#Influenza A and B viruses with reduced #baloxavir susceptibility display attenuated in vitro #fitness but retain ferret #transmissibility (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.]

Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility

Jeremy C. Jones, Philippe Noriel Q. Pascua, Thomas P. Fabrizio, Bindumadhav M. Marathe, Patrick Seiler, Subrata Barman, Richard J. Webby, Robert G. Webster, and Elena A. Govorkova

PNAS first published March 26, 2020 | DOI: https://doi.org/10.1073/pnas.1916825117

Contributed by Robert G. Webster, February 12, 2020 (sent for review October 2, 2019; reviewed by Rodney S. Daniels and Lieve Naesens)



The emergence of influenza viruses with reduced susceptibility to baloxavir marboxil (BXM) would limit the clinical utility of this novel antiviral. To assess the risk of such resistance emerging, we evaluated influenza A and B viruses carrying BXM-reduced susceptibility substitutions and compared their fitness to that of their drug-susceptible wild-type (I38-WT) counterparts. The 38T/F/M substitutions inhibited activity of the virus PA protein, and two of them (38T/F) hindered virus replication in cells. Even so, 38T/F/M viruses could transmit between ferrets, the gold-standard model for human transmission. These findings argue that there is a risk of transmission of BXM-resistant viruses from treated individuals. Whether such viruses could compete with WT viruses in spreading through the wider untreated community is less clear.



Baloxavir marboxil (BXM) was approved in 2018 for treating influenza A and B virus infections. It is a first-in-class inhibitor targeting the endonuclease activity of the virus polymerase acidic (PA) protein. Clinical trial data revealed that PA amino acid substitutions at residue 38 (I38T/F/M) reduced BXM potency and caused virus rebound in treated patients, although the fitness characteristics of the mutant viruses were not fully defined. To determine the fitness impact of the I38T/F/M substitutions, we generated recombinant A/California/04/2009 (H1N1)pdm09, A/Texas/71/2017 (H3N2), and B/Brisbane/60/2008 viruses with I38T/F/M and examined drug susceptibility in vitro, enzymatic properties, replication efficiency, and transmissibility in ferrets. Influenza viruses with I38T/F/M substitutions exhibited reduced baloxavir susceptibility, with 38T causing the greatest reduction. The I38T/F/M substitutions impaired PA endonuclease activity as compared to that of wild-type (I38-WT) PA. However, only 38T/F A(H3N2) substitutions had a negative effect on polymerase complex activity. The 38T/F substitutions decreased replication in cells among all viruses, whereas 38M had minimal impact. Despite variable fitness consequences in vitro, all 38T/M viruses disseminated to naive ferrets by contact and airborne transmission, while 38F-containing A(H3N2) and B viruses failed to transmit via the airborne route. Reversion of 38T/F/M to I38-WT was rare among influenza A viruses in this study, suggesting stable retention of 38T/F/M genotypes during these transmission events. BXM reduced susceptibility-associated mutations had variable effects on in vitro fitness of influenza A and B viruses, but the ability of these viruses to transmit in vivo indicates a risk of their spreading from BXM-treated individuals.

influenza – endonuclease inhibitor – baloxavir marboxil – PA protein – I38T substitution



1 To whom correspondence may be addressed. Email: Jeremy.jones@stjude.org or robert.webster@stjude.org.

Author contributions: J.C.J., P.N.Q.P., T.P.F., R.J.W., R.G.W., and E.A.G. designed research; J.C.J., P.N.Q.P., B.M.M., and P.S. performed research; J.C.J., P.N.Q.P., T.P.F., and S.B. contributed new reagents/analytic tools; J.C.J., P.N.Q.P., T.P.F., and E.A.G. analyzed data; and J.C.J., P.N.Q.P., R.J.W., R.G.W., and E.A.G. wrote the paper.

Reviewers: R.S.D., The Francis Crick Institute; and L.N., Katholieke Universiteit Leuven.

Competing interest statement: E.A.G. reports receiving consultant fees and travel support from Genentech/Roche for serving on an advisory board. The other authors declare no conflicts of interest.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1916825117/-/DCSupplemental.

Published under the PNAS license.

Keywords: Seasonal Influenza; Antivirals; Drugs Resistance; Baloxavir.


The #Outbreak of #Coronavirus Disease 2019 Interfered with #Influenza in #Wuhan (SSRN, abstract)

[Source: SSRN, full page: (LINK). Abstract, edited.]

The Outbreak of Coronavirus Disease 2019 Interfered with Influenza in Wuhan

22 Pages Posted: 25 Mar 2020

Xianlong Zhou, Wuhan University – Emergency Center; Guoyong Ding, Shandong First Medical University – School of Public Health; Ting Shu, Chinese Academy of Sciences (CAS) – State Key Laboratory of Virology; Shouzhi Fu, Wuhan Third Hospital – Department of Emergency & Intensive Care Unit; Weiwei Tong, Gennlife (Beijing) Biotechnology Co. Ltd.; Xiaopeng Tu, Wuhan University – Emergency Center; Shunqing Li, Wuhan University – Emergency Center; Di Wu, Chinese Academy of Sciences (CAS) – State Key Lab of Virology; Yang Qiu, Chinese Academy of Sciences (CAS) – State Key Laboratory of Virology; Jiangtao Yu, Wuhan University – Emergency Center; Song Cao, Wuhan Third Hospital – Department of Emergency & Intensive Care Unit; Cheng Jiang, Wuhan University – Emergency Center; Haoli Ma, Wuhan University – Department of Biological Repositories; Shaoping Li, Wuhan University – Emergency Center; Jian Xia, Wuhan University – Emergency Center; Zhigang Zhao, Wuhan University – Emergency Center; Zhiyong Peng, Wuhan University – Department of Critical Care Medicine; Yufeng Yuan, Wuhan University – Department of Hepatobiliary and Pancreatic Surgery; Mingxia Yu, Wuhan University – Department of Clinical Laboratory; Yirong Li, Wuhan University – Department of Clinical Laboratory; Zhiqiang Li, Wuhan University – Department of Neurosurgery; Weijia Xing, Chinese Academy of Sciences (CAS) – State Key Lab of Virology; Xi Zhou, Chinese Academy of Sciences (CAS) – State Key Lab of Virology; Yan Zhou, Wuhan University – Emergency Center




Influenza co-circulates with coronavirus disease 2019 (COVID-19) in the space and time. Given the current situation of COVID-19 pandemic and influenza seasonal epidemic worldwide, there are lots of concerns about the potential co-infections or interactions between these two respiratory viruses. We aimed to study the potential interactions between them in Wuhan.


We obtained the epidemiological, demograhic and laboratory data from the COVID-19 and influenza cases visited the study hospital between January 2017 and February 2020. The co-infections of SARS-CoV-2 and influenza virus were retrospectively investigated in COVID-19 and influenza cases, and prospectively detected in the cases with fever and any other respiratory symptom visited the same hospital during February 14-24, 2020.


COVID-19 incidence dramatically increased in the end of January 2020 and reached the peak on February 4 in the study hospital. The seasonal epidemic of influenza was interrupted in January. A sharp decline of influenza A incidence and a premature plummet of influenza B incidence were observed. Negative correlations between the epidemic curves of COVID-19 and influenza A (r=-0.49, p<0.05) or influenza B (r=-0.51, p<0.05) were uncovered. Nine co-infections were retrospectively identified in 1054 cases of COVID-19 or influenza (0.9%, 95% CI: 0.4-1.6%). No co-infection was prospectively detected in 179 patients with fever and any respiratory symptom.


The emergence of COVID-19 interfered influenza epidemic in 2019-2020 season in Wuhan. Enhancing the surveillance of influenza could potentially facilitate better judgment about the real situation of COVID-19 pandemic, which could be hidden in massive influenza cases.


Funding Statement: Supported by the National Natural Science Foundation of China (81900097, 81903401), the Emergency Response Project of Hubei Science and Technology Department (2020FCA023), the National Science and Technology Major Project (2018ZX10101004), the Young Taishan Scholars Program of Shandong Province of China (tsqn20161046), the Shandong Province Higher Educational Young and Innovation Technology Supporting Program (2019KJL004), the Academic Promotion Program of Shandong First Medical University (2019RC010) and the Emergency Diagnostic and Therapeutic Center of Central China.

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: This study was approved by the Medical Ethics Committee, Zhongnan Hospital of Wuhan University (Clinical Ethical Approval No. 2020020). Written informed consent was obtained from the patients of respiratory symptoms group, and waived for the patients in other groups.

Keywords: Coronavirus Disease 2019; Influenza; Interference; Wuhan

Suggested Citation: Zhou, Xianlong and Ding, Guoyong and Shu, Ting and Fu, Shouzhi and Tong, Weiwei and Tu, Xiaopeng and Li, Shunqing and Wu, Di and Qiu, Yang and Yu, Jiangtao and Cao, Song and Jiang, Cheng and Ma, Haoli and Li, Shaoping and Xia, Jian and Zhao, Zhigang and Peng, Zhiyong and Yuan, Yufeng and Yu, Mingxia and Li, Yirong and Li, Zhiqiang and Xing, Weijia and Zhou, Xi and Zhou, Yan, The Outbreak of Coronavirus Disease 2019 Interfered with Influenza in Wuhan (3/12/2020). Available at SSRN: https://ssrn.com/abstract=3555239 or http://dx.doi.org/10.2139/ssrn.3555239

Keywords: SARS-CoV-2; COVID-19; Seasonal Influenza; Hubei; China.


The #Clinical Characteristics of #Pneumonia Patients Co-Infected With 2019 Novel #Coronavirus and #Influenza Virus in #Wuhan, #China (J Med Virol., abstract)

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

J Med Virol 2020 Mar 20 [Online ahead of print]

The Clinical Characteristics of Pneumonia Patients Co-Infected With 2019 Novel Coronavirus and Influenza Virus in Wuhan, China

Qiang Ding 1, Panpan Lu 1, Yuhui Fan 1, Yujia Xia 1, Mei Liu 2

Affiliations: 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. 2 Department of Gastroenterology, Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany.

PMID: 32196707 DOI: 10.1002/jmv.25781



The outbreak of 2019 novel coronavirus (COVID-19) infection emerged in Wuhan, China on December 2019. Since then the novel coronavirus pneumonia disease has been spreading quickly and many countries and territories have been affected, with major outbreaks in China, South Korea, Italy and Iran. Influenza virus has been known as a common pathogen in winter and it can cause pneumonia. It was found clinically that very few patients were diagnosed with both COVID-19 and influenza virus. 5 out of the 115 patients confirmed with COVID-19 were also diagnosed with influenza virus infection, with three cases being influenza A and two cases being influenza B. In this study, we describe the clinical characteristics of those patients who got infected with COVID-19 as well as influenza virus. Common symptoms at onset of illness included fever (5 [100%] patients), Cough (5 [100%] patients), shortness of breath (5 [100%] patients), nasal tampon (3 [60%] patients), pharyngalgia (3 [60%] patients), myalgia (2 [40%] patients), fatigue (2 [40%] patients), headache (2 [40%] patients), and expectoration (2 [40%] patients). The laboratory results showed that compared to the normal values, the patients’ lymphocytes were reduced (4 [80%] patients), and liver function ALT and AST (2 [40%] patients, 2 [40%] patients) and C-reactive protein (4 [80%] patients) were increased when admitted to hospital. They stayed in hospital for 14, 30, 17, 12, and 19 days (28.4±7.02), respectively. The main complications for the patients were acute respiratory distress syndrome (ARDS) (1 [20%] patients), acute liver injury (3 [60%] patients), and diarrhea (2 [40%] patients). All patients were given antiviral therapy (including oseltamivir), oxygen inhalation, and antibiotics. Three patients were treated with glucocorticoids including two treated with oral glucocorticoids. One of the five patients had transient hemostatic medication for hemoptysis. Fortunately, all patients did not need ICU care and were discharged from hospital without death. In conclusion, those patients with both COVID-19 and influenza virus infection did not appear to show a more severe condition because based on the laboratory findings, imaging studies, and patient prognosis, they showed similar clinical characteristics as those patients with COVID-19 infection only. However, it is worth noting that the symptoms of nasal tampon and pharyngalgia may be more prone to appear for those co-infection patients. This article is protected by copyright. All rights reserved.

Keywords: COVID-19; Clinical characteristics; Co-infection; Influenza virus.

This article is protected by copyright. All rights reserved.

Keywords: SARS-CoV-2; COVID-19; Seasonal Influenza; China.


#Hemagglutinin and #neuraminidase #antibodies are induced in an #age- and subtype- dependent manner after #influenza virus infection (J Virol., abstract)

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

Hemagglutinin and neuraminidase antibodies are induced in an age- and subtype- dependent manner after influenza virus infection.

Sook-San Wong, Ben Waite, Jacqui Ralston, Tim Wood, G Edwin Reynolds, Ruth Seeds, E. Claire Newbern, Mark G. Thompson, Q. Sue Huang, Richard J. Webby, the SHIVERS Investigation Team

DOI: 10.1128/JVI.01385-19



Despite evidence that antibodies targeting the influenza virus neuraminidase (NA) protein can be protective and are broadly cross-reactive, the immune response to NA during infection is poorly understood compared to the response to hemagglutinin (HA) protein. As such, we compared the antibody profile to HA and NA in two naturally-infected human cohorts in Auckland, New Zealand; a serosurvey cohort, consisting of pre- and post-influenza season sera from PCR-confirmed influenza cases (n=50), and an immunology cohort, consisting of paired sera collected after PCR-confirmation of infection (n=94). The induction of both HA and NA-antibodies in these cohorts was influenced by age and subtype. Seroconversion to HA was more frequent in those < 20 years old (yo) for influenza A (Serosurvey, p=0.01, Immunology, p=0.02), but not influenza B virus infection. Seroconversion to NA was not influenced by age or virus type. Adults ≥ 20 yo infected with influenza A viruses were more likely to show NA-only seroconversion compared to children (56% vs 14% [5 – 19 yo] and 0% [0 – 4 yo] respectively). Conversely, children infected with influenza B viruses were more likely than adults to show NA-only seroconversion (88% [0 – 4 yo] and 75% [5 – 19 yo] vs 40% [ ≥ 20 yo]). These data indicate a potential role for immunological memory in the dynamics of HA and NA-antibody responses. A better mechanistic understanding of this phenomenon will be critical for any future vaccines aimed at eliciting NA immunity.



Data on the immunologic responses to neuraminidase (NA) is lacking when compared to what is available on hemagglutinin (HA) responses, despite growing evidence that NA-immunity can be protective and broadly cross-reactive. Understanding these NA responses during natural infection is key to exploiting these properties for improving influenza vaccines. Using two community-acquired influenza cohorts, we showed that the induction of both HA and NA-antibody after infection is influenced by age and subtypes. Such response dynamics suggests the influence of immunological memory and understanding how this process is regulated will be critical to any vaccine effort targeting NA-immunity.

Copyright © 2020 Wong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Seasonal Influenza; Serology; Seroprevalence.


Comparison of alpha-spending plans for near #realtime #monitoring for #GBS after #influenza #vaccination during the 2010/11 influenza season (Vaccine, abstract)

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

Vaccine. 2020 Jan 10. pii: S0264-410X(19)31674-3. doi: 10.1016/j.vaccine.2019.12.032. [Epub ahead of print]

Comparison of alpha-spending plans for near real-time monitoring for Guillain-Barré after influenza vaccination during the 2010/11 influenza season.

Sandhu SK1, Hua W2, MaCurdy TE3, Franks RL4, Avagyan A4, Chillarige Y4, Wernecke M4, Kelman J5, Ball R2.

Author information: 1 Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. Electronic address: sukhminder.sandhu@fda.hhs.gov. 2 Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. 3 Stanford University, Stanford, CA, USA; Acumen LLC, Burlingame, CA, USA. 4 Acumen LLC, Burlingame, CA, USA. 5 Centers for Medicare and Medicaid Services, Washington, DC, USA.




Near real-time surveillance of the influenza vaccine, which is administered to a large proportion of the US population every year, is essential to ensure safety of the vaccine. For efficient near real-time surveillance, it is key to select appropriate parameters such as monitoring start date, number of interim tests and a scheme for spending a pre-defined total alpha across the entire influenza season. Guillain-Barré Syndrome, shown to be associated with the 1976 influenza vaccine, is used to evaluate how choices of these parameters can affect whether or not a signal is detected and the time to signal. FDA has been monitoring for the risk of GBS after influenza vaccination for every influenza season since 2008.


Using Medicare administrative data and the Updating Sequential Probability Ratio Test methodology to account for claims delay, we evaluated a number of different alpha-spending plans by varying several parameters.


For relative risks of 5 or greater, almost all alpha-spending plans have 100% power; however, for relative risks of 1.5 or lower, the constant and O’Brien-Fleming plans have increasingly more power. For RRs of 1.5 and greater, the Pocock plan signals earliest but would not signal at a RR of 1.25, as observed in prior influenza seasons. There were no remarkable differences across the different plans in regards to monitoring start dates defined by the number of vaccinations; reducing the number of interim tests improves performance only marginally.


A constant alpha-spending plan appears to be robust, in terms of power and time to detect a signal, across a range of these parameters, including alternate monitoring start dates based on either cumulative vaccinations or GBS claims observed, frequency of monitoring, hypothetical relative risks, and vaccine uptake patterns.

Published by Elsevier Ltd.

KEYWORDS: Alpha-spending; Guillain-Barré Syndrome; Immunization; Influenza; Sequential test; Vaccine

PMID: 31932134 DOI: 10.1016/j.vaccine.2019.12.032

Keywords: Drugs safety; Seasonal Influenza; Vaccines; GBS.


Early Administration of #Oseltamivir Within 48 Hours After Onset of Flulike Symptoms Can Reduce the #Risk of Influenza B Virus-Associated #Pneumonia in Hospitalized #Pediatric Patients with Influenza B Virus Infection (Pediatr Infect Dis J., abstract)

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

Pediatr Infect Dis J. 2020 Feb;39(2):e20-e22. doi: 10.1097/INF.0000000000002528.

Early Administration of Oseltamivir Within 48 Hours After Onset of Flulike Symptoms Can Reduce the Risk of Influenza B Virus-Associated Pneumonia in Hospitalized Pediatric Patients with Influenza B Virus Infection.

Dai Z1, Zhang L, Yu Q, Liu L, Yang M, Fan K.

Author information: 1 From the Department of Accident and Emergency, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.



We conducted a retrospective study to identify the risk factors for pneumonia in hospitalized pediatric patients with influenza B infection. Receiving oseltamivir within the first 48 hours of onset and frequent cough was respectively considered as a protective factor and a risk factor for the influenza B virus-associated pneumonia in hospitalized pediatric patients. Early administration of oseltamivir can reduce the risk of influenza B virus-associated pneumonia.

PMID: 31929434 DOI: 10.1097/INF.0000000000002528

Keywords: Seasonal Influenza; Influenza B; Antivirals; Oseltamivir; Pneumonia; Pediatrics.


#Necrotizing #tracheobronchitis causing airway obstruction complicated by #H1N1pdm09 #influenza: A case report (Medicine (Baltimore), abstract)

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

Medicine (Baltimore). 2020 Jan;99(1):e18647. doi: 10.1097/MD.0000000000018647.

Necrotizing tracheobronchitis causing airway obstruction complicated by pandemic 2009 H1N1 influenza: A case report.

Chang J1, Kim TO2, Yoon JY2, Kho BG2, Shin HJ2, Kwon YS2, Kim YI2, Lim SC2.

Author information: 1 Department of Internal Medicine, Mokpo Hankook Hospital, Jeollanamdo. 2 Department of Pulmonology and Critical Care Medicine, Chonnam National University Hospital, Gwangju, South Korea.




Influenza is an infection caused by the influenza virus, and its symptoms are mostly mild and self-limiting. However, influenza can cause severe or fatal complications in high-risk patients. Although tracheobronchitis is one of the common complications of influenza, necrotizing tracheobronchitis is very rare. Herein, we describe a case of necrotizing tracheobronchitis causing airway obstruction complicated by pandemic 2009 H1N1 influenza.


A 60-year-old man presented with fever and dyspnea. On arrival at the emergency room (ER), the patient received oxygen 4 L/minute via a nasal prolong owing to mild hypoxemia. And invasive mechanical ventilation was needed 5 hours after arrival at the ER due to progressive hypoxemia.


Fiberoptic bronchoscopy was performed owing to bloody secretion in the endotracheal tube and revealed diffuse tracheobronchitis with necrotic and hemorrhagic materials obstructing the trachea and bronchus. The pandemic 2009 H1N1 influenza virus was detected from the bronchial washing sample; no other microorganism was detected.


He received peramivir plus oseltamivir and broad-spectrum antibiotics.


The bloody secretion continued. He developed cardiac arrest due to airway obstruction on the 6th day of admission. After cardiac arrest, his condition progressed to multi-organ failure, and the patient died on the 10th day of admission.


We suggest that necrotizing tracheobronchitis be considered in patients with influenza who present with unexplained hypoxemia.

PMID: 31895828 DOI: 10.1097/MD.0000000000018647

Keywords: Seasonal Influenza; H1N1pdm09; Tracheobronchitis.