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Limitations of current influenza vaccines and potential solutions. 

Limitations of current influenza vaccines and potential solutions. 

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Vaccination is the most effective method to prevent influenza infection. However, current influenza vaccines have several limitations. Relatively long production times, limited vaccine capacity, moderate efficacy in certain populations and lack of cross-reactivity are important issues that need to be addressed. We give an overview of the current st...

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... Replication-defective viral vectors are widely used in non-replicating viral vaccination platforms. These are based on a weak strain of [73][74][75] (Fig. 3, Table 1). ...
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Background With the emergence of Corona virus Disease-2019, a novel worldwide health disaster is threatening the population. The WHO declared COVID-19 as a pandemic in December 2019, when it first surfaced in Hunan seafood market in Wuhan, South China, and quickly spread far and wide. Different corona virus variants are currently causing concern all across the world. Main body It has become critical for our scientists to develop a viable method to prevent infection or the pandemic from spreading globally. Antiviral medicines, oxygen therapy, and immune system stimulation are all used to treat the condition. SARS-CoV-2 undergoes mutation and due to evolutionary pressures, different mutant strains caused various symptoms in different geographical regions and the epidemic is spreading and becoming more fragile, posing a greater risk of mortality. Vaccines are tools to increase our immunity as a precaution, and increasing the global immunization rate can help improve the situation. Recent developments in the field of vaccine platforms are discussed here. Short conclusion Vaccines are of highest priority to control and eradicate the viral infectious disease COVID-19 more than any other protective solutions. A number of mutations have occurred and some variants such as alpha, beta, gamma, and delta, and it has now progressed to the new version Omicron, which is a variant of concern. Booster doses are anticipated to function as a barrier to the capacity of the most recent known variety, and more research is needed to determine how effective they will be. This page discusses various technologies employed in the field of COVID-19 vaccine, as well as potential barriers and recent developments in this field.
... As possible reasons for failure, we could mention that: 1. RNA viruses frequently mutate to generate new variants to evade pre-existing immunity; 2. It is hard to make the immune system to react to conserved viral elements; and 3. For ill-defined reasons many people do not develop long-lasting immune memory after infection or vaccination [24][25][26]. SARS-CoV-2 is also an RNA virus, and therefore prone to mutations, though, it was initially thought to mutate at a slightly lower rate than other RNA viruses [27]. Thus, through mutations, it is expected to evade pre-existing immunity sooner or later, especially if we focus the vaccine on a single antigenic target such as the spike protein that is critical for the virus to propagate. ...
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This analysis piece will attempt to examine some of the critical pandemic-related measures implemented in the United States from an immunological perspective and pinpoint caveats that should have been considered before their implementation. I also discuss alternative measures grounded in scientific data that were not thoroughly explored and likely could have helped fight the pandemic.
... Virosomes retain the receptor-binding capability and membrane fusion activity of viral HA but, lacking the viral RNA, they are unable to induce infection in cells after binding. Moreover, this binding capability increases their immunogenicity compared to subunit and split-virion influenza vaccines [108]. Virosomes act as a perfect delivery system, being able to move antigens into the cytosol of antigen-presenting cells (APCs) and induce cytotoxic T lymphocyte (CTL) responses [109]. ...
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Vaccinations are one of the most important preventive tools against infectious diseases. Over time, many different types of vaccines have been developed concerning the antigen component. Adjuvants are essential elements that increase the efficacy of vaccination practises through many different actions, especially acting as carriers, depots, and stimulators of immune responses. For many years, few adjuvants have been included in vaccines, with aluminium salts being the most commonly used adjuvant. However, recent research has focused its attention on many different new compounds with effective adjuvant properties and improved safety. Modern technologies such as nanotechnologies and molecular biology have forcefully entered the production processes of both antigen and adjuvant components, thereby improving vaccine efficacy. Microparticles, emulsions, and immune stimulators are currently in the spotlight for their huge potential in vaccine production. Although studies have reported some potential side effects of vaccine adjuvants such as the recently recognised ASIA syndrome, the huge worth of vaccines remains unquestionable. Indeed, the recent COVID-19 pandemic has highlighted the importance of vaccines, especially in regard to managing future potential pandemics. In this field, research into adjuvants could play a leading role in the production of increasingly effective vaccines.
... Despite surveillance programs, past experiences have highlighted the sheer unpredictability of both seasonal epidemics and pandemic flu events, thus making current flu vaccination approaches vastly inadequate and leaving societies extremely vulnerable. Furthermore, long and complicated production cycles of the flu vaccines with limited production capacity represent another bottleneck that precludes their use in the face of pandemics that demand mass vaccination in a short time frame (8). To address these shortcomings, the development of broadly protective "universal" flu vaccines has been explored (9). ...
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Significance Although the need for a universal influenza vaccine has long been recognized, only a handful of candidates have been identified so far, with even fewer advancing in the clinical pipeline. The 24–amino acid ectodomain of M2 protein (M2e) has been developed over the past two decades. However, M2e-based vaccine candidates have shortcomings, including the need for several administrations and the lack of sustained antibody titers over time. We report here a vaccine targeting strategy that has the potential to confer sustained and strong protection upon a single shot of a small amount of M2e antigen. The current COVID-19 pandemic has highlighted the importance of developing versatile, powerful platforms for the rapid deployment of vaccines against any incoming threat.
... In contrast, live-attenuated vaccines are intranasally administered in some countries. Although liveattenuated vaccines can induce strong mucosal immune responses and cellular immunity, their use is limited to subjects between 2 and 49 years of age and has a risk of genetic reversion into a high pathogenic strain [171]. The second is the antigenic change of the influenza virus [172]. ...
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... The inability to use HPAIV as a seed virus and the difficulty predicting the antigenic shift of AIV indicate the need for new AIV vaccines based on epitopes common to various AIV subtypes and that can provide universal protection. Most universal vaccines currently under development are based on conserved epitopes in in matrix protein 2 (sM2), the stalk domain of HA (HA2), and other AIV structural proteins (12)(13)(14). A recombinant protein composed of both sM2 and HA2 (sM2HA2) has been shown to produce cross-reactive responses (15). ...
... A recombinant protein composed of both sM2 and HA2 (sM2HA2) has been shown to produce cross-reactive responses (15). However, the major limiting factor in the further development of vaccine remains the poor immunogenicity of antigens when administered alone (14,16). ...
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... Currently, the most widely used vaccines against influenza consist of inactivated vaccines, in which the two main surface antigens, hemagglutinin and neuraminidase are purified and enriched (15). To ensure effective protection, these vaccines include multiple virus strains and, in some cases, adjuvants (16). Recently, RNA-based vaccines have emerged as a promising alternative to conventional influenza vaccines, given their streamlined manufacturing and their proven ability to induce potent humoral and cell-mediated responses (17)(18)(19)(20)(21). Preclinical studies investigating the mode of action of a new self-amplifying mRNA (SAM) vaccine technology, recently showed that a SAM vaccine encoding for a H1N1 influenza hemagglutinin (SAM-H1) induced high functional antibody titers and high frequencies of cytotoxic and cytokinepolypositive CD8+ T cells, resulting in cross-protection against heterologous strains (18). ...
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CD8+ T cells play a key role in mediating protective immunity after immune challenges such as infection or vaccination. Several subsets of differentiated CD8+ T cells have been identified, however, a deeper understanding of the molecular mechanism that underlies T-cell differentiation is lacking. Conventional approaches to the study of immune responses are typically limited to the analysis of bulk groups of cells that mask the cells' heterogeneity (RNA-seq, microarray) and to the assessment of a relatively limited number of biomarkers that can be evaluated simultaneously at the population level (flow and mass cytometry). Single-cell analysis, on the other hand, represents a possible alternative that enables a deeper characterization of the underlying cellular heterogeneity. In this study, a murine model was used to characterize immunodominant hemagglutinin (HA533-541)-specific CD8+ T-cell responses to nucleic- and protein-based influenza vaccine candidates, using single-cell sorting followed by transcriptomic analysis. Investigation of single-cell gene expression profiles enabled the discovery of unique subsets of CD8+ T cells that co-expressed cytotoxic genes after vaccination. Moreover, this method enabled the characterization of antigen specific CD8+ T cells that were previously undetected. Single-cell transcriptome profiling has the potential to allow for qualitative discrimination of cells, which could lead to novel insights on biological pathways involved in cellular responses. This approach could be further validated and allow for more informed decision making in preclinical and clinical settings.
... Therefore, regarding nasal gamma-based vaccine development, the use of proper adjuvants may provide a rational approach for increasing vaccine efficacy [9,11]. Of note, vaccine adjuvant incorporation strategy may also be beneficial for decreasing the reactogenicity of whole inactivated Flu viruses by reducing vaccine doses required to achieve sufficient protective immunity [11,12]. ...
... Vaccination has been developing as the most assured strategy of reducing the problems associated with antiviral therapy in patients contending with the influenza virus, particularly of reducing medical expenses [30]. However, the efficacy of current vaccine platforms can be limited by (a) the high prevalence of antigenic variations in the influenza viruses; (b) the lack of cross-protective immunity [12,31]; (c) poor immunogenicity among people with risk factors for infection; and (d) vaccine shortage at pandemic events due to their lengthy production time [12,32,33]. Accordingly, the genesis of a novel, more sophisticated generation of vaccines should be considered [12]. ...
... Vaccination has been developing as the most assured strategy of reducing the problems associated with antiviral therapy in patients contending with the influenza virus, particularly of reducing medical expenses [30]. However, the efficacy of current vaccine platforms can be limited by (a) the high prevalence of antigenic variations in the influenza viruses; (b) the lack of cross-protective immunity [12,31]; (c) poor immunogenicity among people with risk factors for infection; and (d) vaccine shortage at pandemic events due to their lengthy production time [12,32,33]. Accordingly, the genesis of a novel, more sophisticated generation of vaccines should be considered [12]. ...
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Background Several studies on gamma-irradiated influenza A virus (γ-Flu) have revealed its superior efficacy for inducing homologous and heterologous virus-specific immunity. However, many inactivated vaccines, notably in nasal delivery, require adjuvants to increase the quality and magnitude of vaccine responses. Methods To illustrate the impacts of co-administration of the gamma-irradiated H1N1 vaccine with poly (I:C) and recombinant murine CCL21, either alone or in combination with each other, as adjuvants on the vaccine potency, mice were inoculated intranasally 3 times at one-week interval with γ-Flu alone or with any of the three adjuvant combinations and then challenged with a high lethal dose (10 LD50) of A/PR/8/34 (H1N1) influenza virus. Virus-specific humoral, mucosal, and cell-mediated immunity, as well as cytokine profiles in the spleen (IFN-γ, IL-12, and IL-4), and in the lung homogenates (IL-6 and IL-10) were measured by ELISA. The proliferative response of restimulated splenocytes was also determined by MTT assay. Results The findings showed that the co-delivery of the γ-Flu vaccine and CCL21 or Poly (I:C) significantly increased the vaccine immunogenicity compared to the non-adjuvanted vaccine, associated with more potent protection following challenge infection. However, the mice given a combination of CCL21 with poly (I:C) had strong antibody- and cell-mediated immunity, which were considerably higher than responses of mice receiving the γ-Flu vaccine with each adjuvant separately. This combination also reduced inflammatory mediator levels (notably IL-10) in lung homogenate samples. Conclusions The results indicate that adjuvantation with the CCL21 and poly (I:C) can successfully induce vigorous vaccine-mediated protection, suggesting a robust propensity for CCL21 plus poly (I:C) as a potent mucosal adjuvant.
... These adverse effects could result from the impurities in these vaccines, such as egg proteins [86]. However, improved technologies in vaccine production have led to safer vaccines with lower impurities and fewer side effects [87]. In WIV, after the incubation and growth in embryonated eggs, virions are chemically inactivated, mainly with formaldehyde or β-propiolactone, then purified ( Figure 5). ...
... The majority of the currently used influenza vaccines are split-virus or subunit vaccines due to their adequate immunogenicity and ease of production. However, they lose some of the inherent immunogenicity because of the lack of the whole virus structure, unlike WIV [87]. The split-virus vaccine can be prepared by disrupting the virus membrane chemically using surfactants such as Triton-100 or Octyl glycoside [89]. ...
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Influenza remains one of the major public health concerns because it causes annual epidemics and can potentially instigate a global pandemic. Numerous countermeasures, including vaccines and antiviral treatments, are in use against seasonal influenza infection; however, their effectiveness has always been discussed due to the ongoing resistance to antivirals and relatively low and unpredictable efficiency of influenza vaccines compared to other vaccines. The growing interest in vaccines as a promising approach to prevent and control influenza may provide alternative vaccine development options with potentially increased efficiency. In addition to currently available inactivated, live-attenuated, and recombinant influenza vaccines on the market, novel platforms such as virus-like particles (VLPs) and nanoparticles, and new vaccine formulations are presently being explored. These platforms provide the opportunity to design influenza vaccines with improved properties to maximize quality, efficacy, and safety. The influenza vaccine manufacturing process is also moving forward with advancements relating to egg- and cell-based production, purification processes, and studies into the physicochemical attributes and vaccine degradation pathways. These will contribute to the design of more stable, optimized vaccine formulations guided by contemporary analytical testing methods and via the implementation of the latest advances in the field.
... Strategies focused on increasing immunogenicity or the spectrum of antiviral coverage include the use of high doses of vaccine, quadrivalent vaccines, adjuvanted vaccines, and those prepared in cell cultures. The elderly and immunocompromised are those who obtain the greatest benefit from these options [72,[93][94][95][96][97][98][99][100][101][102][103][104][105][106][107]. ...
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Background: Cardiovascular mortality is decreasing but remains the leading cause of death world-wide. Respiratory infections such as influenza significantly contribute to morbidity and mortality in patients with cardiovascular disease. Despite of proven benefits, influenza vaccination is not fully implemented, especially in Latin America. Objective: The aim was to develop a regional consensus with recommendations regarding influenza vaccination and cardiovascular disease. Methods: A multidisciplinary team composed by experts in the management and prevention of cardiovascular disease from the Americas, convened by the Inter-American Society of Cardiology (IASC) and the World Heart Federation (WHF), participated in the process and the formulation of statements. The modified RAND/UCLA methodology was used. This document was supported by a grant from the WHF. Results: An extensive literature search was divided into seven questions, and a total of 23 conclusions and 29 recommendations were achieved. There was no disagreement among experts in the conclusions or recommendations. Conclusions: There is a strong correlation between influenza and cardiovascular events. Influenza vaccination is not only safe and a proven strategy to reduce cardiovascular events, but it is also cost saving. We found several barriers for its global implementation and potential strategies to overcome them.