#Oseltamivir aziridines are potent #influenza #neuraminidase #inhibitors and imaging agents

 

Significance

Influenza remains a major global health threat. We introduce oseltamivir-based aziridines that unite transition-state mimicry for tight binding with aziridine-enabled covalent capture of the catalytic tyrosine. This dual function yields potent, mechanism-based neuraminidase inhibition and enables activity-based quantification of active enzyme directly in complex samples. Across N1, N2, and influenza B enzymes, selected compounds show high potency against diverse viral neuraminidases and in live virus replication assays. By combining a clinically grounded scaffold with a reactivity handle, these molecules bridge therapeutic and diagnostic needs and offer a practical platform for neuraminidase imaging and antiviral development.

Abstract

Influenza neuraminidase (NA) is a critical target for seasonal and pandemic antivirals, including the strains of current concern. Current treatments, such as Zanamivir and Oseltamivir, are limited by noncovalent binding and emerging resistance. We hypothesized that Oseltamivir aziridines would unite transition-state mimicry for tight binding, with aziridine-enabled covalent capture of the catalytic tyrosine, thereby supporting both therapy and activity-based quantification. Here, we present oseltamivir-based aziridines, inspired by cyclophellitol chemistry, that act as covalent inhibitors and activity-based probes via an N-acylaziridine warhead. Free-energy calculations, and NMR observations, indicate a 4H5 half-chair preference consistent with the NA transition state, and selected analogues inhibit multiple NA subtypes with low nanomolar binding constants. Diverse evidence establishes covalency: time-dependent inactivation, inhibitor washout, intact-mass shifts, MS/MS identification of a tyrosine adduct, and QM/MM reaction profiles, while cryoEM of N1 aligns with the proposed binding mode, revealing an elimination product. The inhibitors demonstrate formidable activity against diverse viral neuraminidases, including H5N1, and further enable imaging and quantification of active NA. With their dual therapeutic and diagnostic potential, these first-in-class inhibitors indeed benefit from transition state mimicry and covalency, and thus offer a powerful platform for antiviral development and neuraminidase imaging, addressing urgent global health needs in influenza treatment and prevention.

Source: 

Link: https://www.pnas.org/doi/10.1073/pnas.2504045123

____

Mapping #global emergence of #pathogens with #epidemic and #pandemic #potential to inform and accelerate pandemic #prevention, #preparedness, readiness and response

 

Abstract

Introduction 

Increasing occurrence of epidemics and pandemics and concurrent emergence of different pathogens calls for multi-sectoral, multi-pathogen preparedness actions. Data on various factors that drive emergence of diverse pathogens can inform evidence-based preparedness by identifying geographies at-risk. When leveraging evidence within a One Health approach, multiple pathogens can be addressed simultaneously, thereby strengthening countries pandemic preparedness efforts. 

Methods 

For seventeen priority pathogens (avian influenza viruses, zoonotic coronaviruses including COVID-19, hemorrhagic fever viruses including Ebola, Henipaviruses, and arboviruses including yellow fever and Zika), we identified global evidence on animal reservoirs, vectors, environmental suitability, and reported human cases. We discriminated geospatially recorded pathogen detections from a background sample and constructed maps using these datasets to generate an evidence-based assessment of emergence risk globally. 

Results 

Seventeen pathogen-specific assessments were combined into a global composite map. Sub-Saharan Africa and South Asia have evidence supporting emergence risk for the greatest number of pathogens (included areas at-risk of all pathogens) and scored highest when strength-of-evidence weightings were factored. The Americas had the lowest tally of considered pathogens. Environmental suitability analyses received the highest weights, reservoir ranges the lowest. 

Discussion 

Preparedness and readiness must consider the range of global biological threats. Our methodology is capable of incorporating changing evidence on emergence potential for multiple pathogens to identify geographies at higher risk with different pathogen combinations. Our maps can contribute to existing decision-support structures, guiding shared interventions and strategic allocation of resources for spillover prevention and pandemic preparedness, thereby enhancing local response capacities applying a multidisciplinary approach.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was concluded in 2024 and supported by the United States Agency for International Development (USAID) before January 22, 2025, the Germany Agency for International Cooperation (GIZ) and the Government of France.

Source: 

Link: https://www.medrxiv.org/content/10.64898/2026.03.20.26347940v1

____

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

 

There is an observation of death of several numbers (30) of crows in the jungle of Tribhuvan University premises.

Source: 

Link: https://wahis.woah.org/#/in-review/7387

____

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

Frequent sightings of wild birds were reported in the vicinity of the farm. The farm comprises multiple poultry sheds having birds of different age (4-56 weeks) groups. On 15 March, a sudden mortality event occurred in one shed, where approximately 100 commercial layer birds died acutely. Since that incident, mortality has been observed across all sheds on the farm.

Commercial Layers of various age (4-56 weeks) group affected since 15 March, 2026 and a large number of chicken appear slightly droopy or depressed, and die suddenly.

Source: 

Link: https://wahis.woah.org/#/in-review/7386

____

#Denmark - #Influenza A #H5N5 viruses of high pathogenicity (Inf. with) (non-poultry including wild birds) (2017-) - Immediate notification

 

{A black headed gull. By © Hans Hillewaert, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5548312}

__

According to article 10.4.1.4 of the Terrestrial Animal Health Code, Member Countries should not impose bans on the trade in poultry commodities in response to notification on the presence of any influenza A virus in birds other than poultry

A wild black-headed gull.

Source: 

Link: https://wahis.woah.org/#/in-review/7385

____

#UK, #England: Notified cases of invasive #meningococcal disease - Updated 23 March 2026 (UKHSA, edited)

 

{Excerpt}

(...)

Daily case figures

-- The number of confirmed and probable cases can change when:

- a case is laboratory confirmed

- when the clinical assessment changes, including when new laboratory results are available

- when further epidemiological information is available

-- The figures in Table 1 cannot be used to identify the number of new confirmed or probable cases from one day to the next. This also applies to total cases.

Table 1. Cases of invasive meningococcal disease linked to Canterbury, Kent by day from 16 March 2026

[Date - Total confirmed cases - Confirmed MenB cases (subset of total confirmed cases) - Probable cases - Total cases]

* 22 March 2026 - 20 [note 2] - 19 -9 - 29

* 21 March 2026 - 20 [note 2] - 19 - 9 - 29

* 20 March 2026 - 23 - 18 - 11 - 34

* 19 March 2026 - 18 - 13 - 11 - 29

* 18 March 2026 - 15 - 9 - 12 - 27

* 17 March 2026 - 9 - 6 - 11 - 20

* 16 March 2026 - [note 1] - 4 - [note 1] - 15

__

Note 1: The distinction between a confirmed case and a probable case was not reported

Note 2: A case initially classified as a confirmed case may be reclassified or discarded when further laboratory results and clinical information is available. This applies to situations where:

- there are other negative results, for example, reference unit results 

and 

- there is an alternative diagnosis or where the clinical picture is no longer consistent with meningococcal infection

__

Note: The case numbers presented in Table 1 were confirmed at specific times of day for each of the releases: 16 March 2026 verified at 5:00pm, 17 March 2026 verified at 3:00pm, 18 March 2026 onwards verified at 12:30pm.

-- There have been 2 deaths since the start of the incident.

(...)

Source: 

Link: https://www.gov.uk/government/publications/invasive-meningococcal-disease-statistical-releases/notified-cases-of-invasive-meningococcal-disease

____

Defining #influenza-specific B cells in #vaccine #responders, non-responders and influenza breakthrough #infections

 

Abstract

Although seasonal influenza vaccination programs are effective at a population level, our data from inactivated influenza vaccine (IIV) cohorts in years 2015-2022 reveal that 50-60% of individuals do not seroconvert following immunization. The underlying mechanisms of vaccine non-responsiveness are far from understood. In this study, we sought to define key determinants of optimal B cell immune responses elicited by seasonal influenza vaccination, and to explore why some individuals fail to elicit humoral immunity following immunization. Immune responses associated with seroconversion and vaccine failure from individuals immunized with IIVs were compared at cellular and molecular levels using single-cell transcriptomics. We analyzed HA-specific B cell immunity across vaccine-responders, breakthrough infections and patients hospitalized with acute influenza. Droplet-based single-cell RNA sequencing and VDJ-sequencing of influenza-specific B cells from stored PBMCs was performed using 10x Genomics. Our results show that atypical B cells are the major subset of B cell responses in vaccine non-responders on day 28 post-vaccination. Conversely, individuals who seroconvert had diverse B cell phenotypes. The use of recombinant influenza-specific HA probes allowed us to dissect expression patterns on influenza HA-specific B cells. We found that HA-specific B cells of vaccine non-responders for A/H1N1 and A/H3N2 components displayed elevated atypical-like markers (CD11c, FcRL-5) at baseline, compared to responders. Analysis of differentially expressed genes (DEGs) between responders and non-responders identified differential expression of HLA-DR, CD74, CD83, and CXCR3 genes. We subsequently demonstrated reduced frequencies of HLA-DR-, CD74- and CD83-expressing B cells in patients hospitalized with influenza, compared to healthy participants. Hospitalized influenza patients also had significantly higher proportions of atypical CD21-CD27- B cells. Overall, our data demonstrate an association between elevated frequencies of atypical-like B cells with both lack of seroconversion following immunization and severe influenza infection. These findings broaden our understanding of humoral immunity in influenza vaccination and infection, providing novel insights for vaccination strategies and design.

Competing Interest Statement

Katherine Kedzierska has received paid honoraria from Pfizer. Hayley McQuilten has a consultancy role for Ena Therapeutics

Funder Information Declared

NHMRC

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.03.19.710321v1

____

Prophylactic and therapeutic efficacy of #monoclonal #antibodies against #H5N1 #influenza virus

 

Highlights

• mAbs could enhance our armamentarium against H5N1 in support of pandemic preparedness

• Several mAbs have shown prophylactic and therapeutic efficacy against H5N1 in animal models

• Anti-IAV mAbs that have advanced in clinical trials could be evaluated against H5N1

• Resistance emergence during mAb treatment was infrequent in pre- and clinical studies

Abstract

Highly pathogenic avian influenza H5N1 continues to pose a serious zoonotic and pandemic threat due to its increasing cross-species transmission and high virulence in humans. Despite the availability of vaccines and antivirals for seasonal influenza, effective prophylactic and treatment options for H5N1 remain limited. Herein we explore the potential action of monoclonal antibodies (mAbs) against H5N1, focusing on those with demonstrated efficacy in animal models. Most of these mAbs target conserved hemagglutinin epitopes and function as broad neutralizing fusion/entry inhibitors; notably, CR9114 targets both groups 1 and 2 influenza A strains as well as B lineages. Other mAbs prevent viral release by targeting neuraminidase, and those directed against the M2 ectodomain and nucleoprotein function through Fc receptor-mediated pathways. These mAbs have shown robust protection against lethal H5N1 challenge in mice, ferrets, and/or non-human primates. Compounds such as CR6261, MEDI8852, and TCN-032 have been evaluated in clinical trials for seasonal influenza, yielding encouraging safety and pharmacokinetics results and notably, no reported emergence of resistance. Despite these positive results their clinical development was prematurely discontinued. Integrating these highly effective mAbs into our H5N1 pandemic preparedness arsenal is a logical next step to provide a robust prophylactic and therapeutic option at the early stages of an outbreak. Future efforts must address regulatory and logistical barriers, invest in stockpiling and emergency use protocols, and support adaptive clinical trial frameworks to ensure rapid deployment when needed.

Source: 

Link: https://www.sciencedirect.com/science/article/pii/S0924857926000737?via%3Dihub

____

The Doge on the Bucintoro near the Riva di Sant'Elena, Francesco Guardi (1766 - 1770)

 

Public Domain.

Source: 

Link: https://www.wikiart.org/en/francesco-guardi/the-doge-on-the-bucintoro-near-the-riva-di-sant-elena-1770

____

#UK, #England: Notified cases of invasive #meningococcal disease (UKHSA, Updated 22 March 2026)

{Excerpt}

(...)

Table 1. Cases of invasive meningococcal disease linked to Canterbury, Kent by day from 16 March 2026

[Date - Total confirmed cases - Confirmed MenB cases (subset of total confirmed cases) - Probable cases - Total cases]

* 21 March 2026 - 20 [note 2] - 19 - 9 - 29 {-5} 

* 20 March 2026 - 23 - 18 - 11 - 34 {+5} 

* 19 March 2026 - 18 - 13 - 11 - 29 {+2}

* 18 March 2026 - 15 - 9 - 12 - 27 {+7}

* 17 March 2026 - 9 - 6 - 11 - 20 {+5}

* 16 March 2026 - [note 1] - 4 - [note 1] - 15

__

Note 1: The distinction between a confirmed case and a probable case was not reported

Note 2: A case initially classified as a confirmed case may be reclassified or discarded when further laboratory results and clinical information is available, that is:

- where there are other negative results, for example, reference unit results 

and 

- where there is an alternative diagnosis or where the clinical picture is no longer consistent with meningococcal infection

The case numbers presented in Table 1 were confirmed at specific times of day for each of the releases: 16 March 2026 verified at 5:00pm, 17 March 2026 verified at 3:00pm, 18 March 2026 onwards verified at 12:30pm.

There have been 2 deaths since the start of the incident.

(...)

Source: 

Link: https://www.gov.uk/government/publications/invasive-meningococcal-disease-statistical-releases/notified-cases-of-invasive-meningococcal-disease

____

#Dispersal, #adaptation and #persistence of #H5N1 in the sub-Antarctic and #Antarctica

 

Abstract

High pathogenicity avian influenza virus (HPAIV) H5N1 reached the sub-Antarctic and Antarctica in 2023, subsequently spreading to remote locations within this region where it had devastating impacts on seal, penguin and albatross populations. The threat to marine wildlife over this broad area exemplifies the need to understand H5N1 long-distance dispersal and evolution. We obtained 104 novel viral genomic sequences from samples that we collected at South Georgia, Kerguelen, Crozet, Prince Edward, Falklands/Malvinas Islands and the Antarctic Peninsula in a region spanning 8,000 kilometers. Using recent phylogeographic modeling advances we show that H5N1 spread encompassed numerous transmission events between distant locations, accumulating mammalian-adaptive mutations in the process. Seals are the most affected species, but we reveal that the long-distance eastward virus dispersal better aligns with the long-distance movements of large petrels and albatrosses. The risk of H5N1 endemisation, dispersal to other locations and ongoing evolution are highly concerning.

Competing Interest Statement

The authors have declared no competing interest.

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.03.20.713283v1

____

#UK, #England: Notified cases of invasive #meningococcal #disease - Updated 21 March 2026 (UKHSA)

 

Overview

-- The UK Health Security Agency (UKHSA) has been investigating an invasive meningococcal disease (IMD) outbreak first detected in March 2026.

-- This release provides an up-to-date count of confirmed or probable notified cases connected to the incident, and will be updated regularly.

-- Case numbers will be recorded at 12:30pm each day, and will include only those defined as either confirmed or probable. These figures will be published the following day at 9:30am.

-- As this is a live incident, there will be additional suspected cases notified to UKHSA, which need to be actively investigated. These will not be reported until the investigation determines that they should be included as either confirmed or probable cases, or discarded as not related to the incident.

-- Case counts attached to the incident are provisional and subject to change (upwards or downwards) as intelligence about their connection to the incident improves, clinical assessment changes, or further microbiological characterisation becomes available. In outbreaks, case definitions are updated as new intelligence comes to light, which may affect the counts.

Notified cases of invasive meningococcal disease linked to Canterbury, Kent

-- As of 12:30pm on 20 March 2026, UKHSA has been notified of 23 confirmed and 11 probable cases of invasive meningococcal disease with epidemiological links to Canterbury, Kent.

- 18 of the 23 confirmed cases are meningococcal group B (MenB).

- All cases have been hospitalised.

- There have been 2 deaths since the start of the incident.

Daily case figures

-- The number of probable cases can change when:

- a case is laboratory confirmed

-- when the clinical assessment changes, including when new laboratory results are available

- when further epidemiological information is available

-- The figures in Table 1 cannot be used to identify the number of new probable cases from one day to the next. This also applies to total cases.

Table 1. Cases of invasive meningococcal disease linked to Canterbury, Kent by day from 16 March 2026

[Date - Total confirmed cases - Confirmed MenB cases (subset of total confirmed cases) - Probable cases - Total cases]

* 20 March 2026 - 23 - 18 - 11 - 34

* 19 March 2026 - 18 - 13 - 11 - 29

* 18 March 2026 - 15 - 9 - 12 - 27

* 17 March 2026 - 9 - 6 - 11 - 20

* 16 March 2026 - [note 1] - 4  - [note 1] - 15

__

Note 1: The distinction between a confirmed case and a probable case was not reported

- The case numbers presented in Table 1 were confirmed at specific times of day for each of the releases: 16 March 2026 verified at 5:00pm, 17 March 2026 verified at 3:00pm, 18 March 2026 onwards verified at 12:30pm.

- There have been 2 deaths since the start of the incident.

Definitions

-- Confirmed MenB case

- For the purposes of the official counts related to the outbreak detected in Kent, a confirmed MenB case is counted only where an individual meets the following criteria:

* a clinical diagnosis of meningitis, sepsis, or other invasive disease (for example orbital cellulitis, septic arthritis)

and at least one of the following:

* Neisseria meningitidis isolated from a normally sterile site

* Gram-negative diplococci identified in a normally sterile site

* meningococcal DNA in a normally sterile site

* meningococcal antigen in blood, cerebrospinal fluid (CSF) or urine

and

* a confirmed meningococcal group B result from the Meningococcal Reference Unit (MRU), UKHSA or accredited laboratory

and

* an onset of infection since 1 March 2026

and

* an epidemiological link to the outbreak (see definition below)

-- Confirmed case (awaiting microbiological group)

- As above, awaiting microbiological group result.

-- Probable case

- For the purposes of the official counts related to the outbreak detected in Kent, a probable case is counted only where an individual meets the following criteria:

* a clinical diagnosis of meningitis or sepsis or other invasive disease where a doctor and/or microbiologist considers that meningococcal infection is the most likely diagnosis

and

* an onset of infection since 1 March 2026

and

* an epidemiological link to the outbreak (see definition below)

-- Epidemiological link to the outbreak

- For the purposes of the official counts related to the outbreak detected in Kent, a case is considered to have an epidemiological link to the outbreak only where the individual meets any of the following criteria:

* lived in or visited Canterbury, Kent since 1 March 2026

or

* close contact with an outbreak confirmed or outbreak probable case

or

* close contact with an individual who, since 1 March 2026, has lived in or visited Canterbury, Kent

or

* close contact with an individual who falls into one or more groups who have been offered chemoprophylaxis as part of this outbreak

-- Data quality assurance

- Data quality was assured via a manual checking process. Case counts attached to the incident are provisional and subject to change (upwards or downwards) as intelligence about their connection to the incident improves, clinical assessment changes or further microbiological characterisation becomes available.

(...)

Source: 

Link: https://www.gov.uk/government/publications/invasive-meningococcal-disease-statistical-releases/notified-cases-of-invasive-meningococcal-disease

____

#Coronavirus Disease Research #References (by AMEDEO, March 21 '26)

 

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History of Mass Transportation: The CZ/CD Diesel Railcar class 680 (1974)

 

By Václav Vyskočil (Upload: Jagro) - www.vlaky.net: [1], CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5776155

Source: 

Link: https://en.wikipedia.org/wiki/List_of_Czech_locomotive_classes

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