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1.
Emerg Infect Dis ; 28(6): 1269-1273, 2022 06.
Article in English | MEDLINE | ID: covidwho-1933531

ABSTRACT

A 11-year-old boy with acute myeloid leukemia was brought for treatment of severe acute respiratory infection in the National Capital Region, New Delhi, India. Avian influenza A(H5N1) infection was laboratory confirmed. Complete genome analysis indicated hemagglutinin gene clade 2.3.2.1a. We found the strain to be susceptible to amantadine and neuraminidase inhibitors.


Subject(s)
Influenza A Virus, H5N1 Subtype , Influenza in Birds , Influenza, Human , Animals , Antiviral Agents/pharmacology , Birds , Child , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Humans , India , Influenza A Virus, H5N1 Subtype/genetics , Influenza, Human/diagnosis , Influenza, Human/drug therapy , Male , Phylogeny
3.
Viruses ; 14(4)2022 03 30.
Article in English | MEDLINE | ID: covidwho-1834926

ABSTRACT

The H9N2 subtype avian influenza viruses (AIVs) have been circulating in China for more than 20 years, attracting more and more attention due to the potential threat of them. At present, vaccination is a common prevention and control strategy in poultry farms, but as virus antigenicity evolves, the immune protection efficiency of vaccines has constantly been challenged. In this study, we downloaded the hemagglutinin (HA) protein sequences of the H9N2 subtype AIVs from 1994 to 2019 in China-with a total of 5138 sequences. The above sequences were analyzed in terms of time and space, and it was found that h9.4.2.5 was the most popular in various regions of China. Furthermore, the prevalence of H9N2 subtype AIVs in China around 2006 was different. The domestic epidemic branch was relatively diversified from 1994 to 2006. After 2006, the epidemic branch each year was h9.4.2.5. We compared the sequences around 2006 as a whole and screened out 15 different amino acid positions. Based on the HA protein of A/chicken/Guangxi/55/2005 (GX55), the abovementioned amino acid mutations were completed. According to the 12-plasmid reverse genetic system, the rescue of the mutant virus was completed using A/PuertoRico/8/1934 (H1N1) (PR8) as the backbone. The cross hemagglutination inhibition test showed that these mutant sites could transform the parental strain from the old to the new antigenic region. Animal experiments indicated that the mutant virus provided significant protection against the virus from the new antigenic region. This study revealed the antigenic evolution of H9N2 subtype AIVs in China. At the same time, it provided an experimental basis for the development of new vaccines.


Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza A Virus, H9N2 Subtype , Influenza in Birds , Amino Acids/genetics , Animals , Chickens , China/epidemiology , Evolution, Molecular , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Hemagglutinins/genetics , Influenza A Virus, H9N2 Subtype/genetics , Phylogeny
4.
PLoS Comput Biol ; 17(12): e1009664, 2021 12.
Article in English | MEDLINE | ID: covidwho-1571973

ABSTRACT

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the viral spike. Because of the high density of spikes on the viral surface, not all antigenic sites are targeted equally by antibodies. We offer here a geometry-based approach to predict and rank the probability of surface residues of SARS spike (S protein) and influenza H1N1 spike (hemagglutinin) to acquire antibody-escaping mutations utilizing in-silico models of viral structure. We used coarse-grained MD simulations to estimate the on-rate (targeting) of an antibody model to surface residues of the spike protein. Analyzing publicly available sequences, we found that spike surface sequence diversity of the pre-pandemic seasonal influenza H1N1 and the sarbecovirus subgenus highly correlates with our model prediction of antibody targeting. In particular, we identified an antibody-targeting gradient, which matches a mutability gradient along the main axis of the spike. This identifies the role of viral surface geometry in shaping the evolution of circulating viruses. For the 2009 H1N1 and SARS-CoV-2 pandemics, a mutability gradient along the main axis of the spike was not observed. Our model further allowed us to identify key residues of the SARS-CoV-2 spike at which antibody escape mutations have now occurred. Therefore, it can inform of the likely functional role of observed mutations and predict at which residues antibody-escaping mutation might arise.


Subject(s)
Evolution, Molecular , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology , Animals , Antibodies, Viral/biosynthesis , Antigens, Viral/chemistry , Antigens, Viral/genetics , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Computational Biology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/genetics , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immune Evasion/genetics , Influenza, Human/immunology , Influenza, Human/virology , Models, Immunological , Molecular Dynamics Simulation , Mutation , Pandemics , Spike Glycoprotein, Coronavirus/chemistry , Viral Envelope Proteins/chemistry
5.
Nanomedicine ; 37: 102438, 2021 10.
Article in English | MEDLINE | ID: covidwho-1306447

ABSTRACT

Highly pathogenic avian influenza viruses (HPAIVs) pose a significant threat to human health, with high mortality rates, and require effective vaccines. We showed that, harnessed with novel RNA-mediated chaperone function, hemagglutinin (HA) of H5N1 HPAIV could be displayed as an immunologically relevant conformation on self-assembled chimeric nanoparticles (cNP). A tri-partite monomeric antigen was designed including: i) an RNA-interaction domain (RID) as a docking tag for RNA to enable chaperna function (chaperna: chaperone + RNA), ii) globular head domain (gd) of HA as a target antigen, and iii) ferritin as a scaffold for 24 mer-assembly. The immunization of mice with the nanoparticles (~46 nm) induced a 25-30 fold higher neutralizing capacity of the antibody and provided cross-protection from homologous and heterologous lethal challenges. This study suggests that cNP assembly is conducive to eliciting antibodies against the conserved region in HA, providing potent and broad protective efficacy.


Subject(s)
Hemagglutinin Glycoproteins, Influenza Virus/immunology , Influenza A Virus, H5N1 Subtype/drug effects , Influenza Vaccines/immunology , Influenza in Birds/immunology , RNA/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , Birds/virology , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Hemagglutinin Glycoproteins, Influenza Virus/therapeutic use , Humans , Influenza A Virus, H5N1 Subtype/immunology , Influenza A Virus, H5N1 Subtype/pathogenicity , Influenza Vaccines/chemistry , Influenza Vaccines/therapeutic use , Influenza in Birds/prevention & control , Influenza in Birds/virology , Mice , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Pandemics , RNA/genetics , RNA/therapeutic use
6.
Vaccine ; 39(33): 4628-4640, 2021 07 30.
Article in English | MEDLINE | ID: covidwho-1292968

ABSTRACT

Current influenza vaccines rely on inducing antibody responses to the rapidly evolving hemagglutinin (HA) and neuraminidase (NA) proteins, and thus need to be strain-matched. However, predictions of strains that will circulate are imperfect, and manufacturing of new vaccines based on them takes months. As an alternative, universal influenza vaccines target highly conserved antigens. In proof of concept studies of universal vaccine candidates in animal models challenge is generally conducted only a short time after vaccination, but protective immunity lasting far longer is important for the intended public health impact. We address the challenge of providing long-term protection. We demonstrate here broad, powerful, and long-lasting immune protection for a promising universal vaccine candidate. A single intranasal dose of recombinant adenoviruses (rAd) expressing influenza A nucleoprotein (A/NP) and matrix 2 (M2) was used. Extending our previous studies of this type of vaccine, we show that antibody and T-cell responses persist for over a year without boosting, and that protection against challenge persists a year after vaccination and remains broad, covering both group 1 and 2 influenza A viruses. In addition, we extend the work to influenza B. Immunization with influenza B nucleoprotein (B/NP)-rAd also gives immune responses that last a year without boosting and protect against challenge with influenza B viruses of mismatched HA lineages. Despite host immunity to adenoviral antigens, effective readministration is possible a year after primary vaccination, as shown by successful immunization to a transgene product the animals had not seen before. Protection against challenge with divergent and highly pathogenic A/H7N9 virus was weaker but was enhanced by a second dose of vaccine. Thus, this mucosal vaccination to conserved influenza antigens confers very long-lasting immune protection in animals against a broad range of influenza A and B viruses.


Subject(s)
Influenza A Virus, H7N9 Subtype , Influenza Vaccines , Orthomyxoviridae Infections , Animals , Antibodies, Viral , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Immunity , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/prevention & control , Vaccination
7.
Viruses ; 13(4)2021 03 24.
Article in English | MEDLINE | ID: covidwho-1231504

ABSTRACT

Influenza virus, a highly mutable respiratory pathogen, causes significant disease nearly every year. Current vaccines are designed to protect against circulating influenza strains of a given season. However, mismatches between vaccine strains and circulating strains, as well as inferior vaccine effectiveness in immunodeficient populations, represent major obstacles. In an effort to expand the breadth of protection elicited by influenza vaccination, one of the major surface glycoproteins, hemagglutinin (HA), has been modified to develop immunogens that display conserved regions from multiple viruses or elicit a highly polyclonal antibody response to broaden protection. These approaches, which target either the head or the stalk domain of HA, or both domains, have shown promise in recent preclinical and clinical studies. Furthermore, the role of adjuvants in bolstering the robustness of the humoral response has been studied, and their effects on the vaccine-elicited antibody repertoire are currently being investigated. This review will discuss the progress made in the universal influenza vaccine field with respect to influenza A viruses from the perspectives of both antigen and adjuvant, with a focus on the elicitation of broadly neutralizing antibodies.


Subject(s)
Adjuvants, Immunologic , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Influenza A virus/immunology , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Animals , Antibodies, Viral/immunology , Clinical Trials as Topic , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Humans , Immunity, Humoral , Influenza Vaccines/genetics , Influenza, Human/immunology , Mice , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , Orthomyxoviridae Infections/virology , Vaccines, Virus-Like Particle/immunology
8.
Sci Transl Med ; 13(583)2021 03 03.
Article in English | MEDLINE | ID: covidwho-1117652

ABSTRACT

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus-associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.


Subject(s)
Hemagglutinin Glycoproteins, Influenza Virus/immunology , Influenza Vaccines/immunology , Primates/immunology , Animals , Antibodies, Viral/biosynthesis , Antibodies, Viral/chemistry , Antigen-Antibody Complex/chemistry , Broadly Neutralizing Antibodies/biosynthesis , Broadly Neutralizing Antibodies/chemistry , COVID-19 , Ferritins/chemistry , Ferritins/immunology , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Humans , Influenza Vaccines/administration & dosage , Influenza Vaccines/chemistry , Influenza, Human/immunology , Influenza, Human/virology , Macaca fascicularis , Models, Molecular , Nanoparticles/chemistry , Pandemics , Primates/virology , Protein Structure, Quaternary , SARS-CoV-2
9.
Science ; 371(6526): 284-288, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-1033401

ABSTRACT

The ability for viruses to mutate and evade the human immune system and cause infection, called viral escape, remains an obstacle to antiviral and vaccine development. Understanding the complex rules that govern escape could inform therapeutic design. We modeled viral escape with machine learning algorithms originally developed for human natural language. We identified escape mutations as those that preserve viral infectivity but cause a virus to look different to the immune system, akin to word changes that preserve a sentence's grammaticality but change its meaning. With this approach, language models of influenza hemagglutinin, HIV-1 envelope glycoprotein (HIV Env), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike viral proteins can accurately predict structural escape patterns using sequence data alone. Our study represents a promising conceptual bridge between natural language and viral evolution.


Subject(s)
Acquired Immunodeficiency Syndrome/immunology , COVID-19/immunology , HIV-1/genetics , Influenza A virus/genetics , Influenza, Human/immunology , SARS-CoV-2/genetics , Acquired Immunodeficiency Syndrome/virology , Binding Sites , COVID-19/virology , Evolution, Molecular , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Humans , Influenza, Human/virology , Mutation , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , env Gene Products, Human Immunodeficiency Virus/chemistry , env Gene Products, Human Immunodeficiency Virus/genetics
10.
J Biol Chem ; 296: 100017, 2021.
Article in English | MEDLINE | ID: covidwho-910220

ABSTRACT

Through annual epidemics and global pandemics, influenza A viruses (IAVs) remain a significant threat to human health as the leading cause of severe respiratory disease. Within the last century, four global pandemics have resulted from the introduction of novel IAVs into humans, with components of each originating from avian viruses. IAVs infect many avian species wherein they maintain a diverse natural reservoir, posing a risk to humans through the occasional emergence of novel strains with enhanced zoonotic potential. One natural barrier for transmission of avian IAVs into humans is the specificity of the receptor-binding protein, hemagglutinin (HA), which recognizes sialic-acid-containing glycans on host cells. HAs from human IAVs exhibit "human-type" receptor specificity, binding exclusively to glycans on cells lining the human airway where terminal sialic acids are attached in the α2-6 configuration (NeuAcα2-6Gal). In contrast, HAs from avian viruses exhibit specificity for "avian-type" α2-3-linked (NeuAcα2-3Gal) receptors and thus require adaptive mutations to bind human-type receptors. Since all human IAV pandemics can be traced to avian origins, there remains ever-present concern over emerging IAVs with human-adaptive potential that might lead to the next pandemic. This concern has been brought into focus through emergence of SARS-CoV-2, aligning both scientific and public attention to the threat of novel respiratory viruses from animal sources. In this review, we summarize receptor-binding adaptations underlying the emergence of all prior IAV pandemics in humans, maintenance and evolution of human-type receptor specificity in subsequent seasonal IAVs, and potential for future human-type receptor adaptation in novel avian HAs.


Subject(s)
Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Influenza A virus/metabolism , Influenza in Birds/epidemiology , Influenza, Human/epidemiology , Pandemics , Polysaccharides/chemistry , Receptors, Virus/metabolism , Adaptation, Physiological , Animals , Binding Sites , Biological Coevolution , Birds/virology , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Humans , Influenza A virus/chemistry , Influenza A virus/genetics , Influenza in Birds/transmission , Influenza in Birds/virology , Influenza, Human/transmission , Influenza, Human/virology , Models, Molecular , Polysaccharides/metabolism , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/genetics , Respiratory System/virology , Sialic Acids/chemistry , Sialic Acids/metabolism , Species Specificity
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