scholarly journals 162. CD377, a Novel Antiviral Fc-conjugate, Demonstrates Potent Viral Burden Reduction Against Influenza a (H1N1) in Mouse and Ferret Models

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S210-S211
Author(s):  
Simon Döhrmann ◽  
Amanda Almaguer ◽  
Nicholas Dedeic ◽  
Karin Amundson ◽  
Kim Shathia ◽  
...  
Keyword(s):  
Viral Load ◽  
Mouse Models ◽  
Influenza A ◽  
Post Challenge ◽  
Lung Burden ◽  
Influenza A H1n1 ◽  
Prevention And Treatment ◽  
2009 H1n1 ◽  
Dose Ranging ◽  
Dose Dependent

Abstract Background AVCs (antiviral Fc-conjugates) are novel, long-acting immunotherapeutic conjugates of potent antivirals conjugated to the Fc domain of human IgG1. CD377, an AVC development candidate for the prevention and treatment of influenza A and B, comprises multiple copies of a novel neuraminidase inhibitor conjugated to IgG1 Fc. CD377 demonstrated potent, broad-spectrum activity in vitro and in lethal mouse models. Herein, we characterize the activity of CD377 on viral lung burden in lethal mouse models and in a ferret model of influenza A (H1N1) infection. Methods BALB/c mice were challenged intranasally with 3 x 102 PFU of influenza A/PR/8/1934 (H1N1) or with 3 x 104 PFU A/CA/07/2009 (H1N1)pdm. Ferrets were challenged sub-lethally at 1 x 106 PFU with influenza A/CA/07/2009 (H1N1)pdm. A single dose of CD377 was given 2 h post-challenge in the mouse (subcutaneous dose ranging from 0.1 – 3 mg/kg) or 24 h prior to challenge in the ferret (intravenous dose ranging from 0.3 – 30 mg/kg). In mice, oral oseltamivir was given at 5 mg/kg (human equivalent dose, HED) or at 50 mg/kg BID x 4 days starting at 2 h post-challenge and in ferrets at 20 mg/kg (4x HED) BID x 4 days starting at 4 h prior to infection. Viral burden was determined on day 4 (mouse) or days 2 and 4 (ferret) post-challenge by plaque assay. Results In mice, CD377 demonstrated dose-dependent reduction in viral lung burden (1.1 logs at 0.1 mg/kg, 2.1 logs at 0.3 mg/kg, 3.1 logs at 1 mg/kg and 3.6 logs at 3 mg/kg) compared to PBS against influenza A/PR/8/1934 (H1N1) (Fig. 1A). In the same study, oseltamivir reduced viral lung burden only by 0.8 logs at both 5 mg/kg (HED) and 50 mg/kg. No significant reduction in lung burden was observed between negative controls, PBS and hIgG1 Fc. Similarly, CD377 demonstrated a dose-dependent, multi-log reduction in viral lung burden against influenza A/CA/07/2009 (H1N1)pdm (Fig. 1B). In ferrets, CD377 reduced viral load with dose dependency at days 2 (Fig. 1C) and 4 post-infection (Fig. 1D). CD377 at 3 mg/kg or higher dose was superior compared to oseltamivir at 4x HED on days 2 and 4 post-challenge. Conclusion CD377 demonstrated superior viral load reduction compared to oseltamivir in lethal influenza A (H1N1) mouse and ferret models. These data support further development of CD377 for prevention and treatment of influenza infection. Disclosures Simon Döhrmann, PhD, Cidara Therapeutics (Shareholder) Amanda Almaguer, Bachelors, Cidara Therapeutics, Inc. (Employee, Shareholder) Nicholas Dedeic, n/a, Cidara Therapeutics (Employee) Karin Amundson, BSc, Cidara Therapeutics (Shareholder) Thomas P. Brady, PhD Chemistry, Cidara Therapeutics (Employee) Alain Noncovich, PhD, Cidara Therapeutics (Shareholder) Grayson Hough, MS - Chemistry, Cidara Therapeutics (Employee) Allen Borchardt, PhD, Cidara Therapeutics (Employee) Jeffrey B. Locke, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Jason Cole, PhD, Cidara Therapeutics (Shareholder) James Levin, PhD, Cidara Therapeutics (Shareholder) Les Tari, PhD, Cidara Therapeutics (Shareholder)

Epidemiological analysis of critically ill adult patients with pandemic influenza A(H1N1) in South Korea

2012 ◽  
Vol 141 (5) ◽  
pp. 1070-1079 ◽  
Author(s):  
S. B. HONG ◽  
E. Y. CHOI ◽  
S. H. KIM ◽  
G. Y. SUH ◽  
M. S. PARK ◽  
...  
Keyword(s):  
South Korea ◽  
Influenza A ◽  
Multivariate Logistic Regression Analysis ◽  
H1n1 Influenza ◽  
Epidemiological Analysis ◽  
Influenza A H1n1 ◽  
Failure Assessment ◽  
2009 H1n1 ◽  
Independent Risk Factors ◽  
Chronic Comorbidities

SUMMARYA total of 245 patients with confirmed 2009 H1N1 influenza were admitted to the intensive-care units of 28 hospitals (South Korea). Their mean age was 55·3 years with 68·6% aged >50 years, and 54·7% male. Nine were obese and three were pregnant. One or more comorbidities were present in 83·7%, and nosocomial acquisition occurred in 14·3%. In total, 107 (43·7%) patients received corticosteroids and 66·1% required mechanical ventilation. Eighty (32·7%) patients died within 30 days after onset of symptoms and 99 (40·4%) within 90 days. Multivariate logistic regression analysis showed that the clinician's decision to prescribe corticosteroids, older age, Sequential Organ Failure Assessment score and nosocomial bacterial pneumonia were independent risk factors for 90-day mortality. In contrast with Western countries, critical illness in Korea in relation to 2009 H1N1 was most common in older patients with chronic comorbidities; nosocomial acquisition occurred occasionally but disease in obese or pregnant patients was uncommon.

Pandemic 2009 Influenza A (H1N1) Virus among Japanese Healthcare Workers: Seroprevalence and Risk Factors

2012 ◽  
Vol 33 (1) ◽  
pp. 58-62 ◽  
Author(s):  
Yoko Nukui ◽  
Shuji Hatakeyama ◽  
Takatoshi Kitazawa ◽  
Tamami Mahira ◽  
Yoshizumi Shintani ◽  
...  
Keyword(s):  
Risk Factors ◽  
Healthcare Workers ◽  
Influenza A ◽  
H1n1 Virus ◽  
Healthcare Personnel ◽  
Care Hospital ◽  
Occupational Risk Factors ◽  
Increased Risk ◽  
Influenza A H1n1 ◽  
2009 H1n1

Objective.To evaluate the seroprevalence and risk factors for 2009 influenza A (H1N1) virus infection among healthcare personnel.Design.Observational cross-sectional study.Patients and Setting.Healthcare workers (HCWs) in an acute care hospital.Methods.Between September 14 and October 4, 2009, before 2009 H1N1 vaccination, we collected serological samples from 461 healthy HCWs. Hemagglutination-inhibition antibody assays were conducted. To evaluate the risk factors of seropositivity for 2009 H1N1 virus, gender, age, profession, work department, usage of personal protective equipment, and seasonal influenza vaccination status data were gathered via questionnaires.Results.Our survey showed that doctors and nurses were at highest risk of seropositivity for the 2009 H1N1 virus (odds ratio [OR], 5.25 [95% confidence interval {CI}, 1.21–22.7]). An increased risk of seropositivity was observed among pediatric, emergency room, and internal medicine staff (adjusted OR, 1.98 [95% CI, 1.07–3.65]). Risk was also higher among HCWs who had high titers of antibodies against the seasonal H1N1 virus (adjusted OR, 1.59 [95% CI, 1.02–2.48]).Conclusions.Seropositivity for the 2009 H1N1 virus was associated with occupational risk factors among HCWs.Infect Control Hosp Epidemiol 2012;33(1):58-62

2009 Pandemic Influenza A H1N1 Vaccination In the Patients with Hematologic Malignancies: Requirement for Repeated Dosing to Optimize Seroprotection

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 677-677
Author(s):  
Hugues de Lavallade ◽  
Paula Lorraine Garland ◽  
Takuya Sekine ◽  
Katja Hoschler ◽  
David Marin ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Influenza A ◽  
Hematologic Malignancies ◽  
B Cell Malignancies ◽  
H1n1 Vaccine ◽  
Influenza A H1n1 ◽  
Antibody Titers ◽  
2009 H1n1 ◽  
The Uk

Abstract Abstract 677 In 2009 the spread of influenza A (H1N1) satisfied the World Health Organization (WHO) criteria for a global pandemic and led to the initiation of a vaccination campaign to ensure protection for the most vulnerable patients. However, the immunogenicity of the 2009 H1N1 vaccine in immunocompromised patients has not been specifically evaluated. Furthermore, the number of doses of vaccine required for effective immunization against H1N1 has not been established. Whereas the European Medicines Agency (EMEA) and the UK Department of Health (DoH) recommended the injection of two doses of inactivated H1N1 vaccine 3 weeks apart in immunocompromised individuals, the Centers for Disease Control and Prevention recommended immunization with one dose of inactivated H1N1 vaccine for patients with cancer receiving chemotherapy, followed by a booster vaccine after completion of treatment if the pandemic continued. The aim of this study was to determine the safety and efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies. We prospectively evaluated the humoral and cellular immune responses to monovalent influenza A/California/2009(H1N1)v-like strain surface antigen vaccine in 97 adults with hematologic malignancies and 25 adult controls. Patients received two intramuscular injections of the vaccine 21 days apart and controls received one dose. Antibody titers, expressed as geometric mean, were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. The induction of virus-specific T-cell responses by H1N1 vaccination was assessed directly ex-vivo by flow cytometric enumeration of antigen-specific CD8+ and CD4+ T-lymphocytes using an intracellular cytokine assay for IFN-γ and TNF-α production on days 0 and 49. Of the 97 patients, 32 had chronic myeloid leukemia (CML) in chronic phase in complete cytogenetic response on the tyrosine kinase inhibitors imatinib or dasatinib, 39 had a B-cell malignancy in complete remission (CR) or untreated, and 26 were recipients of allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR at least 6 months beyond transplant and without evidence of graft versus host disease. The vaccine was well tolerated, with no obvious difference in side effects for patients and controls. By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (p<0.001), 46% of allo-SCT recipients (p<0.001) and 85% of CML patients (p=0.086). The effect of a booster dose was assessed with a paired sample analysis. After a second vaccine dose, the seroprotection rates increased to 68% (p=0.008), 73% (p=0.031), and 95% (p=0.5) in patients with B-cell malignancies, allo-SCT recipients and CML patients respectively. Patients vaccinated within 6 months of rituximab-based chemotherapy failed to mount a seroprotective antibody response. We also assessed the cellular response to H1N1 vaccine. Prior to vaccination, pre-existing T-cells against H1N1 could be detected in 10/23 controls compared to 2/25 allo-SCT recipients (p=0.007), 2/28 patients with B-cell malignancies (p=0.003) and 6/28 of CML patients (p=0.131). These pre-existing H1N1 T-cell responses may be related to previous exposure to 2009 H1N1 virus but more likely are due to the presence of cross-reactive seasonal and pandemic H1N1 specific T-cells. Following vaccination, H1N1-specific T-cells were induced in a significant proportion of allo-SCT recipient (10/25, p=0.008) and patients with B-cell malignancies (10/28; p=0.008), but not in CML patients or healthy controls. The limited ability of vaccines to significantly increase pre-existing influenza-specific T-cells has been previously reported although the mechanism for this phenomenon is not fully elucidated. These data demonstrate efficacy of H1N1 vaccine in the majority of patients with hematologic malignancies and unequivocally support the EMEA and the UK DoH official guidelines for the administration of 2 vaccine doses in immunocompromised patients to induce protective immune response against 2009 H1N1 influenza. Based on the WHO analyses, it is expected that the pandemic 2009 H1N1 virus will remain globally predominant in 2010–2011. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in patients with hematologic malignancies. Disclosures: Marin: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.

scholarly journals Convalescent Plasma Treatment Reduced Mortality in Patients With Severe Pandemic Influenza A (H1N1) 2009 Virus Infection

2011 ◽  
Vol 52 (4) ◽  
pp. 447-456 ◽  
Author(s):  
Ivan FN Hung ◽  
Kelvin KW To ◽  
Cheuk-Kwong Lee ◽  
Kar-Lung Lee ◽  
Kenny Chan ◽  
...  
Keyword(s):  
Intensive Care ◽  
Viral Load ◽  
Treatment Group ◽  
Respiratory Tract ◽  
Plasma Treatment ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Control Group ◽  
Severity Scores ◽  
Influenza A H1n1

Background. Experience from treating patients with Spanish influenza and influenza A(H5N1) suggested that convalescent plasma therapy might be beneficial. However, its efficacy in patients with severe pandemic influenza A(H1N1) 2009 virus (H1N1 2009) infection remained unknown. Methods. During the period from 1 September 2009 through 30 June 2010, we conducted a prospective cohort study by recruiting patients aged ≥18 years with severe H1N1 2009 infection requiring intensive care. Patients were offered treatment with convalescent plasma with a neutralizing antibody titer of ≥1:160, harvested by apheresis from patients recovering from H1N1 2009 infection. Clinical outcome was compared with that of patients who declined plasma treatment as the untreated controls. Results. Ninety-three patients with severe H1N1 2009 infection requiring intensive care were recruited. Twenty patients (21.5%) received plasma treatment. The treatment and control groups were matched by age, sex, and disease severity scores. Mortality in the treatment group was significantly lower than in the nontreatment group (20.0% vs 54.8%; P =  .01). Multivariate analysis showed that plasma treatment reduced mortality (odds ratio [OR], .20; 95% confidence interval [CI], .06-.69; P =  .011), whereas complication of acute renal failure was independently associated with death (OR, 3.79; 95% CI, 1.15-12.4; P =  .028). Subgroup analysis of 44 patients with serial respiratory tract viral load and cytokine level demonstrated that plasma treatment was associated with significantly lower day 3, 5, and 7 viral load, compared with the control group (P &lt;  .05). The corresponding temporal levels of interleukin 6, interleukin 10, and tumor necrosis factor α (P &lt;  .05) were also lower in the treatment group. Conclusions. Treatment of severe H1N1 2009 infection with convalescent plasma reduced respiratory tract viral load, serum cytokine response, and mortality.

Establishment of BALB/C mouse models of influenza A H1N1 aerosol inhalation

2019 ◽  
Vol 91 (11) ◽  
pp. 1918-1929
Author(s):  
Xin‐Yan Hao ◽  
Feng‐Di Li ◽  
Qi Lv ◽  
Yan‐Feng Xu ◽  
Yun‐Lin Han ◽  
...  
Keyword(s):  
Mouse Models ◽  
Influenza A ◽  
Aerosol Inhalation ◽  
Influenza A H1n1

Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 vaccine in a large cohort of autoimmune rheumatic diseases

2011 ◽  
Vol 70 (6) ◽  
pp. 1068-1073 ◽  
Author(s):  
Carla G S Saad ◽  
Eduardo F Borba ◽  
Nadia E Aikawa ◽  
Clovis A Silva ◽  
Rosa M R Pereira ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Influenza A ◽  
Geometric Mean ◽  
Vaccine Safety ◽  
Primary Antiphospholipid Syndrome ◽  
H1n1 Vaccine ◽  
Link Type ◽  
Autoimmune Rheumatic Disease ◽  
Influenza A H1n1 ◽  
2009 H1n1

BackgroundDespite the WHO recommendation that the 2010–2011 trivalent seasonal flu vaccine must contain A/California/7/2009/H1N1-like virus there is no consistent data regarding its immunogenicity and safety in a large autoimmune rheumatic disease (ARD) population.Methods1668 ARD patients (systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic sclerosis, psoriatic arthritis (PsA), Behçet's disease (BD), mixed connective tissue disease, primary antiphospholipid syndrome (PAPS), dermatomyositis (DM), primary Sjögren's syndrome, Takayasu's arteritis, polymyositis and Granulomatosis with polyangiitis (Wegener's) (GPA)) and 234 healthy controls were vaccinated with a non-adjuvanted influenza A/California/7/2009(H1N1) virus-like strain flu. Subjects were evaluated before vaccination and 21 days post-vaccination. The percentage of seroprotection, seroconversion and the factor increase in geometric mean titre (GMT) were calculated.ResultsAfter immunisation, seroprotection rates (68.5% vs 82.9% p<0.0001), seroconversion rates (63.4% vs 76.9%, p<0.001) and the factor increase in GMT (8.9 vs 13.2 p<0.0001) were significantly lower in ARD than controls. Analysis of specific diseases revealed that seroprotection significantly reduced in SLE (p<0.0001), RA (p<0.0001), PsA (p=0.0006), AS (p=0.04), BD (p=0.04) and DM (p=0.04) patients than controls. The seroconversion rates in SLE (p<0.0001), RA (p<0.0001) and PsA (p=0.0006) patients and the increase in GMTs in SLE (p<0.0001), RA (p<0.0001) and PsA (p<0.0001) patients were also reduced compared with controls. Moderate and severe side effects were not reported.ConclusionsThe novel recognition of a diverse vaccine immunogenicity profile in distinct ARDs supports the notion that a booster dose may be recommended for diseases with suboptimal immune responses. This large study also settles the issue of vaccine safety.(ClinicalTrials.gov #NCT01151644)

scholarly journals Immunogenicity Associated with the Routine Use of an Influenza A H1N1 Vaccine in Health Care Personnel in Guangzhou, China

2010 ◽  
Vol 17 (9) ◽  
pp. 1478-1480 ◽  
Author(s):  
Biao Di ◽  
Xinhong Xu ◽  
Tiegang Li ◽  
Enjie Lu ◽  
Jibin Wu ◽  
...  
Keyword(s):  
Health Care ◽  
Influenza A ◽  
Vaccination Campaign ◽  
Negative Control ◽  
Health Care Personnel ◽  
Seroprotection Rate ◽  
H1n1 Vaccine ◽  
Influenza A H1n1 ◽  
2009 H1n1 ◽  
Antibody Levels

ABSTRACT We present immunogenicity data on the routine vaccination of 103 health care personnel during the 2009 H1N1 national vaccination campaign. The seroprotection rate (percentage of samples with hemagglutination inhibition titers of ≥1:40) was 83.2% at 30 days postvaccination, lower than those obtained in previously published controlled trials. Low baseline antibody levels and an increase in seroprotection in a negative-control cohort suggest that the virus remains prevalent.

scholarly journals A Recombinant Influenza A/H1N1 Carrying A Short Immunogenic Peptide of MERS-CoV as Bivalent Vaccine in BALB/c Mice

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 281 ◽  
Author(s):  
Mahmoud M. Shehata ◽  
Ahmed Kandeil ◽  
Ahmed Mostafa ◽  
Sara H. Mahmoud ◽  
Mokhtar R. Gomaa ◽  
...  
Keyword(s):  
Vaccine Strain ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Bivalent Vaccine ◽  
Immunogenic Peptide ◽  
Novel Approach ◽  
Influenza A H1n1 ◽  
Chimeric Construct ◽  
2009 H1n1 ◽  
Potential Use

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) became a global human health threat since its first documentation in humans in 2012. An efficient vaccine for the prophylaxis of humans in hotspots of the infection (e.g., Saudi Arabia) is necessary but no commercial vaccines are yet approved. In this study, a chimeric DNA construct was designed to encode an influenza A/H1N1 NA protein which is flanking immunogenic amino acids (aa) 736–761 of MERS-CoV spike protein. Using the generated chimeric construct, a novel recombinant vaccine strain against pandemic influenza A virus (H1N1pdm09) and MERS-CoV was generated (chimeric bivalent 5 + 3). The chimeric bivalent 5 + 3 vaccine strain comprises a recombinant PR8-based vaccine, expressing the PB1, HA, and chimeric NA of pandemic 2009 H1N1. Interestingly, an increase in replication efficiency of the generated vaccine strain was observed when compared to the PR8-based 5 + 3 H1N1pdm09 vaccine strain that lacks the MERS-CoV spike peptide insert. In BALB/c mice, the inactivated chimeric bivalent vaccine induced potent and specific neutralizing antibodies against MERS-CoV and H1N1pdm09. This novel approach succeeded in developing a recombinant influenza virus with potential use as a bivalent vaccine against H1N1pdm09 and MERS-CoV. This approach provides a basis for the future development of chimeric influenza-based vaccines against MERS-CoV and other viruses.

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