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1.
Med Sci Monit ; 28: e936495, 2022 May 20.
Article in English | MEDLINE | ID: covidwho-1954994

ABSTRACT

BACKGROUND The aim of this study was to determine the level of anti-hemagglutinin antibodies in the serum of recovered patients during the SARS-CoV-2 pandemic in the 2019/2020 epidemic season in Poland, and the course of COVID-19. MATERIAL AND METHODS The material for the study consisted of the sera of COVID-19 convalescents obtained from the following 9 Regional Blood Donation and Blood Supply Centers located in 8 voivodeships. The hemagglutination inhibition reaction assay (HAI) using 8 viral hemagglutination units was used to determine antibody levels, in accordance with WHO recommendations. RESULTS This research confirms that a patient's declared severity of the course of SARS-CoV-2 infection is influenced by the patient's age and concomitant diseases. There was no statistically significant correlation between the level of anti-hemagglutinin antibodies and the severity of the course of a SARS-CoV-2 infection. Based on the serological tests conducted, it can be unequivocally concluded that both vaccinated and influenza-infected patients had a response rate in line with the requirements of the European Commission and the Committee for Medicinal Products for Human Use hemagglutinin antibodies for 4 influenza virus antigens tested. CONCLUSIONS Patients who confirmed their antibody levels with the Commission of the European Communities and the Committee for Propriety Medicinal Products (CPMP) requirements had a mild COVID-19 course. The results of our research emphasize the role of anti-hemagglutinin antibodies in the course of SARS-CoV-2 infection. COVID-19 convalescents have a higher response rate against all 4 types of anti-hemagglutinin antibodies analyzed.


Subject(s)
COVID-19 , Influenza, Human , Antibodies, Viral , COVID-19/epidemiology , Hemagglutinins , Humans , Pandemics , Poland/epidemiology , SARS-CoV-2 , Seasons
2.
J Vis Exp ; (184)2022 06 14.
Article in English | MEDLINE | ID: covidwho-1911779

ABSTRACT

Surface plasmon resonance (SPR) is used to measure hemagglutinin (HA) binding to domain-swapped Cyanovirin-N (CV-N) dimer and to monitor interactions between mannosylated peptides and CV-N's high-affinity binding site. Virus envelope spikes gp120, HA, and Ebola glycoprotein (GP) 1,2 have been reported to bind both high- and low-affinity binding sites on dimeric CVN2. Dimannosylated HA peptide is also bound at the two low-affinity binding sites to an engineered molecule of CVN2, which is bearing a high-affinity site for the respective ligand and mutated to replace a stabilizing disulfide bond in the carbohydrate-binding pocket, thus confirming multivalent binding. HA binding is shown to one high-affinity binding site of pseudo-antibody CVN2 at a dissociation constant (KD) of 275 nM that further neutralizes human immunodeficiency virus type 1 (HIV-1) through oligomerization. Correlating the number of disulfide bridges in domain-swapped CVN2, which are decreased from 4 to 2 by substituting cystines into polar residue pairs of glutamic acid and arginine, results in reduced binding affinity to HA. Among the strongest interactions, Ebola GP1,2 is bound by CVN2 with two high-affinity binding sites in the lower nanomolar range using the envelope glycan without a transmembrane domain. In the present study, binding of the multispecific monomeric CV-N to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein is measured at KD = 18.6 µM as compared with nanomolar KD to those other virus spikes, and via its receptor-binding domain in the mid-µ-molar range.


Subject(s)
COVID-19 , Hemorrhagic Fever, Ebola , Antiviral Agents/pharmacology , Carrier Proteins/metabolism , Disulfides , Glycoproteins/metabolism , Hemagglutinins , Humans , Peptides/metabolism , SARS-CoV-2 , Surface Plasmon Resonance
4.
Lancet Infect Dis ; 22(7): 1062-1075, 2022 07.
Article in English | MEDLINE | ID: covidwho-1900308

ABSTRACT

BACKGROUND: One strategy to develop a universal influenza virus vaccine is to redirect the immune system to the highly conserved haemagglutinin stalk domain by sequentially administering vaccines expressing chimeric (c) haemagglutinins with a conserved stalk domain and divergent head domain, to which humans are naive. We aimed to assess the reactogenicity, safety, and immunogenicity of adjuvanted and unadjuvanted investigational supra-seasonal universal influenza virus vaccines (SUIVs) in healthy young adults. METHODS: In this observer-masked, randomised, controlled, phase 1-2 trial, we recruited adults aged 18-39 years with no clinically significant conditions from six centres in Belgium and the USA. Participants were randomly assigned to ten equally sized groups via an online system with the MATerial Excellence programme. Vaccines contained heterosubtypic group 1 H8, H5, or H11 haemagglutinin heads, an H1 haemagglutinin stalk, and an N1 neuraminidase (cH8/1N1, cH5/1N1, and cH11/1N1; haemagglutinin dose 15 µg/0·5 mL), administered on days 1 and 57, with a month 14 booster. SUIVs were evaluated in the sequences: cH8/1N1-placebo-cH5/1N1, cH5/1N1-placebo-cH8/1N1, or cH8/1N1-cH5/1N1-cH11/1N1, adjuvanted with either AS03 or AS01, or not adjuvanted. The last group received inactivated quadrivalent influenza vaccine (IIV4)-placebo-IIV4. Primary outcomes were safety (analysed in the exposed population) and immunogenicity in terms of the anti-H1 stalk humoral response at 28 days after vaccination (analysed in the per-protocol population, defined as participants who received the study vaccines according to the protocol). This trial is registered with ClinicalTrials.gov, NCT03275389. FINDINGS: Between Sept 25, 2017, and March 26, 2020, 507 eligible participants were enrolled. 468 (92%) participants received at least one dose of study vaccine (exposed population), of whom 244 (52%) were included in the per-protocol population at final analysis at month 26. The safety profiles of all chimeric vaccines were clinically acceptable, with no safety concerns identified. Injection-site pain was the most common adverse event, occurring in 84-96% of participants receiving an adjuvanted SUIV or non-adjuvanted IIV4 and in 40-50% of participants receiving a non-adjuvanted SUIV. Spontaneously reported adverse events up to 28 days after vaccination occurred in 36-60% of participants, with no trends observed for any group. 17 participants had a serious adverse event, none of which were considered to be causally related to the vaccine. Anti-H1 stalk antibody titres were highest in AS03-adjuvanted groups, followed by AS01-adjuvanted and non-adjuvanted groups, and were higher after cH8/1N1 than after cH5/1N1 and after a two-dose primary schedule than after a one-dose schedule. Geometric mean concentrations by ELISA ranged from 21 938·1 ELISA units/mL (95% CI 18 037·8-26 681·8) in the IIV4-placebo-IIV4 group to 116 596·8 ELISA units/mL (93 869·6-144 826·6) in the AS03-adjuvanted cH8/1N1-cH5/1N1-cH11/1N1 group 28 days after the first dose and from 15 105·9 ELISA units/mL (12 007·7-19 003·6) in the non-adjuvanted cH5/1N1-placebo-cH8/1N1 group to 74 639·7 ELISA units/mL (59 986·3-92 872·6) in the AS03-adjuvanted cH8/1N1-cH5/1N1-cH11/1N1 group 28 days after the second dose. INTERPRETATION: The stalk domain seems to be a rational target for development of a universal influenza virus vaccine via administration of chimeric haemagglutinins with head domains to which humans are naive. FUNDING: GlaxoSmithKline Biologicals.


Subject(s)
Influenza Vaccines , Influenza, Human , Adjuvants, Immunologic , Adjuvants, Pharmaceutic , Antibodies, Viral , Hemagglutinins , Humans , Immunogenicity, Vaccine , Virion , Young Adult
5.
Cell Rep ; 39(9): 110897, 2022 May 31.
Article in English | MEDLINE | ID: covidwho-1866954

ABSTRACT

Influenza viruses circulated at very low levels during the beginning of the COVID-19 pandemic, and population immunity against these viruses is low. An H3N2 strain (3C.2a1b.2a2) with a hemagglutinin (HA) that has several substitutions relative to the 2021-22 H3N2 vaccine strain is dominating the 2021-22 Northern Hemisphere influenza season. Here, we show that one of these substitutions eliminates a key glycosylation site on HA and alters sialic acid binding. Using glycan array profiling, we show that the 3C.2a1b.2a2 H3 maintains binding to an extended biantennary sialoside and replicates to high titers in human airway cells. We find that antibodies elicited by the 2021-22 Northern Hemisphere influenza vaccine poorly neutralize the 3C.2a1b.2a2 H3N2 strain. Together, these data indicate that 3C.2a1b.2a2 H3N2 viruses efficiently replicate in human cells and escape vaccine-elicited antibodies.


Subject(s)
COVID-19 , Influenza, Human , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinins , Humans , Influenza A Virus, H3N2 Subtype/genetics , Pandemics , Seasons
6.
Front Immunol ; 13: 873191, 2022.
Article in English | MEDLINE | ID: covidwho-1825483

ABSTRACT

Influenza virus hemagglutinin (HA) stalk-specific antibodies have been shown to potently induce Fc-mediated effector functions which are important in protection from disease. In placebo-controlled maternal influenza (MatFlu) vaccination trials of pregnant women living with or without HIV, reduced risk of influenza illness was associated with high HA stalk antibody titers following trivalent inactivated vaccination (TIV). However, the mechanisms of immunity conferred by the HA stalk antibodies were not well understood. Here, we investigated HA stalk-specific Fc effector functions including antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent complement deposition (ADCD), and FcγRIIa and FcγRIIIa binding in response to seasonal influenza vaccination. These were measured pre- and 1-month post-vaccination in 141 HIV-uninfected women (67 TIV and 74 placebo recipients) and 119 women living with HIV (WLWH; 66 TIV and 53 placebo recipients). In contrast to HIV-uninfected women, where HA stalk-specific ADCP and FcγRIIa binding were significantly boosted, WLWH showed no increase in response to vaccination. HA stalk-specific ADCC potential and FcγRIIIa binding were not boosted regardless of HIV status but were higher in WLWH compared with HIV-uninfected women prior to vaccination. HA stalk-specific ADCD was significantly increased by vaccination in all women, but was significantly lower in the WLWH both pre- and post- vaccination. Co-ordination between HA stalk-specific ADCP and ADCD in WLWH was improved by vaccination. Fc polyfunctionality was enhanced by vaccination in HIV-uninfected women and driven by the HA stalk antibody titers. However, in the WLWH, higher pre-vaccination Fc polyfunctionality was maintained post-vaccination but was decoupled from titer. Overall, we showed differential regulation of Fc effector HA stalk responses, suggesting that HIV infection results in unique humoral immunity in response to influenza vaccination, with relevance for future strategies that aim to target the HA stalk in this population.


Subject(s)
HIV Infections , Influenza, Human , Antibodies, Viral , Female , Hemagglutinin Glycoproteins, Influenza Virus , Hemagglutinins , Humans , Influenza, Human/prevention & control , Male , Pregnancy , Vaccination
7.
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
8.
Acta Biochim Pol ; 69(2): 459-464, 2022 Apr 28.
Article in English | MEDLINE | ID: covidwho-1818860

ABSTRACT

The aim of the study was to prove the level of antibodies against haemagglutinin in the sera of people from seven age groups in the epidemic season 2020/2021 in Poland to determine the differentiation of the antibody level and the protection rate depending on age. The level of anti-haemagglutinin antibodies was established by haemagglutinin inhibition test (HAI). A total of 700 randomly selected sera from people belonging to 7 different age groups were tested. The results confirmed the presence of antibodies against the following influenza antigens: A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus, A/Hong Kong/2671/2019 (H3N2)-like virus, B/Washington/02/2019 (B/Victoria lineage)-like virus and B/Phuket/3073/2013 (B/Yamagata lineage)-like virus. The level of haemagglutinin antibodies varied between the studied age groups, with the highest values in the 5-9 age group and the lowest in the 0-4 age group. It was also proven that the protection rate was the highest for the A/Hong Kong/2671/2019(H3N2)-like virus antigen, which exceeded the protection level in the 5 age groups. Considering the very low percentage of people vaccinated in the epidemic season 2020/2021 in Poland, which amounted to only 6.1%, the results should be interpreted as the immune system's response to an infection with influenza virus.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Antibodies, Viral , Hemagglutinins , Humans , Influenza A Virus, H3N2 Subtype , Influenza B virus , Influenza, Human/prevention & control , Poland/epidemiology , SARS-CoV-2 , Seasons
9.
Expert Rev Mol Diagn ; 22(2): 137, 2022 02.
Article in English | MEDLINE | ID: covidwho-1706100
10.
Nanoscale ; 14(8): 3250-3260, 2022 Feb 24.
Article in English | MEDLINE | ID: covidwho-1684132

ABSTRACT

Various vaccine strategies have been developed to provide broad protection against diverse influenza viruses. The hemagglutinin (HA) stem is the major potential target of these vaccines. Enhancing immunogenicity and eliciting cross-protective immune responses are critical for HA stem-based vaccine designs. In this study, the A helix (Ah) and CD helix (CDh) from the HA stem were fused with ferritin, individually, or in tandem, yielding Ah-f, CDh-f and (A + CD)h-f nanoparticles (NPs), respectively. These NPs were produced through a prokaryotic expression system. After three immunizations with AS03-adjuvanted NPs in BALB/c mice via the subcutaneous route, CDh-f and (A + CD)h-f induced robust humoral and cellular immune responses. Furthermore, CDh-f and (A + CD)h-f conferred complete protection against a lethal challenge of H3N2 virus, while no remarkable immune responses and protective effects were detected in the Ah-f group. These results indicate that the CDh-based nanovaccine represents a promising vaccine platform against influenza, and the epitope-conjugated ferritin NPs may be a potential vaccine platform against other infectious viruses, such as SARS-COV-2.


Subject(s)
COVID-19 , Influenza Vaccines , Nanoparticles , Orthomyxoviridae Infections , Animals , Antibodies, Viral , Epitopes , Hemagglutinin Glycoproteins, Influenza Virus , Hemagglutinins , Humans , Immunity , Influenza A Virus, H3N2 Subtype , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/prevention & control , SARS-CoV-2
11.
Expert Rev Mol Diagn ; 22(2): 135, 2022 02.
Article in English | MEDLINE | ID: covidwho-1575996
12.
Adv Sci (Weinh) ; 8(23): e2100118, 2021 12.
Article in English | MEDLINE | ID: covidwho-1482096

ABSTRACT

Recently, viral infectious diseases, including COVID-19 and Influenza, are the subjects of major concerns worldwide. One strategy for addressing these concerns focuses on nasal vaccines, which have great potential for achieving successful immunization via safe, easy, and affordable approaches. However, conventional nasal vaccines have major limitations resulting from fast removal when pass through nasal mucosa and mucociliary clearance hindering their effectiveness. Herein a nanoparticulate vaccine (NanoVac) exhibiting photochemical immunomodulation and constituting a new self-assembled immunization system of a photoactivatable polymeric adjuvant with influenza virus hemagglutinin for efficient nasal delivery and antigen-specific immunity against pathogenic influenza viruses is described. NanoVac increases the residence period of antigens and further enhances by spatiotemporal photochemical modulation in the nasal cavity. As a consequence, photochemical immunomodulation of NanoVacs successfully induces humoral and cellular immune responses followed by stimulation of mature dendritic cells, plasma cells, memory B cells, and CD4+ and CD8+ T cells, resulting in secretion of antigen-specific immunoglobulins, cytokines, and CD8+ T cells. Notably, challenge with influenza virus after nasal immunization with NanoVacs demonstrates robust prevention of viral infection. Thus, this newly designed vaccine system can serve as a promising strategy for developing vaccines that are active against current hazardous pathogen outbreaks and pandemics.


Subject(s)
Hemagglutinins/chemistry , Influenza Vaccines/administration & dosage , Light , Nanoparticles/chemistry , Orthomyxoviridae Infections/prevention & control , Adjuvants, Immunologic/administration & dosage , Administration, Inhalation , Animals , Antigens/administration & dosage , Antigens/chemistry , Antigens/immunology , Dendritic Cells/cytology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Hemagglutinins/administration & dosage , Hemagglutinins/immunology , Humans , Immunity, Cellular , Immunity, Humoral , Influenza Vaccines/chemistry , Influenza Vaccines/immunology , Influenza, Human/immunology , Influenza, Human/prevention & control , Influenza, Human/virology , Interferon-gamma/metabolism , Male , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , Photosensitizing Agents/chemistry , Polymers/chemistry
13.
Viruses ; 13(10)2021 09 30.
Article in English | MEDLINE | ID: covidwho-1481008

ABSTRACT

Measles virus (MeV) genotype B3 is one globally significant circulating genotype. Here, we present a systematic description of long-term evolutionary characterizations of the MeV genotype B3's hemagglutinin (H) gene in the elimination era. Our results show that the B3 H gene can be divided into two main sub-genotypes, and the highest intra-genotypic diversity was observed in 2004. MeV genotype B3's H gene diverged in 1976; its overall nucleotide substitution rate is estimated to be 5.697 × 10-4 substitutions/site/year, and is slowing down. The amino acid substitution rate of genotype B3's H gene is also decreasing, and the mean effective population size has been in a downward trend since 2000. Selection pressure analysis only recognized a few sites under positive selection, and the number of positive selection sites is getting smaller. All of these observations may reveal that genotype B3's H gene is not under strong selection pressure, and is becoming increasingly conservative. MeV H-gene or whole-genome sequencing should be routine, so as to better elucidate the molecular epidemiology of MeV in the future.


Subject(s)
Hemagglutinins, Viral/genetics , Measles virus/genetics , China , Evolution, Molecular , Genetic Variation/genetics , Genotype , Hemagglutinins/genetics , Humans , Measles/virology , Molecular Epidemiology/methods , Phylogeny , Sequence Analysis, DNA/methods
14.
J Clin Apher ; 36(6): 882-885, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1441998

ABSTRACT

The risk of a hemolytic reaction during the transfusion of ABO non-identical PC is determined by the presence of natural anti-A IgM antibodies, the titer of which may increase after infections. The aim of the study was to evaluate the titer of anti-A isohemagglutinins in platelet concentrate (PC) obtained by apheresis from group O donors who experienced SARS-CoV-2 infection, and to compare the titer before and after infection. A retrospective single-center analysis of 21 PC donors with a previous COVID-19 history was performed. The results showed neither a statistically important increase in the anti-A IgM antibody titers nor a significant correlation between the anti-A IgM antibody level and anti-SARS-CoV-2S1 antibody titer in the donors with an asymptomatic or mild COVID-19. Further population-based studies on anti-A titers are necessary for a comprehensive assessment of this phenomenon.


Subject(s)
COVID-19/blood , COVID-19/immunology , Hemagglutinins/blood , Plateletpheresis , SARS-CoV-2 , ABO Blood-Group System/immunology , Adult , Antibodies, Viral/blood , Blood Donors , Cohort Studies , Female , Humans , Immunoglobulin M/blood , Male , Middle Aged , Platelet Transfusion/adverse effects , Retrospective Studies , SARS-CoV-2/immunology , Transfusion Reaction/blood , Transfusion Reaction/etiology , Transfusion Reaction/immunology , Young Adult
15.
Int J Clin Pract ; 75(11): e14624, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1398444

ABSTRACT

AIMS: The relationship between the innate immune system that creates the polysaccharide antibody response and COVID-19 is not fully understood. In this study, it was aimed to determine the predictive values of isohaemagglutinins in COVID-19 severity/mortality. METHODS: Approximately 15 440 patients diagnosed with COVID-19 were examined, and a total of 286 patients with anti-B and anti-A1 IgM isohaemagglutinins test results were randomly enrolled in the study. These patients were stratified into two groups according to anti-A1 (n: 138 blood type B or O) and anti-B (n: 148 blood type A) IgM isohaemagglutinins. Anti-A1 or/and anti-B IgM, biochemical parameters, symptoms, chronic diseases, hospitalisation status, intubation status, admission to intensive care unit (ICU) and exitus status were recorded and evaluated for all patients. RESULTS: Anti-A1 IgM and anti-B IgM were significantly lower in ICU patients (7.5 ± 9.9 vs 18.0 ± 20.4 and 5.5 ± 6.3 vs 19.3 ± 33.6 titres, respectively; P < .01) and in exitus patients (3.8 ± 3.6 vs 16.7 ± 18.7 and 3.5 ± 4.7 vs 16.9 ± 29.6 titres respectively; P < .01). In the ROC analysis performed to differentiate between exitus and discharge within groups, the sensitivity of anti-B IgM and anti-A1 IgM at cut-off ≤4 was 88.9% and 79.6%, specificity 66.0% and 73.4%, and AUC 0.831 and 0.861, respectively (P < .01). Anti-A1 IgM decreased the mortality risk 0.811 times per unit while anti-B IgM decreased 0.717 times (P < .01). CONCLUSION: Anti-B and anti-A1 isohaemagglutinins, which are an expression of the innate immune system, can be used to predict the severity and mortality of COVID-19 disease.


Subject(s)
COVID-19 , Hemagglutinins , Humans , Immunity, Innate , Immunoglobulin M , Intensive Care Units , SARS-CoV-2
16.
Adv Healthc Mater ; 10(10): e2002142, 2021 05.
Article in English | MEDLINE | ID: covidwho-1384090

ABSTRACT

Despite remarkable successes of immunization in protecting public health, safe and effective vaccines against a number of life-threatening pathogens such as HIV, ebola, influenza, and SARS-CoV-2 remain urgently needed. Subunit vaccines can avoid potential toxicity associated with traditional whole virion-inactivated and live-attenuated vaccines; however, the immunogenicity of subunit vaccines is often poor. A facile method is here reported to produce lipid nanoparticle subunit vaccines that exhibit high immunogenicity and elicit protection against influenza virus. Influenza hemagglutinin (HA) immunogens are functionalized on the surface of liposomes via stable metal chelation chemistry, using a scalable advanced microfluidic mixing technology (NanoAssemblr). Immunization of mice with HA-liposomes elicits increased serum antibody titers and superior protection against highly pathogenic virus challenge compared with free HA protein. HA-liposomal vaccines display enhanced antigen deposition into germinal centers within the draining lymph nodes, driving increased HA-specific B cell, and follicular helper T cell responses. This work provides mechanistic insights into highly protective HA-liposome vaccines and informs the rational design and rapid production of next generation nanoparticle subunit vaccines.


Subject(s)
COVID-19 , Influenza Vaccines , Orthomyxoviridae Infections , Animals , Antibodies, Viral , Germinal Center , Hemagglutinin Glycoproteins, Influenza Virus , Hemagglutinins , Humans , Liposomes , Mice , Orthomyxoviridae Infections/prevention & control , SARS-CoV-2 , T-Lymphocytes, Helper-Inducer
17.
Emerg Infect Dis ; 27(7): 1953-1957, 2021 07.
Article in English | MEDLINE | ID: covidwho-1348448

ABSTRACT

Four cases of oseltamivir-resistant influenza A(H1N1)pdm09 virus infection were detected among inhabitants of a border detention center in Texas, USA. Hemagglutinin of these viruses belongs to 6B.1A5A-156K subclade, which may enable viral escape from preexisting immunity. Our finding highlights the necessity to monitor both drug resistance and antigenic drift of circulating viruses.


Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza, Human , Antiviral Agents/therapeutic use , Drug Resistance, Viral , Hemagglutinins , Humans , Influenza, Human/drug therapy , Neuraminidase , Oseltamivir/therapeutic use , Texas , Viral Proteins
18.
Cell Biol Int ; 45(11): 2199-2200, 2021 11.
Article in English | MEDLINE | ID: covidwho-1347395
19.
Cell Biol Int ; 45(11): 2198, 2021 11.
Article in English | MEDLINE | ID: covidwho-1340242
20.
Antioxid Redox Signal ; 35(13): 1081-1092, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1306508

ABSTRACT

Aims: Influenza A virus hemagglutinin (HA) binding to sialic acid on lung epithelial cells triggers membrane fusion and infection. Host thiol isomerases have been shown to play a role in influenza A virus infection, and we hypothesized that this role involved manipulation of disulfide bonds in HA. Results: Analysis of HA crystal structures revealed that three of the six HA disulfides occur in high-energy conformations and four of the six bonds can exist in unformed states, suggesting that the disulfide landscape of HA is generally strained and the bonds may be labile. We measured the redox state of influenza A virus HA disulfide bonds and their susceptibility to cleavage by vascular thiol isomerases. Using differential cysteine alkylation and mass spectrometry, we show that all six HA disulfide bonds exist in unformed states in ∼1 in 10 recombinant and viral surface HA molecules. Four of the six H1 and H3 HA bonds are cleaved by the vascular thiol isomerases, thioredoxin and protein disulphide isomerase, in recombinant proteins, which correlated with surface exposure of the disulfides in crystal structures. In contrast, viral surface HA disulfide bonds are impervious to five different vascular thiol isomerases. Innovation: It has been assumed that the disulfide bonds in mature HA protein are intact and inert. We show that all six HA disulfide bonds can exist in unformed states. Conclusion: These findings indicate that influenza A virus HA disulfides are naturally labile but not substrates for thiol isomerases when expressed on the viral surface.


Subject(s)
Disulfides/metabolism , Hemagglutinins/metabolism , Influenza A virus/chemistry , Disulfides/chemistry , Hemagglutinins/chemistry , Influenza A virus/metabolism , Models, Molecular
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