antigen of the influenza virus mutation. Consequently, flu vaccines require annual updates to match the circulating strains.
Conventional influenza vaccine manufacturing processes (Nuwarda, R. F. et al. 2021)
Current seasonal flu vaccines are quadrivalent, which means the vaccine can stimulate the immune system to defend against four different strains of the influenza virus out of a total of 198 potential strains. However, influenza viruses evolve rapidly, and mutations create new strains that the current vaccine may not target. This means annual reformulation and vaccination are necessary, which can be costly and time-consuming. At the same time, rapidly modifying strains lowers the effectiveness of the seasonal flu vaccine. Studies have shown that during a severe flu season, when the vaccine does not match the circulating strains, the vaccine's effectiveness can be as low as 10% to 20%. (Nypaver, Dehlinger, and Carter 2021) As a result, a vaccine with long-term immunity and higher effectiveness is needed. As the universal flu vaccine develops, not only can the government spend less money on flu vaccine reformulation, people can also get better immunity to influenza. Therefore, our study will focus on the potential approach to a universal flu vaccine that provides long-term and effective immunity.
Our Design
Our project aims to create a next-generation, broad-spectrum influenza vaccine by leveraging the latest advances in synthetic biology, immunology, and bioinformatics. The core of our design is a focus on the hemagglutinin (HA) stem region—a part of the influenza virus that remains highly conserved across different subtypes and is less likely to mutate than other regions. By concentrating the immune response on this stable region, our goal is to achieve a vaccine that provides long-lasting and cross-protective immunity against a wide array of influenza strains.
To accomplish this, we started by conducting comprehensive sequence conservation and epitope prediction analyses, utilizing both traditional bioinformatics tools and machine learning models. These analyses allowed us to pinpoint a specific, 16-amino-acid peptide sequence within the HA2 stem that is present in multiple influenza A and B subtypes. This sequence was selected not only for its high degree of conservation but also for its predicted ability to stimulate both B-cell and T-cell immune responses.
A key aspect of our approach is the careful attention given to safety. Rather than expressing any full-length or functional viral protein—which could pose biosafety concerns—we specifically use only a truncated, non-functional peptide. This 16-amino-acid segment is far too short to exhibit any biological activity of the original influenza HA protein, and it cannot contribute to viral replication, assembly, or infection. Its role is exclusively as an immune system stimulant. The use of such a minimal, well-characterized peptide eliminates any realistic risk of reconstituting a functional influenza protein or virus. This strategy was informed by machine learning analyses to further ensure the absence of unintended biological function.
To enhance the immunogenicity of this short peptide and ensure it elicits a robust and long-lasting immune response, we utilize ferritin as a display and carrier platform. Ferritin is a globular, iron-storage protein that naturally self-assembles into nanoparticles and is found in virtually all living organisms. These nanoparticles provide a scaffold that allows multiple copies of our influenza peptide to be presented in a repetitive, highly ordered array, mimicking the antigen organization seen on viral surfaces. Ferritin is recognized as one of the safest vaccine carriers, offering high stability, biocompatibility, and no inherent toxicity or pathogenicity.
A significant advantage of using ferritin as our vaccine carrier is its remarkable stability at room temperature. Ferritin nanoparticles are highly resistant to thermal degradation and can maintain their structural integrity and antigenicity even after extended storage at ambient conditions. This property is particularly valuable for vaccine distribution, especially in regions with limited cold-chain infrastructure. By increasing the storage time and stability of the vaccine at room temperature, ferritin-based vaccines have the potential to greatly reduce logistical costs and expand access to immunization in resource-limited settings.
The recombinant fusion of our designed peptide and ferritin is achieved using standard molecular cloning techniques in Escherichia coli BL21, a non-pathogenic laboratory strain widely used for protein expression. All work with genetically modified organisms will be conducted under appropriate containment and biosafety protocols. No live engineered bacteria or viral vectors are intended for administration in any downstream applications; only the purified recombinant protein will be considered for future vaccine formulations.
Importantly, we believe that our design is not limited to influenza. By simply changing the displayed peptide or epitope, our ferritin-based nanoparticle platform can be readily adapted to create vaccines against a variety of other pathogens that share similar challenges, such as high mutation rates or the need for cross-protective immunity. This modular approach not only supports rapid vaccine development for emerging infectious diseases but also provides a flexible and scalable solution for global health challenges.
SDGs
In 2015, all the United Nations Member States adopted the 2030 Agenda for Sustainable Development which include 17 Sustainable Development Goals (SDGs), dispicting a shared future for humanity and our planet. Considering the implementation of SDGs in our project, our goals have aligned with several SDGs: Goal 3, Good Health and Well-being and Goal 10, Reduce Inequality. To "ensure healthy lives and promoting well-being for all at all ages", our project focuses on influenza which is one of the most widespread communicable disease globally. Vaccination is one of the most cost-effective ways of saving lives from influenza. Thus, presenting a universal flu vaccine that can provide long-term and more effective immunity against influenza viruses promotes good health and well-being. Additionally, a universal flu vaccine can prevent influenza from affecting marginalized groups, such as those in middle and low income countries. As World Health Organization (WHO) data shows, most middle and low income countries don't purchase enough seasonal flu vaccine which means most of their population don't get effective immunization against influenza virus. Nevertheless, a universal vaccine only requires one shot to be immunized for years, which lowers the overall spend on flu vaccines. As a result, a universal flu vaccine encourages middle and low income population to get vaccinated, reducing the inequality of flu immunization among marginalized groups.
Reference
- Javanian, M., Barary, M., Ghebrehewet, S., Koppolu, V., Vasigala, V., & Ebrahimpour, S. (2021). A brief review of influenza virus infection. Journal of Medical Virology, 93(8), 4638-4646.
- Nuwarda, R. F., Alharbi, A. A., & Kayser, V. (2021). An overview of influenza viruses and vaccines. Vaccines, 9(9), 1032.
- Alshahrani, A. M., Okmi, E., Sullivan, S. G., Tempia, S., Barakat, A., Naja, H. A. E., ... & Asiri, A. M. (2025). Uncovering the burden of influenza-associated illness across levels of severity in the kingdom of Saudi Arabia across three seasons. Journal of Epidemiology and Global Health, 15(1), 1-12.
- CDC. 2025. “People at Increased Risk for Flu Complications.” Influenza (Flu). https://www.cdc.gov/flu/highrisk/index.htm.
- Taubenberger, J. K., & Morens, D. M. (2008). The pathology of influenza virus infections. Annual Review of Pathology, 3, 499–522. https://doi.org/10.1146/annurev.pathmechdis.3.121806.154316.
- Webster, R. G., Bean, W. J., Gorman, O. T., Chambers, T. M., & Kawaoka, Y. (1992). Evolution and ecology of influenza A viruses. Microbiological Reviews, 56(1), 152–179. https://doi.org/10.1128/mr.56.1.152-179.1992.