Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 159 3 Current Antigen Targets in Influenza Vaccines The development of universal influenza vaccines requires the identification and targeting of conserved viral components that can induce broad, long-lasting immune responses across various influenza subtypes. Among the key targets are hemagglutinin (HA), neuraminidase (NA), and matrix protein 2 (M2), which play crucial roles in the viral life cycle and immune response elicitation (Viboud et al., 2020; Wang et al., 2022). 3.1 Hemagglutinin (HA) Hemagglutinin (HA) is a surface glycoprotein of the influenza virus that plays a critical role in the virus's ability to bind and enter host cells. It is the primary target for neutralizing antibodies and is, therefore, a major component of current influenza vaccines. However, HA is also prone to antigenic drift, necessitating frequent updates to seasonal vaccines. Universal vaccine development has focused on targeting the more conserved stem (or stalk) region of HA rather than the highly variable head region. The HA stalk is less subject to antigenic variation and can elicit broadly neutralizing antibodies capable of providing cross-protection against different influenza subtypes (Zost et al., 2019). Recent studies have demonstrated that vaccines designed to target the HA stalk can induce robust and durable immune responses, making it a promising candidate for universal vaccines (Kim et al., 2017). Additionally, innovative approaches combining HA with other antigens, such as the matrix protein 2 (M2e), have shown enhanced protection and broader immunity in preclinical models. 3.2 Neuraminidase (NA) Neuraminidase (NA) is another surface glycoprotein of the influenza virus, responsible for the release of newly formed viral particles from infected cells. Although traditionally considered a secondary target compared to HA, recent research has highlighted its importance in immune protection. NA contains conserved epitopes that are less susceptible to antigenic drift, making it an attractive target for universal vaccines. Studies have shown that vaccines incorporating NA can enhance cross-protection and reduce disease severity, even in the presence of antigenic mismatch (Skarlupka et al., 2021). The combination of HA and NA in a vaccine formulation has been found to induce a more balanced immune response, reducing the dominance of HA and improving overall vaccine efficacy. Advances in understanding NA's role in immunity and its potential to elicit broadly neutralizing antibodies support its inclusion in future universal vaccine designs. 3.3 Matrix protein 2 (M2) Matrix protein 2 (M2) is a small ion channel protein found on the surface of the influenza virus, with its ectodomain (M2e) being highly conserved across all influenza A strains. Despite its low immunogenicity, M2e is a promising target for universal vaccines due to its minimal antigenic variation and essential role in the viral life cycle. Immunization strategies focusing on M2e have demonstrated cross-protection against multiple influenza subtypes, including highly pathogenic strains (Kim et al., 2022). Combining M2e with other antigens, such as HA or NA, has shown synergistic effects, enhancing immune responses and providing broader protection (Blokhina et al., 2020). Additionally, vaccines targeting M2e have the potential to provide durable immunity, as evidenced by studies demonstrating long-lasting protection without the need for frequent boosters (Lo et al., 2021). The integration of M2e into multivalent vaccine formulations is a key strategy in the ongoing development of universal influenza vaccines. 4 Innovative Strategies for Antigen Design 4.1 Epitope-Focused design Epitope-focused design is a critical strategy in the development of universal influenza vaccines, aiming to target conserved regions of the virus that can induce broad and robust immune responses. Traditional vaccines typically target variable regions of the virus, such as the head domain of hemagglutinin (HA), which undergoes frequent mutations, leading to reduced vaccine efficacy over time. In contrast, epitope-focused design seeks to direct the
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