Universal H1N1 influenza vaccine development

Moise, Leonard; Terry, Frances; Ardito, Matthew; Tassone, Ryan; Latimer, Howard J.; Boyle, Christine; Martin, William; Groot, Anne S. De

doi:10.4161/hv.25598

Cited by 22 publications

(8 citation statements)

References 43 publications

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“…Positive predictions were defined as epitopes in the top 5th percentile (scoring > 1.64 on the EpiMatrix z-scale) and binding HLA at any affinity. Overall, the agreement with predictions, both positive and negative was 73%, which is consistent with prior studies 24,25 . With respect to each allele assayed, the values are 55% for DRB1*0101, 64% for DRB1*0301, 45% for DRB1*0401, 64% for DRB1*0701, and 91% for DRB1*1501.…”

Section: Resultssupporting

confidence: 90%

Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice

Shattuck

Dyer

Desrosiers

et al. 2014

Human Vaccines & Immunotherapeutics

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Ticks are notorious vectors of disease for humans, and many species of ticks transmit multiple pathogens, sometimes in the same tick bite. Accordingly, a broad-spectrum vaccine that targets vector ticks and pathogen transmission at the tick/host interface, rather than multiple vaccines against every possible tickborne pathogen, could become an important tool for resolving an emerging public health crisis. The concept for such a tick protective vaccine comes from observations of an acquired tick resistance (ATR) that can develop in non-natural hosts of ticks following sensitization to tick salivary components. Mice are commonly used as models to study immune responses to human pathogens but normal mice are natural hosts for many species of ticks and fail to develop ATR. We evaluated HLA DR3 transgenic (tg) “humanized” mice as a potential model of ATR and assessed the possibility of using this animal model for tick protective vaccine discovery studies. Serial tick infestations with pathogen-free Ixodes scapularis ticks were used to tick-bite sensitize HLA DR3 tg mice. Sensitization resulted in a cytokine skew favoring a Th2 bias as well as partial (57%) protection to infection with Lyme disease spirochetes (Borrelia burgdorferi) following infected tick challenge when compared to tick naïve counterparts. I. scapularis salivary gland homogenate (SGH) and a group of immunoinformatic-predicted T cell epitopes identified from the I. scapularis salivary transcriptome were used separately to vaccinate HLA DR3 tg mice, and these mice also were assessed for both pathogen protection and epitope recognition. Reduced pathogen transmission along with a Th2 skew resulted from SGH vaccination, while no significant protection and a possible T regulatory bias was seen in epitope-vaccinated mice. This study provides the first proof-of-concept for using HLA DR tg “humanized” mice for studying the potential tick protective effects of immunoinformatic- or otherwise-derived tick salivary components as tickborne disease vaccines.

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Section: Resultssupporting

confidence: 90%

Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice

Shattuck

Dyer

Desrosiers

et al. 2014

Human Vaccines & Immunotherapeutics

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“…The retrieved sequence was parsed into overlapping 9-mer frames and screened for the presence of predicted class II restricted T cell epitopes using the EpiMatrix system 45 . ClustiMer, an algorithm used to identify short amino acid sequences containing multiple HLA binding motifs, was used to identify potential T cell epitope clusters contained within the H7 HA sequence 46 . Finally, the JanusMatrix algorithm was used to identify putative T cell epitopes contained within H7 HA which share TCR contacts with putative epitopes present in the human genome 47 .…”

Section: Methodsmentioning

confidence: 99%

A humanized mouse model identifies key amino acids for low immunogenicity of H7N9 vaccines

Wada

Nithichanon

Nobusawa

et al. 2017

Sci Rep

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Influenza vaccines of H7N9 subtype are consistently less immunogenic in humans than vaccines developed for other subtypes. Although prior immunoinformatic analysis identified T-cell epitopes in H7 hemagglutinin (HA) which potentially enhance regulatory T cell response due to conservation with the human genome, the links between the T-cell epitopes and low immunogenicity of H7 HA remains unknown due to the lack of animal models reproducing the response observed in humans. Here, we utilized a humanized mouse model to recapitulate the low immunogenicity of H7 HA. Our analysis demonstrated that modification of a single H7 epitope by changing 3 amino acids so that it is homologous with a known H3 immunogenic epitope sequence significantly improved the immunogenicity of the H7 HA in the humanized mouse model, leading to a greater than 4-fold increase in HA-binding IgG responses. Thus, we provide experimental evidence for the important contribution of this H7-specific T cell epitope in determining the immunogenicity of an influenza vaccine. Furthermore, this study delineates strategies that can be used for screening and selecting vaccine strains using immunoinformatics tools and a humanized mouse model.

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“…Figure 3B shows recent HLA binding studies for HLA class II-restricted epitopes, performed at EpiVax (published and unpublished). Additional T cell epitope and HLA binding validation studies have been published in the course of grant-funded research collaborations, describing T cell immune responses to predicted epitopes in vitro using human lymphocytes [see (4,(24)(25)(26)(27)(28)(29)(30)(31)(32)] and also in prospective, in vivo immunogenicity and vaccine efficacy studies in murine models [see (10,18,(33)(34)(35)(36)(37)(38)].…”

Section: Assessing Protein Antigens For Immunogenic Potential Using Ementioning

confidence: 99%

“…Specifically, new information on cross-conservation between pathogen T cell epitopes and the human genome (and microbiome) is emerging, and has important implications for vaccine design. For example, "memory" of cross-conserved T cell epitopes has been defined as a key contributor to the strength of protection generated by vaccines (2)(3)(4). These discoveries are coming to light through the application of new tools that examine T cell epitopes and their role in vaccines, using the power of immunoinformatics.…”

Section: Introductionmentioning

confidence: 99%

Better Epitope Discovery, Precision Immune Engineering, and Accelerated Vaccine Design Using Immunoinformatics Tools

et al. 2020

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Computational vaccinology includes epitope mapping, antigen selection, and immunogen design using computational tools. Tools that facilitate the in silico prediction of immune response to biothreats, emerging infectious diseases, and cancers can accelerate the design of novel and next generation vaccines and their delivery to the clinic. Over the past 20 years, vaccinologists, bioinformatics experts, and advanced programmers based in Providence, Rhode Island, USA have advanced the development of an integrated toolkit for vaccine design called iVAX, that is secure and user-accessible by internet. This integrated set of immunoinformatic tools comprises algorithms for scoring and triaging candidate antigens, selecting immunogenic and conserved T cell epitopes, re-engineering or eliminating regulatory T cell epitopes, and re-designing antigens to induce immunogenicity and protection against disease for humans and livestock. Commercial and academic applications of iVAX have included identifying immunogenic T cell epitopes in the development of a T-cell based human multi-epitope Q fever vaccine, designing novel influenza vaccines, identifying cross-conserved T cell epitopes for a malaria vaccine, and analyzing immune responses in clinical vaccine studies. Animal vaccine applications to date have included viral infections of pigs such as swine influenza A, PCV2, and African Swine Fever. "Rapid-Fire" applications for biodefense have included a demonstration project for Lassa Fever and Q fever. As recent infectious disease outbreaks underscore the significance of vaccine-driven preparedness, the integrated set of tools available on the iVAX toolkit stand ready to help vaccine developers deliver genome-derived, epitope-driven vaccines.

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Universal H1N1 influenza vaccine development

Cited by 22 publications

References 43 publications

Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice

Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice

A humanized mouse model identifies key amino acids for low immunogenicity of H7N9 vaccines

Better Epitope Discovery, Precision Immune Engineering, and Accelerated Vaccine Design Using Immunoinformatics Tools

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