scholarly journals A Peptide Vaccine Candidate Tailored to Individuals' Genetics Mimics the Multi-Targeted T Cell Immunity of COVID-19 Convalescent Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Eszter Somogyi ◽  
Zsolt Csiszovszki ◽  
Levente Molnár ◽  
Orsolya Lőrincz ◽  
József Tóth ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccine Candidate ◽  
Natural Infection ◽  
Peptide Vaccine ◽  
Cell Activity ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Human Immune System ◽  
Cell Responses ◽  
Cell Immunity

Long-term immunity to coronaviruses likely stems from T cell activity. We present here a novel approach for the selection of immunoprevalent SARS-CoV-2-derived T cell epitopes using an in silico cohort of HLA-genotyped individuals with different ethnicities. Nine 30-mer peptides derived from the four major structural proteins of SARS-CoV-2 were selected and included in a peptide vaccine candidate to recapitulate the broad virus-specific T cell responses observed in natural infection. PolyPEPI-SCoV-2-specific, polyfunctional CD8+ and CD4+ T cells were detected in each of the 17 asymptomatic/mild COVID-19 convalescents' blood against on average seven different vaccine peptides. Furthermore, convalescents' complete HLA-genotype predicted their T cell responses to SARS-CoV-2-derived peptides with 84% accuracy. Computational extrapolation of this relationship to a cohort of 16,000 HLA-genotyped individuals with 16 different ethnicities suggest that PolyPEPI-SCoV-2 vaccination will likely elicit multi-antigenic T cell responses in 98% of individuals, independent of ethnicity. PolyPEPI-SCoV-2 administered with Montanide ISA 51 VG generated robust, Th1-biased CD8+, and CD4+ T cell responses against all represented proteins, as well as binding antibodies upon subcutaneous injection into BALB/c and hCD34+ transgenic mice modeling human immune system. These results have implications for the development of global, highly immunogenic, T cell-focused vaccines against various pathogens and diseases.

scholarly journals Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection

2020 ◽  
Author(s):  
Jianmin Zuo ◽  
Alex Dowell ◽  
Hayden Pearce ◽  
Kriti Verma ◽  
Heather Long ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Antibody Level ◽  
Primary Infection ◽  
Natural Infection ◽  
T Cell Responses ◽  
Symptomatic Infection ◽  
Cell Responses ◽  
Cell Immunity

Abstract The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a ‘setpoint’ for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.

scholarly journals Virus-Specific T-Cell Immunity Correlates with Control of GB Virus B Infection in Marmosets

2007 ◽  
Vol 82 (6) ◽  
pp. 3054-3060 ◽  
Author(s):  
David J. Woollard ◽  
Gholamreza Haqshenas ◽  
Xuebin Dong ◽  
Bridget F. Pratt ◽  
Stephen J. Kent ◽  
...  
Keyword(s):  
T Cell ◽  
Epitope Mapping ◽  
Small Animal ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Nonstructural Proteins ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Cell Immunity ◽  
Ifn Γ

ABSTRACT GB virus B (GBV-B) is a hepatotropic virus that is closely related to hepatitis C virus (HCV). GBV-B causes acute hepatitis in infected marmosets and tamarins and is therefore a useful small-animal model for the study of HCV. We investigated virus-specific T-cell responses in marmosets infected with GBV-B. Gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses in the peripheral blood of two marmosets were assessed throughout the course of GBV-B infection. These T-cell responses were directed against the GBV-B nonstructural proteins 3 (NS3), 4A (NS4A), and 5B (NS5B), and their appearance was temporally associated with clearance of viremia. These marmosets were then rechallenged with GBV-B at least 3 months after clearance of the primary infection to determine if the animals were protected from reinfection. There was no detectable viremia following reinfection, although a sharp increase in T-cell responses against GBV-B proteins was observed. Epitope mapping of T-cell responses to GBV-B was performed with liver and blood samples from both marmosets after rechallenge with GBV-B. Three shared, immunodominant T-cell epitopes within NS3 were identified in animals with multiple common major histocompatibility complex class I alleles. IFN-γ ELISPOT responses were also detected in the livers of two marmosets that had resolved a primary GBV-B infection. These responses were high in frequency and were directed against epitopes within GBV-B NS3, NS4A, and NS5B proteins. These results indicate that virus-specific T-cell responses are detectable in the liver and blood of GBV-B-infected marmosets and that the clearance of GBV-B is associated with the appearance of these responses.

scholarly journals Comprehensive Screening of Mouse T-Cell Epitopes in Human Herpesvirus 6B Glycoprotein H/L/Q1/Q2 Tetramer Complex

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Mie Okutani ◽  
Akiko Kawabata ◽  
Mitsuhiro Nishimura ◽  
Satoshi Nagamata ◽  
Soichiro Kuwabara ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccine Candidate ◽  
Human Herpesvirus ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Dna Encoding ◽  
Cell Responses ◽  
Exanthem Subitum ◽  
Complex Protein ◽  
Tetrameric Complex

Human herpesvirus 6 (HHV-6) infects over 90% of people. The HHV-6 subtype, HHV-6B in particular, is often associated with exanthem subitum in early childhood. Exanthem subitum is usually self-limiting and good prognosis disease; however, some infants primarily infected with HHV-6B develop encephalitis/encephalopathy, and half of the patients developed encephalopathy reported to have neurological sequelae. Furthermore, after primary infection, HHV-6B remains in a latent state and sometimes reactivated in immunosuppressed patients, causing life-threatening severe encephalopathy. However, effective immunotherapies or vaccines for controlling HHV-6B infection and reactivation have not yet been established. Recently, we have found that the HHV-6B tetrameric glycoprotein (g) complex, gH/gL/gQ1/gQ2 is a promising vaccine candidate, and currently under preclinical development. To confirm our vaccine candidate protein complex induce detectable T-cell responses, in this study, we comprehensively screened CD4+ and CD8+ T-cell epitopes in the gH/gL/gQ1/gQ2 tetrameric complex protein in mice immunisation model. Both BALB/c and C57BL/6 mice were immunised with the tetrameric complex protein or plasmid DNA encoding gH, gL, gQ1, and gQ2, and then restimulated with 162 20-mer peptides covering the whole gH/gL/gQ1/gQ2 sequences; multiple CD4+ and CD8+ T-cell-stimulating peptides were identified in both BALB/c and C57BL/6 mice. Our study demonstrates that gH/gL/gQ1/gQ2 tetramer-targeted vaccination has potential to induce T-cell responses in two different strains of mice and supports the future development and application of T-cell-inducing vaccine and immunotherapies against HHV-6B.

scholarly journals Phase I Trial of a Multi-Peptide COVID-19 Vaccine for the Induction of SARS-CoV-2 T-Cell Immunity

2021 ◽  
Author(s):  
Juliane Walz ◽  
Jonas Heitmann ◽  
Tatjana Bilich ◽  
Claudia Tandler ◽  
Annika Nelde ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Phase I ◽  
T Cell Responses ◽  
T Cell Response ◽  
T Cell Immunity ◽  
T Cell Epitopes ◽  
Serious Adverse Events ◽  
Cell Responses ◽  
Cell Immunity

Abstract T-cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T-cell epitopes derived from various viral proteins, combined with the toll-like receptor 1/2 agonist XS15 emulsified in MontanideTM ISA51 VG, aiming to induce superior SARS-CoV-2 T-cell immunity to combat COVID-19. We conducted a Phase I open-label trial, including 36 participants aged 18 to 80 years, who received one single subcutaneous CoVAC-1 vaccination. The primary endpoint was safety analyzed until day 56. Immunogenicity in terms of CoVac-1-induced T-cell response was analyzed as main secondary endpoint until day 28. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study subjects, while systemic reactogenicity was absent or mild. SARS-CoV-2-specific T-cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T-helper 1 CD4+ and CD8+ T cells. CoVac-1-induced interferon-γ T-cell responses by far surpassed those detected in COVID-19 convalescents and were unaffected by current SARS-CoV-2 variants of concern (VOC). Together, CoVac-1 showed a favorable safety profile and induced broad, potent, and VOC-independent T-cell responses, supporting the presently ongoing evaluation in a Phase II trial for patients with B-cell/antibody deficiency. Funded by the Ministry of Science, Research and the Arts Baden-Württemberg, Germany; ClinicalTrials.gov number, NCT04546841.

scholarly journals Quantitation of CD8+ T Cell Responses to Newly Identified HLA-A*0201–restricted T Cell Epitopes Conserved Among Vaccinia and Variola (Smallpox) Viruses

2003 ◽  
Vol 197 (7) ◽  
pp. 927-932 ◽  
Author(s):  
Masanori Terajima ◽  
John Cruz ◽  
Gregory Raines ◽  
Elizabeth D. Kilpatrick ◽  
Jeffrey S. Kennedy ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccinia Virus ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitopes ◽  
Primary Immunization ◽  
Cell Responses ◽  
Human T Cell ◽  
Cell Immunity ◽  
Ifn Γ

Immunization with vaccinia virus resulted in long-lasting protection against smallpox and was the approach used to eliminate natural smallpox infections worldwide. Due to the concern about the potential use of smallpox virus as a bioweapon, smallpox vaccination is currently being reintroduced. Severe complications from vaccination were associated with congenital or acquired T cell deficiencies, but not with congenital agammaglobulinemia, suggesting the importance of T cell immunity in recovery from infection. In this report, we identified two CD8+ T cell epitopes restricted by the most common human major histocompatibility complex (MHC) class I allele, HLA-A*0201. Both epitopes are highly conserved in vaccinia and variola viruses. The frequency of vaccinia-specific CD8+ T cell responses to these epitopes measured by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay and HLA/peptide tetramer staining peaked 2 wk after primary immunization and then declined, but were still detectable 1 to 3 yr after primary immunization. 2 wk after immunization, IFN-γ–producing cells specific to these two epitopes were 14% of total vaccinia virus-specific IFN-γ–producing cells in one donor, 35% in the second donor, and 6% in the third donor. This information will be useful for studies of human T cell memory and for the design and analyses of the immunogenicity of experimental vaccinia vaccines.

scholarly journals Immunogenicity and Efficacy of a Novel Multi-Antigenic Peptide Vaccine Based on Cross-Reactivity between Feline and Human Immunodeficiency Viruses

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 136 ◽  
Author(s):  
Bikash Sahay ◽  
Alek Aranyos ◽  
Meerambika Mishra ◽  
Andrew McAvoy ◽  
Marcus Martin ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Peptide Vaccine ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Cell Immunity ◽  
Evolutionarily Conserved ◽  
Human Immunodeficiency Viruses ◽  
Hiv 1

For the development of an effective HIV-1 vaccine, evolutionarily conserved epitopes between feline and human immunodeficiency viruses (FIV and HIV-1) were determined by analyzing overlapping peptides from retroviral genomes that induced both anti-FIV/HIV T cell-immunity in the peripheral blood mononuclear cells from the FIV-vaccinated cats and the HIV-infected humans. The conserved T-cell epitopes on p24 and reverse transcriptase were selected based on their robust FIV/HIV-specific CD8+ cytotoxic T lymphocyte (CTL), CD4+ CTL, and polyfunctional T-cell activities. Four such evolutionarily conserved epitopes were formulated into four multiple antigen peptides (MAPs), mixed with an adjuvant, to be tested as FIV vaccine in cats. The immunogenicity and protective efficacy were evaluated against a pathogenic FIV. More MAP/peptide-specific CD4+ than CD8+ T-cell responses were initially observed. By post-third vaccination, half of the MAP/peptide-specific CD8+ T-cell responses were higher or equivalent to those of CD4+ T-cell responses. Upon challenge, 15/19 (78.9%) vaccinated cats were protected, whereas 6/16 (37.5%) control cats remained uninfected, resulting in a protection rate of 66.3% preventable fraction (p = 0.0180). Thus, the selection method used to identify the protective FIV peptides should be useful in identifying protective HIV-1 peptides needed for a highly protective HIV-1 vaccine in humans.

scholarly journals Identification of Novel Candidate CD8+ T Cell Epitopes of the SARS-CoV2 with Homology to Other Seasonal Coronaviruses

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 972
Author(s):  
Pradeep Darshana Pushpakumara ◽  
Deshan Madhusanka ◽  
Saubhagya Dhanasekara ◽  
Chandima Jeewandara ◽  
Graham S. Ogg ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitopes ◽  
Conservation Analysis ◽  
Cell Responses ◽  
Immune Epitope ◽  
Cell Immunity ◽  
High Degree ◽  
Immune Epitope Database

Cross-reactive T cell immunity to seasonal coronaviruses (HCoVs) may lead to immunopathology or protection during SARS-CoV2 infection. To understand the influence of cross-reactive T cell responses, we used IEDB (Immune epitope database) and NetMHCpan (ver. 4.1) to identify candidate CD8+ T cell epitopes, restricted through HLA-A and B alleles. Conservation analysis was carried out for these epitopes with HCoVs, OC43, HKU1, and NL63. 12/18 the candidate CD8+ T cell epitopes (binding score of ≥0.90), which had a high degree of homology (>75%) with the other three HCoVs were within the NSP12 and NSP13 proteins. They were predicted to be restricted through HLA-A*2402, HLA-A*201, HLA-A*206, and HLA-B alleles B*3501. Thirty-one candidate CD8+ T cell epitopes that were specific to SARS-CoV2 virus (<25% homology with other HCoVs) were predominantly identified within the structural proteins (spike, envelop, membrane, and nucleocapsid) and the NSP1, NSP2, and NSP3. They were predominantly restricted through HLA-B*3501 (6/31), HLA-B*4001 (6/31), HLA-B*4403 (7/31), and HLA-A*2402 (8/31). It would be crucial to understand T cell responses that associate with protection, and the differences in the functionality and phenotype of epitope specific T cell responses, presented through different HLA alleles common in different geographical groups, to understand disease pathogenesis.

scholarly journals Novel Mumps Virus Epitopes Reveal Robust Cytotoxic T Cell Responses After Natural Infection but Not After Vaccination

2021 ◽  
Author(s):  
Patricia Kaaijk ◽  
Maarten Emmelot ◽  
Hugo Meiring ◽  
Cecile van Els ◽  
Jelle de Wit
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Natural Infection ◽  
T Cell Responses ◽  
Mumps Virus ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Cell Immunity ◽  
Hla Class I Molecules

Abstract Mumps is nowadays re-emerging despite vaccination. The contribution of T cell immunity to protection against mumps has not been clearly defined. Previously, we described a set of 41 peptides that were eluted from human leukocyte antigen (HLA) class I molecules of mumps virus (MuV)-infected cells. Here, we confirmed immunogenicity of five novel HLA-B*07:02- and HLA-A*01:01-restricted MuV T cell epitopes from this set of peptides. High frequencies of T cells against these five MuV epitopes could be detected ex vivo in all tested mumps patients. Moreover, these epitope-specific T cells derived from mumps patients displayed strong cytotoxic activity. In contrast, only marginal T cell responses against these novel MuV epitopes could be detected in recently vaccinated persons, corroborating earlier findings. Identifying which MuV epitopes are dominantly targeted in the mumps-specific CD8+ T- response is an important step towards better understanding in the discrepancies between natural infection or vaccination-induced cell-mediated immune protection

scholarly journals Distinguishing COVID-19 infection and vaccination history by T cell reactivity

2021 ◽  
Author(s):  
Esther Dawen Yu ◽  
Eric Wang ◽  
Emily Garrigan ◽  
Benjamin Goodwin ◽  
Aaron Sutherland ◽  
...  
Keyword(s):  
T Cell ◽  
Classification Scheme ◽  
Natural Infection ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Cell Reactivity ◽  
Original Cohort ◽  
Cell Responses ◽  
Time Post Infection ◽  
Classification Tool

SARS-CoV-2 infection and COVID-19 vaccines elicit memory T cell responses. Here, we report the development of two new pools of Experimentally-defined T cell epitopes derived from the non-spike Remainder of the SARS-CoV-2 proteome (CD4RE and CD8RE). The combination of T cell responses to these new pools and Spike (S) were used to discriminate four groups of subjects with different SARS-CoV-2 infection and COVID-19 vaccine status: non-infected, non-vaccinated (I-V-); infected and non-vaccinated (I+V-); infected and then vaccinated (I+V+); and non-infected and vaccinated (I-V+). The overall classification accuracy based on 30 subjects/group was 89.2% in the original cohort and 88.5% in a validation cohort of 96 subjects. The T cell classification scheme was applicable to different mRNA vaccines, and different lengths of time post-infection/post-vaccination. T cell responses from breakthrough infections (infected vaccinees, V+I+) were also effectively segregated from the responses of vaccinated subjects using the same classification tool system. When all five groups where combined, for a total of 239 different subjects, the classification scheme performance was 86.6%. We anticipate that a T cell-based immunodiagnostic scheme able to classify subjects based on their vaccination and natural infection history will be an important tool for longitudinal monitoring of vaccination and aid in establishing SARS-CoV-2 correlates of protection.

scholarly journals Increased Immune Response Variability during Simultaneous Viral Coinfection Leads to Unpredictability in CD8 T Cell Immunity and Pathogenesis

2015 ◽  
Vol 89 (21) ◽  
pp. 10786-10801 ◽  
Author(s):  
Laurie L. Kenney ◽  
Markus Cornberg ◽  
Alex T. Chen ◽  
Sebastien Emonet ◽  
Juan Carlos de la Torre ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
T Cell Epitopes ◽  
Cell Memory ◽  
Cell Responses ◽  
Cell Immunity ◽  
Cd8 T Cell Memory

ABSTRACTT cell memory is usually studied in the context of infection with a single pathogen in naive mice, but how memory develops during a coinfection with two pathogens, as frequently occurs in nature or after vaccination, is far less studied. Here, we questioned how the competition between immune responses to two viruses in the same naive host would influence the development of CD8 T cell memory and subsequent disease outcome upon challenge. Using two different models of coinfection, including the well-studied lymphocytic choriomeningitis (LCMV) and Pichinde (PICV) viruses, several differences were observed within the CD8 T cell responses to either virus. Compared to single-virus infection, coinfection resulted in substantial variation among mice in the size of epitope-specific T cell responses to each virus. Some mice had an overall reduced number of virus-specific cells to either one of the viruses, and other mice developed an immunodominant response to a normally subdominant, cross-reactive epitope (nucleoprotein residues 205 to 212, or NP205). These changes led to decreased protective immunity and enhanced pathology in some mice upon challenge with either of the original coinfecting viruses. In mice with PICV-dominant responses, during a high-dose challenge with LCMV clone 13, increased immunopathology was associated with a reduced number of LCMV-specific effector memory CD8 T cells. In mice with dominant cross-reactive memory responses, during challenge with PICV increased immunopathology was directly associated with these cross-reactive NP205-specific CD8 memory cells. In conclusion, the inherent competition between two simultaneous immune responses results in significant alterations in T cell immunity and subsequent disease outcome upon reexposure.IMPORTANCECombination vaccines and simultaneous administration of vaccines are necessary to accommodate required immunizations and maintain vaccination rates. Antibody responses generally correlate with protection and vaccine efficacy. However, live attenuated vaccines also induce strong CD8 T cell responses, and the impact of these cells on subsequent immunity, whether beneficial or detrimental, has seldom been studied, in part due to the lack of known T cell epitopes to vaccine viruses. We questioned if the inherent increased competition and stochasticity between two immune responses during a simultaneous coinfection would significantly alter CD8 T cell memory in a mouse model where CD8 T cell epitopes are clearly defined. We show that some of the coinfected mice have sufficiently altered memory T cell responses that they have decreased protection and enhanced immunopathology when reexposed to one of the two viruses. These data suggest that a better understanding of human T cell responses to vaccines is needed to optimize immunization strategies.

Sign in / Sign up

Export Citation Format

Share Document