Publications
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Tripp RA, Power UF, Openshaw PJM, et al., 2017, Respiratory Syncytial Virus (RSV): Targeting the G Protein Provides a New Approach for an Old Problem., Journal of Virology, Vol: 92, ISSN: 1098-5514
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) annually affecting >2 million children in the US <5 years old. In the elderly (>65 years old), RSV results in ∼175,000 hospitalizations annually in the US with worldwide incidence ∼34 million. There is no approved RSV vaccine and treatments are limited. Recently, a Phase 3 trial in the elderly using a recombinant RSV F protein vaccine failed to meet its efficacy objectives, namely prevention of moderate-to-severe RSV-associated LRTI and reduced incidence of acute respiratory disease. Moreover, a recent Phase 3 trial evaluating suptavumab (REGN2222), an antibody to RSV F protein, did not meet its primary endpoint of preventing medically attended RSV infections in pre-term infants. Despite these setbacks, numerous efforts targeting the RSV F protein with vaccines, antibodies, and small molecules continue based on the commercial success of a monoclonal antibody (mAb) against the RSV F protein (palivizumab). As the understanding of RSV biology has improved, the other major coat protein, the RSV G protein, has re-emerged as an alternative target reflecting progress in understanding its roles in infecting bronchial epithelial cells and in altering the host immune response. In mouse models, a high-affinity, strain-independent human mAb to the RSV G protein has shown potent direct antiviral activity combined with the alleviation of virus-induced immune system effects that contribute to disease pathology. This mAb, being prepared for clinical trials, provides a qualitatively new approach to managing RSV for populations not eligible for prophylaxis with palivizumab.
Sheerin D, Openshaw PJ, Pollard AJ, 2017, Issues in vaccinology: Present challenges and future directions., European Journal of Immunology, Vol: 47, Pages: 2017-2025, ISSN: 0014-2980
Vaccination is a principal and highly cost-effective means of controlling infectious diseases, providing direct protection against pathogens by conferring long-lasting immunological memory and inducing population-level herd immunity. Despite rapid ongoing progress in vaccinology, there remain many obstacles to the development and deployment of novel or improved vaccines; these include the underlying science of how to induce and sustain appropriate protective immune responses as well as bureaucratic, logistic and socio-political hurdles. The failure to distribute and administer existing vaccines to at-risk communities continues to account for a large proportion of infant mortality worldwide: almost 20 million children do not have access to basic vaccines and several million still die each year as a result. While emerging epidemic or pandemic diseases pose a significant threat to global health and prosperity, there are many infectious diseases which provide a continuous or cyclical burden on healthcare systems which also need to be addressed. Gaps in knowledge of the human immune system stand in the way of developing technologies to overcome individual and pathogenic variation. The challenges in tackling infectious disease and directions that the field of preventive medicine may take to improve the current picture of global health are the focus of this review.
Marchant A, Sadarangani M, Garand M, et al., 2017, Maternal immunisation: collaborating with mother nature, Lancet Infectious Diseases, Vol: 17, Pages: E197-E208, ISSN: 1473-3099
Maternal immunisation has the potential to substantially reduce morbidity and mortality from infectious diseases after birth. The success of tetanus, influenza, and pertussis immunisation during pregnancy has led to consideration of additional maternal immunisation strategies to prevent group B streptococcus and respiratory syncytial virus infections, among others. However, many gaps in knowledge regarding the immunobiology of maternal immunisation prevent the optimal design and application of this successful public health intervention. Therefore, we did an innovative landscape analysis to identify research priorities. Key topics were delineated through review of the published literature, consultation with vaccine developers and regulatory agencies, and a collaborative workshop that gathered experts across several maternal immunisation initiatives—group B streptococcus, respiratory syncytial virus, pertussis, and influenza. Finally, a global online survey prioritised the identified knowledge gaps on the basis of expert opinion about their importance and relevance. Here we present the results of this worldwide landscape analysis and discuss the identified research gaps.
Heath PT, Culley FJ, Jones CE, et al., 2017, Group B streptococcus and respiratory syncytial virus immunisation during pregnancy: a landscape analysis, Lancet Infectious Diseases, Vol: 17, Pages: e223-e234, ISSN: 1473-3099
Group B streptococcus and respiratory syncytial virus are leading causes of infant morbidity and mortality worldwide. No licensed vaccines are available for either disease, but vaccines for both are under development. Severe respiratory syncytial virus disease can be prevented by passively administered antibody. The presence of maternal IgG antibody specific to respiratory syncytial virus is associated with reduced prevalence and severity of respiratory syncytial virus disease in the first few weeks of life, whereas maternal serotype-specific anticapsular antibody is associated with protection against both early-onset and late-onset group B streptococcus disease. Therefore, vaccination in pregnancy might protect infants against both diseases. This report describes what is known about immune protection against group B streptococcus and respiratory syncytial virus, identifies knowledge gaps regarding the immunobiology of both diseases, and aims to prioritise research directions in maternal immunisation.
Cole SL, Dunning J, Kok WL, et al., 2017, M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza., JCI Insight, Vol: 2, ISSN: 2379-3708
In each influenza season, a distinct group of young, otherwise healthy individuals with no risk factors succumbs to life-threatening infection. To better understand the cause for this, we analyzed a broad range of immune responses in blood from a unique cohort of patients, comprising previously healthy individuals hospitalized with and without respiratory failure during one influenza season, and infected with one specific influenza A strain. This analysis was compared with similarly hospitalized influenza patients with known risk factors (total of n = 60 patients recruited). We found a sustained increase in a specific subset of proinflammatory monocytes, with high TNF-α expression and an M1-like phenotype (independent of viral titers), in these previously healthy patients with severe disease. The relationship between M1-like monocytes and immunopathology was strengthened using murine models of influenza, in which severe infection generated using different models (including the high-pathogenicity H5N1 strain) was also accompanied by high levels of circulating M1-like monocytes. Additionally, a raised M1/M2 macrophage ratio in the lungs was observed. These studies identify a specific subtype of monocytes as a modifiable immunological determinant of disease severity in this subgroup of severely ill, previously healthy patients, offering potential novel therapeutic avenues.
Thwaites RS, Ito K, Chingono JMS, et al., 2017, Nasosorption is a minimally invasive diagnostic procedure for measurement of viral load and markers of mucosal inflammation in RSV bronchiolitis, The Journal of Infectious Diseases, Vol: 215, Pages: 1240-1244, ISSN: 1537-6613
Background.Existing respiratory mucosal sampling methods are flawed, particularly in a pediatric bronchiolitis setting.Methods.Twenty-four infants with bronchiolitis were recruited: 12 were respiratory syncytial virus (RSV)–positive, 12 were RSV-negative. Infants were sampled by nasosorption and nasopharyngeal aspiration (NPA).Results.Nasosorption was well tolerated and identified all RSV+ samples. RSV load measured by nasosorption (but not NPA) correlated with length of hospital stay (P = .04) and requirement for mechanical ventilation (P = .03). Nasosorption (but not NPA) levels of interferon γ, interleukin 1β, CCL5/RANTES, and interleukin 10 (IL-10) were elevated in RSV+ bronchiolitis (all P < .05), furthermore CCL5 and IL-10 correlated with RSV load (P < .05).Conclusions.Nasosorption allowed measurement of RSV load and the mucosal inflammatory response in infants.
Openshaw PJM, 2017, RSV takes control of neonatal Breg cells: two hands on the wheel, Immunity, Vol: 46, Pages: 171-173, ISSN: 1074-7613
The viral attachment protein of RSV has many surprising features, especially its mimicry of fractalkine (CX3CL1). Zhivaki et al. (2017) now show that, in addition to using this homology to attach to ciliated cells, it activates human neonatal regulatory B cells, thereby inhibiting immunological responses.
Openshaw PJM, Chiu C, Culley FJ, et al., 2017, Protective and Harmful Immunity to RSV Infection, Annual Review of Immunology, Vol: 35, Pages: 501-532, ISSN: 0732-0582
Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus.
Thwaites RS, Gunawardana NC, Broich VL, et al., 2017, Activation of the complement, coagulation and fibrinolysis pathways after nasal allergen challenge, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Publisher: Elsevier, Pages: AB384-AB384, ISSN: 0091-6749
Fraser CS, Jha A, Openshaw PJM, 2016, Vaccines in the prevention of viral pneumonia, CLINICS IN CHEST MEDICINE, Vol: 38, Pages: 155-169, ISSN: 0272-5231
Gunawardana N, Campbell G, Lindsley S, et al., 2016, The effect of vitamin D supplementation on cathelicidin levels, vitamin D receptor (VDR) and E-cadherin expression after nasal allergen challenge in allergic rhinitis, Annual Meeting of the British-Society-for-Allergy-and-Clinical-Immunology (BSACI), Publisher: WILEY-BLACKWELL, Pages: 1666-1666, ISSN: 0954-7894
Jha A, Dunning J, Tunstall T, et al., 2016, Asthma patients hospitalized with influenza lack mucosal and systemic type 2 inflammation, European Respiratory Society Congress, Publisher: European Respiratory Society, ISSN: 0903-1936
Background: Asthmatic persons tend to suffer from severe influenza, but the reasons for enhanced severity are unknown. Objectives: To determine the clinicopathological correlates of this susceptibility, we examined nasal and systemic immune responses in adults admitted to hospital with influenza-like illnesses. Methods: We studied 210 patients admitted with influenza-like illness at 11 hospitals in the UK across 2 winter seasons (2009/10 and 2010/11). Of these, 133 (63%) had confirmed influenza and 40/133 (30%) were asthmatic. We measured a panel of cytokines and chemokines in serum and nasal mucosal lining fluid and compared results in asthmatics, non-asthmatics and healthy control volunteers. Results: Asthma patients were more often female than non-asthmatics (70% vs 39% respectively), required less mechanical ventilation (15% vs 37.6%) and had shorter hospital stays (mean 8.3 vs 15.3 days, all P <0.05). Despite having equivalent nasopharyngeal influenza viral load, asthmatics had higher serum IFN-α levels but lower serum TNF-α, IL-5, IL-6 and CXCL8 (all P<0.05). In the nasal mucosa, asthmatics and non-asthmatics had comparable levels of soluble mediators. In particular, asthmatics showed no evidence of increased type 2 inflammation (IL-5 and IL-13) or deficient interferon responses. Conclusions: Adult asthmatics hospitalised with influenza show a propensity to be female with markedly reduced morbidity and systemic inflammation than non-asthmatics. Against expectation, asthmatics did not have increased type 2 inflammation. This study highlights the importance of defining underlying immune responses to infection in individual patients to enable future delivery of personalized therapy.
Openshaw P, 2016, Brexit: A view from the BSI, European Journal of Immunology, Vol: 46, Pages: 2065-2067, ISSN: 0014-2980
Mazein A, De Meulder B, Lefaudeux D, et al., 2016, LSC Abstract - The AsthmaMap: Towards a community-driven reconstruction of asthma-relevant pathways and networks, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Schuijs MJ, Hartmann S, Selkirk ME, et al., 2016, The Helminth-Derived Immunomodulator AvCystatin Reduces Virus Enhanced Inflammation by Induction of Regulatory IL-10+ T Cells., PLOS One, Vol: 11, ISSN: 1932-6203
Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease.
Jha A, Progatzky F, Wane M, et al., 2016, Human nasal mucosal responses to TLR agonists are mirrored by the zebrafish gill, British Association of Lung Research Summer Congress
Introduction: There are few reliable ways to study respiratory mucosal immune responses to viruses, viral-type toll-like receptor (TLR) agonists and vaccines. To investigate innate immune responses to TLR agonists (TLR3: poly IC/ poly ICLC; TLR7/8: resiquimod), we compared the effects on human nasal mucosa and zebrafish gills in vivo. Methods: Nasal challenge of adult volunteers was performed with saline, poly IC (n=4), poly ICLC (n=4) or resiquimod (n=8; 5 non-atopic, 3 atopic). Nasal mucosal lining fluid (MLF) was obtained by nasosorption at regular intervals up to 24 hours after challenge; nasal obstruction was monitored by peak nasal inspiratory flow (PNIF) and total nasal symptom scores (TNSS). Cytokines and interferons were measured in MLF using electrochemiluminescence on the Meso Scale Discovery (MSD) platform. Adult zebrafish gills were exposed to the same TLR agonists and gene expression was quantified in gill tissue at similar time-points. Results: Nasal challenge with TLR3 agonists failed to elicit any significant responses when compared to saline. In contrast resiquimod (10μg/100μl per nostril) caused a potent induction of cytokines with an early release (1-3 hours) of IFN-α2a, TNF-α and IL-1β and a later release (after 4 hours) of IFN-γ. The 3 volunteers with the highest levels of IFN-α2a were atopic. Six volunteers were asymptomatic and two volunteers had flu-like symptoms. There were no significant changes in clinical correlates of nasal obstruction. After resiquimod administration, but not TLR3 agonists, zebrafish gills showed an immune profile remarkably analogous to human nasal responses. Conclusion: The TLR7/8 agonist resiquimod is a potent mucosal inducer of IFN-α2a, IFN-γ and proinflammatory cytokines, whilst TLR3 agonists failed to stimulate mucosal innate immune responses. Zebrafish gills accurately mimic human nasal mucosal responses following exposure to TLR agonists, offering translational app
Jha A, Jarvis H, Fraser C, et al., 2016, Respiratory Syncytial Virus, SARS, MERS and other Viral Lung Infections, Editors: Hui, Rossi, Johnston, Publisher: European Respiratory Society, Pages: 84-109, ISBN: 978-1-84984-069-9
RSV infection has an estimated global incidence of 33 million cases in children <5 years of age, with 10% requiring hospital admission and up to 199 000 dying of the disease. There is growing evidence that severe infantile RSV bronchiolitis, a condition characterised by an inflammatory reaction to the virus, is associated with later childhood wheeze in somevulnerable children; however, a direct causal relationship with asthma has not yet been established. RSV infection is also increasingly recognised as a cause of morbidity and mortality in those with underlying airway disease, the immunocompromised and frail elderlypersons. Novel molecular-based diagnostic tools are becoming established, but treatment remains largely supportive, with palivizumab the only licensed agent currently available for passive prophylaxis of selected pre-term infants. While effective treatments remain elusive,there is optimism about the testing of novel antiviral drugs and the development of vaccines that may induce long-lasting immunity without the risk of disease augmentation.
Jozwik A, Habibi MS, Paras A, et al., 2016, Erratum: RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nature Communications, Vol: 7, ISSN: 2041-1723
Gunawardana NC, Campbell G, Lindsley S, et al., 2016, The Effect of Vitamin D Supplementation on Mucosal IL-5, MMP9 and Cathelicidin after Nasal Allergen Challenge with Grass Pollen, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Publisher: MOSBY-ELSEVIER, Pages: AB73-AB73, ISSN: 0091-6749
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Jozwik A, Habibi MS, Paras A, et al., 2015, RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nature Communications, Vol: 6, Pages: 1-17, ISSN: 2041-1723
In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyze phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. These are more highly differentiated but express fewer cytotoxicity markers than in blood, but their abundance prior to infection correlates with protection from more severe disease.
Van Essen GEA, Openshaw P, Myles P, et al., 2015, How should influenza be treated? Focus on antivirals, VACCINE, Vol: 33, Pages: 7033-7036, ISSN: 0264-410X
Dhariwal J, Kitson J, Jones RE, et al., 2015, Nasal Lipopolysaccharide Challenge and Cytokine Measurement Reflects Innate Mucosal Immune Responsiveness, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundPractical methods of monitoring innate immune mucosal responsiveness are lacking. Lipopolysaccharide(LPS) is a component of the cell wall of Gram negative bacteria and a potentactivator of Toll-like receptor (TLR)-4. To measure LPS responsiveness of the nasalmucosa, we administered LPS as a nasal spray and quantified chemokine and cytokine levelsin mucosal lining fluid (MLF).MethodsWe performed a 5-way cross-over, single blind, placebo-controlled study in 15 healthy nonatopicsubjects (n = 14 per protocol). Doses of ultrapure LPS (1, 10, 30 or 100μg/100μl) orplacebo were administered by a single nasal spray to each nostril. Using the recently developedmethod of nasosorption with synthetic adsorptive matrices (SAM), a series of sampleswere taken. A panel of seven cytokines/chemokines were measured by multiplex immunoassayin MLF. mRNA for intercellular cell adhesion molecule-1 (ICAM-1) was quantifiedfrom nasal epithelial curettage samples taken before and after challenge.ResultsTopical nasal LPS was well tolerated, causing no symptoms and no visible changes to thenasal mucosa. LPS induced dose-related increases in MLF levels of IL-1β, IL-6, CXCL8 (IL-8) and CCL3 (MIP-1α) (AUC at 0.5 to 10h, compared to placebo, p<0.05 at 30 and 100μgLPS). At 100μg LPS, IL-10, IFN-α and TNF-α were also increased (p<0.05). Dose-relatedchanges in mucosal ICAM-1 mRNA were also seen after challenge, and neutrophilsappeared to peak in MLF at 8h. However, 2 subjects with high baseline cytokine levelsshowed prominent cytokine and chemokine responses to relatively low LPS doses (10μgand 30μg LPS).
Habibi MS, Jozwik A, Makris S, et al., 2015, Impaired antibody-mediated protection and defective IgA B cell memory in experimental infection of adults with respiratory syncytial virus, American Journal of Respiratory and Critical Care Medicine, Vol: 191, ISSN: 1535-4970
Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) re-infects throughout life. After >40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection. Objectives: Characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development. Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B cell frequencies and antibody longevity. Measurements and Main Results: Despite moderately high levels of pre-existing serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from PCR-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects, but correlated with plasmablasts that peaked around day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, where virus-specific IgA memory B cells were readily recovered. Conclusions: This observed specific defect in IgA memory may partly explain RSV's ability to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.
Nyland GA, Mckenzie BC, Myles PR, et al., 2015, Effect of ethnicity on care pathway and outcomes in patients hospitalized with influenza A(H1N1)pdm09 in the UK, EPIDEMIOLOGY AND INFECTION, Vol: 143, Pages: 1129-1138, ISSN: 0950-2688
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Chiu C, Openshaw PJ, 2015, Antiviral B cell and T cell immunity in the lungs, NATURE IMMUNOLOGY, Vol: 16, Pages: 18-26, ISSN: 1529-2908
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Dodd JS, Affendi SS, Openshaw PJ, 2014, Timing of NKT-cell activation dictates the pulmonary immune response to respiratory syncytial virus (RSV) challenge, IMMUNOLOGY, Vol: 143, Pages: 101-101, ISSN: 0019-2805
Openshaw PJ, 2014, Rational and practical hurdles in vaccine development for respiratory disease, IMMUNOLOGY, Vol: 143, Pages: 31-31, ISSN: 0019-2805
Gonzalez LM, Jozwik AA, Habibi MS, et al., 2014, Quality of antigen-specific B-cell responses as a correlate of protection against RSV, IMMUNOLOGY, Vol: 143, Pages: 75-75, ISSN: 0019-2805
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Jozwik A, Habibi M, Paras A, et al., 2014, Human T-cell responses to RSV infection in the lower airway, IMMUNOLOGY, Vol: 143, Pages: 76-76, ISSN: 0019-2805
Elderfield RA, Watson SJ, Godlee A, et al., 2014, Accumulation of human-adapting mutations during circulation of A(H1N1)pdm09 influenza virus in humans in the United Kingdom, Journal of Virology, Vol: 88, Pages: 13269-13283, ISSN: 0022-538X
The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to α-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves.
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