ETIDIOH - NEW

Abstract Highly pathogenic avian influenza of the H5N1 subtype has shown recent unprecedented expansion in its geographic and host range , increasing the pandemic threat . The younger age of H5N1 versus H7N9 avian influenza in humans has previously been attributed to imprinted pre-immunity to hemagglutinin stalk (HA2) epitopes shared with group 1 ( H1N1, H2N2 ) versus group 2 ( H3N2 ) influenza A subtypes predominating in the human population before versus after 1968, respectively. Here we review the complex immuno-epidemiological interactions underpinning influenza risk assessment and extend the imprinting hypothesis to include a potential role for cross-protective neuraminidase (NA) imprinting . We compare H5N1 distributions and case fatality ratios by age and birth cohort (as proxy for HA2 and/or NA imprinting epoch) not only to H7N9 but also H5N6 and H9N2 avian influenza, representing more varied conditions of zoonotic influenza relatedness to human subtypes of the past century. We...

Abstract Avian H15 influenza viruses are closely related to H7 viruses, but feature a unique 9-amino acid insertion in their hemagglutinin head domain , creating an additional site for antigenic variation . Here, we characterized a panel of mouse monoclonal antibodies (mAbs) raised against the A/wedge-tailed shearwater/Western Australia/2576/1979 ancestral strain , and a human mAb isolated from an H7N9 vaccinee . We found differences in binding and neutralization profiles against the ancestral strain and drifted strains of H15 isolated after 2008. MAbs that have hemagglutination inhibition activity against the ancestral strain do not show binding to drifted strains , hinting at antigenic differences in the receptor binding site . We show that the mAbs protect in vivo and elucidate mAb-antigen interactions using negative stain and cryo-electron microscopy. The characterization of H15 antigenicity and mechanisms of antibody-mediated neutralization expands our knowledge of this rare avian...

Abstract The ongoing spread of highly pathogenic avian influenza H5N1 clade 2.3.4.4b virus in animals and occasional spillover to humans have raised concerns about a potential H5N1 pandemic. Although recent studies have shown that pre-existing human antibodies can recognize H5N1 neuraminidase , there is a lack of molecular understanding of how this cross-reactivity develops. Using a phage display antibody library derived from 245 healthy donors , this study isolates an antibody, known as HB420 , that cross-reacts with the neuraminidases of human H3N2 and avian H5N1 clade 2.3.4.4b viruses and confers protection in vivo. Cryo-EM analysis shows that HB420 targets the neuraminidase active site by mimicking sialic acid binding through a single Asp residue. Additionally, the inferred germline of HB420 is N2-specific but acquires cross-reactivity to H5N1 neuraminidase through somatic hypermutations . Overall, our findings provide insights into how neuraminidase antibody evolves breadth, which...

Abstract Introduction Middle East respiratory syndrome (MERS) is a zoonotic viral respiratory disease caused by the Middle East respiratory syndrome coronavirus (MERS-CoV), associated with severe clinical outcomes and high mortality. Objectives Our study examined the kinetics of anti-MERS-CoV IgM and IgG antibodies during the acute and convalescent phases of infection, focusing on their correlations with clinical variables such as age and viral load. Methods Serum samples were collected from PCR-confirmed MERS-CoV patients (n = 23) during both phases and compared to healthy controls (n = 23) using validated ELISA-based assays. Results IgM levels peaked in the acute phase and declined significantly in the convalescent phase , while IgG levels were sustained and markedly higher during recovery . Correlation analyses revealed positive relationships between antibody levels and patient age (acute IgM: r = 0.56, p < 0.01; convalescent IgG: r = 0.59, p < 0.01) and viral loads (acute IgM...

Abstract Frequent SARS-CoV-2 vaccination in vulnerable populations has raised concerns that this may contribute to T cell exhaustion , which could negatively affect the quality of immune protection. Herein, we examined the impact of repeated SARS-CoV-2 vaccination on T cell phenotypic and functional exhaustion in frail older adults in long-term care (n = 23), individuals on immunosuppressive drugs (n = 10), and healthy adults (n = 43), in Canada . Spike-specific CD4+ and CD8+ T cell levels did not decline in any cohort following repeated SARS-CoV-2 vaccination, nor did the expression of exhaustion markers on spike-specific or total T cells increase. T cell production of multiple cytokines (i.e. polyfunctionality) in response to the spike protein of SARS-CoV-2 did not decline in any cohort following repeated vaccination. None of the cohorts displayed elevated levels of terminally differentiated T cells following multiple SARS-CoV-2 vaccinations. Thus, repeated SARS-CoV-2 vaccination was...

Highlights •  Different immune responses in mice vaccinated with influenza A(H5N1) than with other subtypes. •  Highly pathogenic avian influenza A(H5N1)-vaccinated mice had altered germinal center responses. •  A(H5N1)-vaccinated mice had fewer dLN germinal centers and more extrafollicular B cells. •  A(H5N1)-vaccinated mice had more dLN follicular helper and regulatory T cells. •  Our study represents a timely assessment of A(H5N1) risk to human health. Abstract Highly pathogenic avian influenza (HPAI) H5N1 virus vaccines typically yield lower neutralizing antibody titers in animals than influenza A virus (IAV) vaccines derived from other viral subtypes. To understand these differences, we compared the cellular immune responses in the draining lymph nodes (dLNs) of mice vaccinated with an inactivated whole H5N1 vaccine to those in mice vaccinated with seasonal H1N1pdm09, H7N9, or H9N2 IAV vaccines . H5N1-vaccinated mice exhibited reduced serum neutralizing ant...

ABSTRACT Recent documented infection with an endemic coronavirus (eCoV) is associated with less severe coronavirus disease 2019 (COVID-19), yet the immune mechanism behind this protection has not been fully explored. We measured both antibody and T-cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in SARS-CoV-2- naïve individuals , classified into two groups: those with or without presumed recent eCoV infections . There was no difference in neutralizing antibodies and T-cell responses against SARS-CoV-2 antigens between the two groups. SARS-CoV-2-naïve individuals with recent presumed eCoV infection, however, had higher and significantly correlated levels of Fc receptor (FcR)-binding antibodies against eCoV spikes (S) and SARS-CoV-2 S2. Recent eCoV infection boosts cross-reactive antibodies that can mediate Fc effector functions, and this may play a role in the observed heterotypic immune protection against severe COVID-19. IMPORTANCE With the recent e...

Abstract Infections by influenza A virus (IAV) are a significant cause of global mortality . The pathogenesis of the infection is usually studied in terms of direct viral-induced damage or the overreactive immune response that continues after the virus is cleared. However, factors such as the initial infectious dose , the early response after infection in different cell types, and the presence of autoantibodies for relevant antiviral cytokines like type I IFNs seem to influence the course of the infection and lead to fatal outcomes . In this article, we address the current knowledge about the early events during influenza virus infection, which are important for their participation in influenza-derived pathogenesis. Source: Viruses,  https://www.mdpi.com/1999-4915/17/5/694 ____

Abstract Recent influenza vaccine formulations have improved the magnitude of B-cell antibody responses in older adults ; however, older adults remain significantly at risk for severe influenza-related illness . Although antibodies are an important metric of vaccine effectiveness, they only represent one aspect of the immune response. In this study, we combined in vitro and ex vivo assays with human samples to investigate B, CD4+ T, and myeloid cell responses to influenza vaccine antigens . We found that older adults mounted equivalent antibody titers to younger adults but had fewer influenza-specific CD4+ T cells and reduced antiviral-associated T helper cell populations. Single-cell transcriptomics revealed that older adults had attenuated interferon transcriptional signatures in T helper and myeloid cell subsets . These data suggest that with aging, transcriptional programming alterations in myeloid cells contribute to reduced antiviral T cell responses, and formulating vaccines tai...

Abstract Immunisation remains the most cost-effective mechanism to combat global influenza infection and is widely employed against seasonal influenza viruses. Zoonotic transmission of avian influenza A viruses represents a significant threat to human health given the lack of population level immunity , which could translate into an influenza pandemic . Therefore, there is a need to better understand pre-existing human immunity against avian influenza strains. as highlighted by the recent rapid, global spread of avian H5Nx clade 2.3.4.4b variants. Here, we sought to quantify the frequencies and specificities of B cells recognising avian hemagglutinin (HA) within unexposed adults , and to characterise the ability of seasonal immunisation to boost cross-reactive immune responses to H5Nx strains, including from clade 2.3.4.4b. Low but detectable serum antibody titres against H5 and H7 avian influenza HA were observed in donors. The frequency of memory B cells with cross-reactive recogniti...

Abstract The unprecedented 2.3.4.4b A(H5N1) outbreak in dairy cattle, poultry, and spillover to humans in the United States (US) poses a major public health threat . Population immunity is a critical component of influenza pandemic risk assessment. We conducted a comprehensive assessment of the population immunity to 2.3.4.4b A(H5N1) viruses and analyzed 1794 sera from 723 people (0.5-88 yrs) in multiple US geographic regions during 2021-2024. Low pre-existing neutralizing and hemagglutinin (HA) head binding antibodies and substantial cross reactive binding antibodies to N1 neuraminidase (NA) of 2.3.4.4b A(H5N1) were detected in US population. Antibodies to group 1 HA stalk were also prevalent with an age-related pattern. A( H1N1 )pdm09 infection and influenza vaccination did not induce neutralizing antibodies but induced significant rise of NA inhibition (NAI) antibodies to N1 of 2.3.4.4b A(H5N1), and group 1 HA stalk antibodies. Understanding population susceptibility to novel influe...

Abstract An exhausted antiviral immune response is observed in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-SARS-CoV-2 syndrome , also termed long COVID . In this study, potential mechanisms behind this exhaustion were investigated. First, the viral load of Epstein–Barr virus (EBV), human adenovirus (HAdV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV6), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was determined in sputum samples (n = 29) derived from ME/CFS patients (n = 13), healthy controls (n = 10), elderly healthy controls (n = 4), and immunosuppressed controls (n = 2). Secondly, autoantibodies (autoAbs) to type I interferon (IFN-I) in sputum were analyzed to possibly explain impaired viral immunity. We found that ME/CFS patients released EBV at a significantly higher level compared to controls (p = 0.0256). HHV6 was present in ~50% of all participants at the same level. HAdV was detected in two cases with immunosuppression an...

ABSTRACT The COVID-19 pandemic has greatly enhanced our understanding of CD8+ T cell immunity and their role in natural infection and vaccine-induced protection. Rapid and early SARS-CoV-2- specific CD8+ T cell responses have been associated with efficient viral clearance and mild disease . Virus-specific CD8+ T cell responses can compensate for waning, morbidity-related , and iatrogenic reduction of humoral immunity. After infection or vaccination, SARS-CoV-2-specific memory CD8+ T cells are formed, which mount an efficient recall response in the event of breakthrough infection and help to protect from severe disease. Due to their breadth and ability to target mainly highly conserved epitopes, SARS-CoV-2-specific CD8+ T cells are also able to cross-recognize epitopes of viral variants , thus maintaining immunity even after the emergence of viral evolution. In some cases, however, CD8+ T cells may contribute to the pathogenesis of severe COVID-19. In particular, delayed and uncontrolle...

Abstract In 2020–2021, a “mysterious illness” struck Senegalese fishermen , causing severe acute dermatitis in over one thousand individuals following exposure through drift-net fishing activity . Here, by performing deep analysis of the environmental samples we reveal the presence of the marine dinoflagellate Vulcanodinium rugosum and its associated cyclic imine toxins . Specifically, we show that the toxin PortimineA, strongly enriched in environmental samples, impedes ribosome function in human keratinocytes , which subsequently activates the stress kinases ZAKα and P38 and promotes the nucleation of the human NLRP1 inflammasome, leading to the release of IL-1β/IL-18 pro-inflammatory cytokines and cell death . Furthermore, cell-based models highlight that naturally occurring mutations in the P38-targeted sites of human NLRP1 are unable to respond to PortimineA exposure. Finally, the development and use of human organotypic skins and zebrafish models of PortimineA exposure demonstrat...

Abstract The emergence of highly pathogenic avian influenza A(H5N1) virus in dairy cattle herds across the United States in 2024 caused several human infections . Understanding the risk for spillover infections into humans is crucial for protecting public health. We investigated whether immunity from influenza A(H1N1)pdm09 (pH1N1) virus would provide protection from death and severe clinical disease among ferrets intranasally infected with H5N1 virus from dairy cows from the 2024 outbreak. We observed differential tissue tropism among pH1N1-immune ferrets. pH1N1-immune ferrets also had little H5N1 viral dissemination to organs outside the respiratory tract and much less H5N1 virus in nasal secretions and the respiratory tract than naive ferrets. In addition, ferrets with pH1N1 immunity produced antibodies that cross-reacted with H5N1 neuraminidase protein. Taken together, our results suggest that humans with immunity to human seasonal influenza viruses may experience milder disease fro...

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly evolved over short timescales, leading to the emergence of more transmissible variants such as Alpha and Delta.  The arrival of the Omicron variant marked a major shift, introducing numerous extra mutations in the spike gene compared with earlier variants. These evolutionary changes have raised concerns regarding their potential impact on immune evasion, disease severity and the effectiveness of vaccines and treatments. In this epidemiological study, we identified two distinct patterns in the protective effect of natural infection against reinfection in the Omicron versus pre-Omicron eras. Before Omicron, natural infection provided strong and durable protection against reinfection, with minimal waning over time. However, during the Omicron era, protection was robust only for those recently infected , declining rapidly over time and diminishing within a year. These results demonstrate that SARS-CoV...

Abstract Early investigation revealed a reduced risk of SARS-CoV-2 infection among social contacts of COVID-19 vaccinated individuals, referred to as indirect protection. However, indirect protection from SARS-CoV-2 infection-acquired immunity and its comparative strength and durability to vaccine-derived indirect protection in the current epidemiologic context of high levels of vaccination, prior infection, and novel variants are not well characterized. Here, we show that both vaccine-derived and infection-acquired immunity independently yield indirect protection to close social contacts with key differences in their strength and waning. Analyzing anonymized SARS-CoV-2 surveillance data from 9,625 residents in California state prisons from December 2021 to December 2022, we find that vaccine-derived indirect protection against Omicron SARS-CoV-2 infection is strongest within three months of COVID-19 vaccination [30% (95% confidence interval: 20–38%)] with subsequent modest protection....

Abstract The repeated spill-over of Influenza A virus H5N1 clade 2.3.4.4b from cattle to humans highlights the risk of a human H5N1 pandemic . Given the impact of pre-existing immunity on the course and severity of viral infections , we assessed in detail the humoral immunity against the H5N1 A/Texas/37/2024 isolate in H5N1-naive individuals . To this end, we performed complementary binding and neutralization assays on 66 subjects and ranked activities among a panel of 76 influenza A virus isolates . We detected low but distinct cross-neutralizing titers against A/Texas/37/2024 with a 3.9 to 15.6-fold reduction compared to selected H1N1 or H3N2 strains. Moreover, by cloning and evaluating 136 monoclonal antibodies from single memory B cells , we identified potent A/Texas/37/2024-neutralizing monoclonal antibodies in five out of six investigated individuals. These antibodies predominantly utilize VH1-69 gene segments, cross-neutralize H1, and compete with antibodies targeting the HA ste...

Abstract In a patient on immunosuppressant treatment , SARS-CoV-2 RNA was documented in different extra-respiratory samples over several months in the absence of positive determinations in upper respiratory samples . Whole -genome sequencing of these samples showed the acquisition of different single-nucleotide polymorphisms over time, suggesting viral evolution and thus viral viability. Source: Viruses,  https://www.mdpi.com/1999-4915/17/2/147 _____

Abstract Influenza vaccine effectiveness and immunogenicity can be compromised with repeated vaccination . We assessed immunological markers in a cohort of healthcare workers (HCW) from six public hospitals around Australia during 2020–2021. Sera were collected pre-vaccination and ~14 and ~180 days post-vaccination and assessed in haemagglutination inhibition assay against egg-grown vaccine and equivalent cell-grown viruses. Responses to vaccination were compared by the number of prior vaccinations. Baseline sera were available for 595 HCW in 2020 and 1031 in 2021. 5% had not been vaccinated during five years prior to enrolment and 55% had been vaccinated every year. Post-vaccination titres for all vaccine antigens were lowest among HCW vaccinated in all 5-prior years and highest among HCW with 0 or 1 prior vaccinations , even after adjustment. This was observed for both influenza A subtypes and was dependent on pre-vaccination titre. Expanded cohorts are needed to better understand ho...