Anti- #neuraminidase and anti- #hemagglutinin #stalk responses to different #influenza A(#H7N9) #vaccine regimens

Abstract

Introduction

Pandemic influenza vaccine development focuses on the hemagglutinin (HA) antigen for potency and immunogenicity. Antibody responses targeting the neuraminidase (NA) antigen, or the HA stalk domain have been implicated in protection against influenza. Responses to the NA and HA-stalk domain following pandemic inactivated influenza are not well characterized in humans.

Material and methods

In a series of clinical trials, we determine the vaccines' NA content and demonstrate that NA inhibition (NAI) antibody responses increase in a dose-dependent manner following a 2-dose priming series with AS03-adjuvanted influenza A(H7N9) inactivated vaccine (A(H7N9) IIV). NAI antibody responses also increase with interval extension of the 2-dose priming series or following a 5-year delayed boost with a heterologous adjuvanted A(H7N9) IIV. Neither concomitant seasonal influenza vaccination given simultaneously or sequentially, nor use of heterologous A(H7N9) IIVs in the 2-dose priming series had an appreciable effect on NAI antibody responses. Anti-HA stalk antibody responses were minimal and not durable.

Conclusions

We provide evidence for strategies to improve anti-neuraminidase responses which can be further standardized for pandemic preparedness.

Source: Vaccine, https://www.sciencedirect.com/science/article/abs/pii/S0264410X24013719?via%3Dihub

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Evidence of #Influenza A(#H5N1) #Spillover #Infections in #Horses, #Mongolia

Abstract

Recent outbreaks of influenza A(H5N1) have affected many mammal species. We report serologic evidence of H5N1 virus infection in horses in Mongolia. Because H3N8 equine influenza virus is endemic in many countries, horses should be monitored to prevent reassortment between equine and avian influenza viruses with unknown consequences.

Source: Emerging Infectious Diseases Journal, https://wwwnc.cdc.gov/eid/article/31/1/24-1266_article

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#USA, #Update on #Delaware #H5 Avian #Influenza Case on Kent County #Farm

DOVER, Del. (January 5, 2025)—The U.S. Department of Agriculture’s National Veterinary Services Laboratory (NVSL) has returned results from the Kent County, Del. poultry farm that was announced presumptive positive for H5 avian influenza on January 3, 2025. The poultry affected had highly pathogenic H5 avian influenza (HPAI) of the Eurasian lineage 2.3.4.4b with early indications that the virus is the D1.1 genotype found in wild birds; however, confirmation of the genotype is determined by sequencing. There is currently no timeline for the receipt of this data by the Delaware Department of Agriculture.

All poultry farms in the state should be monitoring flocks for any signs of increased mortality. Producers should pay particular attention to whether birds show signs of respiratory illness or distress, such as sneezing, gasping for air, coughing, and/or runny nose. Other signs of HPAI in poultry can include swelling around the eyes, neck, and head; purple discoloration of the wattles, combs, and legs; tremors, drooping wings, circling, twisting of the head and neck, or any combination; watery, green diarrhea; lack of energy, poor appetite; and a drop in egg production, or soft or thin-shelled, misshapen eggs.

Commercial poultry producers should follow the protocol of notifying the company they grow for when they see any signs of HPAI.

Backyard flock owners who notice any of the signs of HPAI or experience increased mortality in their flock should email the Delaware Poultry Health Hotline at poultry.health@delaware.gov or call 302-698-4507 and provide your contact information, flock size, location, and concerns. Backyard flock owners will be contacted if a sample needs to be taken. Do not take dead or sick birds to a lab to be tested or move them off-site.

Backyard flock owners should keep their flock from commingling with wild birds and keep them under cover to protect them from coming into contact with infected wild bird droppings. The H5N1 virus has infected a small number of people across the U.S., and there has been no documented transmission between people in the U.S. to date. While continuing testing of people in close contact with animals infected with HPAI indicates a low risk to the general public’s health, backyard flock owners should keep birds in outdoor coops and not bring birds that have been living outside into the home. Children and pets should be kept away from wild birds and bird droppings.

When adding birds to your flock, make sure to purchase them from a reputable source. The baby chicks purchased at local farm stores come from NPIP-certified flocks tested and shown to be free from avian influenza. When they are between two days and two weeks old, these chicks will typically leave the store with their new owner, so they are considered low-risk for having the disease. However, once they are about three weeks old, they are more susceptible to contracting the virus from their new environment. Make sure to keep new birds or returning show birds separated from the established home flocks for 30 days.

The Delaware Department of Agriculture requires the registration of all locations where live poultry is kept, which allows timely information on disease incidents to be sent to all poultry producers. Registration forms are available online at https://de.gov/poultry.

Delawareans are reminded not to touch or handle injured, sick, or dead birds and to use the DNREC Division of Fish and Wildlife’s Sick and Dead Wildlife Reporting Form should they encounter dead or sick birds. Wild birds should not be reported to the Delaware Poultry Health Hotline, as that reporting hotline is reserved for backyard flocks and farms with poultry.

(...)

Source: Government of Delaware State, https://news.delaware.gov/2025/01/05/update-on-delaware-h5-avian-influenza-case-on-kent-county-farm/

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#China, National sentinel #surveillance of acute #respiratory infectious #diseases (Week 52, 2024)

{Excerpt}

In the 52nd week of 2024 ( December 23rd to December 29th ), respiratory samples from outpatient influenza-like cases and hospitalized severe acute respiratory infection cases collected in sentinel hospitals across the country (excluding Hong Kong, Macao and Taiwan) were tested for 10 viruses including the new coronavirus, influenza virus, respiratory syncytial virus, adenovirus, human metapneumovirus, parainfluenza virus, common coronavirus, bocavirus, rhinovirus and enterovirus, as well as multiple respiratory pathogens including Mycoplasma pneumoniae.

1. Test results

The pathogens detected positive in respiratory samples of influenza-like cases in outpatient and emergency departments of sentinel hospitals were mainly influenza virus, human metapneumovirus, and rhinovirus; the pathogens detected positive in respiratory samples of hospitalized severe acute respiratory infection cases were mainly influenza virus, Mycoplasma pneumoniae, and human metapneumovirus. The specific results are shown in Table 1 , Figure 1 , and Figure 2. The test results showed differences between the north and south regions and between different age groups, as shown in Table 2 and Table 3 .

2. Analysis and health tips

The results showed that the overall acute respiratory infectious diseases are showing a continuous upward trend, and the trends of infections caused by different pathogens are different. Influenza is generally in the seasonal epidemic period, and the influenza virus positive rate is rising rapidly. Among them, the influenza virus positive rate of outpatient influenza-like cases nationwide increased by 6.2% compared with last week ; the level of influenza activity varies among provinces, and the increase in northern provinces is slightly obvious, but still lower than the same period last year. Recently, the positive rate of respiratory syncytial virus in cases aged 0 to 4 years and the positive rate of human metapneumovirus in cases aged 14 years and below have fluctuated upward, and the upward trend is more obvious in northern provinces. The positive rate of rhinovirus continues to decline; the positive rate of Mycoplasma pneumoniae in northern provinces continues to decline, and Mycoplasma pneumoniae infection in southern provinces is still at a low level. The positive rate of adenovirus fluctuates and declines. Other respiratory pathogens such as the new coronavirus are at a low epidemic level.

We are still in the season of high incidence of respiratory infectious diseases. In order to reduce the spread of diseases and reduce the harm of diseases, the public is advised to take the following protective measures:

( 1 ) Maintain good hygiene habits: cover your mouth and nose with a tissue, towel or elbow when coughing or sneezing; wash your hands frequently with soap and water for at least 20 seconds, or use alcohol-based hand sanitizer; avoid touching your eyes, nose, and mouth with your hands to reduce the risk of pathogen transmission.

( 2 ) Promote a healthy lifestyle: A balanced diet, moderate exercise and adequate rest can help enhance immunity. If you have a fever, cough or other respiratory infection symptoms, it is recommended to rest at home, avoid going to work or school while sick, wear a mask when in contact with family members, and keep the room well ventilated.

( 3 ) Wear a mask scientifically: Wear a mask throughout the medical treatment process; it is recommended to wear a mask in crowded places or when taking public transportation (such as airplanes, trains, subways, etc.).

( 4 ) Actively vaccinate: People with weak immunity (such as pregnant women, young children, the elderly and patients with chronic diseases) should be vaccinated with relevant vaccines to prevent respiratory infectious diseases in a timely manner according to vaccination guidelines, including influenza vaccine, new coronavirus vaccine and pneumococcal vaccine. In particular, as the level of influenza activity has increased recently, people of appropriate age who have not received influenza vaccination should be vaccinated as soon as possible. 

(...)

Source: China Centers for Disease Control and Prevention, https://www.chinacdc.cn/jksj/jksj04_14275/202501/t20250102_303654.html

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#Detection of #Hemagglutinin #H5 #influenza A virus #RNA and model of potential inputs in an #urban #California #sewershed

Abstract

In 2024, the highly pathogenic avian influenza A H5N1 caused outbreaks in wild birds, poultry, cows, and other mammals in the United States with 61 human cases also reported by the CDC. Detection of influenza A H5 RNA in wastewater has been previously reported in sewersheds in Texas and North Carolina with nearby impacted dairy herds following the emergence of H5N1 in dairy cows. Here, we conduct retrospective testing of total influenza A and H5 hemagglutinin genes in wastewater as well presenting and applying new assays for detection of H1 and H3 genes across a respiratory virus season in an urban California sewershed from September 2023-May 2024. Total influenza A, H1, and H3 were regularly detected, while H5 was first detected in March. We developed a model that uses Monte Carlo simulations and previously published parameters to estimate numbers of infected people, poultry, wild birds, or liters of H5-contaminated milk required to result in measured H5 concentrations in wastewater. Our findings demonstrate that in this California sewershed, contaminated milk or infected poultry were the most likely sources of H5 to wastewater. We created a publicly available tool to apply the H5 input model in other sewersheds estimate required inputs.

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2024.12.31.24319823v1

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Acute #Encephalopathy Associated with #Human #Adenovirus Type 14 Infection in 7-Year-Old Girl, #Japan

Abstract

Only 2 cases of human adenovirus type 14 (HAdV-14) have been reported in Japan since 1980. We report a 7-year-old girl with acute encephalopathy associated with HAdV-14 infection genetically similar to strains from the United States. The patient had not had contact with international travelers. HAdV-14 surveillance should be strengthened in Japan.

Source: Emerging Infectious Diseases Journal, https://wwwnc.cdc.gov/eid/article/31/2/24-1168_article

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Two #genotypes of #H3N2 #swine #influenza viruses identified in #pigs from #Shandong Province, #China

 {Summary}

Swine influenza virus (SIV) is a highly contagious pathogen that poses significant economic challenges to the swine industry and carries zoonotic potential, underscoring the need for vigilant surveillance. In this study, we performed a comprehensive genetic and molecular analysis of H3N2 SIV isolates obtained from 372 swine samples collected in Shandong Province, China. Phylogenetic analysis revealed two distinct genotypes. The surface genes of both genotypes clustered with the human-like H3N2 lineage, while the internal genes of one genotype clustered with the 2009 pandemic H1N1 (pdm/09) lineage. In the second genotype, the NS gene clustered with the classical swine (CS) H1N1 lineage, while the remaining internal genes clustered with pdm/09, suggesting stable integration of pdm/09 gene segments into H3N2 SIV. Homology analysis showed over 96% genetic similarity between the isolates and reference strains from China and Brazil, suggesting potential transmission through swine trade or human movement. Molecular characterization identified amino acid substitutions in the HA protein (190D, 226I, and 228S), potentially enhancing the virus’s affinity for human-like receptors, thereby increasing the zoonotic risk. Key mutations in the PB2 (271A, 591R), PA (336M, 356R, 409N), and M2 (S31N) proteins, along with novel drug resistance mutations, indicate the potential for enhanced virulence and drug resistance in these isolates. Moreover, glycosylation site analysis revealed four differences, and antigenic site analysis showed 13 differences between the HA proteins of the isolates and the WHO-recommended vaccine strain A/Cambodia/E0826360/2020 for the 2021–2022 season, which may reduce vaccine efficacy. Serological analysis revealed that 11 out of the tested serum samples were positive for H3N2 antibodies, resulting in an overall positivity rate of 0.42%. These findings emphasize the urgent need for strengthened SIV surveillance in China to monitor the risk of human transmission and ensure better preparedness for future influenza outbreaks.

Source: Frontiers in Cellular and Infection Microbiology, https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1517023/full

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#USA, #Wastewater #Data for Avian #Influenza A(#H5) (As of Dec. 28 '24)

 {Excerpt}

Time Period: December 22 - December 28, 2024

-- H5 Detection: 44 sites (18.6%)

-- No Detection: 192 sites (81.4%)

-- No samples in last week: 150 sites

(...)

Source: US Centers for Disease Control and Prevention, https://www.cdc.gov/nwss/rv/wwd-h5.html

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#USA, #Delaware Announces First Presumptive Positive #H5 Avian #Influenza Case Detected on Kent County {#Poultry} #Farm in 2025

{Excerpt}

DOVER, Del. (January 3, 2025) – The Delaware Department of Agriculture announced this morning that preliminary testing of a commercial broiler flock in Kent County, Del., has returned presumptive positive H5 from the University of Delaware’s Lasher Laboratory in Georgetown, part of the National Animal Health Laboratory Network. Additional samples have been sent to the U.S. Department of Agriculture’s National Veterinary Services Laboratory (NVSL) for further confirmation.

State officials have quarantined the affected premises, and the birds on the property are being depopulated to prevent the spread of the disease. Birds from the affected flock will not enter the food system.

Avian influenza is a highly contagious airborne respiratory virus that spreads quickly among birds through nasal and eye secretions and manure. The virus can be spread from flock to flock, including flocks of wild birds, through contact with infected poultry, equipment, and the clothing and shoes of caretakers. This virus affects poultry, like chickens, ducks, and turkeys, and some wild bird species, such as ducks, geese, shorebirds, and raptors.

Last week, Delaware announced presumptive positive H5 results in snow geese found at Prime Hook Beach. The state is still awaiting confirmatory results from NVSL. With the assistance of the public, more than 850 wild birds, a majority of them snow geese but including Canada geese, other waterfowl, vultures, and other birds, were reported dead via the DNREC Division of Fish and Wildlife’s Sick and Dead Wildlife Reporting Form. While some of these may be duplicate reports, or deaths due to other causes, officials know that more birds have succumbed to the virus, dying in places out of sight.

To better protect their flocks, poultry producers and backyard flock owners must realize that what occurs in wild birds does impact the health of their birds and that this is not only a problem along Delaware’s coast, which is where many of the reported dead birds have been located so far. In the evening hours, snow geese fly to water to roost, where they can then spread the virus in their flock. Those birds that are not sick or are strong enough to fly in the morning will then take flight, moving inland to open space, including farm fields, to forage. At this time that virus can be introduced to poultry farms and areas where backyard flocks are commingling with wildlife or are not under cover, protecting them from infected wild bird droppings. Snow geese are very mobile, flying as far into Maryland or New Jersey in a day.

Considering this new case and the prevalence of the virus in the wild bird population, all poultry owners need to increase their vigilance in protecting their flocks from contracting avian influenza by following these steps:

• Limit, monitor, and record any movement of people, vehicles, or animals on or off your farm.

• Permit only essential workers and vehicles to enter the farm to limit the chances of bringing the virus from an outside source.

• Avoid visiting other poultry farms and any unnecessary travel off the farm.

• Disinfect equipment, vehicles, footwear, and other items that come into contact with flocks.

• Keep your flock away from wild or migratory birds, especially waterfowl.

• Isolate any ill animals and contact your veterinarian.

(...)

Source: Government of Delaware, https://dhss.delaware.gov/dhss/

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

Backyard reared non-poultry birds in Rheinland-Pfalz Region.

Source: WOAH, https://wahis.woah.org/#/in-review/6149

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Random forest #algorithm reveals novel sites in #HA #protein that shift #receptor binding preference of the #H9N2 avian #influenza virus

Abstract

A switch from avian-type α-2,3 to human-type α-2,6 receptors is an essential element for the initiation of a pandemic from an avian influenza virus. Some H9N2 viruses exhibit a preference for binding to human-type α-2,6 receptors. This identifies their potential threat to public health. However, our understanding of the molecular basis for the switch of receptor preference is still limited. In this study, we employed the random forest algorithm to identify the potentially key amino acid sites within hemagglutinin (HA), which are associated with the receptor binding ability of H9N2 avian influenza virus (AIV). Subsequently, these sites were further verified by receptor binding assays. A total of 12 substitutions in the HA protein (N158D, N158S, A160N, A160D, A160T, T163I, T163V, V190T, V190A, D193N, D193G, and N231D) were predicted to prefer binding to α-2,6 receptors. Except for the V190T substitution, the other substitutions were demonstrated to display an affinity for preferential binding to α-2,6 receptors by receptor binding assays. Especially, the A160T substitution caused a significant upregulation of immune-response genes and an increased mortality rate in mice. Our findings provide novel insights into understanding the genetic basis of receptor preference of the H9N2 AIV.

Source: Virologica Sinica, https://www.sciencedirect.com/science/article/pii/S1995820X24002116?via%3Dihub

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Highly Pathogenic Avian #Influenza (HPAI) #H5N1 virus in #Finland in 2021-2023 – Genetic diversity of the viruses and infection kinetics in #human dendritic cells

Abstract

Highly pathogenic avian influenza (HPAI) H5N1 is known for its virulence and zoonotic potential, infecting birds and mammals, thus raising public health concerns. Since 2021 its spread among birds has led to cross-species transmission causing epizootics among mammals, eventually impacting fur animal farms in Finland in 2023. To analyze the infectivity of the Finnish H5N1 isolates in human cells, representatives of diverse H5N1 isolates were selected based on the genetic differences, host animal species, and the year of occurrence. The infection kinetics of the selected H5N1 isolates from wild pheasant and fox, and fur animals blue fox and white mink were examined in human monocyte-derived dendritic cells (moDCs) with H5N1 human isolate as a control. Although the isolate from pheasant (a wild bird) showed weakly reduced replication and viral protein expression in human cells compared to mammalian isolates, no discernible differences in virus replication in moDCs was observed. This study revealed similar infectivity in human moDCs for all five H5N1 isolates, regardless of the observed genetic differences. While H5N1 human infections remain rare, the virus poses a risk for widespread epizootics in mammals such as fur animal farms and, more recently, dairy cattle.

Source: Emerging Microbes & Infections, https://www.tandfonline.com/doi/full/10.1080/22221751.2024.2447618

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Are we serologically prepared against an avian #influenza #pandemic and could seasonal flu #vaccines help us?

ABSTRACT

The current situation with H5N1 highly pathogenic avian influenza virus (HPAI) is causing a worldwide concern due to multiple outbreaks in wild birds, poultry, and mammals. Moreover, multiple zoonotic infections in humans have been reported. Importantly, HPAI H5N1 viruses with genetic markers of adaptation to mammals have been detected. Together with HPAI H5N1, avian influenza viruses H7N9 (high and low pathogenic) stand out due to their high mortality rates in humans. This raises the question of how prepared we are serologically and whether seasonal vaccines are capable of inducing protective immunity against these influenza subtypes. An observational study was conducted in which sera from people born between years 1925–1967, 1968–1977, and 1978–1997 were collected before or after 28 days or 6 months post-vaccination with an inactivated seasonal influenza vaccine. Then, hemagglutination inhibition, viral neutralization, and immunoassays were performed to assess the basal protective immunity of the population as well as the ability of seasonal influenza vaccines to induce protective responses. Our results indicate that subtype-specific serological protection against H5N1 and H7N9 in the representative Spanish population evaluated was limited or nonexistent. However, seasonal vaccination was able to increase the antibody titers to protective levels in a moderate percentage of people, probably due to cross-reactive responses. These findings demonstrate the importance of vaccination and suggest that seasonal influenza vaccines could be used as a first line of defense against an eventual pandemic caused by avian influenza viruses, to be followed immediately by the use of more specific pandemic vaccines.

Source: mBio, https://journals.asm.org/doi/10.1128/mbio.03721-24

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#Vaccination with different group 2 #influenza #subtypes alters epitope targeting and breadth of #hemagglutinin stem–specific human B cells

Abstract

The conserved influenza hemagglutinin stem, which is a target of cross-neutralizing antibodies, is now used in vaccine strategies focused on protecting against influenza pandemics. Antibody responses to group 1 stem have been extensively characterized, but little is known about group 2. Here, we characterized the stem-specific repertoire of individuals vaccinated with one of three group 2 influenza subtypes (H3, H7, or H10). Epitope mapping revealed two epitope supersites on the group 2 stem. Antibodies targeting the central epitope were broadly cross-reactive, whereas antibodies targeting the lower epitope had narrower breadth but higher potency against H3 subtypes. The ratio of B cells targeting each of the supersites varied with the vaccine subtype, leading to differences in the cross-reactivity of the B cell response. Our findings suggest that vaccine strategies targeting both group 2 stem epitopes would be complementary, eliciting broader and more potent protection against both seasonal and pandemic influenza strains.

Source: Science Translational Medicine, https://www.science.org/doi/10.1126/scitranslmed.adr8373

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Prior #infection with IBDV prolonged the shedding of a #mallard #H3N8 #influenza A virus (IAV) challenge from oropharyngeal cavity of some #chickens {...}

Abstract

Infectious bursal disease virus (IBDV) is endemic worldwide and causes immunosuppression in chickens. We hypothesized that a previous history of IBDV in chickens would render them more susceptible to infection by influenza A viruses (IAVs) from aquatic waterfowl reservoirs. To model this, we inoculated 14 day old specific pathogen free (SPF) chickens with a low pathogenicity avian influenza (LPAI) virus strain from a mallard (A/Mallard/Alberta/156/01 (H3N8)) and compared replication and shedding between immunocompetent chickens and chickens that had immune dysregulation due to a prior IBDV infection with strain F52/70 (genogroup A1B1) at 2 days of age. The mallard IAV strain replicated in the upper respiratory tract of the chickens, and virus was shed from the oropharyngeal cavity, but there was no shedding from the cloaca, and no transmission to sentinel chickens. Replication of the mallard IAV in the chicken host was associated with amino acid substitutions in the polymerase complex and HA. IBDV infection increased the average fold change of IAV replication in the trachea of chickens, prolonged the shedding of infectious IAV from 5 to 6 days in some chickens, increased the number of amino acid substitutions detected in the IAV population from 13 to 30, and significantly increased the number of mutations per IAV sample from 2.50 (SD +/- 1.83) in the Mock/IAV group to 4.75 (SD +/- 1.81) in the IBDV/IAV group (p < 0.01). Taken together, IBDV infection prolonged the shedding of the mallard IAV in some chickens and changed IAV intra-host evolution.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.12.31.630863v1?rss=1

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Identification of a broad-inhibition #influenza #neuraminidase #antibody from pre-existing memory B cells

Highlights

-- Both NA-specific antibodies and memory B cells are detected in healthy adults

-- NA broad-inhibition monoclonal antibodies are derived from classical memory B cells

-- Broad inhibition monoclonal antibodies target the NA conserved enzymatic epitopes

-- NA broad-inhibition antibodies protect mice against H1N1 and H5N1-clade 2.3.4.4b

Summary

Identifying broadly reactive B precursor cells and conserved epitopes is crucial for developing a universal flu vaccine. In this study, using influenza neuraminidase (NA) mutant probes, we find that human pre-existing NA-specific memory B cells (MBCs) account for ∼0.25% of total MBCs, which are heterogeneous and dominated by class-unswitched MBCs. In addition, we identify three NA broad-inhibition monoclonal antibodies (mAbs) (BImAbs) that block the activity of NA derived from different influenza strains, including the recent cow H5N1. The cryoelectron microscopy (cryo-EM) structure shows that the BImAb targets the conserved NA enzymatic pocket and a separate epitope in the neighboring NA monomer. Furthermore, the NA BImAbs protect mice from the lethal challenge of the human pandemic H1N1 and H5N1. Our work demonstrates that the NA broad-inhibition precursor MBCs exist in healthy adults and could be targeted by the NA-based universal flu vaccine.

Source: Cell Host Microbe, https://www.sciencedirect.com/science/article/abs/pii/S1931312824004670?via%3Dihub

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#Combination #chemotherapy, a potential #strategy for reducing the emergence of #drug-resistant #influenza A variants

Natalia A. Ilyushina {a b}, Nicolai V. Bovin {c}, Robert G. Webster {a d}, Elena A. Govorkova  {a b}

a} Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA; b} The D.I. Ivanovsky Institute of Virology, Gamaleya 16, Moscow 123098, Russia; c} Shemyakin Institute of Bioorganic Chemistry, 16/10 Miklukho-Maklaya, Moscow 117997, Russia; d} Department of Pathology, University of Tennessee, Memphis, TN 38105, USA

Received 21 November 2005, Accepted 26 January 2006, Available online 21 February 2006.

Abstract

Rapid development of resistant influenza variants after amantadine treatment is one of the main drawbacks of M2 blockers. On the other hand, the emergence of variants with low susceptibility to the neuraminidase (NA) inhibitors is limited. In the present study we examined whether combination therapy with two classes of anti-influenza drugs can affect the emergence of resistant variants in vitro. We observed that virus yields of human A/Nanchang/1/99 (H1N1), A/Panama/2007/99 (H3N2), and A/Hong Kong/156/97 (H5N1) viruses in MDCK cells were significantly reduced (P < 0.005) when the cells were treated with the combination of amantadine and low doses of oseltamivir carboxylate (≤1 μM). After five sequential passages in MDCK cells, the M2 protein of viruses cultivated with amantadine alone mutated at positions V27A and S31N/I. Viruses cultivated with oseltamivir carboxylate (≥0.001 μM) possessed mutations in the hemagglutinin (HA) protein. These variants showed reduced efficiency of binding to sialic acid receptors and decreased sensitivity to NA inhibitor in plaque reduction assay. Importantly, no mutations in the HA, NA, and M2 proteins were detected when the drugs were used in combination. Our results suggest that combination chemotherapy with M2 blocker and NA inhibitor reduced the emergence of drug-resistant influenza variants in vitro. This strategy could be an option for the control of influenza virus infection, and combinations with other novel drugs should be explored.

Source: Antiviral Research, https://www.sciencedirect.com/science/article/abs/pii/S0166354206000349

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#USA, #NIH officials assess #threat of #H5N1

 {Excerpt, edited}

What

Highly pathogenic H5N1 avian influenza A virus (HPAI H5N1) remains a low risk to the general public, and public health experts in the United States believe that available treatments and vaccines, as well as those in development, are sufficient to prevent severe disease. However, the National Institutes of Health (NIH) and its federal partners remain focused on monitoring the virus and evaluating changes, according to leading officials at the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH.

In a commentary published in the New England Journal of Medicine, NIAID Director Jeanne M. Marrazzo, M.D., M.P.H., and Michael G. Ison, M.D., M.S., chief of the Respiratory Diseases Branch in NIAID’s Division of Microbiology and Infectious Diseases, say people should find a balance between enhanced vigilance and “business as usual” with respect to HPAI H5N1.

Since 1996, HPAI H5N1 influenza viruses have circulated in at least 23 countries. In late 2021, HPAI H5N1 spread from Europe to North America causing sporadic infections among wild birds and poultry farms. In 2022, the virus spread to South America where it devastated birds and marine mammals. In March 2024, USDA scientists identified HPAI H5N1 in U.S. dairy cows, and it subsequently reached herds in 16 states. The virus has been detected in dairy herds in three states over the past 30 days, according to USDA/APHIS. In 2024, the virus has caused 66 confirmed and 7 probable cases of influenza in people in the U.S. and one case in Canada. These human cases have been caused by either the H5N1 type circulating in birds (D1.1) or the type circulating in dairy cows (B3.13).

Against this backdrop, Drs. Marrazzo and Ison say there are four keys to controlling the current outbreak. The first imperative is timely, effective collaborations among investigators in human and veterinary medicine, public health, health care, and occupational workers, such as dairy and poultry workers.

This involves cultivating trust not only between numerous entities, but with people seeking care for symptoms of concern, including conjunctivitis, the authors write. Fortunately, so far most U.S. cases of HPAI H5N1 have been mild and resolved on their own without the need for treatment.

Their second key is a focus on the Canadian HPAI H5N1 patient, who developed respiratory failure and required life-saving medical intervention and treatment before recovering. The authors write that mutations found in the virus in this patient highlight an urgent need for vigilant disease surveillance to identify and assess viral changes to evaluate the risk for person-to-person transmission. Effective surveillance, they say, requires that complete genomic sequencing data from animals and people are made rapidly and readily available.

Without information pertaining to where and when isolates were collected, the data cannot be linked phylogenetically to other reported sequences, limiting insight into how the virus is spreading, they write. These data would also provide opportunity for early detection of mutations that might portend avidity for human respiratory epithelium, which may require as little as one mutation in the virus.

Third, researchers must continue to develop and test medical countermeasures—such as vaccines and therapies that eliminate or alleviate disease—against H5N1 and other influenza viruses. Fortunately, current vaccine candidates neutralize the circulating strains, which so far are susceptible to antivirals that could mitigate transmission and severity of illness, they write.

Lastly, Drs. Marrazzo and Ison encourage people to take precautions to prevent exposure to the virus and minimize the risk of infection. For example, people who work with poultry and cows should use personal protective equipment and educate themselves about occupational risks when working with birds and mammals, as CDC and USDA have repeatedly recommended.

Ideally, following these four steps will help scientists and public health officials investigating HPAI H5N1 to answer the many remaining questions more quickly about how the virus is spreading, evolving, and affecting people, other mammals, and birds.

Article: M Ison and J Marrazzo. The Emerging Threat of H5N1 to Human Health. NEJM DOI: 10.1056/NEJMe2416323 (2024).

Who: NIAID Director Jeanne M. Marrazzo, M.D., M.P.H., and Michael G. Ison, M.D., M.S., chief of the Respiratory Diseases Branch in NIAID’s Division of Microbiology and Infectious Diseases, are available for comment.

(...)

Source: US National Institute of Health, https://www.nih.gov/news-events/news-releases/nih-officials-assess-threat-h5n1

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