Journal of Vaccine Research 2024, Vol.14, No.2, 40-53 http://medscipublisher.com/index.php/jvr 47 5 Preclinical and Clinical Studies 5.1 Animal models and immunogenicity Preclinical studies have demonstrated the potential of universal influenza vaccines to provide broad and long-lasting protection against diverse influenza strains. For instance, a study using a recombinant adenovirus (rAd) expressing influenza A nucleoprotein (A/NP) and matrix 2 (M2) in mice showed that a single intranasal dose could induce antibody and T-cell responses that persisted for over a year without boosting. This vaccine provided broad protection against both group 1 and 2 influenza A viruses, as well as influenza B viruses, even a year after vaccination (Lo et al., 2021). Another study highlighted the importance of targeting conserved antigens, such as the hemagglutinin (HA) stalk, to elicit broadly cross-reactive antibodies. This approach has shown promising results in animal models, suggesting that it could be a viable strategy for developing universal influenza vaccines (Jang and Seong, 2019). In addition to the rAd-based vaccine, other preclinical studies have explored different vaccine platforms and formulations. For example, a plant-derived virus-like particle (VLP) vaccine candidate was tested in both young and older adults. The vaccine induced significant homologous and heterologous antibody responses, as well as antigen-specific CD4+ T cells producing interferon-gamma (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-α). These findings support the potential of VLP-based vaccines to provide broad and durable protection against influenza (Pillet et al., 2019). 5.2 Phase I/II clinical trials Phase I and II clinical trials have been crucial in evaluating the safety and immunogenicity of universal influenza vaccine candidates in humans. A randomized, placebo-controlled phase I trial tested a chimeric hemagglutinin-based vaccine in healthy adults. The vaccine was found to be safe and induced a broad, strong, and durable immune response targeting the conserved HA stalk domain. This suggests that chimeric hemagglutinins could be developed as universal vaccines that protect broadly against influenza viruses (Nachbagauer et al., 2021). Another phase I study tested a similar chimeric HA-based vaccine regimen, which included both live-attenuated and inactivated vaccines. The results showed that the vaccine regimens were tolerable and elicited cross-reactive serum IgG antibodies targeting the HA stalk domain, providing proof-of-principle for this approach in humans (Bernstein et al., 2019). In a phase II trial, the immunogenicity and safety of an oral influenza vaccine, VXA-A1.1, were evaluated using a human influenza challenge model. The vaccine was well tolerated and generated protective immunity against virus shedding, similar to a licensed intramuscular inactivated influenza vaccine (IIV). These results represent a significant step forward in developing a safe and effective oral influenza vaccine (Liebowitz et al., 2020). Another phase II trial tested the FLU-v vaccine, composed of synthetic peptides with conserved epitopes from influenza A and B strains. The trial aimed to evaluate the vaccine's ability to elicit both cell-mediated and humoral immunity, providing broad protection against multiple influenza strains. 5.3 Phase III clinical trials Phase III clinical trials are essential for confirming the efficacy and safety of universal influenza vaccine candidates in larger populations. A systematic review of universal influenza vaccines in clinical trials during the 2010-2019 decade identified three vaccines currently in phase III trials. These vaccines have the potential to provide significant improvements over seasonal influenza vaccines by offering broader and more durable protection (Corder et al., 2020). One such phase III trial evaluated the immunogenicity and safety of an inactivated quadrivalent influenza vaccine (IIV4) in a healthy population aged 3 years and older. The vaccine demonstrated good immunogenicity and safety, adding protection against an additional influenza B strain without increasing safety concerns (Chu et al., 2020). Another phase III trial examined the safety, immunogenicity, and lot-to-lot consistency of an IIV4 candidate in children, adolescents, and adults. The vaccine was well tolerated, induced robust antibody responses to all four influenza strains, and met all European Medicines Agency (EMA) immunogenicity criteria for adults. These
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