268 results on '"John J Treanor"'
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2. Social networks based on frequency of roost cohabitation do not reflect association rates of Myotis lucifugus within their roosts
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Austin G. Waag, Joseph S. Johnson, Jess Kropczynski, and John J. Treanor
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0106 biological sciences ,social network analysis ,radio‐frequency identification ,010603 evolutionary biology ,01 natural sciences ,Social group ,03 medical and health sciences ,little brown bat ,Association (psychology) ,high‐frequency RFID ,Ecology, Evolution, Behavior and Systematics ,QH540-549.5 ,030304 developmental biology ,Nature and Landscape Conservation ,0303 health sciences ,Social network ,biology ,Ecology ,National park ,business.industry ,Social network analysis (criminology) ,Myotis lucifugus ,biology.organism_classification ,Geography ,Cohabitation ,Social relationship ,association index ,passive integrated transponder ,business - Abstract
Bats are a group of mammals well known for forming dynamic social groups. Studies of bat social structures are often based upon the frequency at which bats occupy the same roosts because observing bats directly is not always possible. However, it is not always clear how closely bats occupying the same roost associate with each other, obscuring whether associations result from social relationships or factors such as shared preferences for roosts. Our goal was to determine if bats cohabitating buildings were also found together inside roosts by using anti‐collision technology for PIT tags, which enables simultaneous detection of multiple tags. We PIT‐tagged 293 female little brown myotis (Myotis lucifugus) and installed antennas within two buildings used as maternity roosts in Yellowstone National Park. Antennas were positioned at roost entryways to generate cohabitation networks and along regions of attic ceilings in each building to generate intraroost networks based on proximity of bats to each other. We found that intraroost and cohabitation networks of buildings were significantly correlated, with the same bats tending to be linked in both networks, but that bats cohabitating the same building often roosted apart, leading to differing assessments of social structure. Cohabitation rates implied that bats associate with a greater number of their roost‐mates than was supported by observations within the roost. This caused social networks built upon roost cohabitation rates to be denser, smaller in diameter, and contain nodes with higher average degree centrality. These results show that roost cohabitation does not reflect preference for roost‐mates in little brown myotis, as is often inferred from similar studies, and that social network analyses based on cohabitation may provide misleading results.
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- 2021
3. Recombinant HA-based vaccine outperforms split and subunit vaccines in elicitation of influenza-specific CD4 T cells and CD4 T cell-dependent antibody responses in humans
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Jennifer L. Nayak, Savannah A. Moritzky, Theresa Fitzgerald, John J. Treanor, Ian Shannon, Angela Branche, Katherine A. Richards, Andrea J. Sant, David J. Topham, and Hongmei Yang
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Pharmacology ,lcsh:Immunologic diseases. Allergy ,Vaccines ,Cd4 t cell ,Influenza vaccine ,ELISPOT ,medicine.medical_treatment ,Immunology ,Biology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Virology ,lcsh:RC254-282 ,Article ,law.invention ,Infectious Diseases ,Cytokine ,Antibody response ,law ,Intracellular staining ,medicine ,Recombinant DNA ,Pharmacology (medical) ,Subunit vaccines ,lcsh:RC581-607 - Abstract
Although traditional egg-based inactivated influenza vaccines can protect against infection, there have been significant efforts to develop improved formats to overcome disadvantages of this platform. Here, we have assessed human CD4 T cell responses to a traditional egg-based influenza vaccine with recently available cell-derived vaccines and recombinant baculovirus-derived vaccines. Adults were administered either egg-derived Fluzone®, mammalian cell-derived Flucelvax® or recombinant HA (Flublok®). CD4 T cell responses to each HA protein were assessed by cytokine EliSpot and intracellular staining assays. The specificity and magnitude of antibody responses were quantified by ELISA and HAI assays. By all criteria, Flublok vaccine exhibited superior performance in eliciting both CD4 T cell responses and HA-specific antibody responses, whether measured by mean response magnitude or percent of responders. Although the mechanism(s) underlying this advantage is not yet clear, it is likely that both qualitative and quantitative features of the vaccines impact the response.
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- 2020
4. Safety and immunogenicity of a SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in healthy adults: interim findings from a phase 2, randomised, dose-finding, multi-centre study
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Agustin Bueso, John J. Treanor, Maria Angeles Ceregido, Shelly Ramirez, Aiying Chen, Matthew Bonaparte, Saranya Sridhar, David Diemert, Helene Janosczyk, Sonal S. Munsiff, Guy de Bruyn, Ya Meng, Marie-Helene Grillet, Catherine Moreau, Onyema Ogbuagu, Roger Masotti, Marguerite Koutsoukos, Fernanda Tavares-Da-Silva, Carlos A. DiazGranados, Denise Lopez, Doris M Rivera M, Brandon Essink, Stephen R. Walsh, Jiayuan Shi, Anne-Laure Chabanon, Nicole Grunenberg, Richard Canter, Vanessa Raabe, Ansoyta Said, Dalia von Barbier, Joaquin Arnel, Enrique Rivas, Bo Fu, Lode Schuerman, Nadine Rouphael, Natalya Romanyak, Michael C. Keefer, Maryam Keshtkar-Jahromi, Lawrence D Sher, Sandra Mendoza, Nelson L. Michael, Judith M. White, Tina Tong, Roman Chicz, Randall Severance, and Stephen Savarino
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medicine.medical_specialty ,Reactogenicity ,biology ,business.industry ,Immunogenicity ,medicine.medical_treatment ,Antigen ,Internal medicine ,Interim ,medicine ,biology.protein ,AS03 ,Antibody ,Adverse effect ,business ,Adjuvant - Abstract
SummaryBackgroundThis study evaluated the safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein candidate vaccine, CoV2 preS dTM.MethodsThis Phase 2, modified double-blind, parallel-group study (NCT04762680) was conducted in adults, including those at increased risk of severe COVID-19. Participants were randomised 1:1:1, stratified by age (18–59/≥60 years), rapid serodiagnostic test (positive/negative) and high-risk medical conditions (yes/no), to receive two injections (day [D]1 and D22) of 5μg, 10μg or 15μg of CoV2 preS dTM antigen with fixed AS03 content. Interim safety and reactogenicity results (to D43) and neutralising antibodies (NAbs) against the D614G variant are presented (primary objectives).FindingsOf 722 participants enrolled and randomised between 24 February and 8 March 2021, 721 received ≥1 injections (5μg, n=240; 10μg, n=239; 15μg, n=242). Four participants reported unsolicited immediate adverse events (AEs), two were vaccine-related (investigator assessment). Five participants reported seven vaccine-related medically-attended AEs. No vaccine-related serious AEs and no AEs of special interest were reported. Solicited reactions (local and systemic) were reported at similar frequencies between study groups; these were mostly mild to moderate and transient, with higher frequency and intensity post-injection 2 than post-injection 1. In SARS-CoV-2 naïve participants at D36, 96·9%, 97.0% and 97·6% of participants had ≥4-fold-rise in NAb titres from baseline in the 5μg-, 10μg- and 15μg-dose groups, respectively. NAb titres increased with antigen dose in younger (GMTs: 2954, 3951 and 5142 for 5μg-, 10μg- and 15μg-dose groups) but not older adults (GMTs: 1628, 1393 and 1736, respectively). NAb titres in non-naïve adults after one injection were higher than titres after two injections in naïve adults.InterpretationTwo injections of CoV2 preS dTM-AS03 demonstrated acceptable safety and reactogenicity, and robust immunogenicity in SARS-CoV-2 naïve and non-naïve adults. These results informed antigen dose selection for progression to Phase 3 evaluation of primary and booster vaccination.
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- 2021
5. Broadly Reactive IgG Responses to Heterologous H5 Prime-Boost Influenza Vaccination Are Shaped by Antigenic Relatedness to Priming Strains
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John J. Treanor, Sheldon Perry, Martin S. Zand, Jiong Wang, Shannon P. Hilchey, Dongmei Li, Alexander Wiltse, and Mark Y. Sangster
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Adult ,0301 basic medicine ,030106 microbiology ,Hemagglutinin (influenza) ,Hemagglutinin Glycoproteins, Influenza Virus ,Booster dose ,Biology ,Antibodies, Viral ,Microbiology ,Virus ,H5 monovalent influenza vaccine (MIV) ,HA imprinting ,Cohort Studies ,03 medical and health sciences ,Antigen ,Immunity ,Virology ,Influenza, Human ,hemagglutinin (HA) antigenic distance ,influenza virus antibody landscape ,Humans ,Antigenic Drift and Shift ,Influenza A Virus, H5N1 Subtype ,Vaccination ,Antigenic shift ,Middle Aged ,QR1-502 ,030104 developmental biology ,Influenza Vaccines ,Immunoglobulin G ,biology.protein ,Antibody ,original antigenic sin (OAS) ,Research Article - Abstract
Prime-boost vaccinations of humans with different H5 strains have generated broadly protective antibody levels. However, the effect of an individual’s H5 exposure history on antibody responses to subsequent H5 vaccination is poorly understood. To investigate this, we analyzed the IgG responses to H5 influenza A/Indonesia/5/2005 (Ind05) virus vaccination in three cohorts: (i) a doubly primed group that had received two H5 virus vaccinations, namely, against influenza A/Vietnam/203/2004 (Vie04) virus 5 years prior and A/Hong Kong/156/1997 (HK97) 11 years prior to the Ind05 vaccination; (ii) a singly primed group that had received a vaccination against Vie04 virus 5 years prior to the Ind05 vaccination; and (iii) an H5-naive group that received two doses of the Ind05 vaccine 28 days apart. Hemagglutinin (HA)-reactive IgG levels were estimated by a multiplex assay against an HA panel that included 21 H5 strains and 9 other strains representing the H1, H3, H7, and H9 subtypes. Relative HA antibody landscapes were generated to quantitatively analyze the magnitude and breadth of antibody binding after vaccination. We found that short-interval priming and boosting with the Ind05 vaccine in the naive group generated a low anti-H5 response. Both primed groups generated robust antibody responses reactive to a broad range of H5 strains after receiving a booster injection of Ind05 vaccine; IgG antibody levels persisted longer in subjects who had been doubly primed years ago. Notably, the IgG responses were strongest against the first priming H5 strain, which reflects influenza virus immune imprinting. Finally, the broad anti-H5 IgG response was stronger against strains having a small antigenic distance from the initial priming strain. IMPORTANCE The antigenic shift and draft of hemagglutinin (HA) in influenza viruses is accepted as one of the major reasons for immune evasion. The analysis of B cell immune responses to influenza infection and vaccination is complicated by the impact of exposure history and antibody cross-reactions between antigenically similar influenza strains. To assist in such analyses, the influenza “antibody landscape” method has been used to analyze and visualize the relationship of antibody-mediated immunity to antigenic distances between influenza strains. In this study, we describe a “relative antibody landscape” method that calculates the antigenic distance between the vaccine influenza strain and other H5 strains and uses this relative antigenic distance to plot the anti-H5 IgG levels postvaccination. This new method quantitatively estimates and visualizes the correlation between the humoral response to a particular influenza strain and the antigenic distance from other strains. Our findings demonstrate the effect of a subject’s H5 exposure history on H5 vaccine responses quantified by the relative antibody landscape method.
- Published
- 2021
6. Repeat vaccination reduces antibody affinity maturation across different influenza vaccine platforms in humans
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Elizabeth M. Coyle, Megan Hahn, Hana Golding, Andrea J. Sant, Tsai-Lien Lin, Surender Khurana, John J. Treanor, and Lisa R. King
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0301 basic medicine ,Male ,viruses ,Antibody Affinity ,General Physics and Astronomy ,Hemagglutinin Glycoproteins, Influenza Virus ,02 engineering and technology ,medicine.disease_cause ,Antibodies, Viral ,Influenza A Virus, H1N1 Subtype ,Influenza A virus ,Child ,lcsh:Science ,Multidisciplinary ,biology ,Vaccination ,virus diseases ,Middle Aged ,021001 nanoscience & nanotechnology ,Cell vaccines ,Outcomes research ,Influenza Vaccines ,Child, Preschool ,Female ,Antibody ,0210 nano-technology ,Adult ,Protein vaccines ,Adolescent ,Influenza vaccine ,Science ,Hemagglutinin (influenza) ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Article ,Affinity maturation ,03 medical and health sciences ,Young Adult ,Influenza, Human ,medicine ,Humans ,Inactivated vaccines ,Hemagglutination assay ,Influenza A Virus, H3N2 Subtype ,Infant ,General Chemistry ,Hemagglutination Inhibition Tests ,Virology ,030104 developmental biology ,biology.protein ,lcsh:Q - Abstract
Several vaccines are approved in the United States for seasonal influenza vaccination every year. Here we compare the impact of repeat influenza vaccination on hemagglutination inhibition (HI) titers, antibody binding and affinity maturation to individual hemagglutinin (HA) domains, HA1 and HA2, across vaccine platforms. Fold change in HI and antibody binding to HA1 trends higher for H1N1pdm09 and H3N2 but not against B strains in groups vaccinated with FluBlok compared with FluCelvax and Fluzone. Antibody-affinity maturation occurs against HA1 domain of H1N1pdm09, H3N2 and B following vaccination with all vaccine platforms, but not against H1N1pdm09-HA2. Importantly, prior year vaccination of subjects receiving repeat vaccinations demonstrated reduced antibody-affinity maturation to HA1 of all three influenza virus strains irrespective of the vaccine platform. This study identifies an important impact of repeat vaccination on antibody-affinity maturation following vaccination, which may contribute to lower vaccine effectiveness of seasonal influenza vaccines in humans, Here, Khurana et al. report the results of a phase 4 clinical trial with three FDA approved influenza vaccines and show that repeat influenza vaccination results in reduced antibody affinity maturation to hemagglutinin domain 1 irrespective of vaccine platform.
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- 2019
7. Differences in the influenza-specific CD4 T cell immunodominance hierarchy and functional potential between children and young adults
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Jennifer L. Nayak, Amy Murphy, Chantelle L. White, Xing Qiu, John J. Treanor, and Ian Shannon
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0301 basic medicine ,Adult ,CD4-Positive T-Lymphocytes ,Male ,lcsh:Medicine ,Stimulation ,Immunodominance ,Biology ,Peripheral blood mononuclear cell ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Antigen ,Immunity ,Influenza, Human ,Humans ,Early childhood ,Young adult ,lcsh:Science ,Antigens, Viral ,B-Lymphocytes ,Multidisciplinary ,Immunodominant Epitopes ,Repertoire ,lcsh:R ,Age Factors ,3. Good health ,030104 developmental biology ,Influenza Vaccines ,Child, Preschool ,Immunology ,Leukocytes, Mononuclear ,Cytokines ,Female ,lcsh:Q ,030217 neurology & neurosurgery - Abstract
Studies of the B cell repertoire suggest that early childhood influenza infections profoundly shape later reactivity by creating an “imprint” that impacts subsequent vaccine responses and may provide lasting protection against influenza strains within the same viral group. However, there is little known about how these early childhood influenza exposures shape CD4 T cell reactivity later in life. To investigate the effect of age on influenza-specific CD4 T cell specificity and functionality, reactivity in cohorts of 2 year old children and young adult subjects was compared. Intracellular cytokine staining was used to determine the viral antigen specificity and expression levels of various cytokines following stimulation of peripheral blood mononuclear cells with complete peptide pools representing the entire translated sequences of the pH1, H3, HA-B, NP, and M1 proteins. We found that the influenza protein-specific immunodominance pattern in children differs from that in young adults, with much lower reactivity to the NP internal virion protein in young children. Alterations in CD4 T cell functionality were also noted, as responding CD4 T cells from children produced less IFNγ and were less likely to express multiple cytokines. These differences in the repertoire of influenza-specific CD4 T cells available for recall on influenza challenge in early childhood could possibly contribute to early imprinting of influenza-specific immunity as well as the increased susceptibility of children to this viral infection.
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- 2019
8. Broadly-reactive IgG responses to heterologous H5 prime-boost influenza vaccination are shaped by antigenic relatedness to priming strains
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Martin S. Zand, Shannon P. Hilchey, John J. Treanor, Jiong Wang, Mark Y. Sangster, Alexander Wiltse, Dongmei Li, and Sheldon Perry
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Vaccination ,Immune system ,biology ,Antigen ,Immunity ,biology.protein ,Antigenic shift ,Hemagglutinin (influenza) ,Antibody ,Virology ,Virus - Abstract
Prime-boost vaccinations of humans with different H5 strains have generated broadly protective antibody levels. However, the effect of an individual’s H5 exposure history on antibody responses to subsequent H5 vaccination is poorly understood. To investigate this, we analyzed the IgG response to H5 A/Indonesia/5/2005 (Ind05) vaccination in three cohorts: (1) a double primed group that received two H5 vaccinations: A/Vietnam/203/2004 (Vie04) 5 years ago and A/Hong Kong/156/1997 (HK97) 11 years ago, (2) a single primed group that received Vie04 5 years ago, and (3) an H5-naïve group that received two doses of the Ind05 vaccine 28 days apart. Hemagglutinin (HA)-reactive IgG levels were estimated by multiplex assay against an HA panel that included 21 H5 strains and 9 other strains representing H1, H3, H7, and H9 subtypes. Relative HA antibody landscapes were generated to quantitatively analyze the magnitude and breadth of antibody binding after vaccination. We found that short-interval prime-boosting with the Ind05 in the naïve group generated a low anti-H5 response. Both primed groups generated robust antibody responses reactive to a broad range of H5 strains after boosting with Ind05; IgG antibody levels persisted longer in subjects who had been double primed years ago. Notably, the IgG responses were strongest against the first priming H5 strain, that reflecting influenza virus immune imprinting. Finally, the broad anti-H5 IgG response was stronger against strains having a small antigenic distance to the initial priming strain.IMPORTANCEThe antigenic shift and draft of hemagglutinin (HA) in influenza viruses is accepted as one of the major reasons for immune evasion. The analysis of B cell immune responses to influenza infection and vaccination is complicated by the impact of exposure history and antibody cross-reaction between antigenically similar influenza strains. To assist in such analyses, the influenza “antibody landscape” method has been used to analyze and visualize the relationship of antibody mediated immunity to the antigenic distance between influenza strains. In this study, we describe a “relative antibody landscape” method, calculating the antigenic distance between the vaccine influenza strain and other H5 strains, and using this relative antigenic distance to plot with the anti-H5 IgG levels post-vaccination. This new method quantitatively estimates and visualizes the correlation between the humoral response to a particular influenza strain, and the antigenic distance to other strains. Our findings demonstrate the effect of H5 exposure history on H5 vaccine responses quantified by the relative antibody landscape method.
- Published
- 2021
9. Adjuvanted recombinant hemagglutinin H7 vaccine to highly pathogenic influenza A(H7N9) elicits high and sustained antibody responses in healthy adults
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Christine M. Oshansky, James King, Di Lu, James Zhou, Corrina Pavetto, Gary Horwith, Karen Biscardi, Bai Nguyen, John J. Treanor, Li-Mei Chen, Brett Jepson, BPI17002 Study Coordination Team, Rick A. Bright, Robert A. Johnson, Vittoria Cioce, and Ruben O. Donis
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0301 basic medicine ,Protein vaccines ,Influenza vaccine ,Immunology ,MF59 ,Hemagglutinin (influenza) ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pandemic ,Medicine ,Pharmacology (medical) ,030212 general & internal medicine ,AS03 ,Adjuvants ,RC254-282 ,Pharmacology ,Hemagglutination assay ,biology ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC581-607 ,Virology ,Influenza A virus subtype H5N1 ,Vaccination ,030104 developmental biology ,biology.protein ,Infectious diseases ,Immunologic diseases. Allergy ,business ,Influenza virus - Abstract
An unprecedented number of human infections with avian influenza A(H7N9) in the fifth epidemic wave during the winter of 2016–2017 in China and their antigenic divergence from the viruses that emerged in 2013 prompted development of updated vaccines for pandemic preparedness. We report on the findings of a clinical study in healthy adults designed to evaluate the safety and immunogenicity of three dose levels of recombinant influenza vaccine derived from highly pathogenic A/Guangdong/17SF003/2016 (H7N9) virus adjuvanted with AS03 or MF59 oil-in water emulsions. Most of the six study groups meet the FDA CBER-specified vaccine licensure criterion of 70% seroprotection rate (SPR) for hemagglutination inhibition antibodies to the homologous virus. A substantial proportion of subjects show high cross-reactivity to antigenically distinct heterologous A(H7N9) viruses from the first epidemic wave of 2013. These results provide critical information to develop a pandemic response strategy and support regulatory requirements for vaccination under Emergency Use Authorization.
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- 2021
10. Improving pandemic preparedness through better, faster influenza vaccines
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David Durham, John J. Treanor, Robert A. Johnson, Jason Asher, Matthew Newland, Ruben O. Donis, and Jonathan Seals
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0301 basic medicine ,Economic growth ,COVID-19 Vaccines ,Time Factors ,Coronavirus disease 2019 (COVID-19) ,Influenza vaccine ,Immunology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Drug Development ,Drug Discovery ,Pandemic ,Influenza, Human ,Influenza A virus ,medicine ,Humans ,030212 general & internal medicine ,Pharmacology ,Government ,Vaccination ,Pandemic influenza ,COVID-19 ,030104 developmental biology ,Influenza Vaccines ,Preparedness ,Molecular Medicine ,Business - Abstract
Introduction. Timely availability of effective influenza vaccine will be critical to mitigate the next influenza pandemic. The mission of Biomedical Advanced Research and Development Authority (BARDA) is to develop medical countermeasures against pandemics, including influenza and other health security threats. Areas covered. Despite considerable gains in pandemic vaccine preparedness since 2009, old and new challenges threaten the pandemic influenza response capabilities of the U.S. Government: insufficient U.S.-based vaccine production, two-dose vaccination regimen, logistically complex adjuvanted formulation, and sustained surge manufacturing capacity despite no commercial market for pandemic vaccines. Although the coronavirus disease 2019 (COVID-19) pandemic has re-exposed these gaps in preparedness and response, previous investments into flexible influenza vaccine technologies proved to be critical to accelerate COVID-19 vaccine development. Expert opinion. BARDA addresses these challenges by implementing a pandemic influenza vaccine strategy with two key goals: 1) accelerating vaccine development and production (faster) and 2) improving vaccine performance (better). This strategy involves an end-to-end approach, including increasing manufacturing and fill-finish capacity; improving release testing speed; and funding clinical trials to improve current vaccine utilization. As demonstrated by the COVID-19 response, continued investments into this pandemic influenza vaccine strategy will further enhance the ability to respond to future emerging pandemic pathogens.
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- 2021
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11. Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-monitored Challenge Model of Coronavirus Disease 2019 (COVID-19) in Healthy Volunteers
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Robert W. Sauerwein, Charlie Weller, Myron M. Levine, Anna P. Durbin, Sheng Li Shi, Peter G. Kremsner, Philip R. Krause, Rosanna Lagos, M. Cristina Cassetti, John J. Treanor, Stanley A. Plotkin, Deborah King, Delese Mimi Darko, Halvor Sommerfelt, Yaseen M. Arabi, Vicente Estrada, Punnee Pitisuttithum, Sudhanshu Vrati, Euzebiusz Jamrozik, Ana Maria Henao Restrepo, Anastazia Older Aguilar, Shobana Balasingam, Kanta Subbarao, and Salim Abdullah
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Microbiology (medical) ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,030231 tropical medicine ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,World Health Organization ,Young Adult ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,experimental challenge ,challenge model ,Healthy volunteers ,adult volunteers ,medicine ,Humans ,030212 general & internal medicine ,Young adult ,Viral shedding ,Intensive care medicine ,Aged ,SARS-CoV-2 ,Transmission (medicine) ,business.industry ,COVID-19 ,Vaccine efficacy ,Healthy Volunteers ,Virus Shedding ,Viewpoints ,Vaccination ,AcademicSubjects/MED00290 ,Infectious Diseases ,business - Abstract
WHO convened an Advisory Group (AG) to consider the feasibility, potential value, and limitations of establishing a closely-monitored challenge model of experimental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) in healthy adult volunteers. The AG included experts in design, establishment, and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (the potential of SARS-CoV-2 to cause severe/fatal illness, its high transmissibility, and lack of a “rescue treatment” to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults.
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- 2021
12. A Mutated PB1 Residue 319 Synergizes with the PB2 N265S Mutation of the Live Attenuated Influenza Vaccine to Convey Temperature Sensitivity
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Andrew W. Smith, Baek Kim, Jordana Schmierer, John J. Treanor, Josephine D'Angelo, Stephen Dewhurst, Andrew Cox, and Dustyn Levenson
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0301 basic medicine ,temperature sensitivity ,Temperature sensitivity ,viruses ,lcsh:QR1-502 ,DNA-Directed DNA Polymerase ,Vaccines, Attenuated ,Virus Replication ,medicine.disease_cause ,Article ,lcsh:Microbiology ,Madin Darby Canine Kidney Cells ,Mice ,Viral Proteins ,03 medical and health sciences ,Dogs ,Influenza A Virus, H1N1 Subtype ,0302 clinical medicine ,Orthomyxoviridae Infections ,Virology ,vaccine ,Influenza A virus ,medicine ,Influenza A Virus ,Animals ,Humans ,Live attenuated influenza vaccine ,030212 general & internal medicine ,Polymerase ,LAIV ,biology ,Strain (biology) ,Temperature ,virus diseases ,RNA-Dependent RNA Polymerase ,Mice, Inbred C57BL ,polymerase ,HEK293 Cells ,030104 developmental biology ,Infectious Diseases ,A549 Cells ,Influenza Vaccines ,Mutation ,Mutation (genetic algorithm) ,biology.protein ,Female - Abstract
Current influenza vaccines have modest efficacy. This is especially true for current live attenuated influenza vaccines (LAIV), which have been inferior to the inactivated versions in recent years. Therefore, a new generation of live vaccines may be needed. We previously showed that a mutation at PB1 residue 319 confers enhanced temperature sensitivity and attenuation in an LAIV constructed in the genetic background of the mouse-adapted Influenza A Virus (IAV) strain A/PR/8/34 (PR8). Here, we describe the origin/discovery of this unique mutation and demonstrate that, when combined with the PB2 N265S mutation of LAIV, it conveys an even greater level of temperature sensitivity and attenuation on PR8 than the complete set of attenuating mutations from LAIV. Furthermore, we show that the combined PB1 L319Q and PB2 N265S mutations confer temperature sensitivity on IAV polymerase activity in two different genetic backgrounds, PR8 and A/Cal/04/09. Collectively, these findings show that the PB2 LAIV mutation synergizes with a mutation in PB1 and may have potential utility for improving LAIVs.
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- 2020
13. Influenza response planning for the centers of excellence for influenza research and surveillance: Science preparedness for enhancing global health security
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John Steel, Angela J. Mehr, Walter A. Orenstein, Julia T. Ostrowsky, Adolfo Garcia-Sastre, David J. Topham, Richard E. Rothman, Richard W. Compans, Andrew Pekosz, John J. Treanor, Kristine A. Moore, Richard J. Webby, Stacey L. Schultz-Cherry, Daniel R. Perez, Michael T. Osterholm, and Lauren M. Sauer
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Pulmonary and Respiratory Medicine ,public health practice ,Process management ,National Institute of Allergy and Infectious Diseases ,Process (engineering) ,Epidemiology ,Science ,Advisory committee ,media_common.quotation_subject ,pandemics ,030312 virology ,Global Health ,medicine.disease_cause ,science preparedness ,03 medical and health sciences ,National Institute of Allergy and Infectious Diseases (U.S.) ,Excellence ,Influenza, Human ,influenza vaccines ,Pandemic ,National Institutes of Health ,Global health ,Influenza A virus ,medicine ,Humans ,influenza A virus ,media_common ,0303 health sciences ,Research ,Public Health, Environmental and Occupational Health ,Original Articles ,Influenza research ,United States ,Health Planning ,Infectious Diseases ,public health preparedness ,Preparedness ,disease outbreaks ,Original Article ,Business ,influenza - Abstract
Background The Centers of Excellence for Influenza Research and Surveillance (CEIRS) network, funded by the US National Institutes of Health, has been operational since 2007 and is tasked with conducting research to improve understanding of influenza viruses. Recently, CEIRS developed an Influenza Response Plan (IRP) to improve science preparedness for the network. Methods Development of the IRP involved a collaborative process between project staff, CEIRS center directors or their designees, and NIAID CEIRS leadership (referred to as the Pandemic Planning Advisory Committee [PPAC]). Project staff identified and summarized the response capabilities of each center and then worked with the PPAC to identify and rank research priorities for an emergency response using a modified Delphi method. Results Key elements of the response plan include tables of response capabilities for each CEIRS center, a framework that outlines and ranks research priorities for CEIRS during an emergency situation, and an operational strategy for executing the research priorities. Conclusions The CEIRS IRP highlights the importance of enhancing science preparedness in advance of an influenza pandemic or other influenza‐related zoonotic incident to ensure that research can be carried out expeditiously and effectively in emergency situations and to improve global health security.
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- 2020
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14. Social networks based on frequency of roost cohabitation do not reflect association rates of
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Austin G, Waag, John J, Treanor, Jess N, Kropczynski, and Joseph S, Johnson
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social network analysis ,association index ,little brown bat ,passive integrated transponder ,radio‐frequency identification ,Yellowstone National Park ,high‐frequency RFID ,Original Research - Abstract
Bats are a group of mammals well known for forming dynamic social groups. Studies of bat social structures are often based upon the frequency at which bats occupy the same roosts because observing bats directly is not always possible. However, it is not always clear how closely bats occupying the same roost associate with each other, obscuring whether associations result from social relationships or factors such as shared preferences for roosts. Our goal was to determine if bats cohabitating buildings were also found together inside roosts by using anti‐collision technology for PIT tags, which enables simultaneous detection of multiple tags. We PIT‐tagged 293 female little brown myotis (Myotis lucifugus) and installed antennas within two buildings used as maternity roosts in Yellowstone National Park. Antennas were positioned at roost entryways to generate cohabitation networks and along regions of attic ceilings in each building to generate intraroost networks based on proximity of bats to each other. We found that intraroost and cohabitation networks of buildings were significantly correlated, with the same bats tending to be linked in both networks, but that bats cohabitating the same building often roosted apart, leading to differing assessments of social structure. Cohabitation rates implied that bats associate with a greater number of their roost‐mates than was supported by observations within the roost. This caused social networks built upon roost cohabitation rates to be denser, smaller in diameter, and contain nodes with higher average degree centrality. These results show that roost cohabitation does not reflect preference for roost‐mates in little brown myotis, as is often inferred from similar studies, and that social network analyses based on cohabitation may provide misleading results., Sociograms depicting connections among little brown myotis within a maternity colony in Yellowstone National Park. Social networks based upon the frequency at which pairs of bats cohabitate the same roost (Panels a and c) connect bats that rarely or never were found roosting along in the same location on attic ceilings (Panels b and d). This comparison shows that co‐roosting associations in little brown myotis do not reflect bats' preference for specific roost‐mates, as is often interpreted in similar studies.
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- 2020
15. History of Live, Attenuated Influenza Vaccine
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John J. Treanor
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Clinical Trials as Topic ,business.industry ,General Medicine ,History, 20th Century ,Vaccines, Attenuated ,Virology ,Infectious Diseases ,Vaccines, Inactivated ,Influenza Vaccines ,Pediatrics, Perinatology and Child Health ,Influenza, Human ,Medicine ,Live attenuated influenza vaccine ,Humans ,business - Published
- 2020
16. A phase 2 study of the bivalent VLP norovirus vaccine candidate in older adults; impact of MPL adjuvant or a second dose
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John J. Treanor, Frank Baehner, Jakob P Cramer, Astrid Borkowski, Jim Sherwood, Stella Lin, Nor investigators, and Nancy Le Cam Bouveret
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medicine.medical_treatment ,030231 tropical medicine ,Population ,Monophosphoryl Lipid A ,Antibodies, Viral ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Double-Blind Method ,medicine ,Humans ,Avidity ,030212 general & internal medicine ,Vaccines, Virus-Like Particle ,Adverse effect ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,General Veterinary ,General Immunology and Microbiology ,business.industry ,Immunogenicity ,Norovirus ,Public Health, Environmental and Occupational Health ,Middle Aged ,Gastroenteritis ,Vaccination ,Infectious Diseases ,Lipid A ,Immunology ,Molecular Medicine ,business ,Adjuvant ,Receptors, Thrombopoietin - Abstract
Introduction Acute norovirus gastroenteritis causes significant morbidity and in uncommon cases fatality in older adults. We investigated the safety and immunogenicity of bivalent virus-like particle (VLP) vaccine candidate formulations with and without monophosphoryl lipid A (adjuvant MPL) in this population. Methods In this phase II, double-blind, controlled trial 294 healthy adults, ≥ 60 years of age, were randomized (1:1:1:1) to four groups to receive one or two intramuscular immunizations 28 days apart, with 26 18–49 year-old controls who received one MPL-free dose. One-dose groups received placebo on Day 1. Vaccine formulations contained 15 μg GI.1 and 50 μg GII.4c VLP antigens and 500 μg Al(OH)3, with or without 15 μg MPL. We measured histo-blood group antigen blocking (HBGA) antibodies and ELISA Ig at Days 1, 8, 29, 57, 211 and 393, and avidity indices and cell-mediated immunity (CMI). Solicited local and systemic adverse events (AE) were assessed for 7 days and unsolicited AEs for 28 days after each injection. Results After one dose HBGA antibodies to both VLP antigens increased with similar kinetics and magnitude in all groups; geometric mean titres (GMTs) persisted above baseline through Day 393. GMTs were similar across age strata (18–49, 60–74, 75–84 and ≥ 85 years of age) and unaffected by a second vaccination or MPL. Total Ig showed similar responses. No clinically relevant differences or changes in avidity or CMI were observed between formulations. Both formulations were well tolerated with no vaccine-related SAEs, the most frequent AEs being mild injection site pain and fatigue. Conclusions Adults over 60 years of age displayed no safety concerns and had similar immune responses to the norovirus VLP vaccine candidate as younger adults, unaffected by increasing age, a second dose or inclusion of MPL. This data supports the further development of the MPL-free vaccine candidate for older adults.
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- 2020
17. Characterizing Emerging Canine H3 Influenza Viruses
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Huihui Kong, Laura Rodriguez, Brian R. Wasik, Hanyuan Zhang, Guojun Wang, Yoshihiro Kawaoka, Kuan-Fu Chen, Pamela Freiden, Nicholas Wohlgemuth, David F. Burke, Ashley L. Fink, Sabra L. Klein, Melissa B. Uccellini, Patrick C. Wilson, Karlie Woodard, Sander Herfst, David J. Topham, Angela Danner, Zhen-Ying Liu, Daniel R. Perez, Cheryl A. Jones, John Steel, Philippe Noriel Q. Pascua, Christopher S. Anderson, Anice C. Lowen, Katherine J. Fenstermacher, Lauren Sauer, Victoria A. Meliopoulos, Jeanne Holden-Wiltse, Richard D. Cummings, Yao-Tsun Li, Gabriele Neumann, Malik Peiris, Elena A. Govorkova, Kaori Sakamoto, Michael C. W. Chan, Derek J. Smith, Benjamin L. Miller, Sanjukta Bandyopadhyay, Colin R. Parrish, Subrata Barman, John J. Treanor, Lucas M. Ferreri, Shamika Danzy, Hui Tao, Ian E. H. Voorhees, Ranawaka A.P.M. Perera, Paul G. Thomas, Scott Krauss, David A. Steinhauer, Adolfo García-Sastre, Pilar Blanco-Lobo, Gavin J. D. Smith, Stacey Schultz-Cherry, Phuong T. M. Nguyen, Luis Martinez-Sobrido, Ron A. M. Fouchier, Masato Hatta, Sean Cherry, Brandi Livingston, Marta L. DeDiego, Gongxun Zhong, Mathilde Richard, David J. Pattinson, Mitra Lewis, Bridgett Sharp, Farah El Najjar, Andrew Pekosz, Jasmina M. Luczo, Stephen M. Tompkins, Charles J. Russell, Bindumadhav M. Marathe, Richard E. Rothman, Carole Henry, Lauren Byrd-Leotis, Mark Y. Sangster, Theresa Fitzgerald, Juan Carlos Dib, Shiho Chiba, Shufang Fan, Kathryn Shaw-Saliba, Aitor Nogales, Guohua Yang, Richard J. Webby, Virology, Martinez-Sobrido, Luis [0000-0001-7084-0804], Zhang, Hanyuan [0000-0002-0736-4603], Nguyen, Phuong [0000-0002-8273-730X], Anderson, Christopher S [0000-0002-8560-3438], Holden-Wiltse, Jeanne [0000-0003-2694-7465], Nogales, Aitor [0000-0002-2424-7900], Wasik, Brian R [0000-0001-5442-3883], Miller, Benjamin L [0000-0001-9168-8047], Henry, Carole [0000-0002-5696-527X], Wilson, Patrick C [0000-0002-3537-1245], Topham, David J [0000-0002-9435-8673], Byrd-Leotis, Lauren [0000-0002-7984-0357], Cummings, Richard D [0000-0002-8918-5034], Luczo, Jasmina M [0000-0002-8036-110X], Tompkins, Stephen M [0000-0002-1523-5588], Sakamoto, Kaori [0000-0003-0592-6403], Steel, John [0000-0003-1217-0990], Klein, Sabra L [0000-0002-0730-5224], Wohlgemuth, Nicholas [0000-0002-6450-6452], Fenstermacher, Katherine J [0000-0003-1139-3711], Pekosz, Andrew [0000-0003-3248-1761], Lewis, Mitra K [0000-0002-4737-4961], Chen, Kuan-Fu [0000-0001-7287-9497], Voorhees, Ian E H [0000-0003-3189-1101], García-Sastre, Adolfo [0000-0002-6551-1827], Perez, Daniel R [0000-0002-6569-5689], Ferreri, Lucas M [0000-0002-1069-9500], Herfst, Sander [0000-0001-9866-8903], Richard, Mathilde [0000-0003-0240-9312], Burke, David [0000-0001-8830-3951], Pattinson, David [0000-0003-0001-8203], Smith, Derek J [0000-0002-2393-1890], Freiden, Pamela [0000-0001-6167-180X], Peiris, Malik [0000-0001-8217-5995], Chan, M C W [0000-0001-8174-8405], Govorkova, Elena A [0000-0001-9067-5682], Marathe, Bindumadhav M [0000-0002-9929-7566], Pascua, Philippe N Q [0000-0001-6777-2994], Smith, Gavin [0000-0001-5031-468X], Schultz-Cherry, Stacey [0000-0002-2021-727X], Apollo - University of Cambridge Repository, Voorhees, Ian EH [0000-0003-3189-1101], Chan, MCW [0000-0001-8174-8405], Pascua, Philippe NQ [0000-0001-6777-2994], Anderson, Christopher S. [0000-0002-8560-3438], Wasik, Brian R. [0000-0001-5442-3883], Miller, Benjamin L. [0000-0001-9168-8047], Wilson, Patrick C. [0000-0002-3537-1245], Topham, David J. [0000-0002-9435-8673], Cummings, Richard D. [0000-0002-8918-5034], Luczo, Jasmina M. [0000-0002-8036-110X], Tompkins, Stephen M. [0000-0002-1523-5588], Klein, Sabra L. [0000-0002-0730-5224], Fenstermacher, Katherine J. [0000-0003-1139-3711], Lewis, Mitra K. [0000-0002-4737-4961], Voorhees, Ian E. H. [0000-0003-3189-1101], Perez, Daniel R. [0000-0002-6569-5689], Ferreri, Lucas M. [0000-0002-1069-9500], Smith, Derek J. [0000-0002-2393-1890], Chan, M. C. W. [0000-0001-8174-8405], Govorkova, Elena A. [0000-0001-9067-5682], Marathe, Bindumadhav M. [0000-0002-9929-7566], and Pascua, Philippe N. Q. [0000-0001-6777-2994]
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RNA viruses ,Viral Diseases ,Influenza Viruses ,Pulmonology ,Physiology ,Pathology and Laboratory Medicine ,Communicable Diseases, Emerging ,Biochemistry ,Fluorescence Microscopy ,Basic research ,Zoonoses ,Immune Physiology ,Research article ,Dog Diseases ,Biology (General) ,Enzyme-Linked Immunoassays ,Mammals ,Mice, Inbred BALB C ,Microscopy ,0303 health sciences ,Immune System Proteins ,Viral Vaccine ,030302 biochemistry & molecular biology ,Eukaryota ,Light Microscopy ,Influenza research ,Infectious Diseases ,Influenza A virus ,Mice, Inbred DBA ,Medical Microbiology ,Viral Pathogens ,Viruses ,Vertebrates ,Pathogens ,Research Article ,medicine.medical_specialty ,QH301-705.5 ,Guinea Pigs ,Immunology ,Microbiology ,Antibodies ,Influenza A Virus, H3N8 Subtype ,03 medical and health sciences ,Dogs ,Virology ,Influenza, Human ,Genetics ,medicine ,Animals ,Humans ,Immunoassays ,Microbial Pathogens ,Molecular Biology ,030304 developmental biology ,Medicine and health sciences ,Biology and life sciences ,business.industry ,Influenza A Virus, H3N2 Subtype ,Public health ,Ferrets ,Organisms ,Proteins ,Influenza a ,RC581-607 ,United States ,Influenza ,Viral Replication ,Mice, Inbred C57BL ,Research and analysis methods ,Viral replication ,Respiratory Infections ,Amniotes ,Immunologic Techniques ,Parasitology ,Immunologic diseases. Allergy ,business ,Orthomyxoviruses - Abstract
The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned., Author summary The 2009 influenza pandemic was a stark reminder that ongoing vigilance is critical to protect the public from an influenza pandemic. The continual evolution of influenza viruses and emergence from animal reservoirs, leads to the need to quickly identify strains that pose a public health risk. In these studies, members of the National Institutes of Allergy and Infectious Diseases (NIAID) Centers for Excellence in Influenza Research and Surveillance (CEIRS) network worked together to demonstrate that the emerging canine H3 influenza viruses posed a low risk to public health and identified several therapeutic options in the event of an emergence. In addition to providing important new basic research, many lessons were learned that may be important in dealing with any emerging disease outbreak.
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- 2020
18. Buildings provide vital habitat for little brown myotis ( Myotis lucifugus ) in a high‐elevation landscape
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John J. Treanor, Alexandra C. Slusher, Joseph S. Johnson, and Michael J. Lacki
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Ecology ,biology ,ecophysiology ,bats ,conservation ,Elevation ,Myotis myotis ,Torpor ,Thermoregulation ,biology.organism_classification ,gestation ,Habitat ,lcsh:QH540-549.5 ,little brown bat ,lcsh:Ecology ,parturition ,Ecology, Evolution, Behavior and Systematics - Abstract
Bats in North America are currently experiencing dramatic population declines due to the disease white‐nose syndrome. The long‐term viability of vulnerable species requires recognition of critical habitats, including those also occupied by humans. Our study aimed to quantify the importance of buildings to little brown myotis (Myotis lucifugus) in Yellowstone National Park, a high‐elevation landscape with relatively few human structures and abundant alternative roosting habitat. We measured roost preferences and thermoregulation in adult male and female bats roosting in buildings, trees, and rocks using temperature‐sensitive radio‐transmitters. We also studied microclimates within each roost type for comparison to roost preferences. We found reproductive females roosting in building attics on 84% of all possible days, while males roosted exclusively in rock crevices or in trees. This dichotomous roosting pattern reflected differences in roost microclimates. All roost types buffered bats from daily minimum ambient temperatures; however, buildings were more insulated from low ambient temperatures during the middle of the maternity season. Male bats roosting in rocks and trees predominantly thermoconformed to roost temperatures, while females roosting in buildings sustained higher body temperatures than males throughout the day. Pregnant and lactating females also used torpor frequently, with skin temperatures reaching
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- 2019
19. Influence of Birth Cohort on Effectiveness of 2015–2016 Influenza Vaccine Against Medically Attended Illness Due to 2009 Pandemic Influenza A(H1N1) Virus in the United States
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Manjusha Gaglani, Kempapura Murthy, Edward A. Belongia, Arnold S. Monto, John J. Treanor, Michael L. Jackson, David E. Wentworth, Richard K. Zimmerman, Rebecca Garten, Min Z. Levine, Jessie R Chung, H. Keipp Talbot, Marie R. Griffin, Lisa A. Jackson, Mary Patricia Nowalk, Huong Q. McLean, Alicia M. Fry, Brendan Flannery, Catherine B. Smith, and Emily T. Martin
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Influenza vaccine ,viruses ,medicine.disease_cause ,Polymerase Chain Reaction ,Virus ,Young Adult ,03 medical and health sciences ,Influenza A Virus, H1N1 Subtype ,0302 clinical medicine ,Internal medicine ,Influenza, Human ,Pandemic ,medicine ,Influenza A virus ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Child ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Age Factors ,Infant ,virus diseases ,Retrospective cohort study ,Odds ratio ,Middle Aged ,United States ,Vaccination ,Treatment Outcome ,030104 developmental biology ,Infectious Diseases ,Influenza Vaccines ,Child, Preschool ,RNA, Viral ,Female ,business ,Cohort study - Abstract
Background The effectiveness of influenza vaccine during 2015-2016 was reduced in some age groups as compared to that in previous 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09 virus)-predominant seasons. We hypothesized that the age at first exposure to specific influenza A(H1N1) viruses could influence vaccine effectiveness (VE). Methods We estimated the effectiveness of influenza vaccine against polymerase chain reaction-confirmed influenza A(H1N1)pdm09-associated medically attended illness from the 2010-2011 season through the 2015-2016 season, according to patient birth cohort using data from the Influenza Vaccine Effectiveness Network. Birth cohorts were defined a priori on the basis of likely immunologic priming with groups of influenza A(H1N1) viruses that circulated during 1918-2015. VE was calculated as 100 × [1 - adjusted odds ratio] from logistic regression models comparing the odds of vaccination among influenza virus-positive versus influenza test-negative patients. Results A total of 2115 A(H1N1)pdm09 virus-positive and 14 696 influenza virus-negative patients aged ≥6 months were included. VE was 61% (95% confidence interval [CI], 56%-66%) against A(H1N1)pdm09-associated illness during the 2010-2011 through 2013-2014 seasons, compared with 47% (95% CI, 36%-56%) during 2015-2016. During 2015-2016, A(H1N1)pdm09-specific VE was 22% (95% CI, -7%-43%) among adults born during 1958-1979 versus 61% (95% CI, 54%-66%) for all other birth cohorts combined. Conclusion Findings suggest an association between reduced VE against influenza A(H1N1)pdm09-related illness during 2015-2016 and early exposure to specific influenza A(H1N1) viruses.
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- 2018
20. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains
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Scott E. Hensley, Patrick C. Wilson, Seth J. Zost, Sarah Cobey, Andrea J. Sant, Megan E. Gumina, John J. Treanor, Sebastian Diaz Perez, Kaela Parkhouse, and Kangchon Kim
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0301 basic medicine ,Glycosylation ,viruses ,Hemagglutinin Glycoproteins, Influenza Virus ,Microbiology ,Virus ,Antigenic drift ,03 medical and health sciences ,chemistry.chemical_compound ,Vaccine strain ,Antigen ,antibody ,vaccine ,Influenza, Human ,Humans ,hemagglutinin ,Clade ,Antigens, Viral ,chemistry.chemical_classification ,Multidisciplinary ,biology ,Influenza A Virus, H3N2 Subtype ,virus diseases ,Biological Sciences ,Virology ,3. Good health ,carbohydrates (lipids) ,030104 developmental biology ,chemistry ,Influenza Vaccines ,embryonic structures ,biology.protein ,Antibody ,influenza ,Glycoprotein - Abstract
Significance The majority of influenza vaccine antigens are prepared in chicken eggs. Human vaccine strains grown in eggs often possess adaptive mutations that increase viral attachment to chicken cells. Most of these adaptive mutations are in the hemagglutinin protein, which functions as a viral attachment factor. Here, we identify a hemagglutinin mutation in the current egg-adapted H3N2 vaccine strain that alters antigenicity. We show that ferrets and humans exposed to the current egg-adapted H3N2 vaccine strain produce antibodies that poorly neutralize H3N2 viruses that circulated during the 2016–2017 influenza season. These studies highlight the challenges associated with producing influenza vaccine antigens in eggs, while offering a potential explanation of why there was only moderate vaccine effectiveness during the 2016–2017 influenza season., H3N2 viruses continuously acquire mutations in the hemagglutinin (HA) glycoprotein that abrogate binding of human antibodies. During the 2014–2015 influenza season, clade 3C.2a H3N2 viruses possessing a new predicted glycosylation site in antigenic site B of HA emerged, and these viruses remain prevalent today. The 2016–2017 seasonal influenza vaccine was updated to include a clade 3C.2a H3N2 strain; however, the egg-adapted version of this viral strain lacks the new putative glycosylation site. Here, we biochemically demonstrate that the HA antigenic site B of circulating clade 3C.2a viruses is glycosylated. We show that antibodies elicited in ferrets and humans exposed to the egg-adapted 2016–2017 H3N2 vaccine strain poorly neutralize a glycosylated clade 3C.2a H3N2 virus. Importantly, antibodies elicited in ferrets infected with the current circulating H3N2 viral strain (that possesses the glycosylation site) and humans vaccinated with baculovirus-expressed H3 antigens (that possess the glycosylation site motif) were able to efficiently recognize a glycosylated clade 3C.2a H3N2 virus. We propose that differences in glycosylation between H3N2 egg-adapted vaccines and circulating strains likely contributed to reduced vaccine effectiveness during the 2016–2017 influenza season. Furthermore, our data suggest that influenza virus antigens prepared via systems not reliant on egg adaptations are more likely to elicit protective antibody responses that are not affected by glycosylation of antigenic site B of H3N2 HA.
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- 2017
21. Maximum Likelihood Estimation of Titer via a Power Family of Four-Parameter Logistic Model
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Jeanne Holden-Wiltse, David J. Topham, Hongmei Yang, and John J. Treanor
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0301 basic medicine ,Statistics and Probability ,Accuracy and precision ,Logistic regression ,Complement Hemolytic Activity Assay ,01 natural sciences ,Article ,Correlation ,010104 statistics & probability ,03 medical and health sciences ,Covariate ,Statistics ,Econometrics ,Humans ,Computer Simulation ,Pharmacology (medical) ,0101 mathematics ,Mathematics ,Pharmacology ,Estimation ,Likelihood Functions ,Hemagglutination Tests ,Function (mathematics) ,Titer ,Logistic Models ,030104 developmental biology ,Data Interpretation, Statistical ,Marginal distribution - Abstract
For many laboratory assays, the readouts are presence or absence of a particular function, and the binary outcomes are correlated. The research interest is often focused on the estimation of titers, at which 50% positivity occurs. The classical approach by Reed and Muench (RM) assumes of a linear dose-response relationship around the potential titer, and uses only information from two points around the potential titer, which is inefficient in both precision and accuracy. While the model-based methods such as four-parameter logistic regression (4PL) use all the data, they do not consider the correlation among binary outcomes from same identities, which may lead to estimates with overstated precision. We propose estimating titers from two different anchors: independent responses from same identities or exchangeable responses from same identities. Marginal distributions of responses are linked to covariates of dilution factors by the 4PL model for independent responses and by a power family of the 4PL models for exchangeable responses. The maximum likelihood procedure is used to get estimates of parameters and titers. The superiority of proposed methods over the classical approach is demonstrated both in simulation studies and in analysis of real data from hemagglutination assays.
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- 2017
22. Seasonal Foraging Strategies of Migrant and Non-Migrant Pronghorn In Yellowstone National Park
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John J. Treanor, Troy L. Davis, Patrick J. White, Kerey K. Barnowe-Meyer, and John A. Byers
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0106 biological sciences ,biology ,National park ,Range (biology) ,Ecology ,Late gestation ,010604 marine biology & hydrobiology ,Foraging ,Forage ,Antilocapra americana ,010603 evolutionary biology ,01 natural sciences ,Animal science ,Diet quality ,biology.animal ,General Earth and Planetary Sciences ,Forb ,General Environmental Science - Abstract
We characterized the seasonal composition and quality of migrant and non-migrant Pronghorn (Antilocapra Americana) diets in Yellowstone National Park during 2006–2007. During winter (January–April), when migrants and non-migrants occupied the same winter range, the overall percent relative density for each forage class in Pronghorn diets (n = 51 composite fecal samples) was 67 + 6% (standard error) shrubs, 17 + 3% forbs, 13 + 3% grasses, and 3 + 1% other. However, spring and summer diets differed for migrants and non-migrants. Diets of migrants (n = 34) to higher-elevation ranges with higher precipitation and forage quality during May–August were dominated by 68 + 2% forbs, whereas summer diets of non-migrants (n = 21) remaining on the winter range were co-dominated by 48 + 2% forbs and 42 + 1% shrubs. Diet quality for migrant Pronghorn, as indexed by fecal nitrogen and DAPA, was also generally higher than for non-migrants during a period when the demands of late gestation and lactation were high...
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- 2017
23. Monoclonal Antibody Responses after Recombinant Hemagglutinin Vaccine versus Subunit Inactivated Influenza Virus Vaccine: a Comparative Study
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Henry A. Utset, Andrea J. Sant, Carole Henry, Nai-Ying Zheng, Patrick C. Wilson, Florian Krammer, Theresa Fitzgerald, Yao-Qing Chen, Min Huang, John J. Treanor, Karlynn E. Neu, Anna-Karin E. Palm, David J. Topham, and Irvin Y. Ho
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Adult ,Male ,Adolescent ,medicine.drug_class ,Immunology ,Hemagglutinin (influenza) ,Sequence Homology ,Hemagglutinin Glycoproteins, Influenza Virus ,Immunodominance ,Monoclonal antibody ,Antibodies, Viral ,Microbiology ,Virus ,Epitope ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Orthomyxoviridae Infections ,Virology ,Influenza, Human ,Vaccines and Antiviral Agents ,medicine ,Animals ,Humans ,Avidity ,030212 general & internal medicine ,Amino Acid Sequence ,030304 developmental biology ,0303 health sciences ,Mice, Inbred BALB C ,biology ,Vaccination ,Antibodies, Monoclonal ,Hemagglutination Inhibition Tests ,Middle Aged ,Antibodies, Neutralizing ,Vaccines, Inactivated ,Influenza A virus ,Influenza Vaccines ,Insect Science ,biology.protein ,Female ,Antibody - Abstract
Vaccination is the best measure of protection against influenza virus infection. Vaccine-induced antibody responses target mainly the hemagglutinin (HA) surface glycoprotein, composed of the head and the stalk domains. Recently two novel vaccine platforms have been developed for seasonal influenza vaccination: a recombinant HA vaccine produced in insect cells (Flublok) and Flucelvax, prepared from virions produced in mammalian cells. In order to compare the fine specificity of the antibodies induced by these two novel vaccine platforms, we characterized 42 Flublok-induced monoclonal antibodies (MAbs) and 38 Flucelvax-induced MAbs for avidity, cross-reactivity, and any selectivity toward the head versus the stalk domain. These studies revealed that Flublok induced a greater proportion of MAbs targeting epitopes near the receptor-binding domain on HA head (hemagglutinin inhibition-positive MAbs) than Flucelvax, while the two vaccines induced similar low frequencies of stalk-reactive MAbs. Finally, mice immunized with Flublok and Flucelvax also induced similar frequencies of stalk-reactive antibody-secreting cells, showing that HA head immunodominance is independent of immune memory bias. Collectively, our results suggest that these vaccine formulations are similarly immunogenic but differ in the preferences of the elicited antibodies toward the receptor-binding domain on the HA head. IMPORTANCE There are ongoing efforts to increase the efficacy of influenza vaccines and to promote production strategies that can rapidly respond to newly emerging viruses. It is important to understand if current alternative seasonal vaccines, such as Flublok and Flucelvax, that use alternate production strategies can induce protective influenza-specific antibodies and to evaluate what type of epitopes are targeted by distinct vaccine formulations.
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- 2019
24. Evidence That Blunted CD4 T-Cell Responses Underlie Deficient Protective Antibody Responses to Influenza Vaccines in Repeatedly Vaccinated Human Subjects
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Hongmei Yang, Ian Shannon, Andrea J. Sant, Katherine A. Richards, Jennifer L. Nayak, and John J. Treanor
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0301 basic medicine ,Adult ,CD4-Positive T-Lymphocytes ,Adolescent ,T Follicular Helper Cells ,Influenza vaccine ,Hemagglutinin Glycoproteins, Influenza Virus ,Antibodies, Viral ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Immunogenicity, Vaccine ,Influenza, Human ,Immunology and Allergy ,Medicine ,Humans ,030212 general & internal medicine ,Cd4 t cell ,business.industry ,Vaccination ,Limiting ,Middle Aged ,Vaccine efficacy ,Orthomyxoviridae ,Influenza B virus ,030104 developmental biology ,Infectious Diseases ,Antibody response ,Vaccines, Inactivated ,Influenza A virus ,Influenza Vaccines ,Immunology ,Protective antibody ,business ,Antibody formation - Abstract
Despite the benefits of yearly influenza vaccination, accumulating evidence suggests that diminished vaccine efficacy may be related to repeated vaccination. Although studied at the level of B-cell responses, CD4 T-cell responses have not yet been examined. In this study, we analyze CD4 T-cell responses to influenza vaccination in subjects who differ in their vaccine history. We find a striking disparity in their responses, with previously vaccinated subjects exhibiting significantly blunted CD4 T-cell responses and diminished antibody responses. These results suggest that limiting CD4 T-cell help mteaserrlie the diminished or altered antibody responses in repeatedly vaccinated subjects.
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- 2019
25. Broad Hemagglutinin-Specific Memory B Cell Expansion by Seasonal Influenza Virus Infection Reflects Early-Life Imprinting and Adaptation to the Infecting Virus
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David J. Topham, Luis Martinez-Sobrido, Aitor Nogales, Florian Krammer, Jiong Wang, Jessica L. Halliley, Phuong Thanh Nguyen, Marta L. DeDiego, Martin S. Zand, Hongmei Yang, Brenda L Tesini, Surender Khurana, Francisco A. Chaves, Preshetha Kanagaiah, Rafi Ahmed, John J. Treanor, Ali H. Ellebedy, Shirin Strohmeier, Mark Y. Sangster, Christopher S. Anderson, Sanjukta Bandyopadhyay, Hana Golding, and Megan Hahn
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Immunology ,Hemagglutinin Glycoproteins, Influenza Virus ,Biology ,medicine.disease_cause ,Antibodies, Viral ,Microbiology ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Influenza A Virus, H1N1 Subtype ,Antigen ,Virology ,Influenza, Human ,medicine ,Influenza A virus ,polycyclic compounds ,Humans ,Original antigenic sin ,Memory B cell ,030304 developmental biology ,0303 health sciences ,B-Lymphocytes ,Influenza A Virus, H3N2 Subtype ,Influenza A virus subtype H5N1 ,Vaccination ,030220 oncology & carcinogenesis ,Insect Science ,Immunoglobulin G ,biology.protein ,Pathogenesis and Immunity ,Seasons ,Antibody ,Immunologic Memory - Abstract
Memory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutinin-specific antibody production and changes in the size and character of hemagglutinin-reactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection “imprints” for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus. IMPORTANCE Rapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs). Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalk-reactive, as well as to head-reactive, MBCs. Our findings provide experimental support for the role of MBCs in maintaining imprinting effects and suggest a mechanism by which imprinting might confer heterosubtypic protection against avian influenza viruses. It will be important to compare our findings to the situation after influenza vaccination.
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- 2019
26. Persistence of Antibodies to 2 Virus-Like Particle Norovirus Vaccine Candidate Formulations in Healthy Adults: 1-Year Follow-up With Memory Probe Vaccination
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Robert L, Atmar, Frank, Baehner, Jakob P, Cramer, Eric, Lloyd, James, Sherwood, Astrid, Borkowski, Paul M, Mendelman, and John J, Treanor
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0301 basic medicine ,Adult ,Male ,Adolescent ,030106 microbiology ,Immunization, Secondary ,medicine.disease_cause ,Placebo ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Immunogenicity, Vaccine ,Double-Blind Method ,Immunity ,Immunology and Allergy ,Medicine ,Humans ,030212 general & internal medicine ,Vaccines, Virus-Like Particle ,Caliciviridae Infections ,biology ,business.industry ,Immunogenicity ,Norovirus ,Vaccination ,Antibody titer ,Viral Vaccines ,Middle Aged ,United States ,Infectious Diseases ,Immunology ,biology.protein ,Blood Group Antigens ,Female ,Antibody ,business ,Intramuscular injection - Abstract
BackgroundWe previously reported the tolerability and immunogenicity 1 month after intramuscular administration of 2 bivalent virus-like particle (VLP)–based candidate norovirus vaccine formulations in adults. We now describe the persistence of immunity and responses to a memory probe vaccination 1 year later.MethodsA total of 454 healthy men and women aged 18–49 years in 3 equal groups received placebo (saline) or 15/50 or 50/50 vaccine formulations (ie, 15 or 50 µg of GI.1 genotype VLPs, respectively, and 50 µg of GII.4c VLPs) with MPL and Al(OH)3. Immunogenicity and safety were assessed up to day 365, when 351 participants received a memory probe vaccination of 15 µg each of GI.1 and GII.4c VLPs with Al(OH)3.ResultsNo safety signals were detected up to 1 year after the first vaccination. Pan-immunoglobulin, immunoglobulin A, and histo-blood group antigen–blocking (HBGA) antibody levels among vaccinees waned but remained higher than levels before vaccination and levels in placebo recipients on days 180 and 365. Memory probe vaccination increased all antibody titers. Levels of HBGA antibodies to GI.1 but not GII.4c were higher after the first vaccination in candidate vaccine groups, compared with those in the placebo group.ConclusionLevels of antibodies to both candidate norovirus VLP formulations persisted above baseline levels for at least 1 year after primary vaccination. HBGA-blocking responses to the memory probe for GI.1 but not GII.4c displayed characteristics of immune memory.Clinical Trials RegistrationNCT02142504.
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- 2019
27. Continuous Readout versus Titer-Based Assays of Influenza Vaccine Trials: Sensitivity, Specificity, and False Discovery Rates
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Jiong Wang, Martin S. Zand, Dongmei Li, Jessica Garigen, and John J. Treanor
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Article Subject ,Serial dilution ,Influenza vaccine ,Hemagglutinin (influenza) ,Enzyme-Linked Immunosorbent Assay ,Hemagglutinin Glycoproteins, Influenza Virus ,Group comparison ,lcsh:Computer applications to medicine. Medical informatics ,Sensitivity and Specificity ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Neutralization Tests ,Influenza, Human ,Medicine ,Microneutralization Assay ,Humans ,Computer Simulation ,False Positive Reactions ,Sensitivity (control systems) ,030304 developmental biology ,0303 health sciences ,Clinical Trials as Topic ,Models, Statistical ,General Immunology and Microbiology ,biology ,business.industry ,Applied Mathematics ,Vaccination ,Reproducibility of Results ,General Medicine ,Gold standard (test) ,030224 pathology ,Virology ,3. Good health ,Titer ,Influenza Vaccines ,Research Design ,Modeling and Simulation ,biology.protein ,Regression Analysis ,lcsh:R858-859.7 ,business ,Algorithms ,Research Article - Abstract
The current gold standard for measuring antibody-based immunity to influenza viruses relies on the hemagglutinin inhibition assay (HAI), an 80-year-old technology, and the microneutralization assay (MN). Both assays use serial dilution to provide a discrete, ranked readout of 8–14 categorical titer values for each sample. In contrast to other methods of measuring vaccine antibody levels that produce a continuous readout (i.e., mPLEX-Flu and ELISA), titering methods introduce imprecision and increase false discovery rates (FDR). In this paper, we assess the degree of such statistical errors, first with simulation studies comparing continuous data with titer data in influenza vaccine study group comparison analyses and then by analyzing actual sample data from an influenza vaccine trial. Our results show the superiority of using continuous, rather than discrete, readout assays. Compared to continuous readout assays, titering assays have a lower statistical precision and a higher FDR. The results suggested that traditional titering assays could lead to increased Type-II errors in the comparison of different therapeutic arms of an influenza vaccine trial. These statistical issues are related to the mathematical nature of titer-based assays, which we examine in detail in the simulation studies. Continuous readout assays are free of this issue, and thus it is possible that comparisons of study groups could provide different results with these two methods as we have shown in our case study.
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- 2019
28. Improved Specificity and False Discovery Rates for Multiplex Analysis of Changes in Strain-Specific Anti-Influenza IgG
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Dongmei Li, Martin S. Zand, Jiong Wang, and John J. Treanor
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Article Subject ,Normal Distribution ,Hemagglutinin (influenza) ,Hemagglutinin Glycoproteins, Influenza Virus ,lcsh:Computer applications to medicine. Medical informatics ,medicine.disease_cause ,Antibodies, Viral ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Influenza, Human ,Influenza A virus ,medicine ,Humans ,Multiplex ,Computer Simulation ,False Positive Reactions ,030212 general & internal medicine ,Prospective Studies ,Antigens ,030304 developmental biology ,Immunoassay ,0303 health sciences ,Likelihood Functions ,General Immunology and Microbiology ,biology ,Strain (chemistry) ,Influenza A Virus, H5N1 Subtype ,Applied Mathematics ,Mean fluorescence intensity ,Reproducibility of Results ,General Medicine ,Virology ,3. Good health ,IgG binding ,Influenza Vaccines ,Modeling and Simulation ,Data Interpretation, Statistical ,Immunoglobulin G ,Sample Size ,biology.protein ,Linear Models ,lcsh:R858-859.7 ,Antibody ,Monte Carlo Method ,Protein Binding ,Research Article - Abstract
We describe a statistical approach to compare absolute antibody concentrations, both within and across subjects, derived from a multidimensional measurement of IgG binding to the influenza surface receptor hemagglutinin (HA). This approach addresses a fundamental problem in the field of vaccine immunology: how to accurately compare the levels of antibodies against multiple influenza strains. The mPlex-Flu assay can simultaneously measure the concentration of IgG antibodies against up to 50 influenza strains with only≤10 μlof serum. It yields mean fluorescence intensity (MFI) over a 4-log range with low inter- and intrasample variability. While comparison of IgG binding to a single HA between subjects is straightforward, variations in binding behavior across influenza strains, coupled with reagent variations, make quantifying and comparing binding between multiple HA subtypes within subjects challenging. In this paper, we first treat such HA variations as an independent antigen and calculate each subtype antibody concentration using its own standard curve, normalizing variations in HA binding. We applied this method to the analyses of data from an H5 influenza clinical vaccine study. The results demonstrated that there are differences in coefficient estimates and in results of “comparing groups” between those with versus those without consideration of subtype antibody variations. Then, we used simulation studies to show the importance of taking the subtype antibody variations into account in HA strain antibody data analysis. Using a common standard curve for all subtype antibodies resulted in both inflated type I error and lowered specificity when comparing different treatment groups. Our results suggest that using individual standard curves for each influenza HA strain, and independently calculating anti-HA IgG concentrations, allows for adjustment of influenza HA subtype variations in treatment group comparisons in clinical vaccine studies. This method facilitates the direct comparison of serum anti-HA IgG concentrations against different influenza HA subtypes for multiplex assays.
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- 2018
29. Gaps in Serologic Immunity against Contemporary Swine-Origin Influenza A Viruses among Healthy Individuals in the United States
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Carolyn Nolan, Theresa Fitzgerald, John J. Treanor, Jacqueline M. Nolting, Joshua N. Lorbach, David J. Topham, and Andrew S. Bowman
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Adult ,Male ,0301 basic medicine ,lcsh:QR1-502 ,serology ,Disease ,Biology ,medicine.disease_cause ,Article ,lcsh:Microbiology ,Serology ,immunology ,03 medical and health sciences ,0302 clinical medicine ,Orthomyxoviridae Infections ,Immunity ,Virology ,Influenza, Human ,Pandemic ,Influenza A virus ,medicine ,Animals ,Humans ,influenza A virus ,Serologic Tests ,030212 general & internal medicine ,Aged ,Swine Diseases ,Transmission (medicine) ,orthomyxovirus ,Outbreak ,swine ,Influenza a ,Middle Aged ,United States ,zoonoses ,030104 developmental biology ,Infectious Diseases ,Female ,Seasons - Abstract
Influenza A Viruses (IAV) in domestic swine (IAV-S) are associated with sporadic zoonotic transmission at the human&ndash, animal interface. Previous pandemic IAVs originated from animals, which emphasizes the importance of characterizing human immunity against the increasingly diverse IAV-S. We analyzed serum samples from healthy human donors (n = 153) using hemagglutination-inhibition (HAI) assay to assess existing serologic protection against a panel of contemporary IAV-S isolated from swine in the United States (n = 11). Age-specific seroprotection rates (SPR), which are the proportion of individuals with HAI &ge, 1:40, corresponded with lower or moderate pandemic risk classifications for the multiple IAV-S examined (one H1-&delta, 1, one H1-&delta, 2, three H3-IVA, one H3-IVB, one H3-IVF). Individuals born between 2004 and 2013 had SPRs of 0% for the five classified H3 subtype IAV-S, indicating youth may be particularly predisposed to infection with these viruses. Expansion of existing immunologic gaps over time could increase likelihood of future IAV-S spillover to humans and facilitate subsequent sustained human-to-human transmission resulting in disease outbreaks with pandemic potential.
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- 2021
30. Influenza Vaccination
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John J. Treanor
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,General Engineering ,MEDLINE ,General Medicine ,Vaccination ,Clinical Practice ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Correspondence ,General Earth and Planetary Sciences ,Live attenuated influenza vaccine ,Medicine ,030212 general & internal medicine ,business ,Intensive care medicine ,General Environmental Science - Published
- 2016
31. Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial
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Karen L. Kotloff, Fatoumata Diallo, Awa Traore, Sharon M. Tennant, Ibrahima Téguété, Doh Sanogo, Julie Villanueva, Boubou Tamboura, Wilbur H. Chen, Moussa Doumbia, Samba O. Sow, Milagritos D. Tapia, Andrea G. Buchwald, Joseph S. Bresee, Flanon Coulibaly, Mamoudou Kodio, Ellen DeMatt, Lauren A.V. Orenstein, Nicholas H Schluterman, Myron M. Levine, William C. Blackwelder, Marcela F. Pasetti, Adama Mamby Keita, Evan W. Orenstein, Fadima Cheick Haidara, Uma Onwuchekwa, and John J. Treanor
- Subjects
Adult ,Pediatrics ,medicine.medical_specialty ,Influenza vaccine ,030231 tropical medicine ,Population ,Meningococcal Vaccines ,Meningococcal vaccine ,Mali ,03 medical and health sciences ,0302 clinical medicine ,Adjuvants, Immunologic ,Influenza, Human ,medicine ,Humans ,Prospective Studies ,030212 general & internal medicine ,Pregnancy Complications, Infectious ,education ,Adverse effect ,Immunization Schedule ,First episode ,education.field_of_study ,Tetanus ,business.industry ,Vaccination ,Infant, Newborn ,Infant ,Articles ,medicine.disease ,Vaccine efficacy ,Infectious Diseases ,Influenza Vaccines ,Health Resources ,Female ,Immunization ,business - Abstract
Summary Background Despite the heightened risk of serious influenza during infancy, vaccination is not recommended in infants younger than 6 months. We aimed to assess the safety, immunogenicity, and efficacy of maternal immunisation with trivalent inactivated influenza vaccine for protection of infants against a first episode of laboratory-confirmed influenza. Methods We did this prospective, active-controlled, observer-blind, randomised phase 4 trial at six referral centres and community health centres in Bamako, Mali. Third-trimester pregnant women (≥28 weeks' gestation) were randomly assigned (1:1), via a computer-generated, centre-specific list with alternate block sizes of six or 12, to receive either trivalent inactivated influenza vaccine or quadrivalent meningococcal vaccine. Study personnel administering vaccines were not masked to treatment allocation, but allocation was concealed from clinicians, laboratory personnel, and participants. Infants were visited weekly until age 6 months to detect influenza-like illness; laboratory-confirmed influenza diagnosed with RT-PCR. We assessed two coprimary objectives: vaccine efficacy against laboratory-confirmed influenza in infants born to women immunised any time prepartum (intention-to-treat population), and vaccine efficacy in infants born to women immunised at least 14 days prepartum (per-protocol population). The primary outcome was the occurrence of a first case of laboratory-confirmed influenza by age 6 months. This trial is registered with ClinicalTrials.gov, number NCT01430689. Findings We did this trial from Sept 12, 2011, to Jan 28, 2014. Between Sept 12, 2011, and April 18, 2013, we randomly assigned 4193 women to receive trivalent inactivated influenza vaccine (n=2108) or quadrivalent meningococcal vaccine (n=2085). There were 4105 livebirths; 1797 (87%) of 2064 infants in the trivalent inactivated influenza vaccine group and 1793 (88%) of 2041 infants in the quadrivalent meningococcal vaccine group were followed up until age 6 months. We recorded 5279 influenza-like illness episodes in 2789 (68%) infants, of which 131 (2%) episodes were laboratory-confirmed influenza. 129 (98%) cases of laboratory-confirmed influenza were first episodes (n=77 in the quadrivalent meningococcal vaccine group vs n=52 in the trivalent inactivated influenza vaccine group). In the intention-to-treat population, overall infant vaccine efficacy was 33·1% (95% CI 3·7–53·9); in the per-protocol population, vaccine efficacy was 37·3% (7·6–57·8). Vaccine efficacy remained robust during the first 4 months of follow-up (67·9% [95% CI 35·1–85·3] by intention to treat and 70·2% [35·7–87·6] by per protocol), before diminishing during the fifth month (57·3% [30·6–74·4] and 60·7 [33·8–77·5], respectively). Adverse event rates in women and infants were similar among groups. Pain at the injection site was more common in women given quadrivalent meningococcal vaccine than in those given trivalent inactivated influenza vaccine (n=253 vs n=132; p
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- 2016
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32. Genomics reveals historic and contemporary transmission dynamics of a bacterial disease among wildlife and livestock
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Patrick J. White, Eric K. Cole, Mark L. Drew, Jack C. Rhyan, William H. Edwards, Rick L. Wallen, P. Ryan Clarke, Jeffrey T. Foster, Christine Quance, Paul C. Cross, Suelee Robbe-Austerman, Kevin P. Drees, John J. Treanor, Neil J. Anderson, Pauline L. Kamath, and Gordon Luikart
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0301 basic medicine ,Livestock ,Time Factors ,animal diseases ,Science ,Wildlife ,Brucella abortus ,General Physics and Astronomy ,Animals, Wild ,Biology ,Models, Biological ,Article ,Brucellosis ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,fluids and secretions ,Species Specificity ,medicine ,Animals ,Seroprevalence ,Ecosystem ,Phylogeny ,Multidisciplinary ,Bacterial disease ,Transmission (medicine) ,business.industry ,Ecology ,Outbreak ,Bayes Theorem ,Genomics ,General Chemistry ,Infectious Disease Epidemiology ,medicine.disease ,030104 developmental biology ,Calibration ,Host-Pathogen Interactions ,business - Abstract
Whole-genome sequencing has provided fundamental insights into infectious disease epidemiology, but has rarely been used for examining transmission dynamics of a bacterial pathogen in wildlife. In the Greater Yellowstone Ecosystem (GYE), outbreaks of brucellosis have increased in cattle along with rising seroprevalence in elk. Here we use a genomic approach to examine Brucella abortus evolution, cross-species transmission and spatial spread in the GYE. We find that brucellosis was introduced into wildlife in this region at least five times. The diffusion rate varies among Brucella lineages (∼3 to 8 km per year) and over time. We also estimate 12 host transitions from bison to elk, and 5 from elk to bison. Our results support the notion that free-ranging elk are currently a self-sustaining brucellosis reservoir and the source of livestock infections, and that control measures in bison are unlikely to affect the dynamics of unrelated strains circulating in nearby elk populations., The role of wild elk in the spread and persistence of bovine brucellosis in the Great Yellowstone area is unclear. Here, Kamath et al. analyse the genomic sequences of 245 Brucella abortus isolates from elk, bison and cattle, supporting the idea that elk is an important reservoir and source of livestock infections.
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- 2016
33. Directed selection of influenza virus produces antigenic variants that match circulating human virus isolates and escape from vaccine‐mediated immune protection
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David J. Topham, Hongmei Yang, Jeanne Holden-Wiltse, Theresa Fitzgerald, Marta L. DeDiego, John J. Treanor, and Christopher S. Anderson
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0301 basic medicine ,human influenza virus ,030106 microbiology ,Immunology ,haemagglutinin ,Hemagglutinin Glycoproteins, Influenza Virus ,Biology ,Antibodies, Viral ,H5N1 genetic structure ,Virus ,Antigenic drift ,Cell Line ,Cohort Studies ,03 medical and health sciences ,Influenza A Virus, H1N1 Subtype ,Influenza, Human ,Antigenic variation ,Immunology and Allergy ,vaccine strain ,Animals ,Humans ,Prospective Studies ,Original antigenic sin ,antigenic drift ,influenza‐specific antibodies ,Influenza A Virus, H3N2 Subtype ,Vaccination ,Ferrets ,Antigenic shift ,Infant ,Original Articles ,influenza virus vaccination ,Virology ,Antigenic Variation ,Immunity, Humoral ,030104 developmental biology ,Treatment Outcome ,Influenza Vaccines ,Child, Preschool ,circulating strains ,Mutagenesis, Site-Directed ,Original Article ,Seasons ,Vaccine failure - Abstract
Summary Influenza vaccination does not provide 100% protection from infection, partly due to antigenic drift of the haemagglutinin (HA) protein. Low serum antibody titres increase the risk of infection. To determine whether there were additional correlates of risk, we examined the relationship between human serum immunity and antigenic variation in seasonal H3N2 influenza viruses. Seasonal H3N2 vaccine strains grown in the presence of heterogeneous human or mono‐specific ferret antisera selected variants with mutations in the HA antigenic sites. Surprisingly, circulating strains infecting human subjects in the same seasons displayed mutations in the same positions, although only in one case did the change correspond to the same amino acid. Serum antibody titres were lower against both the in vitro selected and clinical isolates compared with the vaccine strains, suggesting that the mutations are relevant to vaccine failure. Antibody titres were also significantly lower in sera from infected subjects than in non‐infected subjects, suggesting relatively poor responses to vaccination in the infected subjects. Collectively, the data suggest that risk from influenza infection is a result of poor response to vaccination, as well as encounter with drifted seasonal influenza virus antigenic variants. The results also show that directed selection under human immune pressure could reveal antigenic variants relevant to real‐world drifted viruses, helping in annual vaccine re‐formulation.
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- 2016
34. Prospects for Broadly Protective Influenza Vaccines
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John J. Treanor
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Epidemiology ,Cross Protection ,CD8 Antigens ,Neuraminidase ,Antibodies, Viral ,medicine.disease_cause ,Adjuvants, Immunologic ,Viral Envelope Proteins ,Political science ,Influenza, Human ,Influenza A virus ,Humans ,Medicine ,Antigens, Viral ,Administration, Intranasal ,Adjuvants, Pharmaceutic ,General Veterinary ,General Immunology and Microbiology ,biology ,business.industry ,Hemagglutination ,Viral Vaccine ,Public Health, Environmental and Occupational Health ,Viral Vaccines ,Influenza research ,Virology ,Influenza B virus ,Infectious Diseases ,Hemagglutinins ,Influenza Vaccines ,CD4 Antigens ,Immunology ,biology.protein ,Molecular Medicine ,Engineering ethics ,business - Abstract
The development of vaccines that could provide broad protection against antigenically variant influenza viruses has long been the ultimate prize in influenza research. Recent developments have pushed us closer to this goal, and such vaccines may now be within reach. This brief review outlines the current approaches to broadly protective vaccines, and the probable hurdles and roadblocks to achieving this goal.
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- 2015
35. State-space modeling to support management of brucellosis in the Yellowstone bison population
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John J. Treanor, Chris Geremia, Rick L. Wallen, Jack C. Rhyan, P. J. White, Mevin B. Hooten, and N. Thompson Hobbs
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education.field_of_study ,Ecology ,National park ,Population ,Brucellosis ,medicine.disease ,law.invention ,Bison bison ,Adaptive management ,Geography ,Transmission (mechanics) ,law ,medicine ,symbols ,symbols.heraldic_charge ,education ,Basic reproduction number ,Ecology, Evolution, Behavior and Systematics ,Horizontal transmission - Abstract
The bison (Bison bison) of the Yellowstone ecosystem, USA, exemplify the difficulty of conserving large mammals that migrate across the boundaries of conservation areas. Bison are infected with brucellosis (Brucella abortus) and their seasonal movements can expose livestock to infection. Yellowstone National Park has embarked on a program of adaptive management of bison, which requires a model that assimilates data to support management decisions. We constructed a Bayesian state-space model to reveal the influence of brucellosis on the Yellowstone bison population. A frequency-dependent model of brucellosis transmission was superior to a density-dependent model in predicting out-of-sample observations of horizontal transmission probability. A mixture model including both transmission mechanisms converged on frequency dependence. Conditional on the frequency-dependent model, brucellosis median transmission rate was 1.87 yr−1. The median of the posterior distribution of the basic reproductive ratio (R0) was...
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- 2015
36. Flu Vaccine—Too Much of a Good Thing?
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John J. Treanor
- Subjects
0301 basic medicine ,Canada ,Influenza vaccine ,MEDLINE ,medicine.disease_cause ,Antigenic distance ,03 medical and health sciences ,0302 clinical medicine ,Influenza, Human ,Major Article ,Influenza A virus ,Humans ,Immunology and Allergy ,Medicine ,030212 general & internal medicine ,Epidemics ,Extramural ,business.industry ,Influenza A Virus, H3N2 Subtype ,Vaccination ,Virology ,Editorial Commentary ,030104 developmental biology ,Infectious Diseases ,Influenza Vaccines ,business - Published
- 2017
37. Influenza Virus Vaccination Elicits Poorly Adapted B Cell Responses in Elderly Individuals
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Sarah F. Andrews, Harry B. Greenberg, Kaval Kaur, Henry A. Utset, David J. Topham, Min Huang, Katerina Hoskova, Yang Li, Sarah Cobey, Patrick C. Wilson, Kenneth E. Schmader, Karla Thatcher Rojas, Florian Krammer, Xiao-Song He, Hildegund C.J. Ertl, Jeanne Holden-Wiltse, Rafi Ahmed, Yao Qing Chen, John J. Treanor, Alexandra Cabanov, Scott E. Hensley, Marcos Costa Vieira, Jens Wrammert, Carole Henry, Nai Ying Zheng, and Anna Karin E. Palm
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Immunoglobulin gene ,Adult ,Influenza vaccine ,Somatic hypermutation ,Hemagglutinin (influenza) ,Microbiology ,Epitope ,Antigenic drift ,Virus ,Article ,03 medical and health sciences ,Epitopes ,Young Adult ,0302 clinical medicine ,Virology ,Humans ,030304 developmental biology ,Aged ,Aged, 80 and over ,0303 health sciences ,B-Lymphocytes ,biology ,Middle Aged ,Orthomyxoviridae ,Healthy Volunteers ,Immunity, Humoral ,Vaccination ,Influenza Vaccines ,Mutation ,biology.protein ,Parasitology ,030217 neurology & neurosurgery - Abstract
Summary Influenza is a leading cause of death in the elderly, and the vaccine protects only a fraction of this population. A key aspect of antibody-mediated anti-influenza virus immunity is adaptation to antigenically distinct epitopes on emerging strains. We examined factors contributing to reduced influenza vaccine efficacy in the elderly and uncovered a dramatic reduction in the accumulation of de novo immunoglobulin gene somatic mutations upon vaccination. This reduction is associated with a significant decrease in the capacity of antibodies to target the viral glycoprotein, hemagglutinin (HA), and critical protective epitopes surrounding the HA receptor-binding domain. Immune escape by antigenic drift, in which viruses generate mutations in key antigenic epitopes, becomes highly exaggerated. Because of this reduced adaptability, most B cells activated in the elderly cohort target highly conserved but less potent epitopes. Given these findings, vaccines driving immunoglobulin gene somatic hypermutation should be a priority to protect elderly individuals.
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- 2018
38. Influenza Challenge and the Challenge of Drug Development
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John J. Treanor
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,Serine Endopeptidases ,Endonucleases ,030112 virology ,Antiviral Agents ,03 medical and health sciences ,0302 clinical medicine ,Infectious Diseases ,Drug development ,Drug Development ,Influenza, Human ,medicine ,Immunology and Allergy ,Humans ,030212 general & internal medicine ,Intensive care medicine ,business - Published
- 2018
39. Safety and Immunogenicity of a Recombinant Influenza Vaccine: A Randomized Trial
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Karen L. Goldenthal, Lisa M. Dunkle, Peter A. Patriarca, Ruvim Izikson, Manon M.J. Cox, and John J. Treanor
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Male ,medicine.medical_specialty ,Adolescent ,Influenza vaccine ,Equivalence Trials as Topic ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,Influenza, Human ,medicine ,Humans ,030212 general & internal medicine ,Seroconversion ,Adverse effect ,Child ,Vaccines, Synthetic ,Hemagglutination assay ,business.industry ,Immunogenicity ,Antibody titer ,Hemagglutination Inhibition Tests ,Vaccination ,Vaccines, Inactivated ,Influenza Vaccines ,Pediatrics, Perinatology and Child Health ,Inactivated vaccine ,Antibody Formation ,Female ,business - Abstract
OBJECTIVES: The recombinant influenza vaccine is well established in adults ≥18 years of age for preventing seasonal influenza disease. In this randomized controlled trial, we compared the safety and immunogenicity of the quadrivalent, recombinant influenza vaccine (RIV4) versus the inactivated influenza vaccine in children and adolescents 6 to 17 years of age. METHODS: Two age cohorts were enrolled sequentially: 159 subjects aged 9 to 17 years and, after reviewing for safety, 60 children aged 6 to 8 years. Enrollment of the younger children was halted prematurely at the onset of the influenza season. Subjects in each cohort were randomly assigned 1:1 to the RIV4 or inactivated vaccine. Hemagglutination inhibition antibody titers were obtained before and 28 days after vaccination. Tolerability and safety were monitored for 7 days and 6 months after vaccination, respectively. RESULTS: Both vaccines were well tolerated in both age groups, and long-term follow-up revealed no vaccine-related adverse events. Overall, immunogenicity (geometric mean titers and seroconversion rate differences) provided comparable antibody responses to most antigens in both vaccines in the older subjects. Low responses to the influenza B Victoria lineage in both vaccines made interpretation difficult. Immunogenicity in younger children was similar, but the truncated sample size was insufficient to support noninferiority comparisons. CONCLUSIONS: Despite low responses to influenza B lineages in both vaccines, the RIV4 provided safety and immunogenicity that were comparable to those of the licensed inactivated vaccine in pediatric subjects, which was most convincing in those aged 9 to 17 years. Future confirmatory clinical efficacy trials may be used to support the recombinant influenza vaccine as an alternative for the pediatric age group of ≥6 years.
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- 2018
40. Vaccines in the Immunocompromised Hosts
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John J. Treanor and Paratosh Prasad
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education.field_of_study ,business.industry ,Population ,chemical and pharmacologic phenomena ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Acquired immune system ,medicine.disease_cause ,Medical care ,Transplant rejection ,Autoimmunity ,Vaccination ,Immune system ,Immunity ,Immunology ,medicine ,bacteria ,business ,education - Abstract
Vaccination remains the single most effective means available to prevent infectious diseases and mitigate their impact on the health of individuals. However, conditions that result in impairment of adaptive immunity both increase the risk and severity of these infections, as well as decreasing the efficacy of immunizations, posing unique challenges to medical care of these vulnerable patients. In addition, the complex relationships between the immunity of the subject and the mechanisms by which vaccines stimulate the immune system raise safety concerns as well, particularly related to the safety of live vaccines in this population, and the possibility that non-specific stimulation of the immune system could precipitate transplant rejection or increasing autoimmunity.
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- 2018
41. Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies
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Anna Karin E. Palm, Linda Yu Ling Lan, Carole Henry, Teddy John Wohlbold, Yunping Huang, David J. Topham, Christopher T. Stamper, Florian Krammer, Min Huang, Rafi Ahmed, John J. Treanor, Maryna C. Eichelberger, Karla Thatcher Rojas, Jens Wrammert, George Georgiou, Yao Qing Chen, Jiwon Lee, Nai Ying Zheng, Ericka Kirkpatrick, Karlynn E. Neu, Patrick C. Wilson, and Hongquan Wan
- Subjects
0301 basic medicine ,medicine.drug_class ,viruses ,030106 microbiology ,Hemagglutinin (influenza) ,Neuraminidase ,Cross Reactions ,medicine.disease_cause ,Monoclonal antibody ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Virus ,Birds ,03 medical and health sciences ,Epitopes ,Mice ,Viral Proteins ,Influenza A Virus, H1N1 Subtype ,Orthomyxoviridae Infections ,Influenza, Human ,Influenza A virus ,medicine ,Animals ,Humans ,Mice, Inbred BALB C ,biology ,Influenza A Virus, H5N1 Subtype ,Influenza A Virus, H3N2 Subtype ,virus diseases ,Antibodies, Monoclonal ,Virology ,Influenza A virus subtype H5N1 ,030104 developmental biology ,HEK293 Cells ,Immunoglobulin G ,biology.protein ,Female ,Antibody - Abstract
Antibodies to the hemagglutinin (HA) and neuraminidase (NA) glycoproteins are the major mediators of protection against influenza virus infection. Here, we report that current influenza vaccines poorly display key NA epitopes and rarely induce NA-reactive B cells. Conversely, influenza virus infection induces NA-reactive B cells at a frequency that approaches (H1N1) or exceeds (H3N2) that of HA-reactive B cells. NA-reactive antibodies display broad binding activity spanning the entire history of influenza A virus circulation in humans, including the original pandemic strains of both H1N1 and H3N2 subtypes. The antibodies robustly inhibit the enzymatic activity of NA, including oseltamivir-resistant variants, and provide robust prophylactic protection, including against avian H5N1 viruses, in vivo. When used therapeutically, NA-reactive antibodies protected mice from lethal influenza virus challenge even 48 hr post infection. These findings strongly suggest that influenza vaccines should be optimized to improve targeting of NA for durable and broad protection against divergent influenza strains.
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- 2017
42. Vaccination with a Recombinant H7 Hemagglutinin-Based Influenza Virus Vaccine Induces Broadly Reactive Antibodies in Humans
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Daniel Kaplan, Florian Krammer, Manon M.J. Cox, Daniel Stadlbauer, John J. Treanor, Raffael Nachbagauer, Abusaleh Masud, Ruvim Izikson, Fatima Amanat, and Arvind Rajabhathor
- Subjects
0301 basic medicine ,lcsh:QR1-502 ,Hemagglutinin (influenza) ,influenza virus vaccine ,Microbiology ,lcsh:Microbiology ,Virus ,Epitope ,Serology ,H7N9 ,03 medical and health sciences ,0302 clinical medicine ,030212 general & internal medicine ,Molecular Biology ,HA stalk ,Hemagglutination assay ,biology ,Therapeutics and Prevention ,Editor's Pick ,Virology ,QR1-502 ,3. Good health ,Vaccination ,030104 developmental biology ,Immunization ,biology.protein ,influenza ,Neuraminidase ,Research Article - Abstract
Zoonotic infections with high case fatality rates caused by avian H7N9 influenza viruses have been reported since early 2013 in China. Since then, the fifth wave of the H7N9 epidemic emerged in China, resulting in higher numbers of laboratory-confirmed cases than in previous years. Recently, H7N9 has started to antigenically drift and split into two new lineages, the Pearl River Delta and Yangtze River Delta clades, which do not match stockpiled H7 vaccines well. Humans are immunologically naive to these subtypes, and an H7N9 strain that acquires the capability of efficient human-to-human transmission poses a credible pandemic threat. Other characteristics of H7N9 are raising concerns as well, like its ability to bind to receptors in the human upper respiratory tract, the recent emergence of highly pathogenic variants, and the ability to quickly gain resistance to neuraminidase inhibitors. Therefore, developing and testing H7N9 vaccines constitutes a priority for pandemic preparedness., Human influenza virus infections with avian subtype H7N9 viruses are a major public health concern and have encouraged the development of effective H7 prepandemic vaccines. In this study, baseline and postvaccination serum samples of individuals aged 18 years and older who received a recombinant H7 hemagglutinin vaccine with and without an oil-in-water emulsion (SE) adjuvant were analyzed using a panel of serological assays. While only a small proportion of individuals seroconverted to H7N9 as measured by the conventional hemagglutination inhibition assay, our data show strong induction of anti-H7 hemagglutinin antibodies as measured by an enzyme-linked immunosorbent assay (ELISA). In addition, cross-reactive antibodies against phylogenetically distant group 2 hemagglutinins were induced, presumably targeting the conserved stalk domain of the hemagglutinin. Further analysis confirmed an induction of stalk-specific antibodies, suggesting that epitopes outside the classical antigenic sites are targeted by this vaccine in the context of preexisting immunity to related H3 hemagglutinin. Antibodies induced by H7 vaccination also showed functional activity in antibody-dependent cell-mediated cytotoxicity reporter assays and microneutralization assays. Additionally, our data show that sera from hemagglutination inhibition seroconverters conferred protection in a passive serum transfer experiment against lethal H7N9 virus challenge in mice. Interestingly, sera from hemagglutination inhibition nonseroconverters also conferred partial protection in the lethal animal challenge model. In conclusion, while recombinant H7 vaccination fails to induce measurable levels of hemagglutination-inhibiting antibodies in most subjects, this vaccination regime induces homosubtypic and heterosubtypic cross-reactive binding antibodies that are functional and partly protective in a murine passive transfer challenge model. IMPORTANCE Zoonotic infections with high case fatality rates caused by avian H7N9 influenza viruses have been reported since early 2013 in China. Since then, the fifth wave of the H7N9 epidemic emerged in China, resulting in higher numbers of laboratory-confirmed cases than in previous years. Recently, H7N9 has started to antigenically drift and split into two new lineages, the Pearl River Delta and Yangtze River Delta clades, which do not match stockpiled H7 vaccines well. Humans are immunologically naive to these subtypes, and an H7N9 strain that acquires the capability of efficient human-to-human transmission poses a credible pandemic threat. Other characteristics of H7N9 are raising concerns as well, like its ability to bind to receptors in the human upper respiratory tract, the recent emergence of highly pathogenic variants, and the ability to quickly gain resistance to neuraminidase inhibitors. Therefore, developing and testing H7N9 vaccines constitutes a priority for pandemic preparedness.
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- 2017
43. A Highly Potent and Broadly Neutralizing H1 Influenza-Specific Human Monoclonal Antibody
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Michael S. Piepenbrink, Christopher F. Fucile, Aitor Nogales, Jiong Wang, Martin S. Zand, Luis Martinez-Sobrido, James J. Kobie, Sandra Ortega, Madhubanti Basu, Alexander F. Rosenberg, John J. Treanor, and Michael C. Keefer
- Subjects
0301 basic medicine ,medicine.drug_class ,030106 microbiology ,lcsh:Medicine ,Hemagglutinin (influenza) ,Monoclonal antibody ,medicine.disease_cause ,Epitope ,Antigenic drift ,Article ,03 medical and health sciences ,Mice ,Influenza A Virus, H1N1 Subtype ,Orthomyxoviridae Infections ,Species Specificity ,medicine ,Influenza A virus ,Animals ,Humans ,lcsh:Science ,Multidisciplinary ,biology ,lcsh:R ,Antibodies, Monoclonal ,Virology ,Antibodies, Neutralizing ,3. Good health ,Immunity, Humoral ,Survival Rate ,030104 developmental biology ,Influenza Vaccines ,Humoral immunity ,Inactivated vaccine ,biology.protein ,lcsh:Q ,Antibody - Abstract
Influenza’s propensity for antigenic drift and shift, and to elicit predominantly strain specific antibodies (Abs) leaves humanity susceptible to waves of new strains with pandemic potential for which limited or no immunity may exist. Subsequently new clinical interventions are needed. To identify hemagglutinin (HA) epitopes that if targeted may confer universally protective humoral immunity, we examined plasmablasts from a subject that was immunized with the seasonal influenza inactivated vaccine, and isolated a human monoclonal Ab (mAb), KPF1. KPF1 has broad and potent neutralizing activity against H1 influenza viruses, and recognized 83% of all H1 isolates tested, including the pandemic 1918 H1. Prophylactically, KPF1 treatment resulted in 100% survival of mice from lethal challenge with multiple H1 influenza strains and when given as late as 72 h after challenge with A/California/04/2009 H1N1, resulted in 80% survival. KPF1 recognizes a novel epitope in the HA globular head, which includes a highly conserved amino acid, between the Ca and Cb antigenic sites. Although recent HA stalk-specific mAbs have broader reactivity, their potency is substantially limited, suggesting that cocktails of broadly reactive and highly potent HA globular head-specific mAbs, like KPF1, may have greater clinical feasibility for the treatment of influenza infections.
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- 2017
44. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 18–49 years of age, naive to 23-valent pneumococcal polysaccharide vaccine
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Allison Thompson, Alejandra Gurtman, Vani Sundaraiyer, John Rubino, Thomas R. Jones, John J. Treanor, LM Baxter, Emilio A. Emini, William C. Gruber, Daniel A. Scott, Beate Schmoele-Thoma, Kristina A. Bryant, and Robert W. Frenck
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Serotype ,Pediatrics ,medicine.medical_specialty ,General Veterinary ,General Immunology and Microbiology ,business.industry ,Immunogenicity ,Public Health, Environmental and Occupational Health ,medicine.disease ,Pneumococcal polysaccharide vaccine ,Pneumococcal conjugate vaccine ,Vaccination ,Pneumococcal infections ,Infectious Diseases ,Tolerability ,Cohort ,Immunology ,medicine ,Molecular Medicine ,business ,medicine.drug - Abstract
Background Based on the success of vaccination with pneumococcal conjugate vaccines (PCVs) in children, recent studies have focused on PCVs in adults. Data from a randomized, double-blind study comparing the immunogenicity, tolerability, and safety of the 13-valent PCV (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in PPSV23-naive adults 60–64 years of age have been published. The same study also included a cohort of adults aged 18–49 years that received open-label PCV13. The purpose of this cohort was to examine the immunogenicity, safety, and tolerability of PCV13 in adult subjects 18–49 years of age compared with adults 60–64 years of age for whom PCV13 is approved. Methods Adults naive to PPSV23 were grouped by age into 2 cohorts: 18–49 years (n = 899; further stratified by age into 3 subgroups 18–29, 30–39, and 40–49 years) and 60–64 years (n = 417). All subjects received 1 dose of PCV13. In both age groups, immunogenicity was assessed by antipneumococcal opsonophagocytic activity (OPA) geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) 1 month after vaccination. Safety and tolerability were evaluated. Results In adults aged 18–49 years, OPA GMTs and IgG GMCs were noninferior for all 13 serotypes and statistically significantly higher for all except 1 serotype (OPA GMT) and 5 serotypes (IgG GMCs) compared with adults 60–64 years. Immune responses were highest in the youngest age subgroup (18–29 years). Local reactions and systemic events were more common in adults 18–49 years compared with 60–64 years and were self-limited. Conclusion Immune responses to PCV13 are robust in adults ≥18 years of age, with highest responses observed in the youngest subgroup. Based on its safety and immunologic profile, PCV13 may serve an important therapeutic role in younger adults, particularly those with underlying medical conditions who have an increased risk of serious pneumococcal infections.
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- 2015
45. Maintenance of brucellosis in Yellowstone bison: linking seasonal food resources, host–pathogen interaction, and life‐history trade‐offs
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Patrick J. White, John J. Treanor, Philip H. Crowley, Chris Geremia, John J. Cox, Michael Ballou, and Duane H. Keisler
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Host–pathogen interaction ,Brucella abortus ,Biology ,leptin ,Age ,Immune system ,interferon-γ ,medicine ,Life history ,Ecology, Evolution, Behavior and Systematics ,Original Research ,Nature and Landscape Conservation ,Ecology ,Trade offs ,Brucellosis ,medicine.disease ,condition ,Food resources ,nutrition ,Infectious disease (medical specialty) ,immune ,diet ,protein ,energy - Abstract
The seasonal availability of food resources is an important factor shaping the life-history strategies of organisms. During times of nutritional restriction, physiological trade-offs can induce periods of immune suppression, thereby increasing susceptibility to infectious disease. Our goal was to provide a conceptual framework describing how the endemic level bovine brucellosis (Brucella abortus) may be maintained in Yellowstone bison based on the seasonality of food resources and the life-history strategies of the host and pathogen. Our analysis was based on active B. abortus infection (measured via bacterial culture), nutritional indicators (measured as metabolites and hormones in plasma), and carcass measurements of 402 slaughtered bison. Data from Yellowstone bison were used to investigate (1) whether seasonal changes in diet quality affect nutritional condition and coincide with the reproductive needs of female bison; (2) whether active B. abortus infection and infection intensities vary with host nutrition and nutritional condition; and (3) the evidence for seasonal changes in immune responses, which may offer protection against B. abortus, in relation to nutritional condition. Female bison experienced a decline in nutritional condition during winter as reproductive demands of late gestation increased while forage quality and availability declined. Active B. abortus infection was negatively associated with bison age and nutritional condition, with the intensity of infection negatively associated with indicators of nutrition (e.g., dietary protein and energy) and body weight. Data suggest that protective cell-mediated immune responses may be reduced during the B. abortus transmission period, which coincides with nutritional insufficiencies and elevated reproductive demands during spring. Our results illustrate how seasonal food restriction can drive physiological trade-offs that suppress immune function and create infection and transmission opportunities for pathogens.
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- 2015
46. Serological Correlates of Protection against a GII.4 Norovirus
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Christine L. Moe, Jennifer Ferreira, Nicole Gregoricus, Jan Vinjé, David Y. Graham, Jill Barrett, Antone R. Opekun, Mary K. Estes, Astrid Borkowski, Mohamed S. Al-Ibrahim, Frank Baehner, Anthony Edmonds, Robert Goodwin, Robert L. Atmar, G. Marshall Lyon, Robert W. Frenck, David I. Bernstein, Wilbur H. Chen, Xi Jiang, John J. Treanor, and Paul M. Mendelman
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Adult ,Male ,Microbiology (medical) ,Adolescent ,viruses ,Clinical Biochemistry ,Immunology ,Enzyme-Linked Immunosorbent Assay ,Antibodies, Viral ,medicine.disease_cause ,Immunoglobulin G ,Serology ,Placebos ,Young Adult ,Double-Blind Method ,Antigen ,medicine ,Humans ,Immunology and Allergy ,Vaccines, Virus-Like Particle ,Caliciviridae Infections ,biology ,Viral Vaccine ,Norovirus ,Antibody titer ,Viral Vaccines ,Middle Aged ,Vaccine efficacy ,Virology ,Immunoglobulin A ,biology.protein ,Female ,Clinical Immunology ,Antibody ,Biomarkers - Abstract
Noroviruses are the leading cause of acute gastroenteritis worldwide, and norovirus vaccine prevention strategies are under evaluation. The immunogenicity of two doses of bivalent genogroup 1 genotype 1 (GI.1)/GII.4 (50 μg of virus-like particles [VLPs] of each strain adjuvanted with aluminum hydroxide and 3- O -desacyl-4′monophosphoryl lipid A [MPL]) norovirus vaccine administered to healthy adults in a phase 1/2 double-blind placebo-controlled trial was determined using virus-specific serum total antibody enzyme-linked immunosorbent assay (ELISA), IgG, IgA, and histoblood group antigen (HBGA)-blocking assays. Trial participants subsequently received an oral live virus challenge with a GII.4 strain, and the vaccine efficacy results were reported previously (D. I. Bernstein et al., J Infect Dis 211:870–878, 2014, doi: 10.1093/infdis/jiu497 ). This report assesses the impact of prechallenge serum antibody levels on infection and illness outcomes. Serum antibody responses were observed in vaccine recipients by all antibody assays, with first-dose seroresponse frequencies ranging from 88 to 100% for the GI.1 antigen and from 69 to 84% for the GII.4 antigen. There was little increase in antibody levels after the second vaccine dose. Among the subjects receiving the placebo, higher prechallenge serum anti-GII.4 HBGA-blocking and IgA antibody levels, but not IgG or total antibody levels, were associated with a lower frequency of virus infection and associated illness. Notably, some placebo subjects without measurable serum antibody levels prechallenge did not become infected after norovirus challenge. In vaccinees, anti-GII.4 HBGA-blocking antibody levels of >1:500 were associated with a lower frequency of moderate-to-severe vomiting or diarrheal illness. In this study, prechallenge serum HBGA antibody titers correlated with protection in subjects receiving the placebo; however, other factors may impact the likelihood of infection and illness after virus exposure. (This study is registered at ClinicalTrials.gov under registration number NCT1609257.)
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- 2015
47. A Single Dose of an Avian H3N8 Influenza Virus Vaccine Is Highly Immunogenic and Efficacious against a Recently Emerged Seal Influenza Virus in Mice and Ferrets
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John J. Treanor, Yumiko Matsuoka, James R. Zengel, Hong Jin, Myeisha Paskel, Kanta Subbarao, Xing Cheng, and Mariana Baz
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Male ,Adolescent ,Immunology ,Hemagglutinin (influenza) ,Biology ,Antibodies, Viral ,medicine.disease_cause ,Microbiology ,H5N1 genetic structure ,Virus ,Influenza A Virus, H3N8 Subtype ,Young Adult ,Dogs ,Orthomyxoviridae Infections ,Virology ,Vaccines and Antiviral Agents ,Influenza A virus ,medicine ,Animals ,Humans ,Live attenuated influenza vaccine ,Neutralizing antibody ,Aged ,Aged, 80 and over ,Recombination, Genetic ,Mice, Inbred BALB C ,Influenza A Virus, H3N2 Subtype ,Vaccination ,Ferrets ,Middle Aged ,Reverse Genetics ,Influenza Vaccines ,Insect Science ,biology.protein ,Female ,Neuraminidase - Abstract
H3N8 influenza viruses are a commonly found subtype in wild birds, usually causing mild or no disease in infected birds. However, they have crossed the species barrier and have been associated with outbreaks in dogs, pigs, donkeys, and seals and therefore pose a threat to humans. A live attenuated, cold-adapted ( ca ) H3N8 vaccine virus was generated by reverse genetics using the wild-type (wt) hemagglutinin (HA) and neuraminidase (NA) genes from the A/blue-winged teal/Texas/Sg-00079/2007 (H3N8) (tl/TX/079/07) wt virus and the six internal protein gene segments from the ca influenza A virus vaccine donor strain, A/Ann Arbor/6/60 ca (H2N2), the backbone of the licensed seasonal live attenuated influenza vaccine. One dose of the tl/TX/079/07 ca vaccine induced a robust neutralizing antibody response against the homologous (tl/TX/079/07) and two heterologous influenza viruses, including the recently emerged A/harbor seal/New Hampshire/179629/2011 (H3N8) and A/northern pintail/Alaska/44228-129/2006 (H3N8) viruses, and conferred robust protection against the homologous and heterologous influenza viruses. We also analyzed human sera against the tl/TX/079/07 H3N8 avian influenza virus and observed low but detectable antibody reactivity in elderly subjects, suggesting that older H3N2 influenza viruses confer some cross-reactive antibody. The latter observation was confirmed in a ferret study. The safety, immunogenicity, and efficacy of the tl/TX/079/07 ca vaccine in mice and ferrets support further evaluation of this vaccine in humans for use in the event of transmission of an H3N8 avian influenza virus to humans. The human and ferret serology data suggest that a single dose of the vaccine may be sufficient in older subjects. IMPORTANCE Although natural infection of humans with an avian H3N8 influenza virus has not yet been reported, this influenza virus subtype has already crossed the species barrier and productively infected mammals. Pandemic preparedness is an important public health priority. Therefore, we generated a live attenuated avian H3N8 vaccine candidate and demonstrated that a single dose of the vaccine was highly immunogenic and protected mice and ferrets against homologous and heterologous H3N8 avian viruses.
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- 2015
48. High-Affinity H7 Head and Stalk Domain–Specific Antibody Responses to an Inactivated Influenza H7N7 Vaccine After Priming With Live Attenuated Influenza Vaccine
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Florian Krammer, Jessica L. Halliley, Hana Golding, Kanta Subbarao, Ka Yan Chung, Hongmei Yang, John J. Treanor, Surender Khurana, Steven F. Baker, Elizabeth M. Coyle, Mark Y. Sangster, Theresa Fitzgerald, David J. Topham, and Luis Martinez-Sobrido
- Subjects
Hemagglutination Inhibition Tests ,Influenza vaccine ,Influenza A Virus, H7N7 Subtype ,Antibodies, Viral ,Vaccines, Attenuated ,medicine.disease_cause ,Epitope ,Cohort Studies ,Major Articles and Brief Reports ,Neutralization Tests ,Influenza, Human ,medicine ,Humans ,Immunology and Allergy ,Live attenuated influenza vaccine ,Neutralizing antibody ,B-Lymphocytes ,biology ,virus diseases ,Antibodies, Neutralizing ,Virology ,Influenza A virus subtype H5N1 ,Vaccination ,Infectious Diseases ,Vaccines, Inactivated ,Influenza Vaccines ,Immunology ,biology.protein ,Antibody - Abstract
Recent studies have shown that live attenuated influenza vaccines (LAIVs) expressing avian influenza virus hemagglutinins (HAs) prime for strong protective antibody responses to an inactivated influenza vaccine (IIV) containing the HA. To better understand this priming effect, we compared H7 HA head and stalk domain-specific B-cell responses in H7N7 LAIV-primed subjects and non-H7-primed controls after a single dose of H7N7 IIV. As previously reported, H7N7 LAIV-primed subjects but not control subjects generated strong hemagglutination-inhibiting and neutralizing antibody responses to the H7N7 IIV. Here, we found that the quantity, epitope diversity, and affinity of H7 head-specific antibodies increased rapidly in only H7N7 LAIV-primed subjects after receipt of the IIV. However, all cohorts generated a vigorous, high-affinity, stalk-specific antibody response. Consistent increases in circulating memory B-cell frequencies after receipt of the IIV reflected the specificity of high-affinity antibody production. Our findings emphasize the value of LAIVs as a vehicle for prepandemic vaccination.
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- 2015
49. A Live Attenuated Equine H3N8 Influenza Vaccine Is Highly Immunogenic and Efficacious in Mice and Ferrets
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James R. Zengel, Myeisha Paskel, Xing Cheng, Yumiko Matsuoka, Kanta Subbarao, Hong Jin, Mariana Baz, and John J. Treanor
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Influenza vaccine ,Cross Protection ,Immunology ,Equine influenza ,Hemagglutinin (influenza) ,Heterologous ,Cross Reactions ,Antibodies, Viral ,Vaccines, Attenuated ,Microbiology ,Virus ,Influenza A Virus, H3N8 Subtype ,Orthomyxoviridae Infections ,Virology ,Vaccines and Antiviral Agents ,Animals ,Live attenuated influenza vaccine ,Neutralizing antibody ,Administration, Intranasal ,Mice, Inbred BALB C ,biology ,Ferrets ,Antibodies, Neutralizing ,Disease Models, Animal ,Influenza Vaccines ,Insect Science ,biology.protein ,Neuraminidase - Abstract
Equine influenza viruses (EIV) are responsible for rapidly spreading outbreaks of respiratory disease in horses. Although natural infections of humans with EIV have not been reported, experimental inoculation of humans with these viruses can lead to a productive infection and elicit a neutralizing antibody response. Moreover, EIV have crossed the species barrier to infect dogs, pigs, and camels and therefore may also pose a threat to humans. Based on serologic cross-reactivity of H3N8 EIV from different lineages and sublineages, A/equine/Georgia/1/1981 (eq/GA/81) was selected to produce a live attenuated candidate vaccine by reverse genetics with the hemagglutinin and neuraminidase genes of the eq/GA/81 wild-type (wt) virus and the six internal protein genes of the cold-adapted ( ca ) A/Ann Arbor/6/60 (H2N2) vaccine donor virus, which is the backbone of the licensed seasonal live attenuated influenza vaccine. In both mice and ferrets, intranasal administration of a single dose of the eq/GA/81 ca vaccine virus induced neutralizing antibodies and conferred complete protection from homologous wt virus challenge in the upper respiratory tract. One dose of the eq/GA/81 ca vaccine also induced neutralizing antibodies and conferred complete protection in mice and nearly complete protection in ferrets upon heterologous challenge with the H3N8 (eq/Newmarket/03) wt virus. These data support further evaluation of the eq/GA/81 ca vaccine in humans for use in the event of transmission of an equine H3N8 influenza virus to humans. IMPORTANCE Equine influenza viruses have crossed the species barrier to infect other mammals such as dogs, pigs, and camels and therefore may also pose a threat to humans. We believe that it is important to develop vaccines against equine influenza viruses in the event that an EIV evolves, adapts, and spreads in humans, causing disease. We generated a live attenuated H3N8 vaccine candidate and demonstrated that the vaccine was immunogenic and protected mice and ferrets against homologous and heterologous EIV.
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- 2015
50. Robust mucosal-homing antibody-secreting B cell responses induced by intramuscular administration of adjuvanted bivalent human norovirus-like particle vaccine
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Sharon E. Frey, David J. Topham, Robert L. Atmar, Jennifer Ferreira, Aarthi Sundararajan, Paul M. Mendelman, Wilbur H. Chen, Mark Y. Sangster, Robert F. Bargatze, and John J. Treanor
- Subjects
Male ,viruses ,Monophosphoryl Lipid A ,CD38 ,Antibodies, Viral ,medicine.disease_cause ,Placebos ,B-Lymphocytes ,B cell ,Mucosal ,biology ,Immunogenicity ,virus diseases ,Middle Aged ,Treatment Outcome ,medicine.anatomical_structure ,Infectious Diseases ,Molecular Medicine ,Female ,Antibody ,Adult ,Adolescent ,Injections, Intramuscular ,Peripheral blood mononuclear cell ,Young Adult ,Adjuvants, Immunologic ,Double-Blind Method ,Antigen ,Immunology and Microbiology(all) ,medicine ,Animals ,Humans ,Vaccines, Virus-Like Particle ,Immunity, Mucosal ,General Veterinary ,General Immunology and Microbiology ,business.industry ,Norovirus ,Public Health, Environmental and Occupational Health ,Viral Vaccines ,Virology ,veterinary(all) ,Immunoglobulin A ,Immunoglobulin G ,Immunology ,biology.protein ,Immunization ,business ,Vaccine - Abstract
Background Two major antigenically heterogenous norovirus genogroups (GI and GII) commonly infect humans and are the leading cause of foodborne, viral gastrointestinal infections in adults. Methods We assessed B cell responses in participants in a double-blind, placebo-controlled, dose-escalation phase 1 study of the safety and immunogenicity of an intramuscular bivalent norovirus virus-like particle (VLP) vaccine. The vaccine contained a GI.1 VLP (Norwalk) and a consensus GII.4 VLP, representing the two major genotypes that cause human disease, and was administered on days 0 and 28 to healthy adults aged 18–49 years. Four separate cohorts received increasing doses of 5 μg, 15 μg, 50 μg, and 150 μg of each VLP adjuvanted in monophosphoryl lipid A and alum. PBMCs were analyzed for B cell activation and mucosal homing markers (flow cytometry) and VLP-specific and total IgG and IgA Ab-secreting cells (ASCs); and serum titers of VLP-specific IgG, IgA, and Pan-Ig were determined. Results The vaccine elicited CD27+ CD38+ plasmablasts and high frequencies of ASCs specific for both VLP antigens in the peripheral blood at 7 days after the first dose. The plasmablasts exhibited a mucosal-homing phenotype and included a high proportion of IgA ASCs. Serum antibodies increased as early as 7 days after the first immunization. Conclusions The data suggest that a single dose of the IM bivalent norovirus vaccine is effective in activating pre-existing B cell memory. The rapid B cell response and the mucosal homing phenotype of induced ASCs are consistent with anamnestic responses in subjects primed by prior oral norovirus infection. This study is registered at ClinicalTrials.gov Identifier NCT01609257 .
- Published
- 2015
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