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Immunosenescence contributes to reduced vaccine response in elderly persons, and is worsened by deficiencies in nutrients such as Vitamin (Vit-D). The immune system is a well-known target of Vit-D, which can both potentiate the innate immune response and inhibit the adaptive system, and so modulate vaccination response. This randomized placebo-controlled double-blind trial investigated whether Vit-D supplementation in deficient elderly persons could improve influenza seroprotection and immune response. Deficient volunteers (Vit-D serum <30 ng/mL) were assigned (V1) to receive either 100,000 IU/15 days of cholecalciferol (D, = 19), or a placebo (P, = 19), over a 3 month period. Influenza vaccination was performed at the end of this period (V2), and the vaccine response was evaluated 28 days later (V3). At each visit, serum cathelicidin, immune response to vaccination, plasma cytokines, lymphocyte phenotyping, and phagocyte ROS production were assessed. Levels of serum 25-(OH)D increased after supplementation (D group, V1 vs. V2: 20.7 ± 5.7 vs. 44.3 ± 8.6 ng/mL, < 0.001). No difference was observed for serum cathelicidin levels, antibody titers, and ROS production in D vs. P groups at V3. Lower plasma levels of TNFα ( = 0.040) and IL-6 ( = 0.046), and higher ones for TFGβ ( = 0.0028) were observed at V3. The Th1/Th2 ratio was lower in the D group at V2 (D: 0.12 ± 0.05 vs. P: 0.18 ± 0.05, = 0.039). Vit-D supplementation promotes a higher TGFβ plasma level in response to influenza vaccination without improving antibody production. This supplementation seems to direct the lymphocyte polarization toward a tolerogenic immune response. A deeper characterization of metabolic and molecular pathways of these observations will aid in the understanding of Vit-D's effects on cell-mediated immunity in aging. This clinical trial was registered at clinicaltrials.gov as NCT01893385.

Baloxavir marboxil (BXM) demonstrated a rapid and profound decline in infectious viral titer 1 day after BXM administration. Rapid reduction in virus titer is a characteristic of BXM. There may be a possibility that drug carryover effects have impacts on the observed antiviral effects due to the poor correlation that was observed between viral titer reduction and alleviation of influenza symptoms. Here, we report possible carryover effects of baloxavir acid (BXA), an active form of BXM, on infectious titer testing. Our findings indicate that there is little impact of BXA carryover on the infectious titer testing.

Influenza virus and coronavirus, belonging to enveloped RNA viruses, are major causes of human respiratory diseases. The aim of this study was to investigate the broad spectrum antiviral activity of a naturally existing sulfated polysaccharide, lambda-carrageenan (λ-CGN), purified from marine red algae. Cell culture-based assays revealed that the macromolecule efficiently inhibited both influenza A and B viruses with EC 50 values ranging from 0.3 to 1.4 μg/ml, as well as currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with an EC 50 value of 0.9 ± 1.1 μg/ml. No toxicity to the host cells was observed at concentrations up to 300 μg/ml. Plaque titration and western blot analysis verified that λ-CGN reduced expression of viral proteins in cell lysates and suppressed progeny virus production in culture supernatants in a dose-dependent manner. This polyanionic compound exerts antiviral activity by targeting viral attachment to cell surface receptors and preventing virus entry. Moreover, its intranasal administration to mice during influenza A viral challenge not only alleviated infection-mediated reductions in body weight but also protected 60% of mice from virus-induced mortality. Thus, λ-CGN could be a promising antiviral agent for preventing infection with several respiratory viruses.

Recent studies have demonstrated that inactivated seasonal influenza vaccines (IIV) may elicit production of heterosubtypic antibodies, which can neutralize avian H5N1 virus in a small proportion of subjects. We hypothesized that prime boost regimens of live and inactivated trivalent seasonal influenza vaccines (LAIV and IIV) would enhance production of heterosubtypic immunity and provide evidence of cross-protection against other influenza viruses. In an open-label study, 26 adult volunteers were randomized to receive one of four vaccine regimens containing two doses of 2009-10 seasonal influenza vaccines administered 8 (±1) weeks apart: 2 doses of LAIV; 2 doses of IIV; LAIV then IIV; IIV then LAIV. Humoral immunity assays for avian H5N1, 2009 pandemic H1N1 (pH1N1), and seasonal vaccine strains were performed on blood collected pre-vaccine and 2 and 4 weeks later. The percentage of cytokine-producing T-cells was compared with baseline 14 days after each dose. Subjects receiving IIV had prompt serological responses to vaccine strains. Two subjects receiving heterologous prime boost regimens had enhanced haemagglutination inhibition (HI) and neutralization (NT) titres against pH1N1, and one subject against avian H5N1; all three had pre-existing cross-reactive antibodies detected at baseline. Significantly elevated titres to H5N1 and pH1N1 by neuraminidase inhibition (NI) assay were observed following LAIV-IIV administration. Both vaccines elicited cross-reactive CD4+ T-cell responses to nucleoprotein of avian H5N1 and pH1N1. All regimens were safe and well tolerated. Neither homologous nor heterologous prime boost immunization enhanced serum HI and NT titres to 2009 pH1N1 or avian H5N1 compared to single dose vaccine. However heterologous prime-boost vaccination did lead to in vitro evidence of cross-reactivity by NI; the significance of this finding is unclear. These data support the strategy of administering single dose trivalent seasonal influenza vaccine at the outset of an influenza pandemic while a specific vaccine is being developed. ClinicalTrials.gov NCT01044095.

Key Points High-resolution structures have recently revealed the subunit and domain organization of the influenza A, influenza B and influenza C virus RNA polymerases. The polymerase basic 1 (PB1) subunit together with the C-terminal domain of polymerase acidic (PA) and the N-terminal one-third of PB2 form the core of the polymerase, which is decorated by several flexible domains, including the PB2 cap-binding and PA endonuclease domains. Crystal structures obtained in the absence and presence of viral genomic RNA have captured the influenza virus RNA polymerase in transcriptionally inactive and transcription pre-initiation states, showing a different arrangement of the peripheral PB2 cap-binding and PA endonuclease domains and suggesting a mechanism for the activation of the cap-snatching function of the polymerase. Structural and biochemical analyses have identified the binding sites of the 5′ and 3′ termini of viral RNAs, the template entry and exit channels, the substrate entry and product exit channels, the polymerase active site and a priming loop. Based on the high-resolution structural information about the influenza virus RNA polymerases, the models for viral transcription and genome replication have been revised. Viral and host factors participate in the regulation of viral transcription and genome replication. However, in many cases, the underlying molecular mechanisms remain unknown. Understanding how the influenza virus RNA synthesis machine works at the molecular level and knowledge of its interaction with viral and host factors might lead to the identification of targets that could be exploited for the development of antivirals to prevent or treat influenza virus infections. In this Review, te Velthuis and Fodor detail the recently obtained high-resolution structures of the influenza virus RNA polymerase and the insights that have been gained into the mechanisms of viral transcription and replication. They also discuss how these structural data could help to identify novel antiviral targets. The genomes of influenza viruses consist of multiple segments of single-stranded negative-sense RNA. Each of these segments is bound by the heterotrimeric viral RNA-dependent RNA polymerase and multiple copies of nucleoprotein, which form viral ribonucleoprotein (vRNP) complexes. It is in the context of these vRNPs that the viral RNA polymerase carries out transcription of viral genes and replication of the viral RNA genome. In this Review, we discuss our current knowledge of the structure of the influenza virus RNA polymerase, and insights that have been gained into the molecular mechanisms of viral transcription and replication, and their regulation by viral and host factors. Furthermore, we discuss how advances in our understanding of the structure and function of polymerases could help in identifying new antiviral targets.

The Respiratory Infections in Andean Peruvian Children (RESPIRA-PERU) study enrolled children who participated in a community-cluster randomized trial of improved stoves, solar water disinfection, and kitchen sinks (IHIP trial) and children from additional Andean households. We quantified the burden of influenza-associated acute respiratory illness (ARI) in this household-based cohort. From May 2009 to September 2011, we conducted active weekly ARI surveillance in 892 children age <3 years, of whom 272 (30.5%) had participated in the IHIP trial. We collected nasal swabs during ARI, tested for influenza and other respiratory viruses by RT-PCR, and determined influenza incidence and risk factors using mixed-effects regression models. The overall incidence of influenza-associated ARI was 36.6/100 child-years; incidence of influenza A, B, and C was 20.5, 8.7, and 5.2/100 child-years, respectively. Influenza C was associated with fewer days of subjective fever (median 1 vs. 2) and malaise (median 0 vs. 2) compared to influenza A. Non-influenza ARI also resulted in fewer days of fever and malaise, and fewer healthcare visits than influenza A-associated ARI. Influenza incidence varied by calendar year (80% occurred in the 2010 season) and IHIP trial participation. Among households that participated in the IHIP trial, influenza-associated ARI incidence was significantly lower in intervention than in control households (RR 0.40, 95% CI: 0.20-0.82). Influenza burden is high among Andean children. ARI associated with influenza A and B had longer symptom duration and higher healthcare utilization than influenza C-associated ARI or non-influenza ARI. Environmental community interventions may reduce influenza morbidity.

Humoral immunity is necessary for controlling viral infection. Ballesteros-Tato and colleagues show that development of follicular regulatory T cells is prevented by high concentrations of interleukin 2 at the peak of viral infection, but resumes at later time points to suppress autoantibody production. Interleukin 2 (IL-2) promotes Foxp3 + regulatory T (T reg ) cell responses, but inhibits T follicular helper (T FH ) cell development. However, it is not clear how IL-2 affects T follicular regulatory (T FR ) cells, a cell type with properties of both T reg and T FH cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented T FR cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some T reg cells downregulated CD25, upregulated Bcl-6 and differentiated into T FR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional T reg cells, IL-2 inhibits T FR cell responses.

Coronavirus disease 2019 (COVID-19) was detected in China during the 2019–2020 seasonal influenza epidemic. Non-pharmaceutical interventions (NPIs) and behavioral changes to mitigate COVID-19 could have affected transmission dynamics of influenza and other respiratory diseases. By comparing 2019–2020 seasonal influenza activity through March 29, 2020 with the 2011–2019 seasons, we found that COVID-19 outbreaks and related NPIs may have reduced influenza in Southern and Northern China and the United States by 79.2% (lower and upper bounds: 48.8%–87.2%), 79.4% (44.9%–87.4%) and 67.2% (11.5%–80.5%). Decreases in influenza virus infection were also associated with the timing of NPIs. Without COVID-19 NPIs, influenza activity in China and the United States would likely have remained high during the 2019–2020 season. Our findings provide evidence that NPIs can partially mitigate seasonal and, potentially, pandemic influenza. Non-pharmaceutical interventions (NPIs) implemented to interrupt COVID-19 transmission may also impact the spread of other infectious diseases. Here, the authors estimate that influenza activity in China and the United States reduced by up to 80% when NPIs were in place in the 2019–2020 season.

Nonpharmaceutical interventions (NPIs) have been employed to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), yet these measures are already having similar effects on other directly transmitted, endemic diseases. Disruptions to the seasonal transmission patterns of these diseases may have consequences for the timing and severity of future outbreaks. Here we consider the implications of SARS-CoV-2 NPIs for two endemic infections circulating in the United States of America: respiratory syncytial virus (RSV) and seasonal influenza. Using laboratory surveillance data from 2020, we estimate that RSV transmission declined by at least 20% in the United States at the start of the NPI period. We simulate future trajectories of both RSV and influenza, using an epidemic model. As susceptibility increases over the NPI period, we find that substantial outbreaks of RSV may occur in future years, with peak outbreaks likely occurring in the winter of 2021–2022. Longer NPIs, in general, lead to larger future outbreaks although they may display complex interactions with baseline seasonality. Results for influenza broadly echo this picture, but are more uncertain; future outbreaks are likely dependent on the transmissibility and evolutionary dynamics of circulating strains.

We compared indicators of influenza activity in 2020 before and after public health measures were taken to reduce coronavirus disease (COVID-19) with the corresponding indicators from 3 preceding years. Influenza activity declined substantially, suggesting that the measures taken for COVID-19 were effective in reducing spread of other viral respiratory diseases.