Susceptibility of #Influenza A, B, C, and D Viruses to #Baloxavir (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 10—October 2019 / Dispatch

Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir

Vasiliy P. Mishin, Mira C. Patel, Anton Chesnokov, Juan De La Cruz, Ha T. Nguyen, Lori Lollis, Erin Hodges, Yunho Jang, John Barnes, Timothy Uyeki, Charles T. Davis, David E. Wentworth, and Larisa V. Gubareva

Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (V.P. Mishin, M.C. Patel, A. Chesnokov, J. De La Cruz, H.T. Nguyen, L. Lollis, E. Hodges, Y. Jang, J. Barnes, T. Uyeki, C.T. Davis, D.E. Wentworth, L.V. Gubareva); Battelle Memorial Institute, Atlanta (M.C. Patel, J. De La Cruz, H.T. Nguyen, L. Lollis)

 

Abstract

Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2–98.3 nmol/L); susceptibility pattern was influenza A ˃ B ˃ C ˃ D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors.

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Favipiravir; Baloxavir; Influenza A; Influenza B; Influenza C; Influenza D; H1N1pdm09; H3N2; H7N9.

——

Advertisements

A Single #Aminoacid #Substitution at Residue 218 of #Hemagglutinin Improves the #Growth of #Influenza A(#H7N9) #CVVs (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

A Single Amino Acid Substitution at Residue 218 of Hemagglutinin Improves the Growth of Influenza A(H7N9) Candidate Vaccine Viruses

Xing Li, Yamei Gao, Zhiping Ye

DOI: 10.1128/JVI.00570-19

 

ABSTRACT

The potential avian influenza pandemic remains a threat to public health, as the avian-originated influenza A(H7N9) virus has caused more than 1560 laboratory-confirmed human infections since 2013, with nearly 40% mortality. Development of low pathogenic candidate vaccine viruses (CVVs) for vaccine production is essential for pandemic preparedness. However, the suboptimal growth of CVVs in mammalian cells and chicken eggs is often a challenge. By introducing a single adaptive substitution, G218E, into the hemagglutinin (HA), we generated reassortant A(H7N9)-G218E CVVs that were characterized by significantly enhanced growth in both cells and eggs. These G218E CVVs retained the original antigenicity as determined by hemagglutination inhibition assay, and effectively protected ferrets from lethal challenge with the highly pathogenic parental virus. We found that the suboptimal replication of the parental H7 CVVs was associated with impeded progeny virus release as a result of strong HA receptor binding relative to weak neuraminidase (NA) cleavage of receptors. In contrast, the G218E-mediated growth improvement was attributed to relatively balanced HA and NA functions, resulted from reduced HA binding to both human- and avian-type receptors, and thus facilitated NA-mediated virus release. Our findings revealed that a single amino acid mutation at residue 218 of the HA improved the growth of A(H7N9) influenza virus by balancing HA and NA functions, shedding light on an alternative approach for optimizing certain influenza CVVs.

 

IMPORTANCE

The circulating avian influenza A(H7N9) has caused recurrent epidemic waves with high mortality in China since 2013, in which the alarming fifth wave crossing 2016 and 2017 was highlighted by large number of human infections and emergence of highly pathogenic avian influenza (HPAI) A(H7N9) strains in human cases. We generated low pathogenic reassortant CVVs derived from the emerging A(H7N9) with improved virus replication and protein yield in both MDCK cells and eggs by introducing a single substitution, G218E, into HA, which was associated with reducing HA receptor binding and subsequently balancing HA-NA functions. The in vitro and in vivo experiments demonstrated comparable antigenicity of the G218E CVVs with that of their WT counterparts, and both the WT and G218E CVVs fully protected ferrets from parental HPAI virus challenge. With high yield traits and the anticipated antigenicity, the G218E CVVs should benefit the pandemic preparedness against the A(H7N9) influenza threat.

Copyright © 2019 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Avian Influenza; H7N9; Vaccines; Pandemic preparedness.

——

The #safety and #immunogenicity of a cell-derived adjuvanted #H5N1 #vaccine – A phase I randomized clinical trial (J Microbiol Immunol Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Microbiol Immunol Infect. 2019 May 18. pii: S1684-1182(18)30176-2. doi: 10.1016/j.jmii.2019.03.009. [Epub ahead of print]

The safety and immunogenicity of a cell-derived adjuvanted H5N1 vaccine – A phase I randomized clinical trial.

Cheng A1, Hsieh SM1, Pan SC1, Li YH2, Hsieh EF2, Lee HC2, Lin TW2, Lai KL3, Chen C2, Shi-Chung Chang S3, Chang SC4.

Author information: 1 Department of Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. 2 Medigen Vaccine Biologics Corporation, Hsinchu, Taiwan. 3 Medigen Biotechnology Corporation, Taipei, Taiwan. 4 Department of Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: changsc@ntu.edu.tw.

 

Abstract

BACKGROUND:

Development of an efficacious egg-free mock-up H5N1 vaccine is key to our preparedness against pandemic avian flu.

METHODS:

This is a single-center, randomized, observer-blinded phase I clinical trial evaluating the safety and immunogenicity of an alum-adjuvanted Madin-Darby canine kidney (MDCK)-derived inactivated whole-virion H5N1 influenza vaccine in healthy adults. Hemagglutination inhibition (HAI) and neutralizing antibody titers were measured using horse and turkey red blood cells (RBCs).

RESULTS:

Thirty-six adult subjects were randomized to receive two doses of 0.5 mL of the MDCK-derived H5N1 alum-adjuvanted vaccine containing 7.5, 15, or 30 μg of hemagglutinin (HA) 21 days apart. The candidate vaccine was well tolerated and safe across the three dosing groups. The most frequent adverse event was injection site pain (46.5%). Both HAI and neutralizing antibody titers increased after each vaccination in all three dosing groups. The best HAI responses, namely a seroconversion rate of 91.7% and a geometric mean ratio of 9.51 were achieved with the HA dose of 30 μg assayed using horse RBCs at day 42. HAI titers against H5N1 avian influenza virus was significantly higher when measured using horse RBCs compared with turkey RBCs.

CONCLUSIONS:

This Phase I trial showed the MDCK-derived H5N1 candidate vaccine is safe and immunogenic. The source of RBCs has a significant impact on the measurement of HAI titers (ClinicalTrials.gov number: NCT01675284.).

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS: Avian influenza; H5N1; Immune response; Influenza A; Vaccination

PMID: 31255574 DOI: 10.1016/j.jmii.2019.03.009

Keywords: Avian Influenza; H5N1; Vaccines.

——

#Outbreak #response as an essential #component of #vaccine #development (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Outbreak response as an essential component of vaccine development

Richard Hatchett, MD, Prof Nicole Lurie, MD

Published: June 27, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30305-6

 

Summary

The Coalition for Epidemic Preparedness Innovations (CEPI) was created as a result of an emerging global consensus that a coordinated, international, and intergovernmental effort was needed to develop and deploy new vaccines to prevent future epidemics. Although some disease outbreaks can be relatively brief, early outbreak response activities can provide important opportunities to make progress on vaccine development. CEPI has identified six such areas and is prepared to work with other organisations in the global community to combat WHO priority pathogens, including the hypothetical Disease X, by supporting early activities in these areas, even when vaccine candidates are not yet available.

Keywords: Pandemic Preparedness; Vaccines.

——

Development of #American-Lineage #Influenza #H5N2 #Reassortant #Vaccine Viruses for #Pandemic #Preparedness (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Jun 11;11(6). pii: E543. doi: 10.3390/v11060543.

Development of American-Lineage Influenza H5N2 Reassortant Vaccine Viruses for Pandemic Preparedness.

Chen PL1,2, Hu AY3, Lin CY4, Weng TC5, Lai CC6,7, Tseng YF8, Cheng MC9,10, Chia MY11,12, Lin WC13, Yeh CT14, Su IJ15, Lee MS16.

Author information: 1 National Institution of Infectious Diseases and Vaccinology, National Health Research Institutes (NHRI), Zhunan, Miaoli 35053, Taiwan. letitia@nhri.org.tw. 2 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan. letitia@nhri.org.tw. 3 National Institution of Infectious Diseases and Vaccinology, National Health Research Institutes (NHRI), Zhunan, Miaoli 35053, Taiwan. alanhu@nhri.org.tw. 4 National Institution of Infectious Diseases and Vaccinology, National Health Research Institutes (NHRI), Zhunan, Miaoli 35053, Taiwan. grayingaries@outlook.com. 5 National Institution of Infectious Diseases and Vaccinology, National Health Research Institutes (NHRI), Zhunan, Miaoli 35053, Taiwan. wtc@nhri.org.tw. 6 National Institution of Infectious Diseases and Vaccinology, National Health Research Institutes (NHRI), Zhunan, Miaoli 35053, Taiwan. laicc2@nhri.org.tw. 7 College of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan. laicc2@nhri.org.tw. 8 National Institution of Infectious Diseases and Vaccinology, National Health Research Institutes (NHRI), Zhunan, Miaoli 35053, Taiwan. yufents@gmail.com. 9 Department of Veterinary Medicine, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan. mccheng@mail.npust.edu.tw. 10 Animal Health Research Institutes, Danshui, New Taipei City 25158, Taiwan. mccheng@mail.npust.edu.tw. 11 National Institution of Infectious Diseases and Vaccinology, National Health Research Institutes (NHRI), Zhunan, Miaoli 35053, Taiwan. chiaminyuan@dragon.nchu.edu.tw. 12 Department of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan. chiaminyuan@dragon.nchu.edu.tw. 13 Institute of Preventive Medicine, National Defence Medical Centre, Taipei 23742, Taiwan. spps057@gmail.com. 14 Institute of Preventive Medicine, National Defence Medical Centre, Taipei 23742, Taiwan. yyhome@mail.ndmctsgh.edu.tw. 15 National Institution of Infectious Diseases and Vaccinology, National Health Research Institutes (NHRI), Zhunan, Miaoli 35053, Taiwan. suihjen0704@stust.edu.tw. 16 National Institution of Infectious Diseases and Vaccinology, National Health Research Institutes (NHRI), Zhunan, Miaoli 35053, Taiwan. minshi@nhri.org.tw.

 

Abstract

Novel low-pathogenic avian influenza (LPAI) H5N2 viruses hit poultry farms in Taiwan in 2003, and evolved into highly pathogenic avian influenza (HPAI) viruses in 2010. These viruses are reassortant viruses containing HA and NA genes from American-lineage H5N2 and six internal genes from local H6N1 viruses. According to a serological survey, the Taiwan H5N2 viruses can cause asymptomatic infections in poultry workers. Therefore, a development of influenza H5N2 vaccines is desirable for pandemic preparation. In this study, we employed reverse genetics to generate a vaccine virus having HA and NA genes from A/Chicken/CY/A2628/2012 (E7, LPAI) and six internal genes from a Vero cell-adapted high-growth H5N1 vaccine virus (Vero-15). The reassortant H5N2 vaccine virus, E7-V15, presented high-growth efficiency in Vero cells (512 HAU, 107.6 TCID50/mL), and passed all tests for qualification of candidate vaccine viruses. In ferret immunization, two doses of inactivated whole virus antigens (3 μg of HA protein) adjuvanted with alum could induce robust antibody response (HI titre 113.14). In conclusion, we have established reverse genetics to generate a qualified reassortant H5N2 vaccine virus for further development.

KEYWORDS: American-lineage H5N2 vaccine; American-lineage reassortant influenza viruses; Pandemic preparedness

PMID: 31212631 DOI: 10.3390/v11060543

Keywords: Avian Influenza; H5N1; H5N2; H6N1; Reassortant Strain; Vaccines.

——

Reactive #school #closure weakens the #network of #social #interactions and reduces the #spread of #influenza (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Reactive school closure weakens the network of social interactions and reduces the spread of influenza

Maria Litvinova, Quan-Hui Liu, Evgeny S. Kulikov, and Marco Ajelli

PNAS first published June 17, 2019 / DOI: https://doi.org/10.1073/pnas.1821298116

Edited by Simon A. Levin, Princeton University, Princeton, NJ, and approved May 21, 2019 (received for review December 18, 2018)

 

Significance

The effectiveness of school-closure policies to mitigate seasonal and pandemic influenza is controversial, mostly because of the lack of empirical evidence about the behavior of the population during the implementation of these policies. In this study, we measure the behavior of the population during regular school/work days and when schools/classes are closed as a consequence of a school-closure policy. We leverage the obtained data to develop an innovative data-driven predictive-modeling framework to reduce the uncertainty surrounding school-closure policies.

 

Abstract

School-closure policies are considered one of the most promising nonpharmaceutical interventions for mitigating seasonal and pandemic influenza. However, their effectiveness is still debated, primarily due to the lack of empirical evidence about the behavior of the population during the implementation of the policy. Over the course of the 2015 to 2016 influenza season in Russia, we performed a diary-based contact survey to estimate the patterns of social interactions before and during the implementation of reactive school-closure strategies. We develop an innovative hybrid survey-modeling framework to estimate the time-varying network of human social interactions. By integrating this network with an infection transmission model, we reduce the uncertainty surrounding the impact of school-closure policies in mitigating the spread of influenza. When the school-closure policy is in place, we measure a significant reduction in the number of contacts made by students (14.2 vs. 6.5 contacts per day) and workers (11.2 vs. 8.7 contacts per day). This reduction is not offset by the measured increase in the number of contacts between students and nonhousehold relatives. Model simulations suggest that gradual reactive school-closure policies based on monitoring student absenteeism rates are capable of mitigating influenza spread. We estimate that without the implemented reactive strategies the attack rate of the 2015 to 2016 influenza season would have been 33% larger. Our study sheds light on the social mixing patterns of the population during the implementation of reactive school closures and provides key instruments for future cost-effectiveness analyses of school-closure policies.

mixing patterns – school-closure strategies – influenza – network science

Keywords: Seasonal Influenza; Pandemic Influenza; Social distancing measures; School closures; Pandemic preparedness.

——

A rapid #research needs appraisal #methodology to identify evidence #gaps to inform #clinical research #priorities in response to #outbreaks-results from the #Lassa fever pilot (BMC Med., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

BMC Med. 2019 Jun 11;17(1):107. doi: 10.1186/s12916-019-1338-1.

A rapid research needs appraisal methodology to identify evidence gaps to inform clinical research priorities in response to outbreaks-results from the Lassa fever pilot.

Sigfrid L1, Moore C2, Salam AP2,3, Maayan N4, Hamel C5, Garritty C5, Lutje V6, Buckley B7, Soares-Weiser K8, Marshall R9, Clarke M10, Horby P2.

Author information: 1 Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. louise.sigfrid@gmail.com. 2 Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. 3 United Kingdom Public Health Rapid Support Team, London, UK. 4 Cochrane Response, Cochrane, London, UK. 5 Knowledge Synthesis Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada. 6 Cochrane Infectious Diseases Group, Liverpool School of Tropical Medicine, Liverpool, UK. 7 Department of Surgery, Philippine General Hospital, National University of the Philippines, Manila, Philippines. 8 Editorial & Methods Department, Cochrane Central Executive, Cochrane, London, UK. 9 , London, UK. 10 Evidence Aid, Centre for Public Health, Queen’s University Belfast, Belfast, UK.

 

Abstract

BACKGROUND:

Infectious disease epidemics are a constant threat, and while we can strengthen preparedness in advance, inevitably, we will sometimes be caught unaware by novel outbreaks. To address the challenge of rapidly identifying clinical research priorities in those circumstances, we developed and piloted a protocol for carrying out a systematic, rapid research needs appraisal (RRNA) of existing evidence within 5 days in response to outbreaks globally, with the aim to inform clinical research prioritization.

METHODS:

The protocol was derived from rapid review methodologies and optimized through effective use of pre-defined templates and global time zones. It was piloted using a Lassa fever (LF) outbreak scenario. Databases were searched from 1969 to July 2017. Systematic reviewers based in Canada, the UK, and the Philippines screened and extracted data using a systematic review software. The pilot was evaluated through internal analysis and by comparing the research priorities identified from the data, with those identified by an external LF expert panel.

RESULTS:

The RRNA pilot was completed within 5 days. To accommodate the high number of articles identified, data extraction was prioritized by study design and year, and the clinical research prioritization done post-day 5. Of 118 potentially eligible articles, 52 met the data extraction criteria, of which 46 were extracted within the 5-day time frame. The RRNA team identified 19 clinical research priorities; the expert panel independently identified 21, of which 11 priorities overlapped. Each method identified a unique set of priorities, showing that combining both methods for clinical research prioritization is more robust than using either method alone.

CONCLUSIONS:

This pilot study shows that it is feasible to carry out a systematic RRNA within 5 days in response to a (re-) emerging outbreak to identify gaps in existing evidence, as long as sufficient resources are identified, and reviewers are experienced and trained in advance. Use of an online systematic review software and global time zones effectively optimized resources. Another 3 to 5 days are recommended for review of the extracted data and to formulate clinical research priorities. The RRNA can be used for a “Disease X” scenario and should optimally be combined with an expert panel to ensure breadth and depth of coverage of clinical research priorities.

KEYWORDS: Clinical research priorities; Emerging infectious diseases; Lassa fever; Outbreak response; Rapid research needs appraisal methodology

PMID: 31185979 DOI: 10.1186/s12916-019-1338-1

Keywords: Lassa Fever; Infectious Diseases; Pandemic preparedness.

—–