Journal of Vaccine Research 2024, Vol.14, No.2, 40-53 http://medscipublisher.com/index.php/jvr 44 The protective efficacy of bnAbs is mediated through several mechanisms. Primarily, these antibodies neutralize the virus by blocking the interaction between viral proteins and host cell receptors. For example, bnAbs targeting the HA stem region prevent the conformational changes required for viral fusion and entry into host cells (Wei et al., 2010; Cho and Wrammert, 2016). Beyond neutralization, bnAbs also exploit Fc-dependent effector functions to confer protection. These functions include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which involve the recruitment of immune effector cells such as natural killer (NK) cells and macrophages. For instance, a study on nonneutralizing antibodies specific for influenza B virus hemagglutinin demonstrated that Fc-dependent effector functions, such as ADCC, were crucial for protection in mice (Arunkumar et al., 2019). Similarly, research has shown that Fc-Fcγ receptor interactions are essential for the in vivo protective efficacy of bnAbs against influenza, regardless of their specific epitope (DiLillo et al., 2016). 3.3 T-Cell responses Cytotoxic T-lymphocytes (CTLs) play a crucial role in the immune response against influenza viruses by targeting and eliminating infected cells. CTLs recognize viral peptides presented by MHC class I molecules on the surface of infected cells, leading to the destruction of these cells and limiting viral replication. The induction of virus-specific CTLs is a key component of broad-protective influenza vaccines, as these cells can target conserved epitopes shared among different influenza subtypes, providing cross-protection. For instance, studies have shown that CTLs contribute significantly to protective immunity against various influenza strains, including H5N1, by targeting conserved viral epitopes (Rimmelzwaan et al., 2007). Additionally, recombinant vaccines incorporating conserved T-cell epitopes have demonstrated the ability to induce functional CTL responses and protect against both influenza and other viral infections (Isakova-Sivak et al., 2020). Cross-reactive T-cell epitopes are critical for the development of universal influenza vaccines. These epitopes are conserved regions of viral proteins that can be recognized by T-cells across different influenza subtypes, enabling the immune system to mount a response against a wide range of influenza viruses. Research has highlighted the importance of these conserved epitopes in eliciting broad and robust T-cell responses. For example, vaccines targeting conserved epitopes of the influenza virus hemagglutinin (HA) stem have been shown to induce cross-protective immune responses, providing complete protection against lethal challenges with diverse influenza strains (Qiao et al., 2022). Furthermore, the use of minigene vaccines encoding CTL epitopes from influenza A virus has demonstrated the feasibility of inducing specific and directed CTL responses, although additional strategies may be required to achieve full protection. 3.4 Innate immune responses Natural killer (NK) cells are a vital component of the innate immune response against influenza infection. NK cells can recognize and kill infected cells without prior sensitization, providing an early defense mechanism. They are activated by cytokines and can produce antiviral cytokines such as IFN-γ, which enhances the overall immune response. Studies have shown that NK cells play a significant role in controlling influenza virus replication and spread, contributing to the early containment of the infection (Oftung et al., 2022). The activation of NK cells by influenza vaccines can enhance the overall efficacy of the vaccine by providing immediate protection and shaping subsequent adaptive immune responses. Pattern recognition receptors (PRRs) are crucial for the detection of influenza viruses and the initiation of innate immune responses. PRRs, such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), recognize viral components and trigger signaling pathways that lead to the production of type I interferons and other pro-inflammatory cytokines. This activation of PRRs is essential for the recruitment and activation of various immune cells, including NK cells and T-cells. The role of PRRs in influenza immunity has been well-documented, with studies demonstrating that the activation of these receptors is necessary for effective antiviral responses and the development of adaptive immunity (Jansen et al., 2019; Oftung et al., 2022). Enhancing PRR activation through vaccine adjuvants or other strategies can improve the efficacy of influenza vaccines by promoting robust and broad immune responses.
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