In this study, we pioneered an alternative technology for manufacturing subunit influenza hemagglutinin (HA)-based vaccines. This innovative method involves harnessing the pupae of the Lepidoptera Trichoplusia ni (T. ni) as natural biofactories in combination with baculovirus vectors (using CrisBio® technology). We engineered recombinant baculoviruses encoding two versions of the HA protein (trimeric or monomeric) derived from a pandemic avian H7N1 virus A strain (A/chicken/Italy/5093/99). These were then used to infect T. ni pupae, resulting in the production of the desired recombinant antigens. The obtained HA proteins were purified using affinity chromatography, consistently yielding approximately 75 mg/L of insect extract. The vaccine antigen effectively immunized poultry, which were subsequently challenged with a virulent H7N1 avian influenza virus. Following infection, all vaccinated animals survived without displaying any clinical symptoms, while none of the mock-vaccinated control animals survived. The CrisBio®-derived antigens induced high titers of HA-specific antibodies in the vaccinated poultry, demonstrating hemagglutination inhibition activity against avian H7N1 and human H7N9 viruses. These results suggest that the CrisBio® technology platform has the potential to address major industry challenges associated with producing recombinant influenza subunit vaccines, such as enhancing production yields, scalability, and the speed of development, facilitating the global deployment of highly effective influenza vaccines.

Influenza pandemics pose a serious risk to the global population, with the potential for high morbidity and mortality. An adjuvanted H5N1 vaccine (aH5N1) has been approved for prophylaxis against the avian influenza virus H5N1, which is a likely cause of future pandemics. In this phase-III, stratified, randomized, controlled, observer-blind, multicenter study, we evaluated the safety and immunogenicity of aH5N1 in four separate groups of adults: adults 18-60 years of age who were healthy or had high-risk medical conditions and older adults ≥61 years of age who were healthy or had high-risk medical conditions. Subjects were randomly assigned to aH5N1 or the comparator, adjuvanted trivalent seasonal influenza vaccine (aTIV). Antibody responses to aH5N1 were increased in all four subgroups and, within each age stratum, largely consistent between healthy subjects and those with medical conditions. Injection-site pain was reported by 66-73% of younger and 36-42% of older-aH5N1 recipients, and fatigue and myalgia were reported by 22-41% of subjects across age and health subgroups. No serious adverse events or deaths were considered related to the study vaccine. In conclusion, aH5N1 increased antibody responses regardless of age or health status and demonstrated a clinically acceptable safety and tolerability profile.

Influenzavirus is among the most relevant candidates for a next pandemic. We review here the phylogeny of former influenza pandemics, and discuss candidate lineages. After briefly reviewing the other existing antiviral options, we discuss in detail the evidences supporting the efficacy of passive immunotherapies against influenzavirus, with a focus on convalescent plasma.

Since the 1990s, endemic North American swine influenza A viruses (swFLUAVs) contained an internal gene segment constellation, the triple reassortment internal gene (TRIG) cassette. In 2009, the H1N1 pandemic (pdmH1N1) virus spilled back into swine but did not become endemic. However, the pdmH1N1 contributed the matrix gene (pdmM) to the swFLUAVs circulating in the pig population, which replaced the classical swine matrix gene (swM) found in the TRIG cassette, suggesting the pdmM has a fitness benefit. Others have shown that swFLUAVs containing the pdmM have greater transmission efficiency compared to viruses containing the swM gene segment. We hypothesized that the matrix (M) gene could also affect disease and utilized two infection models, resistant BALB/c and susceptible DBA/2 mice, to assess pathogenicity. We infected BALB/c and DBA/2 mice with H1 and H3 swFLUAVs containing the swM or pdmM and measured lung virus titers, morbidity, mortality, and lung histopathology. H1 influenza strains containing the pdmM gene caused greater morbidity and mortality in resistant and susceptible murine strains, while H3 swFLUAVs caused no clinical disease. However, both H1 and H3 swFLUAVs containing the pdmM replicated to higher viral titers in the lungs and pdmM containing H1 viruses induced greater histological changes compared to swM H1 viruses. While the surface glycoproteins and other gene segments may contribute to swFLUAV pathogenicity in mice, these data suggest that the origin of the matrix gene also contributes to pathogenicity of swFLUAV in mice, although we must be cautious in translating these conclusions to their natural host, swine.
OBJECTIVE: The 2009 pandemic H1N1 virus rapidly spilled back into North American swine, reassorting with the already genetically diverse swFLUAVs. Notably, the M gene segment quickly replaced the classical M gene segment, suggesting a fitness benefit. Here, using two murine models of infection, we demonstrate that swFLUAV isolates containing the pandemic H1N1 origin M gene caused increased disease compared to isolates containing the classical swine M gene. These results suggest that, in addition to other influenza virus gene segments, the swFLUAV M gene segment contributes to pathogenesis in mammals.

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Although the most recent respiratory virus pandemic was triggered by a Coronavirus, sustained and elevated prevalence of highly pathogenic avian influenza viruses able to infect mammalian hosts highlight the continued threat of pandemics of influenza A virus (IAV) to global health. Retrospective analysis of pandemic outcomes, including comparative investigation of intervention efficacy in different regions, provide important contributions to the evidence base for future pandemic planning. The swine-origin IAV pandemic of 2009 exhibited regional variation in onset, infection dynamics and annual infection attack rates (IARs). For example, the UK experienced three severe peaks of infection over two influenza seasons, whilst Australia experienced a single severe wave. We adopt a seasonally forced 2-subtype model for the transmission of pH1N12009 and seasonal H3N2 to examine the role vaccination campaigns may play in explaining differences in pandemic trajectories in temperate regions. Our model differentiates between the nature of vaccine- and infection-acquired immunity. In particular, we assume that immunity triggered by infection elicits heterologous cross-protection against viral shedding in addition to long-lasting neutralising antibody, whereas vaccination induces imperfect reduction in susceptibility. We employ an Approximate Bayesian Computation (ABC) framework to calibrate the model using data for pH1N12009 seroprevalence, relative subtype dominance, and annual IARs for Australia and the UK. Heterologous cross-protection substantially suppressed the pandemic IAR over the posterior, with the strength of protection against onward transmission inversely correlated with the initial reproduction number. We show that IAV pandemic timing relative to the usual seasonal influenza cycle influenced the size of the initial waves of pH1N12009 in temperate regions and the impact of vaccination campaigns.

UNASSIGNED: The dramatic global impact of the coronavirus pandemic has increased consideration on epidemiological progressions of pandemics. Measures implemented to reduce viral transmission have been largely historical, comparable in nature with the 1918 and 2009 influenza pandemics, demonstrating the importance of clinicians\' awareness on historical pandemics. Despite this, literature suggests medical students\' knowledge on previous pandemics is poor.
UNASSIGNED: This study aims to gather stakeholder information from UK medical students on the importance of including the history of pandemics in the medical school curriculum.
UNASSIGNED: A cross-sectional cohort study conducted via a mixed question type online survey was distributed to all UK medical schools to explore stakeholder views. Grounded theory emergent coding was used to generate themes to free-text answers and SPSS and Excel were used to analyse quantitative data using pivot tables and Fishers exact tests.
UNASSIGNED: Two hundred and forty-one students consented to take part from eight medical schools in the UK with 98% of these students completing the questionnaire. 34% of students reported having teaching on pandemics with 78% of students stating it would be beneficial. Knowledge was poor with 5.7% of students achieving 100% on knowledge-based questions. 72% of students believed that learning about the history of medicine would be beneficial with 87% of these students referring to \'benefiting (the) future\' in their answers. Additionally, 79% of students thought it would be beneficial to learn about historical pandemics with reference to the current COVID-19 pandemic.
UNASSIGNED: To date, this is the only UK based study assessing stakeholders\' views on including the history of pandemics in the medical school curriculum. Our findings demonstrate that medical students wish to have more historical content included in their degree to better prepare tomorrow\'s doctors for situations that may occur when history repeats itself.

Considering the large number of individuals who have already been infected and may have reinfection, the post-infection effects of COVID-19 are of great importance for clinical practice and predicting disease trends. However, our understanding of the potential long-term effects, particularly on immunity, after recovering from COVID-19 remains limited. The aim of this study was to investigate the abnormal immunological factors that contribute to the prolonged immunological effects of COVID-19. Two groups of patients were enrolled in the study, including 11 individuals with various autoimmune diseases (AIDs) and 16 patients diagnosed with systemic lupus erythematosus (SLE). Detailed clinical symptoms were closely monitored, and peripheral mononuclear cells were analyzed using flow cytometry. The clinical status was evaluated using the SLE Disease Activity Index (SLEDAI) and the Clinical Global Impressions (CGI) index. The proportions of follicular T helper cells (Tfh) exhibited significant increases in both cohorts (AID: p = 0.03; SLE: p = 0.0008). Conversely, the percentages of Foxp3+ and CD4+ regulatory T cells (Treg) were reduced in patients following COVID-19 infection (AID: p = 0.009, 0.05, resp.; SLE: p = 0.02, 0.0009, resp.). The percentages of Th2 and Th17 cells were significantly increased in SLE patients (p < 0.05). Exacerbated conditions were observed in SLE patients two months after infection (SLEDAI, p < 0.05). Our findings show that COVID-19 infection increases Tfh cells and decreases Treg cells in patients of AIDs, worsening pathogenetic immune status in post-recovery populations.

Avian influenza (AI) virus detections occurred frequently in 2022 and continue to pose a health, economic, and food security risk. The most recent global analysis of official reports of animal outbreaks and human infections with all reportable AI viruses was published almost a decade ago. Increased or renewed reports of AI viruses, especially high pathogenicity H5N8 and H5N1 in birds and H5N1, H5N8, and H5N6 in humans globally, have established the need for a comprehensive review of current global AI virus surveillance data to assess the pandemic risk of AI viruses.
This study aims to provide an analysis of global AI animal outbreak and human case surveillance information from the last decade by describing the circulating virus subtypes, regions and temporal trends in reporting, and country characteristics associated with AI virus outbreak reporting in animals; surveillance and reporting gaps for animals and humans are identified.
We analyzed AI virus infection reports among animals and humans submitted to animal and public health authorities from January 2013 to June 2022 and compared them with reports from January 2005 to December 2012. A multivariable regression analysis was used to evaluate associations between variables of interest and reported AI virus animal outbreaks.
From 2013 to 2022, 52.2% (95/182) of World Organisation for Animal Health (WOAH) Member Countries identified 34 AI virus subtypes during 21,249 outbreaks. The most frequently reported subtypes were high pathogenicity AI H5N1 (10,079/21,249, 47.43%) and H5N8 (6722/21,249, 31.63%). A total of 10 high pathogenicity AI and 6 low pathogenicity AI virus subtypes were reported to the WOAH for the first time during 2013-2022. AI outbreaks in animals occurred in 26 more Member Countries than reported in the previous 8 years. Decreasing World Bank income classification was significantly associated with decreases in reported AI outbreaks (P<.001-.02). Between January 2013 and June 2022, 17/194 (8.8%) World Health Organization (WHO) Member States reported 2000 human AI virus infections of 10 virus subtypes. H7N9 (1568/2000, 78.40%) and H5N1 (254/2000, 12.70%) viruses accounted for the most human infections. As many as 8 of these 17 Member States did not report a human case prior to 2013. Of 1953 human cases with available information, 74.81% (n=1461) had a known animal exposure before onset of illness. The median time from illness onset to the notification posted on the WHO event information site was 15 days (IQR 9-30 days; mean 24 days). Seasonality patterns of animal outbreaks and human infections with AI viruses were very similar, occurred year-round, and peaked during November through May.
Our analysis suggests that AI outbreaks are more frequently reported and geographically widespread than in the past. Global surveillance gaps include inconsistent reporting from all regions and human infection reporting delays. Continued monitoring for AI virus outbreaks in animals and human infections with AI viruses is crucial for pandemic preparedness.

The numerous influenza infections that occur every year present a major public health problem. Influenza vaccines are important for the prevention of the disease; however, their effectiveness against infection can be suboptimal. Particularly in the elderly, immune induction can be insufficient, and the vaccine efficacy against infection is usually lower than that in young adults. Vaccine efficacy can be improved by the addition of adjuvants, and an influenza vaccine with an oil-in-water adjuvant MF59, FLUAD, has been recently licensed in the United States and other countries for persons aged 65 years and older. Although the adverse effects of adjuvanted vaccines have been a concern, many adverse effects of currently approved adjuvanted influenza vaccines are mild and acceptable, given the overriding benefits of the vaccine. Since sufficient immunity can be induced with a small amount of vaccine antigen in the presence of an adjuvant, adjuvanted vaccines promote dose sparing and the prompt preparation of vaccines for pandemic influenza. Adjuvants not only enhance the immune response to antigens but can also be effective against antigenically different viruses. In this narrative review, we provide an overview of influenza vaccines, both past and present, before presenting a discussion of adjuvanted influenza vaccines and their future.