scholarly journals Influenza H1 Mosaic Hemagglutinin Vaccine Induces Broad Immunity and Protection in Mice

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 195 ◽  
Author(s):  
Brigette N. Corder ◽  
Brianna L. Bullard ◽  
Jennifer L. DeBeauchamp ◽  
Natalia A. Ilyushina ◽  
Richard J. Webby ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza Vaccine ◽  
Protective Immunity ◽  
Influenza A ◽  
T Cell Responses ◽  
Antibody Responses ◽  
T Cell Epitopes ◽  
Wild Type ◽  
Cell Responses ◽  
Universal Influenza Vaccine

Annually, influenza A virus (IAV) infects ~5–10% of adults and 20–30% of children worldwide. The primary resource to protect against infection is by vaccination. However, vaccination only induces strain-specific and transient immunity. Vaccine strategies that induce cross-protective immunity against the broad diversity of IAV are needed. Here we developed and tested a novel mosaic H1 HA immunogen. The mosaic immunogen was optimized in silico to include the most potential B and T cell epitopes (PBTE) across a diverse population of human H1 IAV. Phylogenetic analysis showed that the mosaic HA localizes towards the non-pandemic 2009 strains which encompasses the broadest diversity in the H1 IAV population. We compared the mosaic H1 immunogen to wild-type HA immunogens and the commercial inactivated influenza vaccine, Fluzone. When analyzed by ELISA, the mosaic immunogen induced stronger antibody responses against all four diverse H1 HA proteins. When analyzing T cell responses, again the mosaic immunogen induced stronger cellular immunity against all 4 diverse HA strains. Not only was the magnitude of T cell responses strongest in mosaic immunized mice, the number of epitopes recognized was also greater. The mosaic vaccinated mice showed strong cross-protection against challenges with three divergent IAV strains. These data show that the mosaic immunogen induces strong cross-protective immunity and should be investigated further as a universal influenza vaccine.

scholarly journals Protection against Vaccinia Virus Challenge by CD8 Memory T Cells Resolved by Molecular Mimicry

2006 ◽  
Vol 81 (2) ◽  
pp. 934-944 ◽  
Author(s):  
Markus Cornberg ◽  
Brian S. Sheridan ◽  
Frances M. Saccoccio ◽  
Michael A. Brehm ◽  
Liisa K. Selin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Molecular Mimicry ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitopes ◽  
Cell Responses

ABSTRACT Live vaccinia virus (VV) vaccination has been highly successful in eradicating smallpox. However, the mechanisms of immunity involved in mediating this protective effect are still poorly understood, and the roles of CD8 T-cell responses in primary and secondary VV infections are not clearly identified. By applying the concept of molecular mimicry to identify potential CD8 T-cell epitopes that stimulate cross-reactive T cells specific to lymphocytic choriomeningitis virus (LCMV) and VV, we identified after screening only 115 peptides two VV-specific immunogenic epitopes that mediated protective immunity against VV. An immunodominant epitope, VV-e7r130, did not generate cross-reactive T-cell responses to LCMV, and a subdominant epitope, VV-a11r198, did generate cross-reactive responses to LCMV. Infection with VV induced strong epitope-specific responses which were stable into long-term memory and peaked at the time virus was cleared, consistent with CD8 T cells assisting in the control of VV. Two different approaches, direct adoptive transfer of VV-e7r-specific CD8 T cells and prior immunization with a VV-e7r-expressing ubiquitinated minigene, demonstrated that memory CD8 T cells alone could play a significant role in protective immunity against VV. These studies suggest that exploiting cross-reactive responses between viruses may be a useful tool to complement existing technology in predicting immunogenic epitopes to large viruses, such as VV, leading to a better understanding of the role CD8 T cells play during these viral infections.

scholarly journals Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C

2016 ◽  
Vol 90 (23) ◽  
pp. 10459-10471 ◽  
Author(s):  
Cibele M. Gaido ◽  
Shane Stone ◽  
Abha Chopra ◽  
Wayne R. Thomas ◽  
Peter N. Le Souëf ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Antibody Responses ◽  
T Cell Proliferation ◽  
T Cell Epitopes ◽  
Future Studies ◽  
Cell Responses ◽  
Asthma Exacerbations ◽  
Antibody Titers ◽  
Vp1 Capsid Protein

ABSTRACTRhinovirus (RV) species A and C are the most frequent cause of respiratory viral illness worldwide, and RV-C has been linked to more severe exacerbations of asthma in young children. Little is known about the immune responses to the different RV species, although studies comparing IgG1 antibody titers found impaired antibody responses to RV-C. Therefore, the aim of this study was to assess whether T-cell immunity to RV-C is similarly impaired. We measured T-cell proliferation to overlapping synthetic peptides covering the entire VP1 capsid protein of an RV-A and RV-C genotype for 20 healthy adult donors. Human leukocyte antigen (HLA) was typed in all the donors in order to investigate possible associations between the HLA type and RV peptide recognition. Total and specific IgG1 antibody titers to the VP1 proteins of both RV-A and RV-C were also measured to examine associations between the antibody and T-cell responses. We identified T-cell epitopes that are specific to and representative of each RV-A and RV-C species. These epitopes stimulated CD4+-specific T-cell proliferation, with similar magnitudes of response for both RV species. All the donors, independent of their HLA-DR or -DQ type, were able to recognize the immunodominant RV-A and -C regions of VP1. Furthermore, the presence or absence of specific antibody titers was not related to changes in T-cell recognition. Our results indicate a dissociation between the antibody and T-cell responses to rhinoviruses. The species-representative T-cell epitopes identified in this study are valuable tools for future studies investigating T-cell responses to the different RV species.IMPORTANCERhinoviruses (RVs) are mostly associated with the common cold and asthma exacerbations, although their contributions to most upper and lower respiratory tract diseases have increasingly been reported. Species C (RV-C) has been associated with more frequent and severe asthma exacerbations in young children and, along with RV-A, is the most clinically relevant species. Little is known about how our immune system responds to rhinoviruses, and there are limited tools to study specific adaptive immunity against each rhinovirus species. In this study, we identified immunodominant T-cell epitopes of the VP1 proteins of RV-A and RV-C, which are representative of each species. The study found that T-cell responses to RV-A and RV-C were of similar magnitudes, in contrast with previous findings showing RV-C-specific antibody responses were low. These findings will provide the basis for future studies on the immune response to rhinoviruses and can help elucidate the mechanisms of severity of rhinovirus-induced infections.

Plasmodium: Mammalian codon optimization of malaria plasmid DNA vaccines enhances antibody responses but not T cell responses nor protective immunity

2009 ◽  
Vol 122 (2) ◽  
pp. 112-123 ◽  
Author(s):  
Carlota Dobaño ◽  
Martha Sedegah ◽  
William O. Rogers ◽  
Sanjai Kumar ◽  
Hong Zheng ◽  
...  
Keyword(s):  
T Cell ◽  
Plasmid Dna ◽  
Protective Immunity ◽  
Dna Vaccines ◽  
Codon Optimization ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Cell Responses

scholarly journals De Novo Generation of Escape Variant-Specific CD8+ T-Cell Responses following Cytotoxic T-Lymphocyte Escape in Chronic Human Immunodeficiency Virus Type 1 Infection

2005 ◽  
Vol 79 (20) ◽  
pp. 12952-12960 ◽  
Author(s):  
Todd M. Allen ◽  
Xu G. Yu ◽  
Elizabeth T. Kalife ◽  
Laura L. Reyor ◽  
Mathias Lichterfeld ◽  
...  
Keyword(s):  
T Cell ◽  
De Novo ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Wild Type ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) evades CD8+ T-cell responses through mutations within targeted epitopes, but little is known regarding its ability to generate de novo CD8+ T-cell responses to such mutants. Here we examined gamma interferon-positive, HIV-1-specific CD8+ T-cell responses and autologous viral sequences in an HIV-1-infected individual for more than 6 years following acute infection. Fourteen optimal HIV-1 T-cell epitopes were targeted by CD8+ T cells, four of which underwent mutation associated with dramatic loss of the original CD8+ response. However, following the G357S escape in the HLA-A11-restricted Gag349-359 epitope and the decline of wild-type-specific CD8+ T-cell responses, a novel CD8+ T-cell response equal in magnitude to the original response was generated against the variant epitope. CD8+ T cells targeting the variant epitope did not exhibit cross-reactivity against the wild-type epitope but rather utilized a distinct T-cell receptor Vβ repertoire. Additional studies of chronically HIV-1-infected individuals expressing HLA-A11 demonstrated that the majority of the subjects targeted the G357S escape variant of the Gag349-359 epitope, while the wild-type consensus sequence was significantly less frequently recognized. These data demonstrate that de novo responses against escape variants of CD8+ T-cell epitopes can be generated in chronic HIV-1 infection and provide the rationale for developing vaccines to induce CD8+ T-cell responses directed against both the wild-type and variant forms of CD8 epitopes to prevent the emergence of cytotoxic T-lymphocyte escape variants.

scholarly journals Screening HLA-A-restricted T cell epitopes of SARS-CoV-2 and the induction of CD8+ T cell responses in HLA-A transgenic mice

2021 ◽  
Author(s):  
Xiaoxiao Jin ◽  
Yan Ding ◽  
Shihui Sun ◽  
Xinyi Wang ◽  
Zining Zhou ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
T Cell Responses ◽  
Poly I:C ◽  
T Cell Epitopes ◽  
Wild Type ◽  
Cell Responses ◽  
Asian Populations ◽  
Donor Pbmcs

AbstractSince severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific T cells have been found to play essential roles in host immune protection and pathology in patients with coronavirus disease 2019 (COVID-19), this study focused on the functional validation of T cell epitopes and the development of vaccines that induce specific T cell responses. A total of 120 CD8+ T cell epitopes from the E, M, N, S, and RdRp proteins were functionally validated. Among these, 110, 15, 6, 14, and 12 epitopes were highly homologous with SARS-CoV, OC43, NL63, HKU1, and 229E, respectively; in addition, four epitopes from the S protein displayed one amino acid that was distinct from the current SARS-CoV-2 variants. Then, 31 epitopes restricted by the HLA-A2 molecule were used to generate peptide cocktail vaccines in combination with Poly(I:C), R848 or poly (lactic-co-glycolic acid) nanoparticles, and these vaccines elicited robust and specific CD8+ T cell responses in HLA-A2/DR1 transgenic mice as well as wild-type mice. In contrast to previous research, this study established a modified DC-peptide-PBL cell coculture system using healthy donor PBMCs to validate the in silico predicted epitopes, provided an epitope library restricted by nine of the most prevalent HLA-A allotypes covering broad Asian populations, and identified the HLA-A restrictions of these validated epitopes using competitive peptide binding experiments with HMy2.CIR cell lines expressing the indicated HLA-A allotype, which initially confirmed the in vivo feasibility of 9- or 10-mer peptide cocktail vaccines against SARS-CoV-2. These data will facilitate the design and development of vaccines that induce antiviral CD8+ T cell responses in COVID-19 patients.

scholarly journals CCR2 Regulates Vaccine-Induced Mucosal T cell Memory to Influenza A Virus

2021 ◽  
Author(s):  
M Suresh ◽  
Woojong Lee ◽  
Brock Kingstad-Bakke ◽  
Ross Kedl ◽  
Yoshihiro Kawaoka
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A Virus ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Influenza A ◽  
T Cell Responses ◽  
Viral Pathogens ◽  
Memory Cd8 T Cells ◽  
Cell Responses

Elicitation of lung tissue-resident memory CD8 T cells (TRMs) is a goal of T-cell based vaccines against respiratory viral pathogens such as influenza A virus (IAV). Chemokine receptor 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 TRMs in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (TC1/TC17/TH1/TH17) IAV nucleoprotein-specific lung TRMs, to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced TRM development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional dendrtitic cells (DCs) and monocyte-derived DCs internalized and processed vaccine antigen in lungs. We also found that Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF-3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127HI/KLRG-1LO, OX40+veCD62L+ve and mucosally imprinted CD69+veCD103+ve effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung TRMs, induced by CCR2 deficiency was linked to dampened expression of T-bet, but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1/T17 functional programming, parenchymal localization of CD8/CD4 effector and memory T cells, recall T cell responses and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced TRMs. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens including IAV and SARS-CoV-2.

scholarly journals CD4 T-Cell Epitopes Associated with Protective Immunity Induced following Vaccination of Mice with an Ehrlichial Variable Outer Membrane Protein

2007 ◽  
Vol 75 (11) ◽  
pp. 5453-5459 ◽  
Author(s):  
Bisweswar Nandi ◽  
Kathryn Hogle ◽  
Nicholas Vitko ◽  
Gary M. Winslow
Keyword(s):  
T Cell ◽  
Outer Membrane ◽  
Protective Immunity ◽  
Outer Membrane Proteins ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
T Cell Epitopes ◽  
Heterologous Immunity ◽  
Cell Responses ◽  
Ifn Γ

ABSTRACT The ehrlichiae express variable outer membrane proteins (OMPs) that play important roles in both pathogenesis and host defense. Previous studies revealed that OMPs are immunodominant B-cell antigens and that passive transfer of anti-OMP antibodies can protect SCID mice from fatal ehrlichial infection. In this study, we used a model of fatal monocytotropic ehrlichiosis caused by Ehrlichia bacteria from Ixodes ovatus (IOE) to determine whether OMP immunization could generate protective immunity in immunocompetent mice. Immunization of C57BL/6 mice with a purified recombinant OMP expressed by IOE omp19 generated protection from fatal IOE infection and elicited robust humoral and CD4 T-cell responses. To identify CD4 T-cell epitopes within OMPs, we performed enzyme-linked immunospot analyses for gamma interferon (IFN-γ) production using a panel of overlapping 16-mer peptides from IOE OMP-19. Five immunoreactive peptides comprising residues 30 to 45, 77 to 92, 107 to 122, 197 to 212, and 247 to 264 were identified; the strongest response was generated against OMP-19107-122. Most of the peptides are conserved between E. muris and E. chaffeensis OMP-19, and they elicited IFN-γ production in CD4 T cells from E. muris-infected mice, indicating that T-cell epitope cross-reactivity likely contributes to heterologous immunity. Accordingly, CD4 T-cell responses to both OMP-19 and OMP-19107-122 were of greater magnitude following high-dose IOE challenge of mice that had been immunized by prior infection with E. muris. Our studies cumulatively identify B- and T-cell epitopes that are associated with protective homologous and heterologous immunity during ehrlichial infection.

scholarly journals Differential kinetics of T cell and antibody responses delineate dominant T cell epitopes in long-term immunity after COVID-19

2020 ◽  
Author(s):  
Tatjana Bilich ◽  
Annika Nelde ◽  
Jonas S. Heitmann ◽  
Yacine Maringer ◽  
Malte Roerden ◽  
...  
Keyword(s):  
T Cell ◽  
Herd Immunity ◽  
T Cell Responses ◽  
Antibody Responses ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Cell Diversity ◽  
Antibody Titers ◽  
Kinetics Of

Abstract Long-term immunity to SARS-CoV-2 is crucial for the development of herd immunity and the aim of vaccination approaches. Reports on rapidly decreasing antibody titers question the efficacy of humoral immunity. The relevance of T cell memory after COVID-19 is yet unclear. Longitudinal analysis of SARS-CoV-2 immunity in convalescents up to six months post-infection revealed decreasing and stable spike and nucleocapsid antibody responses, respectively. In contrast, T cell responses remained robust and even increased in frequency and intensity. Single epitope mapping of T cell diversity over time identified ORF-independent, dominant T cell epitopes mediating long-term SARS-CoV-2 T cell responses and may be fundamental for vaccine design.

scholarly journals Recombinant Live Attenuated Influenza Vaccine Viruses Carrying Conserved T Cell Epitopes of Human Adenoviruses Induce Functional Cytotoxic T Cell Responses and Protect Mice against both Infections

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 196 ◽  
Author(s):  
Irina Isakova-Sivak ◽  
Victoria Matyushenko ◽  
Ekaterina Stepanova ◽  
Anastasia Matushkina ◽  
Tatiana Kotomina ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza Vaccine ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
T Cell Epitopes ◽  
Human Adenoviruses ◽  
Cell Responses ◽  
Live Attenuated Influenza Vaccine

Human adenoviruses (AdVs) are one of the most common causes of acute respiratory viral infections worldwide. Multiple AdV serotypes with low cross-reactivity circulate in the human population, making the development of an effective vaccine very challenging. In the current study, we designed a cross-reactive AdV vaccine based on the T-cell epitopes conserved among various AdV serotypes, which were inserted into the genome of a licensed cold-adapted live attenuated influenza vaccine (LAIV) backbone. We rescued two recombinant LAIV-AdV vaccines by inserting the selected AdV T-cell epitopes into the open reading frame of full-length NA and truncated the NS1 proteins of the H7N9 LAIV virus. We then tested the bivalent vaccines for their efficacy against influenza and human AdV5 in a mouse model. The vaccine viruses were attenuated in C57BL/6J mice and induced a strong influenza-specific antibody and cell-mediated immunity, fully protecting the mice against virulent influenza virus infection. The CD8 T-cell responses induced by both LAIV-AdV candidates were functional and efficiently killed the target cells loaded either with influenza NP366 or AdV DBP418 peptides. In addition, high levels of recall memory T cells targeted to an immunodominant H2b-restricted CD8 T-cell epitope were detected in the immunized mice after the AdV5 challenge, and the magnitude of these responses correlated with the level of protection against pulmonary pathology caused by the AdV5 infection. Our findings suggest that the developed recombinant vaccines can be used for combined protection against influenza and human adenoviruses and warrant further evaluation on humanized animal models and subsequent human trials.

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