Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 164 response, particularly T cells secreting granzyme B, indicating that the vaccine effectively enhances cellular immune responses (Adapted from Liao et al., 2020). In clinical trials, these chimeric HA vaccines have also shown promising results. A phase I trial tested a chimeric HA-based vaccine regimen in healthy adults, which included both live-attenuated and AS03-adjuvanted inactivated vaccines. The trial found that the vaccines were safe and induced broad, durable antibody responses targeting the HA stalk domain, supporting their potential as universal influenza vaccines (Nachbagauer et al., 2021). Additionally, another study highlighted that these vaccines could boost pre-existing anti-stalk antibodies, further enhancing their protective efficacy (Nachbagauer et al., 2019). 6.2 VLP-Based vaccines Virus-like particles (VLPs) are a promising platform for influenza vaccine development due to their ability to mimic the native structure of viruses without being infectious. VLP-based vaccines present multiple copies of antigens in a highly organized, repetitive structure, which can enhance the immune response. Studies have demonstrated that VLPs displaying the HA stem can elicit strong humoral and cellular immune responses. For instance, a study on chimeric VLPs co-displaying HA stem and the C-terminal fragment of DnaK significantly improved immune protection in mice, providing heterologous protection against different influenza strains (Liu et al., 2022). Moreover, VLP-based vaccines have shown cross-protective efficacy in preclinical models. A study involving VLPs containing a chimeric cytokine with M2 protein and HA proteins demonstrated increased survival rates in mice exposed to lethal doses of influenza viruses. This indicates the potential of VLPs in developing universal vaccines that can provide protection across multiple subtypes of influenza A viruses (Nerome et al., 2023). 6.3 Nanoparticle vaccines Nanoparticle vaccines represent a cutting-edge approach in universal influenza vaccine development. These vaccines use nanoparticles to present antigens in a way that enhances their immunogenicity. Nanoparticles can be engineered to display multiple influenza antigens simultaneously, which can focus the immune response on conserved regions and generate broadly neutralizing antibodies. A study demonstrated the use of SpyCatcher-based platforms to create nanoparticles displaying a diverse array of HA trimers from different influenza A strains, showing strong antibody responses in mice (Cohen et al., 2021). In addition to their strong immunogenicity, nanoparticle vaccines can be tailored for specific immune outcomes. For example, nanoparticles that co-display HA and other conserved influenza proteins have shown promise in preclinical studies, enhancing both humoral and cellular responses. These findings suggest that nanoparticle vaccines could play a crucial role in the next generation of universal influenza vaccines. 7 Challenges and Future Directions 7.1 Addressing immunodominance Immunodominance refers to the immune system's tendency to focus on certain dominant epitopes, often variable regions, while ignoring more conserved subdominant regions. This presents a significant challenge for universal influenza vaccine development, as current vaccines typically elicit immune responses to the highly variable head domain of hemagglutinin (HA) rather than the conserved stalk domain. Strategies to overcome this issue include the design of chimeric HA constructs that divert the immune response away from the immunodominant head and toward the conserved stalk, which is less prone to antigenic drift. Recent studies have shown that chimeric HA-based vaccines can successfully induce antibodies targeting the HA stalk, demonstrating their potential for broad protection (Zost et al., 2019). Additionally, nanoparticle-based vaccines and computationally designed immunogens are being explored to present conserved epitopes in a way that makes them more immunogenic, thus encouraging a more balanced immune response (Cohen et al., 2021). However, the challenge remains to refine these strategies to ensure that they consistently direct the immune response toward the desired conserved regions across diverse populations.
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