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1.
Immunity ; 54(9): 2159-2166.e6, 2021 09 14.
Article in English | MEDLINE | ID: mdl-34464596

ABSTRACT

The emergence of SARS-CoV-2 antigenic variants with increased transmissibility is a public health threat. Some variants show substantial resistance to neutralization by SARS-CoV-2 infection- or vaccination-induced antibodies. Here, we analyzed receptor binding domain-binding monoclonal antibodies derived from SARS-CoV-2 mRNA vaccine-elicited germinal center B cells for neutralizing activity against the WA1/2020 D614G SARS-CoV-2 strain and variants of concern. Of five monoclonal antibodies that potently neutralized the WA1/2020 D614G strain, all retained neutralizing capacity against the B.1.617.2 variant, four also neutralized the B.1.1.7 variant, and only one, 2C08, also neutralized the B.1.351 and B.1.1.28 variants. 2C08 reduced lung viral load and morbidity in hamsters challenged with the WA1/2020 D614G, B.1.351, or B.1.617.2 strains. Clonal analysis identified 2C08-like public clonotypes among B cells responding to SARS-CoV-2 infection or vaccination in 41 out of 181 individuals. Thus, 2C08-like antibodies can be induced by SARS-CoV-2 vaccines and mitigate resistance by circulating variants of concern.


Subject(s)
Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Germinal Center/immunology , Lung/virology , SARS-CoV-2/physiology , Animals , Cells, Cultured , Clone Cells , Cricetinae , Disease Models, Animal , Humans , Neutralization Tests , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Viral Load
2.
Nature ; 603(7902): 687-692, 2022 03.
Article in English | MEDLINE | ID: mdl-35062015

ABSTRACT

The recent emergence of B.1.1.529, the Omicron variant1,2, has raised concerns of escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against B.1.1.529 is their activity in preclinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of several B.1.1.529 isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2)-expressing mice and hamsters. Despite modelling data indicating that B.1.1.529 spike can bind more avidly to mouse ACE2 (refs. 3,4), we observed less infection by B.1.1.529 in 129, C57BL/6, BALB/c and K18-hACE2 transgenic mice than by previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease and pathology with B.1.1.529 were also milder than with historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from the SAVE/NIAID network with several B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.


Subject(s)
COVID-19/pathology , COVID-19/virology , Disease Models, Animal , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Cricetinae , Female , Humans , Lung/pathology , Lung/virology , Male , Mesocricetus , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Viral Load
3.
Nature ; 605(7911): 640-652, 2022 05.
Article in English | MEDLINE | ID: mdl-35361968

ABSTRACT

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Biological Evolution , COVID-19 Vaccines , Humans , National Institute of Allergy and Infectious Diseases (U.S.) , Pandemics/prevention & control , Pharmacogenomic Variants , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , United States/epidemiology , Virulence
4.
Clin Infect Dis ; 2023 Jan 05.
Article in English | MEDLINE | ID: mdl-36610728

ABSTRACT

BACKGROUND: Influenza A/H5N8 viruses infect poultry and wild birds in many countries. In 2021, the first human A/H5N8 cases were reported. METHODS: We conducted a phase I, cohort-randomized, double-blind, controlled trial of inactivated influenza A/H5N8 vaccine (clade 2.3.4.4c) administered with or without adjuvant. Cohort 1 subjects received either two doses of AS03-adjuvanted vaccine containing 3.75 µg or 15 µg hemagglutinin (HA); two doses of 15 µg HA unadjuvanted vaccine; or one dose of AS03-adjuvanted vaccine (3.75 µg or 15 µg HA), followed by one dose of non-adjuvanted vaccine (same HA content). Cohort 2 subjects received two doses of MF59-adjuvanted vaccine containing 3.75 µg or 15 µg HA, or 15 µg HA of non-adjuvanted vaccine. Subjects were followed for 13 months for safety and immunogenicity. RESULTS: We enrolled 386 adult subjects in good health. Solicited adverse events were generally mild and more common among subjects who received adjuvanted vaccines. Antibody responses (hemagglutination inhibition or microneutralization assays) were highest in the two-dose AS03 group, followed by the one-dose AS03 group, the MF59 groups, and the non-adjuvanted groups. Antibody levels returned to baseline 12 months after the second vaccination in all groups except the 15 µg AS03-adjuvanted group. Cross-reactive antibodies to clade 2.3.4.4b strains isolated from recent human cases were demonstrated in a subset of both 15 µg adjuvanted groups. CONCLUSIONS: Two doses of influenza A/H5N8 vaccine were well-tolerated. Immunogenicity improved with receipt of two doses of adjuvanted vaccine and higher antigen content. (Funded by the National Institute of Allergy and Infectious Diseases.

5.
Emerg Infect Dis ; 28(12): 2534-2537, 2022 12.
Article in English | MEDLINE | ID: mdl-36417959

ABSTRACT

In August 2021, we detected highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b viruses in poultry in southern Benin. The isolates were genetically similar to H5N1 viruses of clade 2.3.4.4b isolated during the same period in Africa and Europe. We also found evidence for 2 separate introductions of these viruses into Benin.


Subject(s)
Influenza A Virus, H5N1 Subtype , Influenza in Birds , Influenza, Human , Animals , Humans , Poultry , Influenza in Birds/epidemiology , Benin/epidemiology , Phylogeny , Birds
6.
Emerg Infect Dis ; 27(9): 2492-2494, 2021 09.
Article in English | MEDLINE | ID: mdl-34424167

ABSTRACT

Migratory birds play a major role in spreading influenza viruses over long distances. We report highly pathogenic avian influenza A(H5N6) viruses in migratory and resident ducks in Bangladesh. The viruses were genetically similar to viruses detected in wild birds in China and Mongolia, suggesting migration-associated dissemination of these zoonotic pathogens.


Subject(s)
Influenza A virus , Influenza in Birds , Animals , Bangladesh/epidemiology , Birds , Influenza in Birds/epidemiology , Poultry
7.
Emerg Infect Dis ; 25(12): 2287-2289, 2019 12.
Article in English | MEDLINE | ID: mdl-31742528

ABSTRACT

In 2015, highly pathogenic avian influenza A(H5N1) viruses reemerged in poultry in West Africa. We describe the introduction of a reassortant clade 2.3.2.1c virus into Togo in April 2018. Our findings signal further local spread and evolution of these viruses, which could affect animal and human health.


Subject(s)
Biological Evolution , Influenza A Virus, H5N1 Subtype/classification , Influenza A Virus, H5N1 Subtype/genetics , Influenza in Birds/epidemiology , Influenza in Birds/virology , Poultry/virology , Animals , Hemagglutinin Glycoproteins, Influenza Virus/genetics , History, 21st Century , Influenza in Birds/history , Neuraminidase/genetics , Public Health Surveillance , Togo/epidemiology , Viral Proteins/genetics
9.
Proc Natl Acad Sci U S A ; 113(13): 3669-74, 2016 Mar 29.
Article in English | MEDLINE | ID: mdl-26976575

ABSTRACT

The influenza endonuclease is an essential subdomain of the viral RNA polymerase. It processes host pre-mRNAs to serve as primers for viral mRNA and is an attractive target for antiinfluenza drug discovery. Compound L-742,001 is a prototypical endonuclease inhibitor, and we found that repeated passaging of influenza virus in the presence of this drug did not lead to the development of resistant mutant strains. Reduced sensitivity to L-742,001 could only be induced by creating point mutations via a random mutagenesis strategy. These mutations mapped to the endonuclease active site where they can directly impact inhibitor binding. Engineered viruses containing the mutations showed resistance to L-742,001 both in vitro and in vivo, with only a modest reduction in fitness. Introduction of the mutations into a second virus also increased its resistance to the inhibitor. Using the isolated wild-type and mutant endonuclease domains, we used kinetics, inhibitor binding and crystallography to characterize how the two most significant mutations elicit resistance to L-742,001. These studies lay the foundation for the development of a new class of influenza therapeutics with reduced potential for the development of clinical endonuclease inhibitor-resistant influenza strains.


Subject(s)
Endonucleases/antagonists & inhibitors , Endonucleases/genetics , Enzyme Inhibitors/pharmacology , Hydroxybutyrates/pharmacology , Influenza A virus/drug effects , Piperidines/pharmacology , Animals , Catalytic Domain/genetics , Crystallography, X-Ray , Dogs , Drug Resistance, Viral/genetics , Endonucleases/metabolism , Genetic Variation , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H1N1 Subtype/enzymology , Influenza A Virus, H1N1 Subtype/genetics , Influenza A virus/enzymology , Influenza A virus/genetics , Kinetics , Madin Darby Canine Kidney Cells , Models, Molecular , Mutagenesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism
10.
J Virol ; 90(22): 10074-10082, 2016 Nov 15.
Article in English | MEDLINE | ID: mdl-27581984

ABSTRACT

Influenza A(H1N1) viruses entered the U.S. swine population following the 1918 pandemic and remained genetically stable for roughly 80 years. In 1998, there was an outbreak of influenza-like illness among swine that was caused by A(H3N2) viruses containing the triple reassortant internal gene (TRIG) cassette. Following the TRIG cassette emergence, numerous reassortant viruses were isolated in nature, suggesting that the TRIG virus had an enhanced ability to reassort compared to the classical swine virus. The present study was designed to quantify the relative reassortment capacities of classical and TRIG swine viruses. Reverse genetic viruses were generated from the classical H1N1 virus A/swine/MN/37866/1999 (MN/99), the TRIG virus A/swine/NC/18161/2002 (NC/02), and a seasonal human H3N2 virus, A/TX/6/1996 (TX/96), to measure in vitro reassortment and growth potentials. After coinfection with NC/02 or MN/99 plus TX/96, H1/H3 double-positive cells were identified. Delayed TX/96 infection was fully excluded by both swine viruses. We then analyzed reassortant H3 viruses. Seventy-seven of 81 (95.1%) TX/96-NC/02 reassortants contained at least one polymerase gene segment from NC/02, whereas only 34 of 61 (55.7%) MN/99-TX/96 reassortants contained at least one polymerase gene segment from MN/99. Additionally, 38 of 81 (46.9%) NC/02-TX/96 reassortants contained all NC/02 polymerase gene segments, while none of the MN/99-TX/96 reassortants contained all MN/99 polymerase genes. There were 21 H3 reassortants between MN/99 and TX/96, compared to only 17 H3 reassortants between NC/02 and TX/96. Overall, the results indicate that there are no distinct differences in the ability of the TRIG to reassort with a human virus compared to the classical swine virus. IMPORTANCE: There appear to be no differences in the abilities of classical swine and TRIG swine viruses to exclude a second virus, suggesting that under the right circumstances both viruses have similar opportunities to reassort. The increased percentage of TRIG polymerase gene segments in reassortant H3 viruses indicates that these viruses may be more compatible with gene segments from other viruses; however, this needs to be investigated further. Nevertheless, the classical swine virus also showed the ability to reassort, suggesting that factors other than reassortment capacity alone are responsible for the different epidemiologies of TRIG and classical swine viruses. The post-TRIG diversity was likely driven by increased intensive farming practices rather than virologic properties. Our results indicate that host ecology can be a significant factor in viral evolution.


Subject(s)
Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H3N2 Subtype/genetics , Orthomyxoviridae Infections/virology , Swine Diseases/virology , Animals , Disease Outbreaks , Swine , United States
11.
J Infect Dis ; 213(3): 407-10, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26068783

ABSTRACT

BACKGROUND: The relationship between influenza virus infectivity and virus shedding, based on different diagnostic methods, has not been defined. METHODS: Three donor ferrets infected with 2009 pandemic influenza A(H1N1) underwent daily quantitative culture, antigen-detection testing, and real-time reverse transcription-polymerase chain reaction (RT-PCR). Eight contacts were sequentially cohoused with each of the donors for 24 hours during days 3-10 after inoculation. RESULTS: Transmission was observed until day 5 after inoculation, corresponding to high culture titers and positive results of antigen-detection tests. Real-time RT-PCR showed no relation to the cessation of transmission. CONCLUSIONS: Antigen-detection testing and virus culture but not real-time RT-PCR identified the end of the infectious period.


Subject(s)
Influenza A Virus, H1N1 Subtype , Orthomyxoviridae Infections/virology , Virus Shedding/physiology , Animals , Antigens, Viral , Ferrets , Orthomyxoviridae Infections/immunology , Real-Time Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , Sensitivity and Specificity , Virus Cultivation
12.
Emerg Infect Dis ; 21(10): 1834-6, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26402228

ABSTRACT

To clarify the epidemiology of influenza A viruses in coordinated swine production systems to which no animals from outside the system are introduced, we conducted virologic surveillance during September 2012-September 2013. Animal age, geographic location, and farm type were found to affect the prevalence of these viruses.


Subject(s)
Epidemiological Monitoring , Influenza A virus/pathogenicity , Livestock/virology , Orthomyxoviridae Infections/veterinary , Swine Diseases/epidemiology , Swine/virology , Animals , United States/epidemiology
13.
Am J Respir Crit Care Med ; 189(4): 449-62, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24308446

ABSTRACT

RATIONALE: Children are an at-risk population for developing complications following influenza infection, but immunologic correlates of disease severity are not understood. We hypothesized that innate cellular immune responses at the site of infection would correlate with disease outcome. OBJECTIVES: To test the immunologic basis of severe illness during natural influenza virus infection of children and adults at the site of infection. METHODS: An observational cohort study with longitudinal sampling of peripheral and mucosal sites in 84 naturally influenza-infected individuals, including infants. Cellular responses, viral loads, and cytokines were quantified from nasal lavages and blood, and correlated to clinical severity. MEASUREMENTS AND MAIN RESULTS: We show for the first time that although viral loads in children and adults were similar, innate responses in the airways were stronger in children and varied considerably between plasma and site of infection. Adjusting for age and viral load, an innate immune profile characterized by increased nasal lavage monocyte chemotactic protein-3, IFN-α2, and plasma IL-10 levels at enrollment predicted progression to severe disease. Increased plasma IL-10, monocyte chemotactic protein-3, and IL-6 levels predicted hospitalization. This inflammatory cytokine production correlated significantly with monocyte localization from the blood to the site of infection, with conventional monocytes positively correlating with inflammation. Increased frequencies of CD14(lo) monocytes were in the airways of participants with lower inflammatory cytokine levels. CONCLUSIONS: An innate profile was identified that correlated with disease progression independent of viral dynamics and age. The airways and blood displayed dramatically different immune profiles emphasizing the importance of cellular migration and localized immune phenotypes.


Subject(s)
Immunity, Innate , Influenza, Human/immunology , Respiratory Mucosa/immunology , Severity of Illness Index , Adolescent , Adult , Age Factors , Biomarkers/metabolism , Chemotaxis, Leukocyte , Child , Child, Preschool , Cohort Studies , Cytokines/metabolism , Female , Flow Cytometry , Hospitalization , Humans , Infant , Influenza, Human/diagnosis , Influenza, Human/therapy , Influenza, Human/virology , Longitudinal Studies , Male , Monocytes/metabolism , Nasal Lavage Fluid/immunology , Prognosis , Respiratory Mucosa/virology , Reverse Transcriptase Polymerase Chain Reaction , Viral Load , Young Adult
14.
EMBO J ; 29(21): 3660-72, 2010 Nov 03.
Article in English | MEDLINE | ID: mdl-20859256

ABSTRACT

It remains uncertain how the DNA sequence of mammalian genes influences the transcriptional response to extracellular signals. Here, we show that the number of CREB-binding sites (CREs) affects whether the related histone acetyltransferases (HATs) CREB-binding protein (CBP) and p300 are required for endogenous gene transcription. Fibroblasts with both CBP and p300 knocked-out had strongly attenuated histone H4 acetylation at CREB-target genes in response to cyclic-AMP, yet transcription was not uniformly inhibited. Interestingly, dependence on CBP/p300 was often different between reporter plasmids and endogenous genes. Transcription in the absence of CBP/p300 correlated with endogenous genes having more CREs, more bound CREB, and more CRTC2 (a non-HAT coactivator of CREB). Indeed, CRTC2 rescued cAMP-inducible expression for certain genes in CBP/p300 null cells and contributed to the CBP/p300-independent expression of other targets. Thus, endogenous genes with a greater local concentration and diversity of coactivators tend to have more resilient-inducible expression. This model suggests how gene expression patterns could be tuned by altering coactivator availability rather than by changing signal input or transcription factor levels.


Subject(s)
CREB-Binding Protein/physiology , E1A-Associated p300 Protein/physiology , Histone Acetyltransferases/metabolism , Trans-Activators/metabolism , Transcription, Genetic , Acetylation , Animals , Binding Sites , Biomarkers/metabolism , Blotting, Western , Cells, Cultured , Chromatin Immunoprecipitation , Cyclic AMP/pharmacology , Embryo, Mammalian/cytology , Embryo, Mammalian/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Expression Profiling , Histones/metabolism , Integrases/metabolism , Mice , Mice, Knockout , Oligonucleotide Array Sequence Analysis , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Small Interfering/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Trans-Activators/antagonists & inhibitors , Trans-Activators/genetics , Transcription Factors
15.
Emerg Microbes Infect ; 13(1): 2353292, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38712345

ABSTRACT

ABSTRACTRapid evolution of highly pathogenic avian influenza viruses (HPAIVs) is driven by antigenic drift but also by reassortment, which might result in robust replication in and transmission to mammals. Recently, spillover of clade 2.3.4.4b HPAIV to mammals including humans, and their transmission between mammalian species has been reported. This study aimed to evaluate the pathogenicity and transmissibility of a mink-derived clade 2.3.4.4b H5N1 HPAIV isolate from Spain in pigs. Experimental infection caused interstitial pneumonia with necrotizing bronchiolitis with high titers of virus present in the lower respiratory tract and 100% seroconversion. Infected pigs shed limited amount of virus, and importantly, there was no transmission to contact pigs. Notably, critical mammalian-like adaptations such as PB2-E627 K and HA-Q222L emerged at low frequencies in principal-infected pigs. It is concluded that pigs are highly susceptible to infection with the mink-derived clade 2.3.4.4b H5N1 HPAIV and provide a favorable environment for HPAIV to acquire mammalian-like adaptations.


Subject(s)
Influenza A Virus, H5N1 Subtype , Mink , Orthomyxoviridae Infections , Swine Diseases , Animals , Mink/virology , Orthomyxoviridae Infections/virology , Orthomyxoviridae Infections/transmission , Orthomyxoviridae Infections/veterinary , Swine , Influenza A Virus, H5N1 Subtype/pathogenicity , Influenza A Virus, H5N1 Subtype/genetics , Influenza A Virus, H5N1 Subtype/physiology , Influenza A Virus, H5N1 Subtype/isolation & purification , Swine Diseases/virology , Swine Diseases/transmission , Spain , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Shedding
16.
bioRxiv ; 2024 Jul 31.
Article in English | MEDLINE | ID: mdl-39131339

ABSTRACT

Outbreaks in the US of highly pathogenic avian influenza virus (H5N1) in dairy cows have been occurring for months creating new possibilities for direct contact between the virus and humans. Eisfeld et al. examined the pathogenicity and transmissibility of a bovine HPAI H5N1 virus isolated from New Mexico in a series of in vitro and in vivo assays. They found the virus has a dual human- and avian virus-like receptor-binding specificity as measured in a solid phase glycan binding assay. Here, we examined the receptor specificity of a bovine HPAI H5N1 virus (A/bovine/OH/B24OSU-432/2024, H5N1, clade 2.3.4.4b) employing four different assays including glycan array technology, bio-layer interferometry (BLI), a solid phase capture assay and hemagglutination of glycan remodeled erythrocytes. As controls, well characterized avian (A/Vietnam/1203/2004, H5N1, clade 1) and human (A/CA/04/2009, H1N1) IAVs were included that bind α2,3- and α2,6-sialosides, respectively. We found that A/bovine/OH/B24OSU-432/2024 preferentially binds to "avian type" receptors (α2,3-sialosides). Furthermore, sequence alignments showed that A/bovine has maintained amino acids in its HA associated with α2,3-sialoside (avian) receptor specificity. We conclude that while we find no evidence that A/bovine has acquired human virus receptor binding specificity, ongoing efforts must be placed on monitoring for this trait.

17.
Commun Biol ; 7(1): 476, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38637646

ABSTRACT

Since late 2021, highly pathogenic avian influenza (HPAI) viruses of A/goose/Guangdong/1/1996 (H5N1) lineage have caused widespread mortality in wild birds and poultry in the United States. Concomitant with the spread of HPAI viruses in birds are increasing numbers of mammalian infections, including wild and captive mesocarnivores and carnivores with central nervous system involvement. Here we report HPAI, A(H5N1) of clade 2.3.4.4b, in a common bottlenose dolphin (Tursiops truncatus) from Florida, United States. Pathological findings include neuronal necrosis and inflammation of the brain and meninges, and quantitative real time RT-PCR reveal the brain carried the highest viral load. Virus isolated from the brain contains a S246N neuraminidase substitution which leads to reduced inhibition by neuraminidase inhibitor oseltamivir. The increased prevalence of A(H5N1) viruses in atypical avian hosts and its cross-species transmission into mammalian species highlights the public health importance of continued disease surveillance and biosecurity protocols.


Subject(s)
Bottle-Nosed Dolphin , Influenza A Virus, H5N1 Subtype , Influenza A virus , Influenza in Birds , Animals , Influenza in Birds/epidemiology , Influenza A Virus, H5N1 Subtype/genetics , Florida/epidemiology , Neuraminidase , Influenza A virus/physiology , Birds
18.
Nat Commun ; 15(1): 4350, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38782954

ABSTRACT

mRNA lipid nanoparticle (LNP) vaccines would be useful during an influenza virus pandemic since they can be produced rapidly and do not require the generation of egg-adapted vaccine seed stocks. Highly pathogenic avian influenza viruses from H5 clade 2.3.4.4b are circulating at unprecedently high levels in wild and domestic birds and have the potential to adapt to humans. Here, we generate an mRNA lipid nanoparticle (LNP) vaccine encoding the hemagglutinin (HA) glycoprotein from a clade 2.3.4.4b H5 isolate. The H5 mRNA-LNP vaccine elicits strong T cell and antibody responses in female mice, including neutralizing antibodies and broadly-reactive anti-HA stalk antibodies. The H5 mRNA-LNP vaccine elicits antibodies at similar levels compared to whole inactivated vaccines in female mice with and without prior H1N1 exposures. Finally, we find that the H5 mRNA-LNP vaccine is immunogenic in male ferrets and prevents morbidity and mortality of animals following 2.3.4.4b H5N1 challenge. Together, our data demonstrate that a monovalent mRNA-LNP vaccine expressing 2.3.4.4b H5 is immunogenic and protective in pre-clinical animal models.


Subject(s)
Antibodies, Viral , Ferrets , Hemagglutinin Glycoproteins, Influenza Virus , Influenza A Virus, H5N1 Subtype , Influenza Vaccines , Nanoparticles , Orthomyxoviridae Infections , mRNA Vaccines , Animals , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage , Female , Mice , Nanoparticles/chemistry , Male , Influenza A Virus, H5N1 Subtype/immunology , Influenza A Virus, H5N1 Subtype/genetics , Antibodies, Viral/immunology , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Orthomyxoviridae Infections/prevention & control , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , mRNA Vaccines/immunology , Antibodies, Neutralizing/immunology , Mice, Inbred BALB C , Influenza in Birds/prevention & control , Influenza in Birds/immunology , Influenza in Birds/virology , Humans , RNA, Messenger/genetics , RNA, Messenger/immunology , RNA, Messenger/metabolism , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H1N1 Subtype/genetics , Birds/virology , Lipids/chemistry , Liposomes
19.
Nat Commun ; 15(1): 3449, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38664384

ABSTRACT

In 2017, a novel influenza A virus (IAV) was isolated from an Egyptian fruit bat. In contrast to other bat influenza viruses, the virus was related to avian A(H9N2) viruses and was probably the result of a bird-to-bat transmission event. To determine the cross-species spill-over potential, we biologically characterize features of A/bat/Egypt/381OP/2017(H9N2). The virus has a pH inactivation profile and neuraminidase activity similar to those of human-adapted IAVs. Despite the virus having an avian virus-like preference for α2,3 sialic acid receptors, it is unable to replicate in male mallard ducks; however, it readily infects ex-vivo human respiratory cell cultures and replicates in the lungs of female mice. A/bat/Egypt/381OP/2017 replicates in the upper respiratory tract of experimentally-infected male ferrets featuring direct-contact and airborne transmission. These data suggest that the bat A(H9N2) virus has features associated with increased risk to humans without a shift to a preference for α2,6 sialic acid receptors.


Subject(s)
Chiroptera , Ducks , Ferrets , Influenza A Virus, H9N2 Subtype , Orthomyxoviridae Infections , Receptors, Cell Surface , Animals , Chiroptera/virology , Humans , Ferrets/virology , Female , Male , Influenza A Virus, H9N2 Subtype/physiology , Influenza A Virus, H9N2 Subtype/pathogenicity , Influenza A Virus, H9N2 Subtype/isolation & purification , Orthomyxoviridae Infections/virology , Orthomyxoviridae Infections/transmission , Mice , Ducks/virology , Virus Replication , Influenza, Human/virology , Influenza, Human/transmission , Lung/virology , Influenza in Birds/virology , Influenza in Birds/transmission , Neuraminidase/metabolism
20.
Cell Rep ; 43(7): 114479, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39003741

ABSTRACT

Highly pathogenic avian influenza (HPAI) viruses have spread at an unprecedented scale, leading to mass mortalities in birds and mammals. In 2023, a transatlantic incursion of HPAI A(H5N5) viruses into North America was detected, followed shortly thereafter by a mammalian detection. As these A(H5N5) viruses were similar to contemporary viruses described in Eurasia, the transatlantic spread of A(H5N5) viruses was most likely facilitated by pelagic seabirds. Some of the Canadian A(H5N5) viruses from birds and mammals possessed the PB2-E627K substitution known to facilitate adaptation to mammals. Ferrets inoculated with A(H5N5) viruses showed rapid, severe disease onset, with some evidence of direct contact transmission. However, these viruses have maintained receptor binding traits of avian influenza viruses and were susceptible to oseltamivir and zanamivir. Understanding the factors influencing the virulence and transmission of A(H5N5) in migratory birds and mammals is critical to minimize impacts on wildlife and public health.


Subject(s)
Birds , Influenza in Birds , Mammals , Animals , Influenza in Birds/virology , Influenza in Birds/transmission , North America/epidemiology , Mammals/virology , Birds/virology , Ferrets , Influenza A virus/pathogenicity , Influenza A virus/genetics , Humans , Phylogeny , Orthomyxoviridae Infections/virology , Orthomyxoviridae Infections/transmission
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