Friday, March 21, 2025

Crucial role for #iron #metabolism in mediating #influenza A virus #infection and associated disease

Abstract

Rationale and Objectives

Iron availability and metabolism are important in the pathogenesis of bacterial infections. More recently, links have been reported between iron and the severity of viral infections. In this study, we characterize a crucial relationship between iron metabolism and IAV infection and disease. 

Methods

Iron-related gene expression was assessed in human airway epithelial cells (AEC) infected with IAV. AECs were cultured with ferric iron, iron-loaded transferrin, or iron chelator, deferoxamine (DFO), prior to infection with IAV. Mice were placed on a high iron diet for 8 weeks prior to infection with IAV or treated with anti-transferrin receptor-1 (TFR1) antibody during IAV infection. The effects of iron modulation and depletion of TFR1-mediated responses on IAV infection were assessed. 

Measurements and main results

Iron-related gene expression and metabolism are altered systemically and in lung tissues and AECs during IAV infections. Increasing iron availability increases viral titer in AECs, while DFO protects against iron-induced increased susceptibility to infection. Increasing systemic iron loading, which increases iron levels in the lung, increases viral titer, proinflammatory responses, airway inflammation, and worsens IAV-induced disease in terms of lung function and weight loss in vivo. Inhibition of TFR1 protects against IAV-induced disease in vivo. 

Conclusion

IAV infections remain a major threat to human health and global economies. Strategies that boost protective, or reduce pathogenic, host responses may provide broadly effective, long-term therapeutic options. We have identified a key role for iron metabolism in modifying host responses to IAV that can be harnessed to protect against disease.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.03.20.644262v1

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#USA, Monitoring for Avian #Influenza #H5 Virus In #Wastewater {week 11-25}



{Excerpt}

Time Period: March 09 - March 15, 2025

-- H5 Detection12 sites (2.7%)

-- No Detection431 sites (97.3%)

-- No samples in last week177 sites




(...)

Source: US Centers for Disease Control and Prevention, https://www.cdc.gov/bird-flu/h5-monitoring/index.html

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#UK - High pathogenicity avian #influenza #H5N1 viruses (#poultry) (Inf. with) - Immediate notification

{Highland Scotland} Flock of 23 chickens and 4 goose. Increased mortality reported. Samples taken were found positive for HPAI H5N1.

Source: WOAH, https://wahis.woah.org/#/in-review/6357

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Analysis on #epidemiological characteristics of #influenza and #genetic characteristics of influenza virus in 2023-2024 surveillance year in #Shandong Province

Abstract

Objective

To analyze the epidemiological, etiological and genetic characteristics of influenza virus in Shandong Province during 2023-2024. 

Methods

The surveillance data of influenza-like illness (ILI) in sentinel hospitals in Shandong from 2023 to 2024 were collected and analyzed. The isolated influenza strains with hemagglutination titers ≥8 were selected for antigenicity analysis, drug susceptibility test, gene sequencing and evolutionary analysis

Results

From 2023 to 2024, the positive rate of influenza virus in Shandong was 8.51% (23 663/277 995), the highest positive rate was in the age group of 5-14 years (15.78%, 6 073/38 478), and the highest positive rate was in the 49th week (35.86%, 2 264/6 313). Both antigenicity analysis and evolutionary analysis showed that the A(H1N1)pdm09 subtype and B(Victoria) strain had good matching effect and close evolutionary distance with the 2023-2024 surveillance year vaccine strain. The A(H3N2) subtype strain did not have a high matching effect with the 2023-2024 vaccine strain and had a long evolutionary distance, but had a close evolutionary distance with the 2024-2025 vaccine strain. Drug susceptibility test showed that oseltamivir sensitivity of influenza A(H1N1)pdm09 strain decreased greatly, and the amino acid site mutation of neuraminidase was H275Y

Conclusions

In the 2023-2024 surveillance year, the peak of influenza virus epidemic in Shandong was mainly occurred in winter and spring, and the age group of 5-14 years was the focus of prevention and control. The dominant strain was subtype A(H3N2), which had poor matching effect with the vaccine strain in the 2023-2024 surveillance year. One A(H1N1)pdm09 resistant strain was found in the drug resistance monitoring work. Follow-up prevention and control work should be strengthen the surveillance for the epidemiological characteristics, genetic variation and drug resistance of influenza viruses, timely understand the epidemic trend and mutation of influenza viruses, timely discover drug-resistant strains of influenza viruses, promote influenza vaccination, and improve of influenza prevention and control.

Source: US National Library of Medicine, https://pubmed.ncbi.nlm.nih.gov/40113394/

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Thursday, March 20, 2025

St. Helena - #Influenza A #H5N1 viruses of high pathogenicity (Inf. with) (non-poultry including wild birds) (2017-) - Immediate notification

On 12th September 2024, a dead Tristan (Brown) Skua (Stercorarius antarcticus hamiltoni) was found at the Gough Island helipad. The following day, a live skua was observed showing suspicious signs of HPAI, including head drooping, lethargy and weakness, and was later reported dead. Between the 12th and 15th September, a total of four skuas were found dead from suspicious causes. Three carcasses were swabbed on the 20th of September and all were confirmed POSITIVE for H5N1 HPAIV by the Animal and Plant Health Agency (Weybridge laboratory) in the UK on the 24th of October 2024. On the day of sampling, the fourth carcass could not be found and was probably taken away by a scavenging skua. Since then, no further signs of HPAI among skuas or in other seabirds breeding on Gough Island, have been observed.

Source: WOAH, https://wahis.woah.org/#/in-review/6354

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Post-pandemic #changes in #population #immunity have reduced the likelihood of emergence of #zoonotic #coronaviruses

Abstract

Infections caused by endemic viruses, and the vaccines used to control them, often provide cross-protection against related viruses. This cross-protection has the potential to alter the transmission dynamics and likelihood of emergence of novel zoonotic viruses with pandemic potential. Here, we investigate how changes in population immunity after the COVID-19 pandemic have impacted the likelihood of emergence of a novel sarbecovirus, termed SARS-CoV-X. We show that sera from patients with different COVID-19 immunological histories possess cross-neutralising antibodies against the spike (S) protein of multiple zoonotic sarbecoviruses. Mathematical simulations using these viruses show a significant reduction in their likelihood of emergence in populations with current levels of SARS-CoV-2 natural and vaccine-derived immunity, with the outcome determined by the extent of cross-protection and the R_0 of the novel virus. We also show that preventative vaccination programs against SARS-CoV-X using currently available COVID-19 vaccines can help resist emergence even in the presence of co-circulating SARS-CoV-2. However, it was possible for a theoretical vaccine with very high specificity to SARS-CoV-2 (i.e., one which elicits very low cross-protection against SARS-CoV-X) to increase the likelihood of SARS-CoV-X emergence, due to its effects on SARS-CoV-2 prevalence and, by extension, the levels of naturally-derived cross-protection in the human population. Overall, our findings show that SARS-CoV-2 circulation and COVID-19 vaccination have generated widespread population immunity against antigenically related sarbecoviruses, and this new immunological barrier is likely to be a strong determinant of the ability of novel sarbecoviruses to emerge in humans.

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2025.03.17.25323820v1

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#Validation of #H5 #influenza virus subtyping #RTqPCR #assay and low prevalence of H5 #detection in 2024-2025 influenza virus season

Abstract

A sustained outbreak of H5N1 influenza virus among wild fowl and domestic livestock has caused more than 70 zoonotic infections in humans in the United States, including one death. The Centers for Disease Control and Prevention has recommended rapid H5 subtyping for all hospitalized cases with influenza A virus infection to enable prompt initiation of antiviral treatment, as well as infection prevention and implementation of public health measures to control spread. To address these needs, we developed a multiplex RT-qPCR assay to subtype H5 influenza virus in nasal, nasopharyngeal, and conjunctival specimens with a limit of detection of 230 copies/mL. No cross-reactivity was observed with other common respiratory viruses, including seasonal H3N2 and H1N1 influenza A viruses. We retrospectively subtyped 590 influenza A-positive clinical specimens processed by University of Washington labs between March 2024 and February 2025, including 512 specimens collected during the 2024-2025 influenza season, and detected no H5 positives. After clinical implementation, we performed 85 clinically ordered H5 subtyping tests in February 2025 and again detected no positives. This work enhances clinical pandemic preparedness activities and highlights the exceedingly low prevalence of H5N1 influenza virus during the 2024-2025 respiratory season.

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2025.03.17.25324122v1

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The #epidemiology of #pathogens with #pandemic potential: A review of key parameters and clustering analysis

Abstract

Introduction 

In the light of the COVID-19 pandemic many countries are trying to widen their pandemic planning from its traditional focus on influenza. However, it is impossible to draw up detailed plans for every pathogen with epidemic potential. We set out to try to simplify this process by reviewing the epidemiology of a range of pathogens with pandemic potential and seeing whether they fall into groups with shared epidemiological traits. 

Methods 

We reviewed the epidemiological characteristics of 19 different pathogens with pandemic potential (those on the WHO priority list of pathogens, different strains of influenza and Mpox). We extracted data on the proportion of presymptomatic transmission, incubation period, serial interval and basic reproduction number (R0) for the targeted pathogens. We applied unsupervised machine learning (specifically K-means and hierarchical clustering) to categorise these pathogens based on these characteristics. 

Results 

Fom 166 studies we extracted 342 epidemiological parameter estimates. The clustering algorithms categorise these pathogens into five archetypes (1) airborne pathogens with high transmission potential, (2) respiratory zoonoses characterized by high case fatality risk, (3) contact zoonoses with high fatality rates, (4) contact zoonoses exhibiting presymptomatic transmission, and (5) vector-borne pathogens capable of secondary human-to-human transmission. 

Conclusion 

Unsupervised learning on epidemiological data can be used to predict distinct pathogen archetypes. This method offers a valuable framework to allocate emerging and novel pathogens into defined groups to evaluate common approaches for their control.

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2025.03.13.25323659v1

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Modelling #practices, #data #provisioning, #sharing and dissemination needs for #pandemic decision-making: a European survey-based modellers’ perspective

Abstract

Introduction

Advanced outbreak analytics played a key role in governmental decision-making as the COVID-19 pandemic challenged health systems globally. This study assessed the evolution of European modelling practices, data usage, gaps, and interactions between modellers and decision-makers to inform future investments in epidemic-intelligence globally. 

Methods

We conducted a two-stage semi-quantitative survey among modellers in a large European epidemic-intelligence consortium. Responses were analysed descriptively across early, mid-, and late-pandemic phases. Policy citations in Overton were used to assess the policy impact of modelling. 

Findings

Our sample included 66 modelling contributions from 11 institutions in four European countries. COVID-19 modeling initially prioritised understanding epidemic dynamics. Evaluating non-pharmaceutical interventions and vaccination impacts became equally important in later phases. 'Traditional' surveillance data (e.g. case linelists) were widely used in near-real time, while real-time non-traditional data (notably social contact and behavioural surveys), and serological data were frequently reported as lacking. Data limitations included insufficient stratification and geographical coverage. Interactions with decision-makers were commonplace and informed modelling scope and, vice versa, supported recommendations. Conversely, fewer than half of the studies shared open-access code. 

Interpretation

We highlight the evolving use and needs of modelling during public health crises. The reported missing of non-traditional surveillance data, even two years into the pandemic, underscores the need to rethink sustainable data collection and sharing practices, including from non-profit providers. Future preparedness should focus on strengthening collaborative platforms, research consortia and modelling networks to foster data and code sharing and effective collaboration between academia, decision-makers, and data providers.

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2025.03.12.25323819v1

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Characterising viral #clearance #kinetics in acute #influenza

Abstract

Pharmacometric assessment of antiviral efficacy in acute influenza informs treatment decisions and pandemic preparedness. We assessed natural viral clearance in untreated acute influenza to guide clinical trial design. Standardized duplicate oropharyngeal swabs were collected daily over 14 days from 80 untreated low-risk Thai adults, with viral densities measured using qPCR. We evaluated three models to describe viral clearance: exponential, bi-exponential, and growth-and-decay. The growth-and-decay model provided the best fit, but the exponential decay model was the most parsimonious. The median viral clearance half-life was 10.3 hours (interquartile range [IQR]: 6.8-15.4), varying by influenza type: 9.6 hours (IQR: 6.2-13.0) for influenza A and 14.0 (IQR: 10.3-19.3) hours for influenza B. Simulated trials using clearance parameters from the exponential decay model, showed that 120 patients per arm provide over 90% power to detect treatments accelerating viral clearance by 40%. However, variation in clearance rates strongly impacted the statistical power; doubling this variation would require 240 patients per arm for an antiviral with a 60% effect size. An alternative sampling strategy with four swabs per day reduces the required sample size to 80 per arm while maintaining over 80% power. We recommend this approach to assess and compare current anti-influenza drugs.

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2025.03.07.25323547v1

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#Antiviral use and the effects of #drug #resistance on the #transmission dynamics of #influenza

Abstract

The effectiveness of antivirals in mitigating influenza outbreaks depends on both their ability to reduce the number of infections and the risk of drug resistance. We extended a previously developed mathematical model to investigate the impact of mitigation strategies, including mono or combination antiviral treatment or chemoprophylaxis and vaccination, on influenza transmission dynamics. Our findings indicate that chemoprophylaxis is more effective than treatment in reducing influenza burden, except when the resistant strain has a high transmission rate, in which case chemoprophylaxis may trigger a resistance-driven secondary infection wave. Combination therapy considerably reduces resistance emergence with similar infection numbers as mono-therapy. Vaccination coverage of at least 80% is required to prevent outbreaks; otherwise, antivirals can contribute to outbreak control provided drug resistance emergence is low. This analysis could inform public health decision-making by providing guidance on effective mitigation strategies for influenza outbreaks, considering their benefits against the risk of drug resistance.

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2025.03.10.25323668v1

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Wednesday, March 19, 2025

#US #CDC A(#H5N1) #Birdflu Response #Update March 19, 2025



{Excerpts}

Recent updates

Laboratory

CDC completed serology testing on blood specimens from close contacts of a child with mild illness in San Francisco who was confirmed to be positive for avian influenza A(H5N1) virus, though, there were no known animal exposures associated with that case. 

-- Serology testing was conducted to look for antibodies to influenza A(H5N1) virus in this child, which would indicate recent infection. 

-- The child's blood was tested and found to have antibodies to avian influenza A(H5N1) virus. 

-- None of the close contacts of the case in San Francisco who were tested had antibodies to avian influenza A(H5N1) virus, which supports the conclusion that none of these close contacts were infected, and that no person-to-person spread occurred among these close contacts. 

-- These findings are reassuring. To date, human-to-human transmission of influenza A(H5) virus has not been identified in the United States.

CDC has sequenced the virus from the most recent Ohio human case. Genetic data have been posted in GISAID (Epi ID 19785793) and have been submitted to GenBank. 

-- Sequencing indicates this is a clade 2.3.4.4b virus of the D1.3 genotype based on classification using USDA's genotyping assignment criteria. 

-- D1.3 viruses, like D1.1 viruses, originated from A3 genotype A(H5N1) viruses that were introduced to North America in 2022 and have subsequently reassorted with North American wild bird avian influenza viruses. 

-- There were no markers that would impact the effectiveness of influenza antivirals or existing candidate vaccine viruses. 

-- Finally, CDC did not identify changes that would make this virus better adapted to spread among or infect mammals. 

-- Attempts to isolate this virus in eggs are ongoing.


Publications

Pre-Existing Antibodies

Historically, the mortality rate from avian influenza observed globally has been around 50%; however, only one of 70 human infections* in the United States to date has resulted in death. 

-- Recent studies have reported that ferrets previously infected with seasonal influenza A(H1N1) virus had less severe illness from H5N1 bird flu. 

-- While more study is needed, pre-existing antibodies could contribute to decreasing the severity of H5 bird flu illness in U.S. cases.

A CDC study published on February 21, 2025, in Emerging Infectious Diseases found that ferrets previously infected with seasonal influenza A(H1N1)pdm09 virus had developed cross-reactive antibodies to some components of an avian influenza A(H5N1) virus. 

-- When these ferrets were later exposed to an avian influenza A(H5N1) virus, they exhibited reduced viral replication and decreased onward spread of avian influenza A(H5N1) virus compared with ferrets that had not been previously infected with A(H1N1)pdm09 virus and did not have these cross-reactive antibodies. 

-- Overall, these findings in ferrets suggested that prior seasonal influenza virus infection with an A(H1N1)pdm09 virus may provide some level of protection against clade 2.3.4.4b avian influenza A(H5N1) viruses.

A second study, published on March 17, 2025, in The Lancet Microbe reported similar findings. 

-- Ferrets with antibodies from previous infection with the seasonal influenza A(H1N1)pdm09 virus [A/California/7/2009] that were later infected with avian influenza A(H5N1) virus had less severe illness and were less likely to spread the virus to other ferrets in the same enclosure compared to ferrets with no preexisting immunity to influenza virus. 

-- This study only looked at prior infection and did not look at the effects of prior vaccination in ferrets, so it's not possible to draw conclusions from this study on the potential effect seasonal flu vaccines might have on reducing severity of H5N1 bird flu illness in ferrets or in people; seasonal influenza vaccines are not designed or intended to prevent H5N1 bird flu disease. 

-- The study also found that when ferrets were exposed to an avian influenza A(H5N1) clade 2.3.4.4b virus [A/Texas/37/2024] via the surface of their eyes, they developed severe and transmissible disease just as they did after respiratory exposure, highlighting the importance of following recommendations for eye protection for people with exposure to animals infected or potentially infected with avian influenza A(H5N1) viruses.


Immune Response from Mild Illness

Another recent report, published on March 7, 2025, in Emerging Infectious Diseases assessed the immune responses of two dairy farm workers in Michigan who tested positive for H5N1 bird flu following work related exposure to infected dairy cows. 

-- One of the two workers, who reported having mild illness with symptoms like eye redness (conjunctivitis) had an immune response resulting in the development of neutralizing antibodies against avian influenza A(H5N1) virus. 

-- Clade 2.3.4.4b avian influenza A(H5N1) virus was isolated from this person. 

-- The other person did not develop neutralizing antibodies. 

-- This is the first study conducted in people to assess immunity to clinically mild illness from A(H5) virus infection. 

-- Prior to this study, limited data were available on immune responses to H5N1 bird flu among people with clinically mild illness like conjunctivitis.


Antiviral susceptibility

CDC regularly performs sequencing of seasonal influenza A and B viruses and novel influenza A viruses, including A(H5N1) viruses, to assess for genetic changes known to be associated with antiviral resistance. 

-- In a new CDC study published in Emerging Infectious Diseases on March 7, 2025, CDC scientists assessed the antiviral susceptibility of clade 2.3.2.1c A(H5N1) viruses and clade 2.3.4.4b A(H5N1) viruses collected from humans in Cambodia, United States, and Chile

-- The study found that except for two viruses isolated from humans in Cambodia, all viruses were susceptible to M2 ion channel-blockers in cell culture-based assays. 

-- All viruses were susceptible to the PA cap-dependent endonuclease inhibitor class of antiviral drugs, baloxavir and tivoxavir, and to the polymerase basic 2 (PB2) inhibitor antiviral drug, pimodivir

-- All viruses also displayed susceptibility to neuraminidase inhibitor class of antiviral drugs, which includes oseltamivir, zanamivir, peramivir, laninamivir, and AV5080. 

-- Oseltamivir was approximately 10-fold less active at inhibiting the neuraminidase activity of clade 2.3.4.4b viruses and approximately 3-fold less active against clade 2.3.2.1c viruses, when compared to seasonal influenza A viruses. 

-- The clinical significance of these laboratory findings, however, is unknown. 

-- Significant reduction in antiviral susceptibility is considered to be greater than 100-fold reduction. 

-- The laboratory findings in this study, therefore, indicate that these A(H5N1) viruses are likely to retain susceptibility to oseltamivir

-- Additionally, these findings do not support changing the current recommendations for antiviral treatment of human infections with novel influenza A viruses, including A(H5). 

-- CDC continues to recommend prompt treatment with oseltamivir for people with confirmed or suspected A(H5N1) virus infection. 

-- Flu antiviral drugs, including oseltamivir, work best when started as soon as possible, ideally within two days after flu symptoms begin.


* One additional case was previously detected in Colorado in a poultry worker who experienced mild illness in 2022.

Source: US Centers for Disease Control and Prevention, https://www.cdc.gov/bird-flu/spotlights/h5n1-response-03192025.html

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Safety and #effectiveness of MVA-BN #vaccination against #mpox in at-risk individuals in #Germany (SEMVAc and TEMVAc): a combined prospective and retrospective cohort study

Summary

Background

More than 115 000 cases of mpox have been confirmed since the onset of a global outbreak in 2022. In addition to global transmission of clade II monkeypox virus (MPXV), the recent spread of clade I has caused a Public Health Emergency of International Concern. The third-generation smallpox vaccine modified vaccinia Ankara–Bavarian Nordic (MVA-BN) was recommended for at-risk populations in 2022, despite a scarcity of data on safety and effectiveness against mpox.

Methods

We did a prospective, multicentre, observational study, enrolling men who have sex with men and transgender people aged 18 years or older with changing sexual partners in Germany (Safety and Effectiveness of MVA-BN Vaccination Against MPXV Infection [SEMVAc]) between July 7, 2022, and Dec 31, 2023, evaluating safety and reactogenicity of one and two doses of subcutaneous MVA-BN. Vaccine effectiveness was estimated using risk ratios from the Kaplan–Meier estimator in an emulated retrospective target trial (Emulated Target Trial for Effectiveness of MVA-BN Vaccination Against mpox Infection in At-risk Individuals [TEMVAc]) from 3027 vaccinated individuals matched (1:1) to 3027 unvaccinated controls. SEMVAc and TEMVAc were registered in the HMA-EMA Catalogue, EUPAS50093, and the German Clinical Trials Register, DRKS00029638, and are complete.

Findings

6459 individuals were prospectively enrolled in SEMVAc. Adverse reactions were infrequent (first dose: 0·35% [95% CI 0·20–0·60] and second dose: 0·14% [0·06–0·33]). Local reactions were more frequent after the first dose (70·2% [95% CI 68·5–71·8]) compared with the second dose (56·8% [54·6–59]), as were systemic reactions (first dose, 22·3% [95% CI 20·9–23·9]; second dose, 17·6% [15·9–19·4]). In TEMVAc, 16 mpox cases were reported in vaccinated individuals versus 32 cases in matched unvaccinated individuals (median follow-up 55 days [IQR 23–89]). Effectiveness by 14 days or later after one dose was 57·8% (95% CI 11·8 to 83·0) overall, 84·1% (42·0 to 100) in people without HIV, but 34·9% (–72·8 to 79·0) in people living with HIV. Breakthrough infections were associated with reduced symptoms, compared with infections in unvaccinated individuals.

Interpretation

MVA-BN vaccination was safe and well tolerated. One dose of MVA-BN offered protection against mpox but effectiveness was reduced in people living with HIV. Although randomised controlled trials remain the preferred approach for assessing vaccine efficacy, combining prospective and retrospective study designs can be valuable during dynamic public health emergencies.

Source: The Lancet Infectious Diseases, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(25)00018-0/fulltext?rss=yes

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Large-scale computational #modelling of #H5 #influenza #variants against #HA1-neutralising #antibodies

Summary

Background

The United States Department of Agriculture has recently released reports that show samples collected from 2022 to 2025 of highly pathogenic avian influenza (H5N1) have been detected in mammals and birds. Up to February 2025, the United States Centres for Disease Control and Prevention reports that there have been 67 humans infected with H5N1 since 2024 with 1 death. The broader potential impact on human health remains unclear.

Methods

In this study, we computationally model 1804 protein complexes consisting of various H5 isolates from 1959 to 2024 against 11 haemagglutinin domain 1 (HA1)-neutralising antibodies. This was performed using AI-based protein folding and physics-based simulations of the antibody-antigen interactions. We analysed binding affinity changes over time and across various antibodies using multiple biochemical and biophysical binding metrics.

Findings

This study shows a trend of weakening binding affinity of existing antibodies against H5 isolates over time, indicating that the H5N1 virus is evolving immune escape from our therapeutic and immunological defences. We also found that based on the wide variety of host species and geographic locations in which H5N1 was observed to have been transmitted from birds to mammals, there is not a single central reservoir host species or location associated with H5N1's spread.

Interpretation

These results indicate that the virus has potential to move from epidemic to pandemic status. This study illustrates the value of high-performance computing to rapidly model protein–protein interactions and viral genomic sequence data at-scale for functional insights into medical preparedness.

Source: EBioMedicine, https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00076-3/fulltext

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Different #genetic #determinants for high #virulence, #transmission and #replication of high pathogenicity #H7N7 avian #influenza virus in #turkeys and #chickens

Abstract

High pathogenicity (HP) avian influenza viruses (AIV) generally evolve from low pathogenicity (LP) precursors after transmission from wild birds to chickens (Gallus gallus domesticus) and turkeys (Meleagris gallopavo), causing severe economic losses worldwide. Turkeys are more susceptible to AIV infection than chickens and are considered potential bridging hosts that facilitate the emergence of HPAIV. Beyond the polybasic cleavage site (pCS) in hemagglutinin (HA), little is known about other virulence determinants of HPAIV in these species. In 2015, HPAIV H7N7 and its LP ancestor were isolated from the same chicken farm, which differed by 16 nonsynonymous mutations across all eight gene segments, in addition to the pCS. Here we identify the genetic determinants, including the pCS, that contributed to the HPAIV H7N7 virulence, transmission, replication, and tissue distribution in chickens and turkeys. Notably, the non-structural (NS1) or matrix (M) proteins’ encoding segments in turkeys, or NS segment in chickens, rendered viruses as virulent and transmissible as the original HPAIV. Endotheliotropism, observed exclusively in chickens, was driven by the pCS and, to a lesser extent, the neuraminidase (NA). In vitro, the M2-V68L mutation influenced NS1 expression and virus morphology in chicken and turkey cells. Additionally, HPAIV NS1 enhanced polymerase activity and effectively suppressed interferon induction, a process further modulated by M2-V68L. These findings underscore the critical role of turkeys as a “hub” in the evolution of HPAIV from LP precursors, offering crucial insights into the genotypic and phenotypic factors that facilitate viral adaptation in different poultry species.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.03.18.643940v1?rss=1

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Tuesday, March 18, 2025

#Baloxavir improves #disease #outcomes in #mice after intranasal or ocular #infection with #Influenza A virus #H5N1-contaminated cow’s #milk

Abstract

Testing approved antivirals against A(H5N1) influenza viruses circulating in peridomestic species, including dairy cows, is critical to public health and pre-pandemic planning. It cannot be tested in humans due to A(H5N1) disease severity. Here, in mice, we demonstrate that US FDA-approved baloxavir treatment mediates improved disease outcomes (survival and viral dissemination) over oseltamivir after lethal intranasal and ocular challenge with A(H5N1)-contaminated cow milk.

Source: Nature Microbiology, https://www.nature.com/articles/s41564-025-01961-5

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#India - High pathogenicity avian #influenza #H5N1 viruses (#poultry) (Inf. with) - Immediate notification

A poultry farm in Telangana Region.

Source: WOAH, https://wahis.woah.org/#/in-review/6323

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Analyses of #phylogenetics, natural #selection, and #protein structure of clade 2.3.4.4b #H5N1 #Influenza A reveal that recent viral lineages have evolved promiscuity ...

Abstract

H5N1 influenza has been circulating in birds from Eurasia and Africa for more than 146 years, but human infection has been sporadic. H5N1 (clade 2.3.4.4b) has recently infected hundreds of species of wild and domestic birds and mammals in North America. Furthermore, as of February 26, 2025, H5N1 has infected 70 humans in the United States, and one infection proved lethal. Furthermore, in attempts to control H5N1 in the United States, 10s of millions of egg-laying chickens have died or been culled. These efforts have led to very high egg prices in the United States. We have developed an analytical bioinformatics and genomics workflow to understand better how H5N1 is circulating in North America and adapting to new host species. Our workflow consists of: 1) Phylogenetic analyses of large viral sequence datasets to identify subclades of viral lineages causing the current outbreaks in humans and farm animals and closely related viral background lineages. 2) Next, we transfer sequence data from subclades of interest with farm animal and human infection, background data, and vaccine candidate data to analyses of natural selection. 3) Once we identify mutations of interest that underlie recent viral adaptation to animal and human infection, we perform computational structural analyses of binding to host proteins for cell receptors and immune processes. Here, we show that H5N1 (clade 2.3.4.4b) is spreading in North America as two distinct subclades of interest for human and animal health. These viral lineages have achieved a vast host range by efficiently binding the viral surface protein Hemagglutinin (HA) to both mammalian and avian receptors. This novel promiscuity of host range is concomitant with the additional strengthening of the polymerase basic 2 (PB2) viral protein's binding for mammalian and avian immune proteins. Once bound, the immune proteins are disabled, thus allowing for more efficient replication of H5N1 in mammalian and avian cells than seen in the recent past. In conclusion, H5N1 (clade 2.3.4.4b) is causing an animal pandemic through promiscuity of host rage and strengthening ability to evade the innate immune systems of both mammalian and avian cells.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.03.15.641219v1?rss=1

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Monday, March 17, 2025

3rd #meeting of #IHR(2005) #Emergency #Committee regarding the upsurge of #mpox 2024

The Director-General of the World Health Organization (WHO) is hereby transmitting the report of the third meeting of the International Health Regulations (2005) (IHR) Emergency Committee (Committee) regarding the upsurge of mpox 2024, held on Tuesday, 25 February 2025, from 12:00 to 17:00 CET.

Concurring with the advice unanimously expressed by the Committee during the meeting, the WHO Director-General determined that the upsurge of mpox 2024 continues to meet the criteria of a public health emergency of international concern (PHEIC) and, accordingly, on 27 February 2025, issued temporary recommendations to States Parties.

The WHO Director-General expresses his most sincere gratitude to the Chair, Members, and Advisors of the Committee.


Proceedings of the meeting

Sixteen (16) Members of, and two Advisors to, the International Health Regulations (2005) (IHR) Emergency Committee (Committee) were convened by teleconference, via Zoom, on Tuesday, 25 February 2025, from 12:00 to 17:00 CET. Fourteen (14) of the 16 Committee Members, and one of the two Advisors to the Committee participated in the meeting.

On behalf of the Director-General of the World Health Organization (WHO), the Deputy Director-General welcomed Members of and Advisors to the Committee, as well as Government Officials designated to present their views to the Committee on behalf of the ten invited States Parties Burundi, Canada, China, the Democratic Republic of the Congo (DRC), Nepal, Nigeria, Rwanda, Sierra Leone, Uganda, United Arab Emirates and United Kingdom of Great Britain and Northern Ireland (United Kingdom).

In his opening remarks, the WHO Deputy Director-General recalled that, on 14 August 2024, the upsurge of mpox was determined to constitute a public health emergency of international concern (PHEIC). He noted that, over the three years from 1 January 2022 through 31 January 2025, almost 130 000 confirmed cases of mpox, including over 280 deaths, were reported to WHO from 130 countries and territories in all six WHO Regions, including seven countries and territories that had reported their first mpox cases since the previous meeting of the Committee on 22 November 2024. The WHO African Region, where some States Parties are continuing to experience sustained community transmission, accounts for 61% of the cases and 72% of the deaths reported globally over the past 12 months.

The WHO Deputy Director-General highlighted that, since the last meeting of the Committee, the epidemiological situation continues to be volatile. Despite observed improvements pertaining to several aspects of the response – emergency coordination, surveillance, laboratory diagnostics, empowerment of communities, furthering equitable access to medical countermeasures and tools – several critical challenges had emerged, including: 

-- (a) rising geopolitical instability in the DRC due to escalating conflict affecting mpox response operations resulting in temporary pauses in operation, relocation of staff and restricted access to affected populations; 

-- (b) concurrent health emergencies requiring States Parties and partners to respond (e.g. Sudan virus disease outbreak in Uganda); and 

-- (c) uncertainties related to the pause in financial support from the United States of America (United States) occurring in the broader landscape of declining foreign assistance. 

To date, globally, one-third of the funds supporting the response to mpox had been pledged by the United States. Without sufficient funds, the ability of States Parties, WHO and partners to maintain, sustain, and expand the response to mpox would be compromised.

The Representative of the Office of Legal Counsel then briefed the Members and Advisors on their roles and responsibilities and identified the mandate of the Committee under the relevant articles of the IHR. The Ethics Officer from the Department of Compliance, Risk Management, and Ethics provided the Members and Advisors with an overview of the WHO Declaration of Interests process. The Members and Advisors were made aware of their individual responsibility to disclose to WHO, in a timely manner, any interests of a personal, professional, financial, intellectual or commercial nature that may give rise to a perceived or actual conflict of interest. They were additionally reminded of their duty to maintain the confidentiality of the meeting discussions and the work of the Committee. Each Member and Advisor was surveyed, with no conflicts of interest identified.

The meeting was handed over to the Chair who introduced the objectives of the meeting, which were to provide views to the WHO Director-General on whether the event continues to constitute a PHEIC, and if so, to provide views on the potential proposed temporary recommendations.


Session open to representatives of States Parties invited to present their views

The WHO Secretariat presented an overview of the global epidemiological situation of mpox, including all circulating clades of monkeypox virus (MPXV). Outside the WHO African Region, cases of mpox reported to WHO are associated with the spread of MPXV clade IIb, with a decline in the number of cases reported in recent months. In the WHO African Region, amid the circulation of multiple MPXV clades, the still growing number of cases reported monthly is driven by the spread of MPXV clade Ib. Since the Committee last met, on 22 November 2024, exported travel-related cases of confirmed MPXV clade Ib infection have been detected in eight additional countries outside the WHO African Region.

The WHO Secretariat then focused on the three countries reporting most cases of MPXV clade Ib since January 2024 – the DRC (over 15 000 cases, including cases in areas where MPXV clade Ia is circulating); Burundi (over 3000 cases, with a sustained decrease reported weekly and a geographic shift to the administrative capital Gitega since the Committee last met); and Uganda (nearly 3000 cases, with an exponential increase in and around the capital Kampala since the Committee last met). Notwithstanding changes in the case definition of mpox cases, uneven surveillance coverage (including due to the conflict in the eastern provinces of the country), and limited laboratory testing capacity in the DRC introducing some challenges in the interpretation of data , the number of mpox cases reported weekly is plateauing and the geographic distribution of cases, in all provinces in the country, remained very similar to the situation presented at the previous meeting of the Committee. Mathematical modelling work suggests that, since the PHEIC was determined in mid-August 2024 in the DRC, the transmission rate has decreased in certain health zones of the North Kivu and South Kivu Provinces, as well as in some health zones of the capital Kinshasa where vaccination efforts are underway.

The spread of MPXV clade Ia and Ib, in North Kivu, South Kivu, and Kinshasa Provinces of the DRC, as well as in Burundi and Uganda, appears to have started among adults, including through sexual networks involving commercial sex workers and their clients, disproportionately affecting the 20–39 years age group. Since then, in North Kivu and South Kivu Provinces of the DRC, more age group became affected reflecting community transmission through close contact, including household, whereas, in the capital Kinshasa, the spread has remained within the adult population. In Burundi and Uganda, the age distribution of mpox cases shows a bimodal pattern, with high incidence observed among young adults and younger children. This pattern reflects both ongoing sexual transmission and close contact transmission in household settings. The strikingly high proportion of cases among younger children (0-9 age group) observed in Burundi is possibly attributable to transmission occurring within health care facilities settings.

In addition to the three aforementioned countries, community transmission of MPXV clade Ib is also observed in Kenya, Rwanda, and Zambia, while travel-related imported cases have been reported both, by countries in the WHO African Region (Angola, Zimbabwe, with cases in Tanzania being under investigation), and by 14 countries in the five remaining WHO Regions. Most travel-related imported cases are male and, in instances where limited secondary transmission in the country of importation has occurred, a few children have been infected through household contact, including child-to-child transmission on one occasion. The five imported cases with sole travel history to the United Arab Emirates may signal wider mpox transmission in that country.

Mortality associated with the different MPXV clades in the WHO African Region, and notwithstanding the limitation of surveillance and laboratory diagnostics in the DRC, clade Ia accounts for the majority of fatal cases (1345), corresponding to an average case fatality rate (CFR%) of 2.5-3%, being highest in children under 1 year of age (4–5%). The CFR attributed with clade Ib infection remains very low at around 0.2%, and similar to the that attributed to clade IIb, with recorded deaths associated with specific risk factors such as uncontrolled HIV and other comorbidities.

The WHO Secretariat also noted an increase in mpox cases reported in West African countries since the PHEIC was determined in mid-August 2024, including the first cases of mpox, due to MPXV clade IIa, reported by Sierra Leone.

The WHO Secretariat presented the assessed risk by MPXV clades and further expressed in terms of overall public health risk where any given clade/s is/are circulating, as: 

-- Clade Ib – high public health risk in the DRC and neighbouring countries; 

-- Clade Ia – moderate public health risk in the DRC

-- Clade II – moderate public health risk in Nigeria and countries of West and Central Africa where mpox is endemic; and 

-- clade IIb – moderate public health risk globally.

The WHO Secretariat subsequently provided an update on response actions taken together with States Parties and partners since the Committee last met. In addition to the overview provided by the WHO Deputy Director-General, and in the epidemiological overview, the WHO Secretariat provided details on progress and challenges focusing on the aspects of the response outlined below.

The coordination of emergency operations by the WHO Secretariat was readjusted – including based on action reviews and leveraging the comparative advantages of WHO, State Parties, and partners –prioritizing a flexible, agile, and delivery-focused response. However, while decentralized field operations have intensified, such shifts take time, particularly in specific settings in the DRC and amid changes in geopolitical partnerships. The operational decentralization continues to emphasize increased laboratory diagnostic support, increased dissemination of standards and guidance to deliver safe clinical care, and empowering communities to enhance their efforts to protect themselves from risks associated with mpox.

Additionally, through the Access and Allocation Mechanism (AAM), WHO and partners (Africa Centres for Disease Control and Prevention (Africa CDC), the Coalition for Epidemic Preparedness Innovations (CEPI), Gavi, The Vaccine Alliance (Gavi), and the United Nations Children’s Fund (UNICEF)) are continuing coordinated and multifaceted efforts to prioritize access to and roll out mpox vaccines in an equitable manner.

With the WHO Mpox global strategic preparedness and response plan, September 2024-February 2025 (SPRP) reaching the end of its initial timeframe, and considering the response strategy it outlines as still fit for purpose, the WHO Secretariat is planning to release an extension of the plan in the coming weeks.

In September 2024, the WHO Secretariat launched an appeal for US$ 87.4 million to support mpox response efforts WHO appeal: mpox public health emergency 2024 with US$ 65.5 million raised by the time of this meeting. The contribution from the United States had accounted for 33% of the funds raised, of which US$ 7.5 million is currently inaccessible due to the freeze of funds from the United States. As part of planning for the extension of the SPRP, the WHO Secretariat is conducting a review of available resources to address priority needs and mitigate potential future gaps in the delivery of the response. While the above-mentioned freeze is expected to primarily impact operations in Burundi, the Central African Republic, the DRC, the Republic of the Congo, and Rwanda, broader challenges are anticipated for the second and third quarters of 2025. Given the evolving epidemiological situation and challenges noted above, the reduction in predictable and flexible funding throughout 2025 will put at risk the progress of the mpox response to date.

Representatives of Burundi, the DRC, Nigeria, Sierra Leone, and Uganda updated the Committee on the mpox epidemiological situation in their countries and their current control and response efforts, needs and challenges, including those related to the freeze of the funds from the United States. The use of mpox vaccine is contemplated in the response plans of the DRC, Nigeria, Sierra Leone, and Uganda. In Burundi, following action review, community-based interventions that are being strengthened in areas experiencing high incident of mpox include risk communication and awareness raising.

Members of, and the Advisor to, the Committee then engaged in questions and answers, revolving around the issues and challenges enumerated below, with the presenters from States Parties and the WHO Secretariat, as well as with representatives of States Parties invited to submit a written statement to the Committee ahead of the meeting – Canada, China, Nepal, the United Arab Emirates, and the United Kingdom.

FundingThe Committee reiterated the importance of efforts to mobilize domestic financial resources to support mpox response activities. Burundi and the DRC indicated the funds allocated to the response by their respective Governments, also providing details of specific activities supported. The DRC indicated that, at present, the freeze of the funds from the United States is impacting the transportation of clinical specimens and laboratory diagnostics, with a decline in the testing rate, and that the Government is exploring solutions with other partners. The WHO Secretariat added that alternative funding sources are being explored with non-traditional donors.

Age distribution of mpox casesThe WHO Secretariat indicated that 

- (a) there are studies ongoing to determine the secondary attack rate by age group and type of exposure; 

- (b) at least in Burundi, there is no evidence of large outbreaks in settings where children are congregating and, hence, supporting evidence of child-to-child transmission; and 

- (c) in the South Kivu Proving of the DRC, it remains unknown the extent to which transmission to children is occurring beyond the household setting.

Impact of vaccination on transmissionThe DRC indicated that, at present, there is no information about whether the use of the limited amount of mpox vaccine available is being effective in interrupting mpox transmission.

The DRC – The DRC indicated that, due to insecurity and to decrease in laboratory testing rate, any apparent decrease of the number of reported mpox cases may represent an artifact and should be interpreted with caution. The WHO Secretariat highlighted that, being mpox a relatively mild illness, the rate of underreporting is unknown and that the trends of mpox surveillance data are critical to monitor the evolution of the situation. With respect to detection of a new MPXV clade Ia lineage in Kinshasa, the WHO Secretariat indicated that the strain, similarly to clade Ib, has increased human-to-human transmission potential.

UgandaUganda elaborated on the shift of the dynamics of mpox transmission from lower to higher income groups. The initial spread of MPXV clade Ib initiated long-distance truck drivers, it continued in fishing communities, and then within commercial sex networks in the capital Kampala. The fact that more affluent individuals are now affected poses a public health risk both, nationally and internationally. Therefore, the use of mpox vaccine is focused among sex workers in Kampala.

NigeriaNigeria indicated that, in the context of the mpox response, the human health and animal health sectors are working very closely and that, despite the numerous research initiatives, to date, there is no evidence of animal involvement in sustaining the mpox outbreak in the human population. Nigeria, with a population of 200 million persons, indicated that 20 000 doses of mpox vaccine have been used in the country, targeting health care workers, female sex workers, and men who have sex with men.

The United Arab EmiratesConsidering that, in five instances, travel-related imported cases of MPXV clade Ib infection had sole travel history to the United Arab Emirates, the representative of the country 

- (a) indicated that the National IHR Focal Point reported to WHO the first case of MPXV clade Ib infection; 

- (b) briefly described the surveillance, laboratory diagnostic, case management, and risk communication approaches in place; 

- (c) indicated that mpox vaccine is available to health care workers and as a post-exposure measure; and 

- (d) recalled that the country is bilaterally supporting the response efforts of some African countries.

The United Kingdom – The United Kingdom 

- (a) described the detection, investigation, and clinical and public health management of the travel-related imported mpox cases; and 

- (b) highlighted that the countries of origin of the imported cases are systematically informed about the occurrences.


Deliberative session

Following the session open to invited States Parties, the Committee reconvened in a closed session to examine the questions in relation to whether the event constitutes a PHEIC or not, and if so, to consider the temporary recommendations drafted by the WHO Secretariat in accordance with IHR provisions.

The Chair reminded the Committee Members of their mandate and recalled that a PHEIC is defined in the IHR as an “extraordinary event, which constitutes a public health risk to other States through the international spread of disease, and potentially requires a coordinated international response”.

The Committee was unanimous in expressing the views that the ongoing upsurge of mpox still meets the criteria of a PHEIC and that the Director-General be advised accordingly

The overarching considerations underpinning the advice of the Committee are 

- (a) the insecurity in the eastern provinces and in the capital of the DRC – the State Party epicenter of the MPXV clade Ib outbreak –, hampering mpox response field operations and with the potential to morph into a larger scale humanitarian response; 

- (b) the freeze of funding by the United States both, of specific mpox response activities as well as of other, directly or indirectly related, aid interventions; and 

- (c) the continuing detection of travel-related imported mpox cases in States Parties within and outside the WHO African Region.

On that basis, the Committee considered that:

The event is “extraordinary” because of 

- (a) the persistent, if not increasing, challenges in gauging the actual magnitude and trend of the MPXV clade Ib outbreak, especially in the DRC. This is thwarting the ability to assess progress, if any, towards controlling the spread of mpox and to adjust response interventions. The Committee’s reading is that, overall, the epidemiological situation is worryingly similar to that observed in November 2024; 

- (b) the unfolding dynamics of MPXV clade Ib transmission, resulting in the shift in age groups affected and, hence, posing challenges in timely targeting response interventions; 

- (c) the co-circulation and the risk of mutations of MPXV clades in the context of sustained community transmission; and 

- (d) the possibility of change in the severity of disease resulting from food insecurity and interruption in the delivery of HIV-related care due to the freeze of aid.

The event “constitutes a public health risk to other States through the international spread of disease” because of 

- (a) the doubling of the number of States Parties having detected travel-related imported cases of MPXV clade Ib infection since the Committee last met, both in the WHO African Region and in all five other WHO Regions; 

- (b) the possible influx of refugees from the eastern provinces of the DRC into neighbouring countries.

The event “requires a coordinated international response” because of the needs 

- (a) to mobilize, and optimize the use, of financial and other resources to sustain response efforts, at the required level, in the medium term, following the freeze of funding by the United States; and 

- (b) to continue facilitating and increasing equitable access to mpox vaccines and diagnostics.


The Committee subsequently considered the draft of the temporary recommendations proposed by the WHO Secretariat

Anticipating the possibility that the WHO Director-General may determine that the event continues to constitute a PHEIC, the Committee had received a proposed set of revised temporary recommendations ahead of the meeting. This reflected the proposal to extend most of the temporary recommendations issued on 27 November 2024. The Committee indicated that it would be giving them further consideration with a view to share its advice in that regard with the WHO Director-General as soon as possible. In such a way, should the WHO Director-General determine that the event continues to constitute a PHEIC, he could proceed, without delay, with issuing such communication together with a prospective revised set of temporary recommendations.

The Committee agreed to finalize the report of its third meeting during the week of 3 March 2025.


Conclusions

The Committee reiterated its concern regarding the continuing spread of MPXV in and beyond Africa, considering global geopolitical developments, the humanitarian situation in the DRC, as well as the foreseeable options and opportunities to secure sustainable funding to support response efforts. The Committee considered that the determination by the WHO Director-General that the upsurge of mpox still constitutes a PHEIC would be warranted. However, the Committee cautioned about the possible unintended consequences of determining an event to constitute a PHEIC for extended periods of time, since this could undermine the global public health alert function intrinsic to such a determination and reduce the leverage of a PHEIC in boosting domestic and international response efforts for future events. To that effect, the Committee reiterated the need to elaborate on considerations, related to the three criteria defining a PHEIC, that would inform its future advice to the WHO Director-General as to the termination of this PHEIC.

The Incident Manager for mpox at WHO headquarters, on behalf of the WHO Deputy Director-General, expressed his gratitude to the Committee’s Officers, its Members and Advisor and closed the meeting.

Source: World Health Organization, https://www.who.int/news/item/17-03-2025-third-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-upsurge-of-mpox-2024

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#Togo - High pathogenicity avian #influenza #H5 viruses (#poultry) (Inf. with) - Immediate notification [FINAL]

 A poultry farm in Centre Region.

Source: WOAH, https://wahis.woah.org/#/in-review/6338

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