Recalling the #Future: #Immunological #Memory Toward Unpredictable #Influenza Viruses (Front Immunol., abstract)

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

Front Immunol. 2019 Jul 2;10:1400. doi: 10.3389/fimmu.2019.01400. eCollection 2019.

Recalling the Future: Immunological Memory Toward Unpredictable Influenza Viruses.

Auladell M1, Jia X1, Hensen L1, Chua B1,2, Fox A3, Nguyen THO1, Doherty PC1,4, Kedzierska K1.

Author information: 1 Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. 2 Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan. 3 WHO Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. 4 Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, United States.



Persistent and durable immunological memory forms the basis of any successful vaccination protocol. Generation of pre-existing memory B cell and T cell pools is thus the key for maintaining protective immunity to seasonal, pandemic and avian influenza viruses. Long-lived antibody secreting cells (ASCs) are responsible for maintaining antibody levels in peripheral blood. Generated with CD4+ T help after naïve B cell precursors encounter their cognate antigen, the linked processes of differentiation (including Ig class switching) and proliferation also give rise to memory B cells, which then can change rapidly to ASC status after subsequent influenza encounters. Given that influenza viruses evolve rapidly as a consequence of antibody-driven mutational change (antigenic drift), the current influenza vaccines need to be reformulated frequently and annual vaccination is recommended. Without that process of regular renewal, they provide little protection against “drifted” (particularly H3N2) variants and are mainly ineffective when a novel pandemic (2009 A/H1N1 “swine” flu) strain suddenly emerges. Such limitation of antibody-mediated protection might be circumvented, at least in part, by adding a novel vaccine component that promotes cross-reactive CD8+ T cells specific for conserved viral peptides, presented by widely distributed HLA types. Such “memory” cytotoxic T lymphocytes (CTLs) can rapidly be recalled to CTL effector status. Here, we review how B cells and follicular T cells are elicited following influenza vaccination and how they survive into a long-term memory. We describe how CD8+ CTL memory is established following influenza virus infection, and how a robust CTL recall response can lead to more rapid virus elimination by destroying virus-infected cells, and recovery. Exploiting long-term, cross-reactive CTL against the continuously evolving and unpredictable influenza viruses provides a possible mechanism for preventing a disastrous pandemic comparable to the 1918-1919 H1N1 “Spanish flu,” which killed more than 50 million people worldwide.

KEYWORDS: B cells; T cells; immunological memory; influenza; vaccine

PMID: 31312199 PMCID: PMC6614380 DOI: 10.3389/fimmu.2019.01400

Keywords: Influenza A; Seasonal Influenza; Pandemic Influenza; Vaccines; Immunology.



#Health #outcomes of young #children born to #mothers who received 2009 #pandemic #H1N1 #influenza #vaccination during #pregnancy: retrospective cohort study (BMJ, abstract)

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

BMJ. 2019 Jul 10;366:l4151. doi: 10.1136/bmj.l4151.

Health outcomes of young children born to mothers who received 2009 pandemic H1N1 influenza vaccination during pregnancy: retrospective cohort study.

Walsh LK1,2, Donelle J3, Dodds L4, Hawken S2,3,5, Wilson K2,3,5, Benchimol EI2,3,6, Chakraborty P2,6, Guttmann A3,7,8, Kwong JC3,7,9,10, MacDonald NE4, Ortiz JR11, Sprague AE1,2,6, Top KA4, Walker MC1,2,5, Wen SW2,5, Fell DB12,3,6.

Author information: 1 Better Outcomes Registry & Network, Ottawa, ON, Canada. 2 University of Ottawa, Ottawa, ON, Canada. 3 ICES, Toronto, ON, Canada. 4 Dalhousie University, Halifax, NS, Canada. 5 Ottawa Hospital Research Institute, Ottawa, ON, Canada. 6 Children’s Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, ON, Canada. 7 Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. 8 Hospital for Sick Children, Toronto, ON, Canada. 9 Public Health Ontario, Toronto, ON, Canada. 10 Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada. 11 University of Maryland School of Medicine, Baltimore, MD, USA. 12 University of Ottawa, Ottawa, ON, Canada




To determine whether any association exists between exposure to 2009 pandemic H1N1 (pH1N1) influenza vaccination during pregnancy and negative health outcomes in early childhood.


Retrospective cohort study.


Population based birth registry linked with health administrative databases in the province of Ontario, Canada.


All live births from November 2009 through October 2010 (n=104 249) were included, and children were followed until 5 years of age to ascertain study outcomes.


Rates of immune related (infectious diseases, asthma), non-immune related (neoplasms, sensory disorders), and non-specific morbidity outcomes (urgent or inpatient health services use, pediatric complex chronic conditions) were evaluated from birth to 5 years of age; under-5 childhood mortality was also assessed. Propensity score weighting was used to adjust hazard ratios, incidence rate ratios, and risk ratios for potential confounding.


Of 104 249 live births, 31 295 (30%) were exposed to pH1N1 influenza vaccination in utero. No significant associations were found with upper or lower respiratory infections, otitis media, any infectious diseases, neoplasms, sensory disorders, urgent and inpatient health services use, pediatric complex chronic conditions, or mortality. A weak association was observed between prenatal pH1N1 vaccination and increased risk of asthma (adjusted hazard ratio 1.05, 95% confidence interval 1.02 to 1.09) and decreased rates of gastrointestinal infections (adjusted incidence rate ratio 0.94, 0.91 to 0.98). These results were unchanged in sensitivity analyses accounting for any potential differential healthcare seeking behavior or access between exposure groups.


No associations were observed between exposure to pH1N1 influenza vaccine during pregnancy and most five year pediatric health outcomes. Residual confounding may explain the small associations observed with increased asthma and reduced gastrointestinal infections. These outcomes should be assessed in future studies.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

PMID: 31292120 DOI: 10.1136/bmj.l4151

Keywords: Pandemic Influenza; H1N1pdm09; Vaccines; Pregnancy.


Serial Section Array Scanning Electron Microscopy Analysis of Cells from #Lung #Autopsy #Specimens Following #Fatal A/ #H1N1pdm09 #Influenza Virus #Infection (J Virol., abstract)

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

Serial Section Array Scanning Electron Microscopy Analysis of Cells from Lung Autopsy Specimens Following Fatal A/H1N1 2009 Pandemic Influenza Virus Infection

Michiyo Kataoka, Kinji Ishida, Katsutoshi Ogasawara, Takayuki Nozaki, Yoh-ichi Satoh, Tetsutaro Sata, Yuko Sato, Hideki Hasegawa, Noriko Nakajima

DOI: 10.1128/JVI.00644-19



A/H1N1 2009 pandemic influenza virus (A/H1N1/pdm09) was first identified as a novel pandemic influenza A virus (IAV) in 2009. Previously, we reported that many viral antigens were detected in type II alveolar epithelial cells (AEC-IIs) within autopsied lung tissue from a patient with A/H1N1/pdm09 pneumonia. It is important to identify the association between the virus and host cells to elucidate the pathogenesis of IAV pneumonia. To investigate the distribution of virus particles and morphological changes in host cells, the autopsied lung specimens from this patient were examined using transmission electron microscopy (TEM) and a novel scanning electron microscopy (SEM) method. We focused on AEC-IIs as viral antigen-positive cells, and on monocytes/macrophages (Ms/MΦs) and neutrophils (Neus) as innate immune cells. We identified virus particles and intranuclear dense tubules, which are associated with matrix 1 (M1) proteins from IAV. Large-scale two-dimensional observation was enabled by digitally ‘stitching’ together contiguous SEM images. A single whole cell analysis using a serial section array (SSA)-SEM identified virus particles in vesicles within the cytoplasm and/or around the cell surface of AEC-IIs, Ms/MΦs, and Neus; however, intranuclear dense tubules were found only in AEC-IIs. Computer-assisted processing of SSA-SEM images from each cell type enabled 3D modeling of the distribution of virus particles within an ACE-II, a M/MΦ, and a Neu.



Generally, it is difficult to observe IAV particles in post-mortem samples from patients with seasonal influenza. In fact, only a few viral antigens are detected in bronchial epithelial cells from autopsied lung sections. Previously, we detected many viral antigens in AEC-IIs from the lung. This was because the majority of A/H1N1/pdm09 in the lung tissue harbored an aspartic acid to glycine substitution at position 222 (D222G) of the hemagglutinin protein. A/H1N1/pdm09 harboring the D222G substitution has a receptor-binding preference for α-2,3-linked sialic acids expressed on human AECs and infects them in the same way as H5N1 and H7N9 avian IAVs. Here, we report the first successful observation of virus particles not only in AEC-IIs, but also in Ms/MΦs and Neus, using electron microscopy. The finding of a M/MΦ harboring numerous virus particles within vesicles and at the cell surface suggests that Ms/MΦs are involved in the pathogenesis of IAV primary pneumonia.

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

Keywords: Influenza A; Seasonal Influenza; Pandemic Influenza; Avian Influenza; H1N1pdm09; H5N1; H7N9; Viral pathogenesis.


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:




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


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).


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.


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 ( 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.


An indirect #comparison meta-analysis of #AS03 and #MF59 #adjuvants in #pandemic #influenza A(#H1N1)pdm09 #vaccines (Vaccine, abstract)

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

Vaccine. 2019 Jun 25. pii: S0264-410X(19)30801-1. doi: 10.1016/j.vaccine.2019.06.039. [Epub ahead of print]

An indirect comparison meta-analysis of AS03 and MF59 adjuvants in pandemic influenza A(H1N1)pdm09 vaccines.

Hauser MI1, Muscatello DJ2, Soh ACY1, Dwyer DE3, Turner RM4.

Author information: 1 University of New South Wales, Sydney, Australia. 2 School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia. Electronic address: 3 Centre for Infectious Diseases and Microbiology Laboratory Services, New South Wales Health Pathology – Institute of Clinical Pathology and Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia. 4 Centre for Biostatistics, Division of Health Sciences, University of Otago, Dunedin, New Zealand. Electronic address:




Although oil-in-water adjuvants improve pandemic influenza vaccine efficacy, AS03 versus MF59 adjuvant comparisons in A(H1N1)pdm09 pandemic vaccines are lacking.


We conducted an indirect-comparison meta-analysis extracting published data from randomised controlled trials in literature databases (01/01/2009-09/09/2018), evaluating immunogenicity and safety of AS03- or MF59-adjuvanted vaccines. We conducted comparisons of log-transformed haemagglutination inhibition geometric mean titre ratio (GMTR; primary outcome) of different regimens of each adjuvant versus unadjuvanted counterparts. Then via test of subgroup differences, we indirectly compared different AS03 versus MF59 regimens.


We identified 22 publications with 10,734 participants. In adults, AS03-adjuvanted vaccines (3.75 µg haemagglutinin) achieved superior GMTR versus unadjuvanted vaccines (all four comparisons); MD = 0.56 (95%CI 0.33 to 0.80, p < 0.001) to 1.18 (95%CI 0.72 to 1.65, p < 0.001). MF59 (full-dose)-adjuvanted vaccines (7.5 µg haemagglutinin) were superior to unadjuvanted vaccines (three of four comparisons); MD = 0.47 (95%CI 0.19 to 0.75, p = 0.001) to 0.80 (95%CI 0.44 to 1.16, p < 0.001). Adult indirect comparisons favoured AS03 over MF59 (six of eight comparisons; p < 0.001 to p = 0.088). Paediatric indirect comparisons favoured MF59-adjuvanted vaccines (two of seven comparisons; p = 0.011, 0.079). However, unadjuvanted control group seroconversion rate was lower in MF59 than AS03 studies (p < 0.001 to p = 0.097). There was substantial heterogeneity, and adult AS03 studies had lower risk of bias.


Despite limited studies, in adults, AS03-adjuvanted vaccines allow antigen sparing versus MF59-adjuvanted and unadjuvanted vaccines, with similar immunogenicity, but higher risk of pain and fatigue (secondary outcomes) than unadjuvanted vaccines. In children, adjuvanted vaccines are also superior, but the better adjuvant is uncertain.

Copyright © 2019 Elsevier Ltd. All rights reserved.

KEYWORDS: Adjuvants; H1N1 subtype; Immunologic; Influenza A virus; Influenza vaccines; Meta-analysis; Pandemics

PMID: 31253447 DOI: 10.1016/j.vaccine.2019.06.039

Keywords: Pandemic Influenza; H1N1pdm09; 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:

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



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.



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 #paediatric #influenza #update 100 years after the #Skyros island #Spanishflu #outbreak (Exp Ther Med., abstract)

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

Exp Ther Med. 2019 Jun;17(6):4327-4336. doi: 10.3892/etm.2019.7515. Epub 2019 Apr 22.

A paediatric influenza update 100 years after the Skyros island Spanish flu outbreak.

Mammas IN1, Theodoridou M2, Thiagarajan P3, Melidou A4, Papaioannou G5, Korovessi P6, Koutsaftiki C7, Papatheodoropoulou A8, Calachanis M9, Dalianis T10, Spandidos DA1.

Author information: 1 Department of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece. 2 First Department of Paediatrics, ‘Aghia Sophia’ Children’s Hospital, University of Athens School of Medicine, 115 27 Athens, Greece. 3 Neonatal Unit, Division for Women’s & Children Health, Noble’s Hospital, IM4 4RJ Douglas, Isle of Man, British Isles. 4 Second Laboratory of Microbiology, School of Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece. 5 Department of Paediatric Radiology, ‘Mitera’ Children’s Hospital, 151 23 Athens, Greece. 6 Department of Paediatrics, ‘Penteli’ Children’s Hospital, 152 36 Penteli, Greece. 7 Paediatric Intensive Care Unit (PICU), ‘Penteli’ Children’s Hospital, 152 36 Penteli, Greece. 8 Paediatric Intensive Care Unit (PICU), ‘P. and A. Kyriakou’ Children’s Hospital, 115 27 Athens, Greece. 9 Department of Paediatric Cardiology, ‘Penteli’ Children’s Hospital, 152 36 Penteli, Greece. 10 Karolinska Institutet, Karolinska University Hospital, SE-117 77 Stockholm, Sweden.



This year marks the 100th anniversary of the 1918 Spanish flu outbreak on the Greek Aegean Sea island of Skyros, which devastated its population in less than 30 days. According to Constantinos Faltaits’s annals published in 1919, the influenza attack on the island of Skyros commenced acutely ‘like a thunderbolt’ on the 27th of October, 1918 and was exceptionally severe and fatal. At that time, the viral cause of the influenza had not been detected, while the total number of victims of the Spanish flu outbreak has been estimated to have surpassed 50 million, worldwide. Almost one century after this Aegean Sea island’s tragedy, the ‘4th Workshop on Paediatric Virology’, organised on the 22nd of September, 2018 in Athens, Greece, was dedicated to the 100 years of the ‘Spanish’ flu pandemic. This review article highlights the plenary and key lectures presented at the workshop on the recent advances on the epidemiology, clinical management and prevention of influenza in childhood.

KEYWORDS: H1N1; Paediatric Intensive Care Unit; antiviral drugs; influenza; myocarditis; neurological complications; paediatric virology; probiotics; radiology; vaccination

PMID: 31186675 PMCID: PMC6507498 DOI: 10.3892/etm.2019.7515

Keywords: Pandemic Influenza; Spanish Flu; Pediatrics; History; Greece.