Journal of Vaccine Research 2024, Vol.14, No.2, 40-53 http://medscipublisher.com/index.php/jvr 43 study suggests that nucleoside-modified mRNA vaccines hold promise as an effective means of combating heterologous influenza virus infections, contributing to the development of broad-spectrum influenza vaccines. 3 Mechanisms of Broad Protection 3.1 Targeting conserved antigens The hemagglutinin (HA) stalk domain is a highly conserved region of the influenza virus, making it an attractive target for universal influenza vaccines. Traditional influenza vaccines primarily target the variable head domain of HA, which necessitates frequent updates to match circulating strains. However, the conserved nature of the HA stalk allows for the development of vaccines that provide broad protection against multiple influenza strains. Studies have shown that vaccines targeting the HA stalk can induce broadly neutralizing antibodies that offer protection against diverse influenza viruses (Krammer and Palese, 2019; Zost et al., 2019; Nachbagauer et al., 2021). For instance, a chimeric HA-based vaccine has demonstrated the ability to elicit strong and durable immune responses targeting the HA stalk, suggesting its potential as a universal influenza vaccine candidate (Nachbagauer et al., 2021). Additionally, nanoparticle-based vaccines incorporating HA stem epitopes have shown promise in eliciting cross-protective immune responses in animal models (Qiao et al., 2022). Neuraminidase (NA) is another conserved antigen that has been relatively underutilized in traditional influenza vaccines. NA plays a crucial role in the viral life cycle by facilitating the release of newly formed viral particles from infected cells. Antibodies targeting NA can inhibit this process, thereby reducing viral spread. Recent research has highlighted the potential of NA as a target for universal influenza vaccines. For example, studies have demonstrated that NA-specific antibodies can provide broad protection against multiple influenza strains, including those with antigenic variations in HA (Kim et al., 2017; Eichelberger and Monto, 2019). Furthermore, vaccines incorporating NA have shown enhanced immune responses and protection in animal models, suggesting that NA should be considered in the formulation of future universal influenza vaccines (Eichelberger and Monto, 2019; Wang et al., 2021). The matrix 2 (M2) protein is a small, highly conserved ion channel protein found in the influenza virus. The extracellular domain of M2 (M2e) is particularly conserved across different influenza strains, making it an attractive target for universal vaccine development. Vaccines targeting M2e have been shown to induce robust immune responses and provide broad protection against various influenza viruses (Bernasconi et al., 2018; Lo et al., 2021). For instance, a study demonstrated that a single intranasal dose of a recombinant adenovirus expressing M2e provided long-lasting immune protection in mice against both group 1 and group 2 influenza A viruses, as well as influenza B viruses (Lo et al., 2021). Additionally, nanoparticle-based vaccines incorporating M2e have shown enhanced immune responses and protection in animal models, further supporting the potential of M2e as a target for universal influenza vaccines (Bernasconi et al., 2018; Wang et al., 2021). 3.2 Broadly neutralizing antibodies (bnAbs) Broadly neutralizing antibodies (bnAbs) have emerged as a promising avenue for achieving broad protection against diverse strains of influenza viruses. These antibodies target conserved regions of viral proteins, primarily hemagglutinin (HA) and neuraminidase (NA), which are less prone to mutation compared to other viral epitopes. Research has identified several bnAbs that target the conserved stem domain of the HA protein, which is shared across multiple influenza subtypes. For instance, Wei et al. demonstrated that a prime-boost vaccination strategy involving HA DNA and a seasonal vaccine elicited bnAbs in mice, ferrets, and nonhuman primates. These antibodies were directed against the conserved HA stem region and provided protection against a wide range of H1N1 strains (Wei et al., 2010). Similarly, studies have shown that bnAbs can target multiple strains of influenza A viruses by binding to highly conserved epitopes on the HA protein (Ekiert and Wilson, 2012; Feng et al., 2018). In addition to HA, neuraminidase (NA) has also been identified as a target for bnAbs. Stadlbauer et al. isolated human monoclonal antibodies from an H3N2-infected donor that exhibited broad protection against both influenza A and B viruses. These antibodies neutralized the virus by binding to the active site of the NA enzyme, thereby inhibiting its activity (Stadlbauer et al., 2019).
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