Journal of Vaccine Research 2024, Vol.14 http://medscipublisher.com/index.php/jvr © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Publisher
Journal of Vaccine Research 2024, Vol.14 http://medscipublisher.com/index.php/jvr © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher is an international Open Access publisher specializing in veterinary vaccine, prophylactic vaccines, therapeutic vaccines, AIDS vaccines, clinical vaccines at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. Publisher MedSci Publisher Editedby Editorial Team of Journal of Vaccine Research Email: edit@jvr.medscipublisher.com Website: http://medscipublisher.com/index.php/jvr Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada Journal of Vaccine Research (ISSN 1927-6486) is an open access, peer reviewed journal published online by MedSciPublisher. The journal is considering all the latest and outstanding research articles, letters and reviews in all aspects of vaccine research, mainly interested in vaccines and vaccination research, immunologic testing including serology, cell-mediated immunity, cell culture, and cytokine assays, veterinary vaccine, prophylactic vaccines, therapeutic vaccines, AIDS vaccines and other clinical vaccines; vaccination research and methodology containing vaccine technology, vaccine adjuvants; as well as the expands field ofvaccines and vaccination research. All the articles published in Journal of Vaccine Research are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
Journal of Vaccine Research (online), 2024, Vol. 14, No. 4 ISSN 1927-6486 http://medscipublisher.com/index.php/jvr © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Strategies for Antigen Design in Universal Influenza Vaccine Development Jianbang Chen Journal of Vaccine Research, 2024, Vol. 14, No. 4, 157-169 Advances in Dengue Vaccine Development: Efficacy, Safety, and Implementation Tiantian Wang Journal of Vaccine Research, 2024, Vol. 14, No. 4, 170-182 The Role of Adjuvants in Enhancing Cancer Vaccine Efficacy Jianmin Liu Journal of Vaccine Research, 2024, Vol. 14, No. 4, 183-195 Long-Term Immunogenicity and Safety Profile of mRNA COVID-19 Vaccines TianZhao Journal of Vaccine Research, 2024, Vol. 14, No. 4, 196-206 Development of Multi-Pathogen Vaccines: Current Advances and Challenges JieZhang Journal of Vaccine Research, 2024, Vol. 14, No. 4, 207-216
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 157 Systematic Review Open Access Strategies for Antigen Design in Universal Influenza Vaccine Development Jianbang Chen Huahai Pharmaceutical Co., Ltd., Taizhou, 317099, Zhejiang, China Corresponding email: chejb@qq.com Journal of Vaccine Research, 2024, Vol.14, No.4 doi: 10.5376/jvr.2024.14.0016 Received: 10 Jun., 2024 Accepted: 11 Jul., 2024 Published: 22 Jul., 2024 Copyright © 2024 Chen, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Chen J.B., 2024, Strategies for antigen design in universal influenza vaccine development, Journal of Vaccine Research, 14(4): 157-169 (doi: 10.5376/jvr.2024.14.0016) Abstract Globally, the variability and antigenic drift of the influenza virus limit the effectiveness of existing seasonal vaccines, making the development of a universal influenza vaccine that provides broad and durable protection critically important. This study reviews the primary strategies for designing antigens for a universal influenza vaccine, focusing on innovative approaches targeting conserved regions of the influenza virus, such as the hemagglutinin (HA) stem, neuraminidase (NA), and matrix protein 2 (M2). It also explores the roles of chemical synthesis, nanoparticle carriers, and novel adjuvants in enhancing antigen immunogenicity. By analyzing current clinical and preclinical research findings, the study identifies key challenges related to antigen immunodominance, infection enhancement, and long-term efficacy and durability. The research concludes with an outlook on future research directions and calls for further scientific exploration to achieve the ultimate goal of a universal influenza vaccine. Keywords Universal influenza vaccine; Antigen design; Hemagglutinin stem; Matrix protein 2 1 Introduction The pursuit of a universal influenza vaccine has garnered significant attention due to the persistent challenge posed by influenza viruses, which undergo frequent antigenic shifts and drifts, rendering current vaccines less effective over time. The development of a vaccine capable of providing broad and long-lasting protection against diverse influenza strains is critical for addressing both seasonal outbreaks and potential pandemics. This paper explores the strategies for designing antigens that could be utilized in the development of such a universal vaccine (Skarlupka et al., 2021). Influenza is a highly contagious respiratory illness caused by influenza viruses, primarily types A and B. The virus's ability to rapidly mutate leads to seasonal epidemics, which result in significant morbidity, mortality, and economic burden globally. According to the World Health Organization (WHO), annual influenza epidemics cause about 3 to 5 million cases of severe illness and approximately 290 000 to 650 000 deaths worldwide. Beyond these seasonal outbreaks, influenza poses a constant threat of pandemics, as seen with the H1N1 pandemic in 2009, which can have devastating consequences on public health systems and economies (Nguyen and Choi, 2021). Current influenza vaccines are primarily strain-specific, targeting surface proteins like hemagglutinin (HA) and neuraminidase (NA). Due to the frequent antigenic drift and shift of these viruses, annual reformulation of vaccines is required, which often leads to a mismatch between the vaccine strains and circulating viruses, thereby reducing vaccine efficacy. Additionally, the immune response generated by these vaccines is typically short-lived, necessitating yearly vaccination. Moreover, the current vaccines predominantly induce strain-specific antibodies that do not provide cross-protection against divergent influenza virus strains, highlighting the need for a more robust and universal vaccine approach (Nguyen and Choi, 2021). This study primarily discusses the current strategies for antigen design in the development of universal influenza vaccines and identifies key antigens and their roles in eliciting broad and cross-reactive immune responses. The research explores the potential of targeting the HA stem, NA, matrix proteins, and internal proteins as antigens to generate durable immunity against multiple influenza subtypes. It also evaluates the advantages and limitations of these antigens, providing a comprehensive overview of the challenges and opportunities in the development of a universal influenza vaccine.
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 158 2 Rationale for Universal Influenza Vaccine Development The development of a universal influenza vaccine (UIV) is a critical objective in public health due to the significant limitations of current seasonal vaccines and the continuous threat posed by influenza viruses (Xu et al., 2024). 2.1 Antigenic drift and shift Influenza viruses are notorious for their ability to undergo frequent genetic changes, which can manifest as either antigenic drift or antigenic shift. Antigenic drift refers to the gradual accumulation of mutations in the virus's surface proteins, particularly hemagglutinin (HA) and neuraminidase (NA), which leads to the emergence of new strains that can evade the immune system. This process is responsible for the need to update seasonal influenza vaccines annually. On the other hand, antigenic shift is a more abrupt and significant genetic change that occurs when two different strains of influenza viruses infect the same cell and exchange genetic material. This can result in a new subtype that is substantially different from previous strains, often leading to pandemics due to the lack of pre-existing immunity in the population (Pica and Palese, 2013; Nguyen and Choi, 2021; Wang et al., 2022). The ability of the influenza virus to undergo these genetic changes poses significant challenges for vaccine development, as current vaccines are designed to target specific strains. As a result, the continuous evolution of the virus necessitates the frequent reformulation of vaccines, often leading to mismatches between the vaccine and circulating strains, which reduces vaccine efficacy (Madsen and Cox, 2020). This highlights the urgent need for a universal influenza vaccine that can provide broad and long-lasting protection against a wide range of influenza strains. 2.2 Limitations of current seasonal vaccines Current seasonal influenza vaccines have several limitations that undermine their effectiveness. These vaccines are primarily designed to target specific strains predicted to circulate in the upcoming flu season. However, the unpredictability of antigenic drift and shift often results in a mismatch between the vaccine strains and the actual circulating viruses, leading to reduced vaccine efficacy. For instance, during the 2017-2018 flu season, the vaccine was only about 40% effective due to such a mismatch (Jang and Seong, 2019). Additionally, the immunity conferred by these vaccines is short-lived, necessitating annual vaccination. This is particularly problematic for at-risk populations, such as the elderly, who may not respond as robustly to vaccination (Paules et al., 2017). Moreover, current vaccines do not provide cross-protection against diverse influenza subtypes, leaving individuals vulnerable to novel strains that may cause pandemics (Petrie and Gordon, 2018). The limitations of these vaccines underscore the need for a universal influenza vaccine that can provide broad and durable protection against multiple strains, reducing the need for annual vaccinations and offering better protection against emerging pandemic strains (Nguyen and Choi, 2021). 2.3 The case for a universal vaccine The development of a universal influenza vaccine (UIV) is essential to overcome the limitations of current seasonal vaccines and to provide long-lasting protection against a wide range of influenza strains. A UIV would target conserved regions of the influenza virus, such as the HA stalk and NA, which are less prone to antigenic drift and shift, thus offering broad-spectrum immunity (Skarlupka et al., 2021). Recent advances in vaccine technology, such as the use of novel adjuvants and delivery platforms, have shown promise in enhancing the immunogenicity of these conserved epitopes, potentially leading to the development of a UIV (Viboud et al., 2020). Furthermore, the integration of computational tools and structural biology has facilitated the rational design of vaccine candidates that can elicit broadly neutralizing antibodies and cross-reactive T cell responses (Sangesland and Lingwood, 2021). The potential of a UIV to provide comprehensive protection against both seasonal and pandemic influenza viruses would be a significant public health achievement, reducing the global burden of influenza and improving pandemic preparedness (Jang and Seong, 2019; Wang et al., 2022).
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
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 160 immune response towards more conserved regions, such as the HA stalk and receptor-binding sites (RBS), which are less prone to antigenic drift and thus offer a more stable target for vaccine-induced immunity. The HA stalk, for instance, is a highly conserved structure across different influenza subtypes, making it an ideal target for broad-spectrum protection (Bajic et al., 2019). Recent advances in computational biology have greatly enhanced the ability to design immunogens that can precisely mimic these conserved epitopes, leading to the generation of broadly neutralizing antibodies (bnAbs). These bnAbs are capable of recognizing and neutralizing a wide range of influenza strains, offering a significant advantage over strain-specific antibodies typically induced by conventional vaccines. For example, computational tools have been used to design novel immunogens that stabilize these conserved epitopes, ensuring that they are presented to the immune system in their native conformation, which is crucial for eliciting an effective immune response (Sesterhenn et al., 2020). Additionally, multi-epitope vaccine constructs have been developed, combining several conserved regions into a single immunogen, thereby increasing the breadth and durability of the immune response. These constructs often include conserved regions from different viral proteins, such as HA, neuraminidase (NA), and matrix protein 2 (M2), to ensure comprehensive protection (Sharma et al., 2021). Despite the promise of epitope-focused design, challenges remain, including the need to overcome the immune system's preference for immunodominant but variable regions, such as the HA head. Efforts are ongoing to fine-tune the presentation of these conserved epitopes to ensure that they elicit a strong and focused immune response. Overall, epitope-focused design represents a promising avenue for the development of a truly universal influenza vaccine, with the potential to provide long-lasting protection against both seasonal and pandemic influenza strains. 4.2 Prime-Boost strategies Prime-boost strategies have emerged as a potent approach in enhancing the efficacy of vaccines, particularly in the context of universal influenza vaccine development. This strategy involves administering a "prime" dose of one type of vaccine, followed by one or more "boost" doses of either the same or a different type of vaccine. The goal is to strengthen and sustain the immune response, particularly against conserved viral antigens that are crucial for broad protection. Prime-boost strategies are especially effective in focusing the immune response on less immunogenic but conserved regions of the virus, such as the HA stalk, which is essential for developing broad-spectrum immunity. A typical prime-boost regimen might involve a DNA vaccine as the prime, which introduces the antigen and initiates the immune response, followed by a viral vector or protein-based boost that amplifies this response. This approach has been shown to significantly enhance both humoral and cellular immunity, resulting in higher titers of neutralizing antibodies and stronger T-cell responses. For instance, studies using a DNA prime followed by a recombinant viral vector boost have demonstrated robust production of stalk-specific antibodies, which are critical for cross-protection against various influenza strains (Goodman et al., 2011). The effectiveness of prime-boost strategies is further supported by clinical trials and preclinical studies that show improved protection against heterologous influenza strains. For example, a study involving a prime-boost regimen using H5N1 DNA and a protein-based boost elicited antibodies capable of neutralizing multiple subtypes of influenza A viruses, highlighting the potential of this approach in achieving cross-protection (Joyce et al., 2016). However, challenges remain, such as the potential for vaccine-associated enhancement of infection and the need to optimize the timing and composition of the prime and boost doses to maximize efficacy while minimizing adverse effects (Jang and Seong, 2014). Moreover, the practicality of implementing prime-boost strategies in large populations, particularly in terms of cost and logistics, is a significant consideration. Despite these challenges, prime-boost strategies hold great promise for the development of universal influenza vaccines, as they offer a means to direct the immune response toward conserved viral components, thereby providing broader and more durable protection.
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 161 4.3 Computational approaches Computational approaches have become indispensable in the field of vaccine design, particularly for developing universal influenza vaccines. These approaches leverage the power of bioinformatics, structural biology, and machine learning to predict, model, and optimize vaccine candidates that can elicit broad and long-lasting immunity. Given the rapid evolution and genetic diversity of influenza viruses, traditional empirical methods have often fallen short in providing effective solutions. In contrast, computational approaches allow for the rational design of immunogens that target conserved regions of the virus, offering a promising path toward a universal vaccine (Zost et al., 2019; Goff et al., 2015). One of the most significant contributions of computational approaches is the development of Computationally Optimized Broadly Reactive Antigens (COBRA). COBRA utilizes consensus sequence algorithms and phylogenetic models to design antigens that can induce cross-reactive immune responses against a wide array of influenza strains. This method has proven effective in creating vaccines that provide protection against both seasonal and pandemic strains of influenza, as demonstrated in preclinical models (Carter et al., 2016). Additionally, computational tools are employed to analyze the structural properties of viral proteins, identify conserved epitopes, and predict their immunogenic potential. This enables the design of epitope-focused vaccines that can elicit broadly neutralizing antibodies targeting conserved regions such as the HA stem and NA active sites (Qiu et al., 2019). Another key area where computational approaches excel is in the optimization of vaccine formulations. By simulating immune responses and predicting antigenic drift, researchers can refine vaccine candidates to enhance their efficacy and durability. Machine learning algorithms further assist in analyzing large datasets, including viral genomic sequences and immune responses, to identify patterns and predict the most effective vaccine combinations. These techniques have also been used to design multi-epitope vaccines that combine several conserved regions, thereby increasing the breadth and effectiveness of the immune response (Wong and Ross, 2016). Despite the advances, challenges remain in integrating these computational approaches with experimental validation. The complexity of immune responses and the dynamic nature of viral evolution require continuous refinement of models and predictions. Nonetheless, the integration of computational tools with traditional vaccine development methodologies holds great promise for creating a universal influenza vaccine that can provide comprehensive protection against future influenza pandemics (Xu and Li, 2024). 5 Role of Adjuvants in Enhancing Antigenicity Adjuvants play a crucial role in enhancing the immune response to vaccines by improving the antigenicity of vaccine components. They achieve this by promoting a stronger and more durable immune response, allowing for lower doses of antigen to be used while maintaining or even improving vaccine efficacy (Paules et al., 2017; Petrie and Gordon, 2018). 5.1 Molecular adjuvants Molecular adjuvants are small molecules or proteins that modulate the immune response by targeting specific pathways involved in immunity. These adjuvants can be designed to enhance both humoral and cellular immune responses, making them particularly valuable in the development of universal influenza vaccines. For example, the STING (Stimulator of Interferon Genes) pathway has been identified as a critical target for molecular adjuvants. Encapsulation of STING agonists, such as cyclic dinucleotides (CDNs), in microparticle delivery systems has shown significant promise. In one study, STING agonists encapsulated in acid-sensitive acetalated dextran microparticles (Ace-DEX MPs) dramatically enhanced type-I interferon responses and boosted antibody titers against influenza, demonstrating the potential of molecular adjuvants in vaccine design (Figure 1) (Junkins et al., 2018). Another study highlighted the use of glycosylphosphatidylinositol-anchored CCL28 and GM-CSF fusion proteins in virus-like particle (VLP) vaccines, which significantly improved humoral and cellular immune responses in mice (Liu et al., 2018).
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 162 Figure 1 cGAMP MPs provide long term protection against lethal influenza challenge (Adapted from Junkins et al., 2018) Note: Note: In experiments involving mice vaccinated with cGAMP MPs and soluble cGAMP, the results showed that mice receiving cGAMP MPs maintained strong body weight and complete protection even after seven months, whereas the control and other groups exhibited poorer outcomes. This indicates that cGAMP MPs not only provide long-lasting immune protection but also significantly enhance vaccine efficacy (Adapted from Junkins et al., 2018). 5.2 Delivery platforms The development of effective delivery platforms is essential for the success of adjuvants, as these platforms ensure that the adjuvants and antigens are delivered to the appropriate cells in the immune system. Nanoparticle-based delivery systems have gained attention due to their ability to mimic pathogen-associated molecular patterns (PAMPs), enhancing both innate and adaptive immune responses. For instance, nanoparticle vaccines based on bacteriophage T4 have shown potential in eliciting strong immune responses without the need for additional adjuvants, suggesting that these platforms could be used to deliver conserved influenza antigens (Tao et al., 2019). Moreover, recent studies have demonstrated that nanoparticle size and surface coating significantly influence the uptake and processing of antigens by dendritic cells, which are critical for initiating immune responses (Chang et al., 2017). These findings underscore the importance of optimizing delivery platforms to enhance the efficacy of molecular adjuvants and the overall vaccine formulation. 5.3 AS03 and other adjuvants AS03, an oil-in-water emulsion adjuvant, has been widely studied and used in influenza vaccines, particularly during the H1N1 pandemic. This adjuvant is known for its ability to enhance both humoral and cellular immune responses, making it a key component in the development of more effective influenza vaccines. Studies have shown that AS03 significantly boosts the production of antibodies, including those against conserved epitopes such as the hemagglutinin (HA) stem, which is critical for cross-protection against various influenza strains. Furthermore, AS03 has been shown to modulate early innate immune responses, including the activation of interferon and JAK-STAT signaling pathways, which are crucial for a robust adaptive immune response (Howard et al., 2019). Additionally, AS03's ability to enhance the immunogenicity of low-dose vaccines makes it an attractive option for dose-sparing strategies, which are particularly valuable in pandemic settings (Yam et al., 2015). Beyond AS03, other adjuvants such as MF59, QS-21, and CpG oligodeoxynucleotides are also being explored for their potential to improve influenza vaccine efficacy. These adjuvants offer different mechanisms of action, such
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 163 as enhancing antigen presentation, promoting the recruitment of immune cells to the site of vaccination, and inducing broader immune responses against heterologous viral strains (Ng et al., 2016; Tregoning et al., 2018). 6 Case Study: Preclinical and Clinical Development The development of universal influenza vaccines has advanced significantly through various preclinical and clinical studies. These studies have focused on novel antigen designs that target conserved regions of the influenza virus, aiming to provide broad and long-lasting protection. 6.1 Chimeric HA-Based vaccines Chimeric hemagglutinin (HA)-based vaccines are designed to elicit immune responses against the conserved stalk domain of the HA protein, rather than the highly variable head domain. This approach aims to generate broadly neutralizing antibodies that can provide cross-protection against multiple influenza subtypes. Preclinical studies have shown that chimeric HA constructs, which combine the stalk domain of one influenza strain with the head domain of another, can effectively focus the immune response on the stalk region. For instance, a study demonstrated that a chimeric HA vaccine with a conserved HA stalk from H1N1 combined with an exotic head domain from H5N1 elicited strong CD4+ and CD8+ T cell responses, providing broad protection against various influenza strains (Figure 2) (Liao et al., 2020). Figure 2 depicts the neutralizing activity of different constructs of chimeric hemagglutinin (cHA) vaccines and their induced CD8+ T cell responses (Adapted from Liao et al., 2020) Note: The experiments demonstrated that the cHA vaccine using the H5 head and H1 stalk structure effectively induced cross-neutralizing activity against both H1N1 and H5N1 viruses. Additionally, the cHA vaccine also induced a strong CD8+ T cell
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.
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 165 7.2 Vaccine-Associated enhancement of infection Vaccine-associated enhancement of infection (VAEI) is a phenomenon where a vaccine inadvertently exacerbates the severity of the disease it is designed to prevent. This can occur through mechanisms such as antibody-dependent enhancement (ADE), where non-neutralizing antibodies facilitate viral entry into host cells, leading to increased viral replication and disease severity. While VAEI has been a concern in the development of vaccines for other viruses like dengue, it remains a potential risk in influenza vaccine development, especially for vaccines targeting conserved epitopes shared by multiple virus strains. Studies have shown that certain adjuvants, such as AS03, can mitigate this risk by promoting the production of broadly neutralizing antibodies and enhancing cellular immune responses (Goff et al., 2015). However, careful evaluation in preclinical and clinical studies is essential to ensure that new vaccine candidates do not inadvertently enhance infection or disease severity in vaccinated individuals. Future research should focus on understanding the immunological mechanisms underlying VAEI and developing vaccine formulations that minimize this risk while maximizing protective efficacy. 7.3 Long-Term efficacy and durability One of the key challenges in universal influenza vaccine development is ensuring long-term efficacy and durability of the immune response. Current seasonal vaccines typically require annual administration due to waning immunity and antigenic drift. In contrast, a universal vaccine would need to provide long-lasting protection against a broad range of influenza strains, including those that may emerge in the future. Recent advances have shown promise in this area; for example, a study demonstrated that a single dose of a recombinant adenovirus-based vaccine expressing conserved influenza antigens could induce immune responses that persisted for over a year without the need for boosting (Lo et al., 2021). Another approach involves the use of nanoparticle vaccines that enhance the longevity of the immune response by improving antigen presentation and retention in germinal centers, where long-term immune memory is generated (Gao et al., 2023). However, further research is needed to optimize these strategies and ensure that they provide robust, durable immunity across different populations and age groups. Addressing these challenges will be critical to realizing the goal of a universal influenza vaccine that can provide sustained protection over time. 8 Concluding Remarks The pursuit of a universal influenza vaccine has advanced considerably, driven by the need to overcome the limitations of current seasonal vaccines. The development of a universal influenza vaccine has focused on several innovative strategies, including targeting conserved regions of the virus, such as the hemagglutinin (HA) stalk, neuraminidase (NA), and matrix protein 2 (M2). Chimeric HA-based vaccines, virus-like particle (VLP)-based vaccines, and nanoparticle vaccines have shown promising results in both preclinical and early clinical studies. These approaches aim to elicit broadly neutralizing antibodies and robust T-cell responses that provide cross-protection against a wide range of influenza subtypes. However, challenges such as immunodominance, vaccine-associated enhancement of infection, and the durability of immune responses remain significant hurdles. Addressing these challenges will be crucial for the successful development and deployment of a universal influenza vaccine. The future of universal influenza vaccine development is promising, but it requires sustained efforts in both research and clinical evaluation. Advances in computational modeling, structural biology, and immunology are expected to play a pivotal role in designing vaccines that can overcome the issue of immunodominance and provide long-lasting protection. Additionally, the integration of novel adjuvants and delivery platforms, such as nanoparticle-based systems, will likely enhance the efficacy and durability of these vaccines. The success of these initiatives will depend on comprehensive preclinical studies and well-designed clinical trials that address safety, immunogenicity, and efficacy across diverse populations. Despite significant progress, the development of a universal influenza vaccine is far from complete. Continued research is essential to address the remaining challenges and to refine the strategies that have shown promise.
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 166 There is a critical need for long-term studies to evaluate the durability of immune responses and to understand the potential risks associated with vaccine-associated enhancement of infection. Furthermore, research should focus on identifying reliable correlates of protection that can guide the design of next-generation vaccines. The scientific community must also prioritize the exploration of new vaccine platforms and adjuvants that can enhance the breadth and depth of immune responses. As global health challenges continue to evolve, the development of a universal influenza vaccine remains a critical goal that warrants ongoing investment and collaboration. Acknowledgments I would like to thank two anonymous peer reviewers for their suggestions on my manuscript. Conflict of Interest Disclosure The author affirms that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Bajic G., van der Poel C.E., Kuraoka M., Schmidt A.G., Carroll M.C., Kelsoe G., and Harrison S.C., 2019, Autoreactivity profiles of influenza hemagglutinin broadly neutralizing antibodies, Scientific Reports, 9(1): 3492. https://doi.org/10.1038/s41598-019-40175-8 PMid:30837606 PMCid:PMC6401307 Blokhina E., Mardanova E., Stepanova L., Tsybalova L., and Ravin N.V., 2020, Plant-produced recombinant influenza A virus candidate vaccine based on flagellin linked to conservative fragments of M2 protein and hemagglutintin, Plants, 9(2): 162. https://doi.org/10.3390/plants9020162 PMid:32013187 PMCid:PMC7076671 Carter D.M., Darby C.A., Lefoley B.C., Crevar C.J., Alefantis T., Oomen R., Anderson S.F., Strugnell T., Cortés-Garcia G., Vogel T.U., Parrington M., Kleanthous H., and Ross T.M., 2016, Design and characterization of a computationally optimized broadly reactive hemagglutinin vaccine for H1N1 influenza viruses, Journal of Virology, 90(9): 4720-4734. https://doi.org/10.1128/JVI.03152-15 PMid:26912624 PMCid:PMC4836330 Chang T.Z., Stadmiller S.S., Staskevicius E., and Champion J.A., 2017, Effects of ovalbumin protein nanoparticle vaccine size and coating on dendritic cell processing, Biomaterials Science, 5(2): 223-233. https://doi.org/10.1039/C6BM00500D PMid:27918020 PMCid:PMC5285395 Cohen A.A., Yang Z., Gnanapragasam P.N.P., Ou S., Dam K.M.A., Wang H., and Bjorkman P.J., 2021, Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers, PloS One, 16(3): e0247963. https://doi.org/10.1371/journal.pone.0247963 PMid:33661993 PMCid:PMC7932532 Gao X., Wang X., Li S., Rahman M.S.U., Xu S., and Liu Y., 2023, Nanovaccines for advancing long-lasting immunity against infectious diseases, ACS Nano, 17(24): 24514-24538. https://doi.org/10.1021/acsnano.3c07741 PMid:38055649 Goff P., Hayashi T., Martínez-Gil L., Corr M., Crain B., Yao S., and Carson D.A., 2015, Synthetic Toll-like receptor 4 (TLR4) and TLR7 ligands as influenza virus vaccine adjuvants induce rapid, sustained, and broadly protective responses, Journal of Virology, 89(6): 3221-3235. https://doi.org/10.1128/JVI.03337-14 PMid:25568203 PMCid:PMC4337541 Goodman A.G., Heinen P.P., Guerra S., Vijayan A., Sorzano C.O., Gómez C.E., and Esteban M., 2011, A human multi-epitope recombinant vaccinia virus as a universal T cell vaccine candidate against influenza virus, PloS One, 6(10): e25938. https://doi.org/10.1371/journal.pone.0025938 PMid:21998725 PMCid:PMC3187825 Howard L.M., Goll J.B., Jensen T.L., Hoek K.L., Prasad N., Gelber C.E., Levy S.E., Joyce S., Link A.J., Creech C.B., and Edwards K.M., 2019, AS03-adjuvanted H5N1 avian influenza vaccine modulates early innate immune signatures in human peripheral blood mononuclear cells, The Journal of Infectious Diseases, 219(11): 1786-1798. https://doi.org/10.1093/infdis/jiy721 PMid:30566602 PMCid:PMC6500554 Jang Y., and Seong B.L., 2014, Options and obstacles for designing a universal influenza vaccine, Viruses, 6(8): 3159-3180. https://doi.org/10.3390/v6083159 PMid:25196381 PMCid:PMC4147691
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 167 Jang Y., and Seong B.L., 2019, The quest for a truly universal influenza vaccine, Frontiers in Cellular and Infection Microbiology, 9: 344. https://doi.org/10.3389/fcimb.2019.00344 PMid:31649895 PMCid:PMC6795694 Joyce M.G., Wheatley A K., Thomas P.V., Chuang G.Y., Soto C., Bailer R.T., Druz A., Georgiev I.S., Gillespie R.A., Kanekiyo M., Kong W.P., Leung K., Narpala S.N., Prabhakaran M.S., Yang E.S., Zhang B., Zhang Y., Asokan M., Boyington J.C., Bylund T., Darko S., Lees C.R., Ransier A., Shen C.H., Wang L.S., Whittle J.R., Wu X.L., Yassine H.M., Santos C., Matsuoka Y., Tsybovsky Y., Baxa U., NISC Comparative Sequencing Program, Mullikin J.C., Subbarao K., Douek D.C., Graham B.S., Koup R.A., Ledgerwood J.E., Roederer M., Shapiro L., Kwong P.D., Mascola J.R., and McDermott A.B., 2016, Vaccine-induced antibodies that neutralize group 1 and group 2 influenza A viruses, Cell, 166(3): 609-623. https://doi.org/10.1016/j.cell.2016.06.043 PMid:27453470 PMCid:PMC4978566 Junkins R.D., Gallovic M.D., Johnson B.M., Collier M.A., Watkins-Schulz R., Cheng N., David C.N., McGee C.E., Sempowski G.D., Shterev I., McKinnon K., Bachelder E.M., Ainslie K.M., and Ting J.P.Y., 2018, A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination, Journal of Controlled Release, 270: 1-13. https://doi.org/10.1016/j.jconrel.2017.11.030 PMid:29170142 PMCid:PMC5808851 Kim E.H., Han G.Y., and Nguyen H., 2017, An adenovirus-vectored influenza vaccine induces durable cross-protective hemagglutinin stalk antibody responses in mice, Viruses, 9(8): 234. https://doi.org/10.3390/v9080234 PMid:28825679 PMCid:PMC5580491 Kim T., Bimler L., Ronzulli S.L., Song A.Y., Johnson S.K., Jones C.A., Tompkins S.M., and Paust S., 2022, A low-dose triple antibody cocktail against the ectodomain of the matrix protein 2 of influenza A is A universally effective and viral escape mutant resistant therapeutic agent, bioRxiv, 2022-04. https://doi.org/10.1101/2022.04.02.486847 Liao H.Y., Wang S.C., Ko Y., Lin K.I., Ma C., Cheng T.J., and Wong C.H., 2020, Chimeric hemagglutinin vaccine elicits broadly protective CD4 and CD8 T cell responses against multiple influenza strains and subtypes, Proceedings of the National Academy of Sciences, 117(30): 17757-17763. https://doi.org/10.1073/pnas.2004783117 PMid:32669430 PMCid:PMC7395492 Liu C.C., Liu D.J., Yue X.Y., Zhong X.Q., Wu X., Chang H.Y., Wang B.Z., Wan M.Y., and Deng L., 2022, Chimeric virus-like particles co-displaying hemagglutinin stem and the C-Terminal fragment of dnak confer heterologous influenza protection in mice, Viruses, 14(10): 2109. https://doi.org/10.3390/v14102109 PMid:36298664 PMCid:PMC9610613 Liu J., Ren Z., Wang H., Zhao Y., Wilker P.R., Yu Z., Sun W.Y., Wang T.C., Feng N., Li Y.G., Wang H.L., Ji X.L., Li N., Yang S.T., He H.B., Qin C., GaoY.W., and Xia X., 2018, Influenza virus-like particles composed of conserved influenza proteins and GPI-anchored CCL28/GM-CSF fusion proteins enhance protective immunity against homologous and heterologous viruses, International Immunopharmacology, 63: 119-128. https://doi.org/10.1016/j.intimp.2018.07.011 PMid:30081250 Lo C., Misplon J. A., Li X., Price G., Ye Z., and Epstein S.L., 2021, Universal influenza vaccine based on conserved antigens provides long-term durability of immune responses and durable broad protection against diverse challenge virus strains in mice, Vaccine, 39(33): 4628-4640. https://doi.org/10.1016/j.vaccine.2021.06.072 PMid:34226103 Madsen A., and Cox R.J., 2020, Prospects and challenges in the development of universal influenza vaccines, Vaccines, 8(3): 361. https://doi.org/10.3390/vaccines8030361 PMid:32640619 PMCid:PMC7563311 Nachbagauer R., Feser J., Naficy A., Bernstein D.I., Guptill J., Walter E.B., Berlanda-Scorza F., Stadlbauer D., Wilson P.C., Aydillo T., Behzadi M.A., Bhavsar D., Bliss C., Capuano C., Carreño J.M., Chromikova V., Claeys C., Coughlan L., Freyn A.W., Gast C., Javier A., Jiang K., Mariottini C., McMahon M., McNeal M., Solórzano A., Strohmeier S., Sun W., Van der Wielen M., Innis B.L., García-Sastre A., Palese P., and Krammer F., 2021, A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial, Nature Medicine, 27(1): 106-114. https://doi.org/10.1038/s41591-020-1118-7 PMid:33288923 Nachbagauer R., Salaun B., Stadlbauer D., Behzadi M.A., Friel D., Rajabhathor A., Choi A., Albrecht R.A., Debois M., García-Sastre A., Rouxel R.N., Sun W., Palese P., Mallett C.P., Innis B.L., Krammer F., and Claeys C., 2019, Pandemic influenza virus vaccines boost hemagglutinin stalk-specific antibody responses in primed adult and pediatric cohorts, NPJ Vaccines, 4(1): 51. https://doi.org/10.1038/s41541-019-0147-z PMid:31839997 PMCid:PMC6898674 Nerome K., Imagawa T., Sugita S., Arasaki Y., Maegawa K., Kawasaki K., Tanaka T., Watanabe S., Nishimura H., Suzuki T., Kuroda K., Kosugi I., and Kajiura Z., 2023, The potential of a universal influenza virus-like particle vaccine expressing a chimeric cytokine, Life Science Alliance, 6(1). https://doi.org/10.26508/lsa.202201548 PMid:36344085 PMCid:PMC9644419
Journal of Vaccine Research 2024, Vol.14, No.4, 157-169 http://medscipublisher.com/index.php/jvr 168 Ng H.I., Fernando G.J.P., Depelsenaire A.C.I., and Kendall M.A.F., 2016, Potent response of QS-21 as a vaccine adjuvant in the skin when delivered with the Nanopatch, resulted in adjuvant dose sparing, Scientific Reports, 6(1): 29368. https://doi.org/10.1038/srep29368 PMid:27404789 PMCid:PMC4941647 Nguyen Q.T., and Choi Y.K., 2021, Targeting antigens for universal influenza vaccine development, Viruses, 13(6): 973. https://doi.org/10.3390/v13060973 PMid:34073996 PMCid:PMC8225176 Paules C.I., Marston H.D., Eisinger R., Baltimore D., and Fauci A.S., 2017, The pathway to a universal influenza vaccine, Immunity, 47(4): 599-603. https://doi.org/10.1016/j.immuni.2017.09.007 PMid:29045889 Petrie J.G., and Gordon A., 2018, Epidemiological studies to support the development of next generation influenza vaccines, Vaccines, 6(2): 17. https://doi.org/10.3390/vaccines6020017 PMid:29587412 PMCid:PMC6027373 Pica N., and Palese P., 2013, Toward a universal influenza virus vaccine: prospects and challenges, Annual Review of Medicine, 64(1): 189-202. https://doi.org/10.1146/annurev-med-120611-145115 PMid:23327522 Qiu X., Duvvuri V.R., and Bahl J., 2019, Computational approaches and challenges to developing universal influenza vaccines, Vaccines, 7(2): 45. https://doi.org/10.3390/vaccines7020045 PMid:31141933 PMCid:PMC6631137 Sangesland M., and Lingwood D., 2021, Antibody focusing to conserved sites of vulnerability: the immunological pathways for 'universal'influenza vaccines, Vaccines, 9(2): 125. https://doi.org/10.3390/vaccines9020125 PMid:33562627 PMCid:PMC7914524 Sesterhenn F., Yang C., Bonet J., Cramer J.T., Wen X., Wang Y., Chiang C.I., Abriata L.A., Kucharska I., Castoro G., Vollers S.S., Galloux M., Dheilly E., Rosset S., Corthésy P., Georgeon S., Villard M., Richard C.A., Descamps D., Delgado T., Oricchio E., Rameix-Welti M.A., Más V., Ervin S., Eléouët J.F., Riffault S., Bates J.T., Julien J.P., Li Y.X., Jardetzky T., Krey T., and Correia B.E., 2020, De novo protein design enables the precise induction of RSV-neutralizing antibodies, Science, 368(6492): eaay5051. https://doi.org/10.1126/science.aay5051 PMid:32409444 PMCid:PMC7391827 Sharma S., Kumari V., Kumbhar B. V., Mukherjee A., Pandey R., and Kondabagil K., 2021, Immunoinformatics approach for a novel multi-epitope subunit vaccine design against various subtypes of Influenza A virus, Immunobiology, 226(2): 152053. https://doi.org/10.1016/j.imbio.2021.152053 PMid:33517154 Skarlupka A.L., Bebin-Blackwell A.G., Sumner S.F., and Ross T.M., 2021, Universal influenza virus neuraminidase vaccine elicits protective immune responses against human seasonal and pre-pandemic strains, Journal of Virology, 95(17): 10-1128. https://doi.org/10.1128/JVI.00759-21 PMid:34160258 PMCid:PMC8354223 Tao P., Zhu J., Mahalingam M., Batra H., and Rao V.B., 2019, Bacteriophage T4 nanoparticles for vaccine delivery against infectious diseases, Advanced Drug Delivery Reviews, 145: 57-72. https://doi.org/10.1016/j.addr.2018.06.025 PMid:29981801 PMCid:PMC6759415 Tregoning J.S., Russell R.F., and Kinnear E., 2018, Adjuvanted influenza vaccines, Human Vaccines and Immunotherapeutics, 14(3): 550-564. https://doi.org/10.1080/21645515.2017.1415684 PMid:29232151 PMCid:PMC5861793 Viboud C., Gostic K.M., Nelson M.I., Price G., Perofsky A., Sun K., Trovão N.S., Cowling B.J., Epstein S.L., and Spiro D.J., 2020, Beyond clinical trials: Evolutionary and epidemiological considerations for development of a universal influenza vaccine, PLoS Pathogens, 16(9): e1008583. https://doi.org/10.1371/journal.ppat.1008583 PMid:32970783 PMCid:PMC7514029 Wang W.C., Sayedahmed E.E., Sambhara S., and Mittal S.K., 2022, Progress towards the development of a universal influenza vaccine, Viruses, 14(8): 1684. https://doi.org/10.3390/v14081684 PMid:36016306 PMCid:PMC9415875 Wong T.M., and Ross T.M., 2016, Use of computational and recombinant technologies for developing novel influenza vaccines, Expert Review of Vaccines, 15(1): 41-51. https://doi.org/10.1586/14760584.2016.1113877 PMid:26595182 Xu L.H., Feng T.T., and Fang K.Y., 2024, Safety and efficacy of mRNA vaccines: insights from clinical trials, International Journal of Clinical Case Reports, 14(3): 117-131. https://doi.org/10.5376/ijccr.2024.14.0014
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