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Influenza is a yearly threat to global public health. Rapid changes in influenza surface proteins resulting from antigenic drift and shift events make it difficult to readily identify antibodies with broadly neutralizing activity against different influenza subtypes with high frequency, specifically antibodies targeting the receptor binding domain (RBD) on influenza HA protein. We developed an optimized computational design method that is able to optimize an antibody for recognition of large panels of antigens. To demonstrate the utility of this multistate design method, we used it to redesign an antiinfluenza antibody against a large panel of more than 500 seasonal HA antigens of the H1 subtype. As a proof of concept, we tested this method on a variety of known antiinfluenza antibodies and identified those that could be improved computationally. We generated redesigned variants of antibody C05 to the HA RBD and experimentally characterized variants that exhibited improved breadth and affinity against our panel. C05 mutants exhibited improved affinity for three of the subtypes used in design by stabilizing the CDRH3 loop and creating favorable electrostatic interactions with the antigen. These mutants possess increased breadth and affinity of binding while maintaining high-affinity binding to existing targets, surpassing a major limitation up to this point.
Copyright © 2019 the Author(s). Published by PNAS.
BACKGROUND - Influenza C virus (ICV) is associated with acute respiratory illness. Yet ICV remains under recognized, with most previous studies using only culture to identify cases.
OBJECTIVES - To develop a sensitive and specific real-time RT-PCR assay for ICV that allows for rapid and accurate detection in a clinical or research setting.
STUDY DESIGN - Multiple ICV sequences obtained from GenBank were analyzed, including 141 hemagglutinin-esterase (HE), 106 matrix (M), and 97 nucleoprotein (NP) sequences. Primers and probes were designed based on conserved regions. Multiple primer-probe sets were tested against multiple ICV strains.
RESULTS - The ICV M and NP genes offered the most conserved sequence regions. Primers and probes based on newer sequence data offered enhanced detection of ICV, especially for low titer specimens. An NP-targeted assay yielded the best performance and was capable of detecting 10-100 RNA copies per reaction. The NP assay detected multiple clinical isolates of ICV collected in a field epidemiology study conducted in Peru.
CONCLUSIONS - We report a new real-time RT-PCR assay for ICV with high sensitivity and specificity.
Copyright © 2017 Elsevier B.V. All rights reserved.
Adjuvants enhance immunity elicited by vaccines through mechanisms that are poorly understood. Using a systems biology approach, we investigated temporal protein expression changes in five primary human immune cell populations: neutrophils, monocytes, natural killer cells, T cells, and B cells after administration of either an Adjuvant System 03 adjuvanted or unadjuvanted split-virus H5N1 influenza vaccine. Monocytes demonstrated the strongest differential signal between vaccine groups. On day 3 post-vaccination, several antigen presentation-related pathways, including MHC class I-mediated antigen processing and presentation, were enriched in monocytes and neutrophils and expression of HLA class I proteins was increased in the Adjuvant System 03 group. We identified several protein families whose proteomic responses predicted seroprotective antibody responses (>1:40 hemagglutination inhibition titer), including inflammation and oxidative stress proteins at day 1 as well as immunoproteasome subunit (PSME1 and PSME2) and HLA class I proteins at day 3 in monocytes. While comparison between temporal proteomic and transcriptomic results showed little overlap overall, enrichment of the MHC class I antigen processing and presentation pathway in monocytes and neutrophils was confirmed by both approaches.
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Glands in frog skin secrete substances that possess broad antimicrobial function. Holthausen et al. mined this soup of natural products and discovered a peptide that destroys diverse human influenza strains (Holthausen et al., 2017). This study points the way to the discovery of novel anti-influenza molecules targeting conserved elements on influenza surface proteins.
Copyright © 2017 Elsevier Inc. All rights reserved.
BACKGROUND - Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.
OBJECTIVE AND METHODS - We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.
RESULTS - Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.
CONCLUSIONS - Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.
TRIAL REGISTRATION - ClinicalTrials.gov NCT01573312.
IMPORTANCE - Few studies have evaluated the relationship between influenza vaccination and pneumonia, a serious complication of influenza infection.
OBJECTIVE - To assess the association between influenza vaccination status and hospitalization for community-acquired laboratory-confirmed influenza pneumonia.
DESIGN, SETTING, AND PARTICIPANTS - The Etiology of Pneumonia in the Community (EPIC) study was a prospective observational multicenter study of hospitalizations for community-acquired pneumonia conducted from January 2010 through June 2012 at 4 US sites. In this case-control study, we used EPIC data from patients 6 months or older with laboratory-confirmed influenza infection and verified vaccination status during the influenza seasons and excluded patients with recent hospitalization, from chronic care residential facilities, and with severe immunosuppression. Logistic regression was used to calculate odds ratios, comparing the odds of vaccination between influenza-positive (case) and influenza-negative (control) patients with pneumonia, controlling for demographics, comorbidities, season, study site, and timing of disease onset. Vaccine effectiveness was estimated as (1 - adjusted odds ratio) × 100%.
EXPOSURE - Influenza vaccination, verified through record review.
MAIN OUTCOMES AND MEASURES - Influenza pneumonia, confirmed by real-time reverse-transcription polymerase chain reaction performed on nasal/oropharyngeal swabs.
RESULTS - Overall, 2767 patients hospitalized for pneumonia were eligible for the study; 162 (5.9%) had laboratory-confirmed influenza. Twenty-eight of 162 cases (17%) with influenza-associated pneumonia and 766 of 2605 controls (29%) with influenza-negative pneumonia had been vaccinated. The adjusted odds ratio of prior influenza vaccination between cases and controls was 0.43 (95% CI, 0.28-0.68; estimated vaccine effectiveness, 56.7%; 95% CI, 31.9%-72.5%).
CONCLUSIONS AND RELEVANCE - Among children and adults hospitalized with community-acquired pneumonia, those with laboratory-confirmed influenza-associated pneumonia, compared with those with pneumonia not associated with influenza, had lower odds of having received influenza vaccination.
Antigenic drift of circulating seasonal influenza viruses necessitates an international vaccine effort to reduce the impact on human health. A critical feature of the seasonal vaccine is that it stimulates an already primed immune system to diversify memory B cells to recognize closely related, but antigenically distinct, influenza glycoproteins (hemagglutinins). Influenza pandemics arise when hemagglutinins to which no preexisting adaptive immunity exists acquire the capacity to infect humans. Hemagglutinin 5 is one subtype to which little preexisting immunity exists and is only a few acquired mutations away from the ability to transmit efficiently between ferrets, and possibly humans. Here, we describe the structure and molecular mechanism of neutralization by H5.3, a vaccine-elicited antibody that neutralizes hemagglutinin 5 viruses and variants with expanded host range. H5.3 binds in the receptor-binding site, forming contacts that recapitulate many of the sialic acid interactions, as well as multiple peripheral interactions, yet is not sensitive to mutations that alter sialic acid binding. H5.3 is highly specific for a subset of H5 strains, and this specificity arises from interactions to the periphery of the receptor-binding site. H5.3 is also extremely potent, despite retaining germ line-like conformational flexibility.
A complex interplay of viral, host, and ecological factors shapes the spatio-temporal incidence and evolution of human influenza viruses. Although considerable attention has been paid to influenza A viruses, a lack of equivalent data means that an integrated evolutionary and epidemiological framework has until now not been available for influenza B viruses, despite their significant disease burden. Through the analysis of over 900 full genomes from an epidemiological collection of more than 26,000 strains from Australia and New Zealand, we reveal fundamental differences in the phylodynamics of the two co-circulating lineages of influenza B virus (Victoria and Yamagata), showing that their individual dynamics are determined by a complex relationship between virus transmission, age of infection, and receptor binding preference. In sum, this work identifies new factors that are important determinants of influenza B evolution and epidemiology.
BACKGROUND AND OBJECTIVES - In the United States, recommendations for annual influenza vaccination gradually expanded from 2004 to 2008, to include all children aged ≥6 months. The effects of these policies on vaccine uptake and influenza-associated health care encounters are unclear. The objectives of the study were to examine the annual incidence of influenza-related health care encounters and vaccine uptake among children age 6 to 59 months from 2000-2001 through 2010-2011 in Davidson County, TN.
METHODS - We estimated the proportion of laboratory-confirmed influenza-related hospitalizations and emergency department (ED) visits by enrolling and testing children with acute respiratory illness or fever. We estimated influenza-related health care encounters by multiplying these proportions by the number of acute respiratory illness/fever hospitalizations and ED visits for county residents. We assessed temporal trends in vaccination coverage, and influenza-associated hospitalizations and ED visit rates.
RESULTS - The proportion of fully vaccinated children increased from 6% in 2000-2001 to 38% in 2010-2011 (P < .05). Influenza-related hospitalizations ranged from 1.9 to 16.0 per 10 000 children (median 4.5) per year. Influenza-related ED visits ranged from 89 to 620 per 10 000 children (median 143) per year. Significant decreases in hospitalizations (P < .05) and increases in ED visits (P < .05) over time were not clearly related to vaccination trends. Influenza-related encounters were greater when influenza A(H3N2) circulated than during other years with median rates of 8.2 vs 3.2 hospitalizations and 307 vs 143 ED visits per 10 000 children, respectively.
CONCLUSIONS - Influenza vaccination increased over time; however, the proportion of fully vaccinated children remained <50%. Influenza was associated with a substantial illness burden particularly when influenza A(H3N2) predominated.
Copyright © 2015 by the American Academy of Pediatrics.