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Neuraminidase of influenza A and B viruses plays a critical role in the virus life cycle and is an important target of the host immune system. Here, we highlight the current understanding of influenza neuraminidase structure, function, antigenicity, immunogenicity, and immune protective potential. Neuraminidase inhibiting antibodies have been recog...
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Context 1
... the inhibition profile of NAI mAbs based on the outcome of both types of assays will thus give an indication on their possible binding site. Table 1 provides an overview of different NA-specific mAbs and their impact on NA activity as determined with a small molecule substrate or in the ELLA. Overall, two different antigenic regions have been described that characterize NAI antibodies: (i) the catalytic site and its rim and (ii) outside of the catalytic site, including the interface between two adjacent monomers. ...Similar publications
Influenza A virus poses a serious threat to human health, causing more than 650,000 deaths annually. While flu vaccines are effective in preventing infection, high rates of antigenic changes of the virus often give rise to vaccine escape mutants. Therefore, a universal vaccine that is effective against different influenza strains will produce broad...
Citations
... Previous vaccines have primarily focused on targeting well-characterized proteins found on the surface of the virus [7]. For instance, the influenza vaccine targets hemagglutinin, a key surface protein, while the measles vaccine targets the measles virus envelope protein. ...
... This is one of the key differences in the correlation between previous vaccines and the vaccine. Another difference lies in the diverse approaches taken in developing the COVID-19 vaccine [7,10]. Vaccine developers had to employ innovative strategies, such as using adenovirus vectors or mRNA technology, due to the urgent need and novel aspects of the virus, which is unlike the more traditional approaches used in the past. ...
Aim
This study aimed to determine the reasons for reluctance to get vaccinated against COVID-19 in the general population in the south of Kerman Province.
Background
Identifying factors that reduce the initial hesitancy towards vaccination and increase the acceptance of the vaccine in the general population can contribute to the ongoing efforts for vaccination against COVID-19.
Materials and Methods
This is a cross-sectional study (descriptive and analytical) that was conducted using a multistage multi-stage sampling method on 341 men and women aged 18 to 85 living in the south of Kerman province in 2021. The data were collected using an electronic questionnaire created by the researcher on the reasons for reluctance to be vaccinated with COVID-19 and analyzed using SPSS-22 software. Independent t-tests, analysis of variance, Kruskal-Wallis, and chi-square tests were used at a significance level of less than 0.05.
Results
Three hundred and forty men and women aged 18 to 85 were examined. Lack of trust in vaccines, government, and health officials were the most frequent reasons for not wanting to get vaccinated. The young age group, women, single people, and those with good economic level, and high education level, were less willing to get vaccinated against COVID-19.
Conclusion
Restoring public trust in public health agencies, pharmaceutical companies, and science while also addressing the complexities of the relationship between the public and government is essential for effectively addressing vaccine hesitancy and increasing vaccine uptake.
... On one hand, many monoclonal antibodies (mAbs) that targeting either the catalytic site or lateral surface as well as the underside of NA protein have been discovered (reviewed in [111,112]). For example, the mAb CD6 binds to a conserved 30-amino-acid spanning epitope on the lateral face of a NA dimer [113]. ...
... All these mAbs inhibit NA activity in enzyme-linked lectin assay (ELLA) with large substrates (e.g. Fetuin), while only the mAbs that are targeting the catalytic site inhibit NA activity in small substrate (MUNANA or NA-STAR) assays [111]. ...
Introduction
Anti-neuraminidase (NA) immunity correlates with the protection against influenza virus infection in both human and animal models. The aim of this review is to better understand the mechanism of anti-NA immunity, and also to evaluate the approaches on developing NA-based influenza vaccines or enhancing immune responses against NA for current influenza vaccines.
Areas covered
In this review, the structure of influenza neuraminidase, the contribution of anti-NA immunity to protection, as well as the efforts and challenges of targeting the immune responses to NA were discussed. We also listed some of the newly discovered anti-NA monoclonal antibodies and discussed their contribution in therapeutic as well as the antigen design of a broadly protective NA vaccine.
Expert opinion
Targeting the immune response to both HA and NA may be critical for achieving the optimal protection since there are different mechanisms of HA and NA elicited protective immunity. Monoclonal antibodies (mAbs) that target the conserved protective lateral face or catalytic sites are effective therapeutics. The epitope discovery using monoclonal antibodies may benefit NA-based vaccine elicited broadly reactive antibody responses. Therefore, the potential for a vaccine that elicits cross-reactive antibodies against neuraminidase is a high priority for next-generation influenza vaccines.
... The three largest segments encode viral RNAdependent RNA polymerases (segments PB1, PB2 and PA), which are responsible for the replication of the viral genome in host cells. Other segments are the nucleoprotein (NP), the matrix protein (M1) and the membrane protein (M2), the nonstructural protein (NS1), the nuclear export protein (NEP) and two segments encoding glycoproteins that envelop the virus, namely haemagglutinin (HA) [1] and neuraminidase (NA) [2]. These two segments play the most important role in the life cycle of the virus, as HA is responsible for binding to cell surface receptors and entering the cell [3], while NA provides the release of new viral particles [2,4]. ...
... Other segments are the nucleoprotein (NP), the matrix protein (M1) and the membrane protein (M2), the nonstructural protein (NS1), the nuclear export protein (NEP) and two segments encoding glycoproteins that envelop the virus, namely haemagglutinin (HA) [1] and neuraminidase (NA) [2]. These two segments play the most important role in the life cycle of the virus, as HA is responsible for binding to cell surface receptors and entering the cell [3], while NA provides the release of new viral particles [2,4]. HA and NA are the most variable antigenically. ...
... If several different IAV strains infect the same host, the genomes of these strains can reorganize and form a new strain. Antigenic shift and antigenic drift together ensure the evolution of influenza viruses, which complicates the development of vaccines and still makes influenza research relevant today [2,3]. ...
Influenza A viruses (IAVs) pose a serious threat to global health. On the one hand, these viruses cause seasonal flu outbreaks in humans. On the other hand, they are a zoonotic infection that has the potential to cause a pandemic. The most important natural reservoir of IAVs are waterfowl. In this study, we investigated the occurrence of IAV in birds in the Republic of Buryatia (region in Russia). In 2020, a total of 3018 fecal samples were collected from wild migratory birds near Lake Baikal. Of these samples, 11 were found to be positive for the H13N8 subtype and whole-genome sequencing was performed on them. All samples contained the same virus with the designation A/Unknown/Buryatia/Arangatui-1/2020. To our knowledge, virus A/Unknown/Buryatia/Arangatui-1/2020 is the first representative of the H13N8 subtype collected on the territory of Russia, the sequence of which is available in the GenBank database. An analysis of reassortments based on the genome sequences of other known viruses has shown that A/Unknown/Buryatia/Arangatui-1/2020 arose as a result of reassortment. In addition, a reassortment most likely occurred several decades ago between the ancestors of the viruses recently collected in China, the Netherlands, the United States and Chile. The presence of such reassortment emphasizes the ongoing evolution of the H13N8 viruses distributed in Europe, North and East Asia, North and South America and Australia. This study underscores the importance of the continued surveillance and research of less-studied influenza subtypes.
... NA is also theorized to cleave decoy receptors in mucus, facilitating infection of underlying epithelial cells. 5 The full quaternary structure of NA is reported. 6 The protein is composed of four identical monomers forming a complex tetrameric structure described as a "mushroomshaped tetramer with circular symmetry." ...
... Several epidemiological and preclinical studies have been conducted and recently reviewed. 5 However, rNA candidate vaccines have yet to be appropriately tested in the clinic. ...
Current influenza vaccines could be augmented by including recombinant neuraminidase (rNA) protein antigen to broaden protective immunity and improve efficacy. Toward this goal, we investigated formulation conditions to optimize rNA physicochemical stability. When rNA in sodium phosphate saline buffer (NaPBS) was frozen and thawed (F/T), the tetrameric structure transitioned from a “closed” to an “open” conformation, negatively impacting functional activity. Hydrogen deuterium exchange experiments identified differences in anchorage binding sites at the base of the open tetramer, offering a structural mechanistic explanation for the change in conformation and decreased functional activity. Change to the open configuration was triggered by the combined stresses of acidic pH and F/T. The desired closed conformation was preserved in a potassium phosphate buffer (KP), minimizing pH drop upon freezing and including 10% sucrose to control F/T stress. Stability was further evaluated in thermal stress studies where changes in conformation were readily detected by ELISA and size exclusion chromatography (SEC). Both tests were suitable indicators of stability and antigenicity and considered potential critical quality attributes (pCQAs). To understand longer-term stability, the pCQA profiles from thermally stressed rNA at 6 months were modeled to predict stability of at least 24-months at 5°C storage. In summary, a desired rNA closed tetramer was maintained by formulation selection and monitoring of pCQAs to produce a stable rNA vaccine candidate. The study highlights the importance of understanding and controlling vaccine protein structural and functional integrity.
... It has long been known to play a role in facilitating the export of viral ribonucleoprotein complexes, and since it is not entirely nonstructural, the designation NEP is more fitting [29]. However, even with small amounts of NEP present in virions, the NS gene as a whole is believed to be under much less selective pressure than genes coding for prominent surface proteins, such as HA and NA, as these are primary targets for neutralizing antibodies of the host immune system [30], resulting in a strong pressure towards immune evasion by antigenic change. We focus on the NS gene precisely because it is only subject to weak selective pressures, and can thus be regarded as undergoing largely neutral genetic drift for long periods of time. ...
Leveraging the simplicity of raw nucleotide distances, we provide an intuitive window into the evolution of the human influenza A `nonstructural' (NS) gene. In an analysis suggested by the eminent Danish biologist Freddy B. Christiansen, we illustrate the existence of a continuous genetic ``backbone'' of influenza A NS genes, steadily increasing in distance to the 1918 root over more than a century. Interestingly, the 2009 influenza pandemic represents a clear departure from this enduring genetic backbone. Utilizing nucleotide distance maps and phylogenetic analyses, we illustrate remaining uncertainties regarding the origin of the 2009 pandemic, highlighting the complexity of influenza evolution. The NS gene is interesting precisely because it experiences neutral genetic drift over long periods of time time, while sudden deviations from this drift pattern can indicate changes in other genes via the hitchhiking effect. Our approach employs two measures based on genotypic distance - the rooted temporal Hamming map and the unrooted temporal Hamming distribution - to analyze the evolutionary dynamics of the NS gene. The rooted Hamming map elucidates distances between a reference sequence and all other sequences over time. In contrast, the unrooted temporal Hamming distribution captures the distribution of genotypic distances between simultaneously circulating viruses, thereby revealing patterns of sequence diversity and epi-evolutionary dynamics. Our study aims to supplement traditional tree-based phylogenetic inference with these direct temporal distance-based measures, offering transparent insights into the evolution of the influenza NS gene.
... One approach to increase the breadth of protection with an influenza vaccine is by delivering HA and NA together in a vaccine [32]. The DNA platform potentially allows for the co-administration of multiple antigens in a single injection, but there is a potential that the expression and immune response to one antigen might dominate over another. ...
Influenza virus represents a challenge for traditional vaccine approaches due to its seasonal changes and potential for zoonotic transmission. Nucleic acid vaccines can overcome some of these challenges, especially through the inclusion of multiple antigens to increase breadth of response. RNA vaccines were an important part of the response to the COVID-19 pandemic, but for future outbreaks DNA vaccines may have some advantages in terms of stability and manufacturing cost that warrant continuing investigation to fully realise their potential. Here we investigate influenza virus vaccines made using a closed loop linear DNA platform, Doggybone™ DNA (dbDNA), produced by a rapid and scalable cell-free method. Influenza vaccines have mostly focussed on Haemagglutinin (HA), but the inclusion of Neuraminidase (NA) may provide additional protection. Here we explored the potential of including NA in a dbDNA vaccine, looking at DNA optimisation, mechanism and breadth of protection. We showed that DNA targeting sequences (DTS) improved immune responses against HA but not NA. We explored whether NA vaccine induced protection against influenza virus infection was cell mediated but depletion of CD8 and NK cells made no impact, suggesting it was antibody mediated. This is reflected in restriction of protection only homologous strains of influenza virus. Importantly, we saw that including both HA and NA in a single combined vaccine did not dampen the immune response to either one. Overall, we show that linear dbDNA can induce an immune response against NA which may offer increased protection in instances of HA mismatch where NA remains more conserved.
... In conclusion, it should be said that studying the immunogenicity of NA in seasonal vaccines will help to improve the effectiveness of influenza vaccination. This can be facilitated by studying the properties of NA when selecting candidates for vaccine strains, standardizing the content of NA in vaccine preparations, and optimizing the manufacturing process to preserve the antigenic structure of NA [49]. Adding a known quantity of conformationally correct NA to current seasonal vaccines may improve efficacy and, potentially, cross-reactivity against drifted strains of influenza [16]. ...
Neuraminidase (NA)-based immunity could reduce the harmful impact of novel antigenic variants of influenza viruses. The detection of neuraminidase-inhibiting (NI) antibodies in parallel with anti-hemagglutinin (HA) antibodies may enhance research on the immunogenicity and duration of antibody responses to influenza vaccines. To assess anti-NA antibodies after vaccination with seasonal inactivated influenza vaccines, we used the enzyme-linked lectin assay, and anti-HA antibodies were detected in the hemagglutination inhibition assay. The dynamics of the anti-NA antibody response differed depending on the virus subtype: antibodies to A/H3N2 virus neuraminidase increased later than antibodies to A/H1N1pdm09 subtype neuraminidase and persisted longer. In contrast to HA antibodies, the fold increase in antibody titers to NA after vaccination poorly depended on the preexisting level. At the same time, NA antibody levels after vaccination directly correlated with titers before vaccination. A difference was found in response to NA antigen between split and subunit-adjuvanted vaccines and in NA functional activity in the vaccine formulations.
... 此外, 稳定 表达甲病毒结构蛋白细胞系的建立可以简化VRP包装 流程, 有利于大规模生产 [43] . [89] . saRNA流感病毒疫苗设 计主要以甲病毒属VEEV复制子或改良的VEEV-SINV 复制子 [90] 为载体表达HA抗原或NA抗原, 制备成单价 或多价流感疫苗. ...
... The NA has a critical role in the virus life cycle, and is an important target of the host immune system [59]. Despite significant HA sequence variation between IAV subtypes [60], the catalytic site residues in NAs are highly conserved [61]. Studies have shown that supplementing influenza vaccines with NA can result in a clear reduction in pulmonary virus titer challenged with a mismatched HA [61][62][63]. ...
... Despite significant HA sequence variation between IAV subtypes [60], the catalytic site residues in NAs are highly conserved [61]. Studies have shown that supplementing influenza vaccines with NA can result in a clear reduction in pulmonary virus titer challenged with a mismatched HA [61][62][63]. Exploring NA in or as vaccines for children and toddlers is worthwhile as that strategy may broaden the immune response and improve protection against drifted or emerging strains, and potentially complement HA-based influenza vaccine strategies including as mRNA vaccines. ...
Introduction:
Influenza virus changes its genotype through antigenic drift or shift making it difficult to develop immunity to infection or vaccination. Zoonotic influenza A virus (IAV) strains can become established in humans. Several impediments to human infection and transmission include sialic acid expression, host anti-viral factors (including interferons), and other elements that govern viral replication. Controlling influenza infection, replication, and transmission is important because IAVs cause annual epidemics and occasional pandemics. Effective seasonal influenza vaccines exist, but these vaccines do not fully protect against novel or pandemic strains.
Areas covered:
With new vaccine production technology, vaccines can be produced rapidly. Universal IAV vaccines are being developed to protect against seasonal, novel, and zoonotic IAVs. These efforts are being enhanced and accelerated by a better understanding the host immune response to influenza viruses.
Expert opinion:
This review discusses several implications for future influenza vaccine development. Host immune responses to influenza virus infection or vaccination can guide vaccine development as anti-influenza immunity is affected by responses influenced by the previous immune history including first and subsequent exposures to influenza virus infections and vaccinations.
... Studies show that the enhancement of fusion and infectivity by NA was related to the sialylation of virion-expressed HA, so NA activity plays a critical role in virion infectivity and HA-mediated membrane fusion [56]. On the other hand, the influenza replication cycle needs to release the least newly formed virions from the infected cell and prevent virion aggregation by removing sialic acid from the viral and host cell membrane [57]. Currently, many NA inhibitors are discovered by structure-activity relationship, and these inhibitors fight against the surge in resistance resulting from naturally occurring mutations. ...
Influenza A viruses cause severe respiratory illnesses in humans and animals. Overreaction of the innate immune response to influenza virus infection results in hypercytokinemia, which is responsible for mortality and morbidity. The influenza A virus surface glycoprotein neuraminidase (NA) plays a vital role in viral attachment, entry, and virion release from infected cells. NA acts as a sialidase, which cleaves sialic acids from cell surface proteins and carbohydrate side chains on nascent virions. Here, we review progress in understanding the role of NA in modulating host immune response to influenza virus infection. We also discuss recent exciting findings targeting NA protein to interrupt influenza-induced immune injury.
