BACKGROUND: The continuing emergence of influenza virus has highlighted the value of public databases and related bioinformatic analysis tools in investigating transcriptomic change caused by different influenza virus infections in human and animal models.
METHODS: We collected a large amount of transcriptome research data related to influenza virus-infected human and animal models in public databases (GEO and ArrayExpress), and extracted and integrated array and metadata. The gene expression matrix was generated through strictly quality control, balance, standardization, batch correction, and gene annotation. We then analyzed gene expression in different species, virus, cells/tissues or after antibody/vaccine treatment and imported sample metadata and gene expression datasets into the database.
RESULTS: Overall, maintaining careful processing and quality control, we collected 8064 samples from 103 independent datasets, and constructed a comparative transcriptomics database of influenza virus named the Flu-CED database (Influenza comparative expression database, https://flu.com-med.org.cn/). Using integrated and processed transcriptomic data, we established a user-friendly website for realizing the integration, online retrieval, visualization, and exploration of gene expression of influenza virus infection in different species and the biological functions involved in differential genes. Flu-CED can quickly query single and multi-gene expression profiles, combining different experimental conditions for comparative transcriptome analysis, identifying differentially expressed genes (DEGs) between comparison groups, and conveniently finding DEGs.
CONCLUSIONS: Flu-CED provides data resources and tools for analyzing gene expression in human and animal models infected with influenza virus that can deepen our understanding of the mechanisms underlying disease occurrence and development, and enable prediction of key genes or therapeutic targets that can be used for medical research.

Influenza virus has presented a considerable healthcare challenge during the past years, particularly in vulnerable groups with compromised immune systems. Therapeutics and vaccination have always been in research annals since the spread of influenza. Efforts have been going on to develop an antiviral therapeutic approach that could assist in better disease management and reduce the overall disease complexity, resistance development, and fatality rates. On the other hand, vaccination presents a chance for effective, long-term, cost-benefit, and preventive response against the morbidity and mortality associated with the influenza. However, the issues of resistance development, strain mutation, antigenic variability, and inability to cure wide-spectrum and large-scale strains of the virus by available vaccines remain there. The article gathers the updated data for the therapeutics and available influenza vaccines, their mechanism of action, shortcomings, and trials under clinical experimentation. A methodological approach has been adopted to identify the prospective therapeutics and available vaccines approved and within the clinical trials against the influenza virus. Review contains influenza therapeutics, including traditional and novel antiviral drugs and inhibitor therapies against influenza virus as well as research trials based on newer drug combinations and latest technologies such as nanotechnology and organic and plant-based natural products. Most recent development of influenza vaccine has been discussed including some updates on traditional vaccination protocols and discussion on next-generation and upgraded novel technologies. This review will help the readers to understand the righteous approach for dealing with influenza virus infection and for deducing futuristic approaches for novel therapeutic and vaccine trials against Influenza.

Severely immunodeficient mice are useful for understanding the pathogenesis of certain tumors and for developing therapeutic agents for such tumors. In addition, engraftment of these mice with human hematopoietic cells can yield information that helps us understand the in vivo molecular mechanisms underlying actual human viral infections. In our present research, we discovered a novel, severely immunodeficient strain of mice having a mutation in exon 57 of the Prkdc gene (PrkdcΔex57/Δex57) in an inbred colony of B10.S/SgSlc mice. Those PrkdcΔex57/Δex57 mice showed thymic hypoplasia and lack of mature T cells and B cells in peripheral lymphoid tissues, resulting in very low levels of production of serum immunoglobulins. In addition, those mice were highly susceptible to influenza viruses due to the lack of acquired immune cells. On the other hand, since they had sufficient numbers of NK cells, they rejected tumor transplants, similarly to Prkdc+/+ mice. Next, we generated Foxn1nu/nuPrkdcΔex57/Δex57Il2rg-/- (NPG) mice on the BALB/cSlc background, which lack all lymphocytes such as T cells, B cells and innate lymphoid cells, including NK cells. As expected, these mice were able to undergo engraftment of human tumor cell lines. These findings suggest that PrkdcΔex57/Δex57 mice will be useful as a novel model of immunodeficiency, while NPG mice will be useful for xenografting of various malignancies.

BACKGROUND: Allergic asthma, one of the most common types of asthma, is thought to be highly susceptible to respiratory viral infections; however, its pathological mechanism needs to be elucidated. Recent studies have found impaired T-cell function in asthmatic mice. Therefore, we aimed to investigate the way by which asthma induction affects T-cell exhaustion in the lungs and assess the relationship between T-cell exhaustion and influenza viral infection.
METHODS: Chronic allergic asthma mice were induced by intranasal injection of ovalbumin for 6 weeks and asthmatic features and T cell populations in lung or airway were assessed. To determine the influenza virus susceptibility, control and asthma mice were challenged with the human influenza virus strain A/Puerto Rico/8/1934 H1N1 and evaluated the survival rate, lung damage, and virus titer.
RESULTS: Six weeks of OVA sensitization and challenge successfully induced chronic allergic asthma in a mouse model showing significant increase of sera IgE level and broncho-pathological features. A significant decrease in interferon-γ-producing T-cell populations and an increase in exhausted T-cell populations in the lungs of OVA-induced asthmatic mice were observed. Asthmatic mice were more susceptible to influenza virus infection than control mice showing lower survival rate and higher virus titer in lung, and a positive correlation existed between T-cell exhaustion in the lung and virus titer.
CONCLUSIONS: Asthma induction in mice results in the exhaustion of T-cell immunity, which may contribute to the defective capacity of viral protection. This study demonstrates a correlation between asthma conditions and viral susceptibility by investigating the functional characteristics of T-cells in asthma. Our results provide insights into the development of strategies to overcome the dangers of respiratory viral disease in patients with asthma.

We measured the association between history of influenza vaccination by age 2 years and influenza virus (IFV) infection at ages 3 and 4 years by relative risk reduction. We also examined the association between history of IFV infection by age 2 years and recurrent IFV infection at age 3 years. This study included 73,666 children from a large Japanese birth cohort. Among children vaccinated never, once or twice when aged under 2 years, 16.0%, 10.8% and 11.3%, respectively, had been infected with IFV by age 3 years, and 19.2%, 14.5% and 16.0%, respectively, by age 4 years. Compared with no history of influenza vaccination, vaccination at ages 1 and/or 2 years reduced the risk of IFV infection at age 3 by 30%-32% and at age 4 by 17%-24%. The relative risk of recurrent IFV infection at ages 3 and 4 years increased in proportion to the number of prior infections by age 2. One-season-prior influenza vaccination history reduced the IFV infection risk at age 3 years by 25%-42%. Influenza vaccination most effectively protected children at age 3 who lacked older sibling(s) and did not attend nursery school. One-season-prior IFV infection increased the relative risk of recurrent infection at age 3 years (1.72-3.33). In conclusion, influenza vaccination-induced protection may partly extend to the next season. Owing to the relative risk reduction by influenza vaccination and the increased relative risk of IFV infection from prior-season infection, annual influenza vaccination is recommended.

We estimated symptomatic and asymptomatic influenza infection frequency in community-dwelling unvaccinated pregnant persons to inform risk communication.
We collected residue sera from multiple antenatal-care blood draws during October 2016-April 2017. We determined influenza infection as seroconversion with ≥ 4-fold rise in antibody titers between any two serum samples by improved hemagglutinin-inhibition assay including ether-treated B antigens. The serology data were linked to the results of nuclei acid testing (rRT-PCR) based on acute respiratory illness (ARI) surveillance.
Among all participants, 43 %(602/1384) demonstrated serology and/or rRT-PCR evidenced infection, and 44 %(265/602) of all infections were asymptomatic. ARI-associated rRT-PCR testing identified only 10 %(61/602) of total infections. Only 1 %(5/420) of the B Victoria cases reported ARI and had a rRT-PCR positive result, compared with 33 %(54/165) of the H3N2 cases. Among influenza ARI cases with multiple serum samples, 19 %(11/58) had seroconversion to a different subtype prior to the illness.
The incidence of influenza B infection in unvaccinated pregnant persons is under-estimated substantially. Non-pharmaceutical intervention may have suboptimal effectiveness in preventing influenza B transmission due to the less clinical manifestation compared to influenza A. The findings support maternal influenza vaccination to protect pregnant persons and reduce consequent household transmission.

Systemically vaccinated individuals against COVID-19 and influenza may continue to support viral replication and shedding in the upper airways, contributing to the spread of infections. Thus, a vaccine regimen that enhances mucosal immunity in the respiratory mucosa is needed to prevent a pandemic. Intranasal/pulmonary (IN) vaccines can promote mucosal immunity by promoting IgA secretion at the infection site. Here, we demonstrate that an intramuscular (IM) priming-IN boosting regimen with an inactivated influenza A virus adjuvanted with the liposomal dual TLR4/7 adjuvant (Fos47) enhances systemic and local/mucosal immunity. The IN boosting with Fos47 (IN-Fos47) enhanced antigen-specific IgA secretion in the upper and lower respiratory tracts compared to the IM boosting with Fos47 (IM-Fos47). The secreted IgA induced by IN-Fos47 was also cross-reactive to multiple influenza virus strains. Antigen-specific tissue-resident memory T cells in the lung were increased after IN boosting with Fos47, indicating that IN-Fos47 established tissue-resident T cells. Furthermore, IN-Fos47 induced systemic cross-reactive IgG antibody titers comparable to those of IM-Fos47. Neither local nor systemic reactogenicity or adverse effects were observed after IN delivery of Fos47. Collectively, these results indicate that the IM/IN regimen with Fos47 is safe and provides both local and systemic anti-influenza immune responses.

Influenza-like illness (ILI) can be caused by a range of respiratory viruses. The present study investigates the contribution of influenza and other respiratory viruses, the occurrence of viral co-infections, and the persistence of the viruses after ILI onset in older adults. During the influenza season 2014-2015, 2366 generally healthy community-dwelling older adults (≥60 years) were enrolled in the study. Viruses were identified by multiplex ligation-dependent probe-amplification assay in naso- and oropharyngeal swabs taken during acute ILI phase, and 2 and 8 weeks later. The ILI incidence was 10.7%, which did not differ between vaccinated and unvaccinated older adults; influenza virus was the most frequently detected virus (39.4%). Other viruses with significant contribution were: rhinovirus (17.3%), seasonal coronavirus (9.8%), respiratory syncytial virus (6.7%), and human metapneumovirus (6.3%). Co-infections of influenza virus with other viruses were rare. The frequency of ILI cases in older adults in this 2014-2015 season with low vaccine effectiveness was comparable to that of the 2012-2013 season with moderate vaccine efficacy. The low rate of viral co-infections observed, especially for influenza virus, suggests that influenza virus infection reduces the risk of simultaneous infection with other viruses. Viral persistence or viral co-infections did not affect the clinical outcome of ILI.

The altered immune response in aged hosts play a vital role in contributing to their increased morbidity and mortality during respiratory virus infections. The aged hosts display impaired antiviral immune response as well as increased risk for long-term pulmonary sequelae post virus clearance. However, the underlying cellular and molecular mechanisms driving these alterations of the immune compartment have not been fully elucidated. During the era of COVID-19 pandemic, a better understanding of such aspects is urgently needed to provide insight that will benefit the geriatric patient care in prevention as well as treatment. Here, we review the current knowledge about the unique immune characteristics of aged hosts during homeostasis and respiratory virus infections.

BACKGROUND: Pharmacoeconomic studies have been less performed in Japan. The objective of this study was to clarify which neuraminidase inhibitor (NI; oseltamivir, zanamivir, laninamivir, and peramivir) is most cost-effective in an adult outpatient setting in Japan.
OBJECTIVE: To clarify which neuraminidase inhibitor (NI; oseltamivir, zanamivir, laninamivir, and peramivir) is most cost-effective in an adult outpatient setting in Japan.
METHODS: Cost-effectiveness analysis was constructed from the healthcare payer\'s perspective. A decision tree model was constructed with probabilities from relevant randomized controlled trials. Costs included medical costs and drug prices. Medical costs were obtained from the medical fee schedule table (2016 version). We also applied authorized medication costs. Outcomes of effectiveness were measured using EQ-5D-3L questionnaires for adult patients who had experienced influenza virus infections previously. Time horizon was 14 days in this study.
RESULTS: Cost-effectiveness ratios for oseltamivir, zanamivir, laninamivir, and peramivir were 393 674 Yen/quality-adjusted life year (QALY; US$3883.41/QALY), 408 241 (US$4027.10), 407 980 (US$4024.53), and 444 264 (US$4382.45), respectively. The cost-effectiveness analysis base-case analysis revealed oseltamivir as the most cost-effective NI. Zanamivir was dominated. Incremental cost effectiveness ratio (ICER) for laninamivir and peramivir were 1 129 459 Yen/QALY (US$11 141.58/QALY) and 1 287 118 (US$12 696.81), respectively. One-way sensitivity analyses revealed that minimum ICERs for laninamivir based on \"quality of life (QOL) values (95% confidence interval)\" was -596 850 Yen/QALY (US-$5887.64/QALY) owing to high cost and less effective. Also, maximum ICER for peramivir based on\"QOL values\" was 14 717 518 Yen/QALY (US$145 181.32/QALY); a value more than the 5 000 000 Yen/QALY threshold.
CONCLUSIONS: The study results reveal oseltamivir as the most cost-effective NI for the treatment of influenza virus infection in an adult outpatient setting. Our findings may provide decision makers with scientific evidence for clinical and economic evaluation to achieve optimal therapeutic outcomes.