A5055980052- Influenza Virus Research Studies
- Respiratory viral infections research
- Immune Response and Inflammation
- SARS-CoV-2 and COVID-19 Research
- Viral gastroenteritis research and epidemiology
- Immunotherapy and Immune Responses
- Animal Disease Management and Epidemiology
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- T-cell and B-cell Immunology
- Animal Virus Infections Studies
- Neuroscience of respiration and sleep
- Neuropeptides and Animal Physiology
- RNA and protein synthesis mechanisms
- Receptor Mechanisms and Signaling
University of Pennsylvania
2016-2022
California University of Pennsylvania
2019
The Wistar Institute
2014-2017
Significance The majority of influenza vaccine antigens are prepared in chicken eggs. Human strains grown eggs often possess adaptive mutations that increase viral attachment to cells. Most these the hemagglutinin protein, which functions as a factor. Here, we identify mutation current egg-adapted H3N2 strain alters antigenicity. We show ferrets and humans exposed produce antibodies poorly neutralize viruses circulated during 2016–2017 season. These studies highlight challenges associated...
T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh GC cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional,...
Abstract Currently available influenza virus vaccines have inadequate effectiveness and are reformulated annually due to viral antigenic drift. Thus, development of a vaccine that confers long-term protective immunity against antigenically distant strains is urgently needed. The highly conserved hemagglutinin (HA) stalk represents one the potential targets broadly protective/universal vaccines. Here, we evaluate potent candidate uses nucleoside-modified purified mRNA encoding full-length HA...
Significance Influenza viruses typically cause a higher disease burden in children and the elderly, who have weaker immune systems. During 2013–2014 influenza season, H1N1 caused an unusually high level of middle-aged adults. Here, we show that recent strains possess mutation allows to avoid responses elicited We current vaccine elicit are predicted be less effective some suggest new viral should incorporated into seasonal vaccines so proper immunity is all humans, regardless age...
Seasonal influenza vaccines offer little protection against pandemic virus strains. It is difficult to create effective prepandemic because it uncertain which subtype will cause the next pandemic. In this work, we developed a nucleoside-modified messenger RNA (mRNA)-lipid nanoparticle vaccine encoding hemagglutinin antigens from all 20 known A subtypes and B lineages. This multivalent elicited high levels of cross-reactive subtype-specific antibodies in mice ferrets that reacted encoded...
Influenza vaccines must be updated regularly because influenza viruses continuously acquire mutations in antibody binding sites of hemagglutinin (HA). The majority H3N2 strains circulating the Northern Hemisphere during 2014–2015 season are antigenically mismatched to A/Texas/50/2012 vaccine strain. Recent possess several new HA mutations, and it is unknown which these contribute mismatch. Here, we use reverse genetics demonstrate that antigenic site B primarily responsible for current Sera...
T follicular helper (Tfh) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population cells, termed cTfh, have similarity to lymphoid Tfh, can provide help, and responded influenza vaccination. However, it is unclear whether human vaccination-induced cTfh respond in an antigen-specific manner they form long-lasting memory. Here, we identified a that expressed multiple activation markers could be readily by coexpression ICOS CD38. This subset more...
During the 2013-2014 influenza season, nearly all circulating 2009 pandemic A(H1N1) virus (A[H1N1]pdm09) strains possessed an antigenically important mutation in hemagglutinin (K166Q). Here, we performed hemagglutination-inhibition (HAI) assays, using sera collected from 382 individuals prior to and determined whether HAI titers were associated with protection A(H1N1)pdm09 infection. Protection was against strain possessing K166Q but not current vaccine strain, which lacks this mutation....
Influenza vaccination aims to prevent infection by influenza virus and reduce associated morbidity mortality; however, vaccine effectiveness (VE) can be modest, especially for subtype A(H3N2). Low VE has been attributed mismatches between the circulating strains vaccine's elicitation of protective immunity in only a subset population. The low H3N2 2012-2013 season was egg-adaptive mutations that created antigenic mismatch actual strain (IVR-165) both intended (A/Victoria/361/2011)...
Unlike conventional influenza vaccines, mRNA vaccination partially overcomes maternal antibody inhibition of de novo immune responses in infant mice.
The H3N2 component of egg-based 2017-2018 influenza vaccines possessed an adaptive substitution that alters antigenicity. Several include antigens are produced through alternative systems, but a systematic comparison different used during the season has not been completed.We compared antibody responses in humans vaccinated with Fluzone (egg-based, n = 23), High-Dose 16), Flublok (recombinant protein-based, or Flucelvax (cell-based, 23) season. We completed neutralization assays using...
Antibodies targeting the receptor binding site (RBS) of influenza virus hemagglutinin (HA) protein are usually not broadly reactive because their footprints typically large and extend to nearby variable HA residues. Here, we identify several human H3N2 RBS-targeting monoclonal antibodies (mAbs) that sensitive substitutions in conventional antigenic sites therefore reactive. However, also an mAb is exceptionally despite being residues outside RBS. We show similar present at measurable levels...
Acute respiratory tract viral infections (ARTIs) cause significant morbidity and mortality. CD8 T cells are fundamental to host responses, but transcriptional alterations underlying anti-viral mechanisms links clinical characteristics remain unclear. cell circuitry in acutely ill pediatric patients with influenza-like illness was distinct for different pathogens. Although changes included expected upregulation of interferon-stimulated genes (ISGs), downregulation prominent upon exposure...
Most human influenza vaccine antigens are produced in fertilized chicken eggs. Recent H3N2 egg-based have limited effectiveness, partially due to egg-adaptive substitutions that alter the antigenicity of hemagglutinin (HA) protein. The nucleoside-modified mRNA encapsulated lipid nanoparticles (mRNA-LNP) platform is a promising alternative for vaccines because mRNA-LNP-derived not subject adaptive pressures arise during production Here, we compared H3N2-specific antibody responses mice...
SUMMARY Antibodies targeting the receptor binding site (RBS) of influenza virus hemagglutinin (HA) protein are usually not broadly-reactive because their footprints typically large and extend to nearby variable HA residues. Here, we identified several human H3N2 RBS-targeting monoclonal antibodies (mAbs) that were sensitive substitutions in conventional antigenic sites broadly-reactive. However, also one mAb was exceptionally broadly reactive despite being residues outside RBS. We determined...
Abstract Background Influenza vaccination aims to prevent infection by influenza virus and reduce associated morbidity mortality; however, vaccine effectiveness (VE) can be modest, especially for subtype A/H3N2. Failure achieve consistently high VE has been attributed both mismatches between the circulating strains vaccine's elicitation of protective immunity in only a subset population. The low H3N2 2012-13 was egg-adaptive mutations that created antigenic mismatch intended...
ABSTRACT Most human influenza vaccine antigens are produced in fertilized chicken eggs. Recent H3N2 egg-based have limited effectiveness, partially due to egg-adaptive substitutions that alter the antigenicity of hemagglutinin (HA) protein. The nucleoside-modified messenger RNA encapsulated lipid nanoparticle (mRNA-LNP) platform is a promising alternative for vaccines because mRNA-LNP-derived not subject adaptive pressures arise during production Here, we compared H3N2-specific antibody...
Antibodies targeting the receptor binding site (RBS) of influenza virus hemagglutinin (HA) protein are usually not broadly-reactive because their footprints typically large and extend to nearby variable HA residues. Here, we identified several human H3N2 RBS-targeting monoclonal antibodies (mAbs) that were sensitive substitutions in conventional antigenic sites broadly-reactive. However, also one mAb was exceptionally broadly reactive despite being residues outside RBS. We determined similar...