scholarly journals Marked enhancement of neutralizing antibody and IFN-γ T-cell responses by GX-19N DNA booster in mice primed with inactivated vaccine

2021 ◽  
Author(s):  
Yong Bok Seo ◽  
Duckhyang Shin ◽  
You Suk Suh ◽  
Juyoung Na ◽  
Ji In Ryu ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Particle ◽  
Dna Vaccine ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
T Cell Response ◽  
Boost Regimen ◽  
Cell Responses ◽  
Vaccination Strategies

In response to the COVID-19 pandemic, an unprecedented level of vaccine development has occurred. As a result, various COVID-19 vaccines have been approved for use. Among these, inactivated virus particle vaccines have been widely used worldwide, but additional vaccination strategies are needed because of the short duration of immune responses elicited by these vaccines. Here, we evaluated homologous and heterologous prime-boost regimens using inactivated virus particle vaccine and GX-19N DNA vaccine for their ability to enhance the protective immune response against SARS-CoV-2. We demonstrated that a heterologous prime-boost regimen with the inactivated virus particle vaccine and GX-19N DNA vaccine resulted in enhanced SRBD- and N-specific antibody responses, compared to the homologous inactivated virus particle vaccine prime-boost vaccination. In addition, the neutralizing antibody response was significantly improved with the heterologous inactivated virus particle prime DNA boost regimen, and the neutralizing antibody induced with the heterologous prime boost regimen did not decrease against the SARS-CoV-2 variant of concern. The heterologous inactivated virus particle prime-DNA boost regimen not only significantly increased S- and N-specific IFN-g T cell responses, but also induced an equivalent level of T cell response against SARS-CoV-2 variant of concerns. Our results provide new insights into prophylactic vaccination strategies for COVID-19 vaccination.

scholarly journals Vaccination with a Shigella DNA Vaccine Vector Induces Antigen-Specific CD8+ T Cells and Antiviral Protective Immunity

2001 ◽  
Vol 75 (20) ◽  
pp. 9665-9670 ◽  
Author(s):  
Mohamed T. Shata ◽  
David M. Hone
Keyword(s):  
T Cell ◽  
Dna Vaccine ◽  
Protective Immunity ◽  
Dna Vaccines ◽  
T Cell Responses ◽  
T Cell Response ◽  
Vaccine Vector ◽  
Host Cells ◽  
Cell Responses ◽  
Hiv 1

ABSTRACT A prototype Shigella human immunodeficiency virus type 1 (HIV-1) gp120 DNA vaccine vector was constructed and evaluated for immunogenicity in a murine model. For comparative purposes, mice were also vaccinated with a vaccinia virus-env(vaccinia-env) vector or the gp120 DNA vaccine alone. Enumeration of the CD8+-T-cell responses to gp120 after vaccination using a gamma interferon enzyme-linked spot assay revealed that a single intranasal dose of the Shigella HIV-1 gp120 DNA vaccine vector elicited a CD8+ T-cell response to gp120, the magnitude of which was comparable to the sizes of the analogous responses to gp120 that developed in mice vaccinated intraperitoneally with the vaccinia-env vector or intramuscularly with the gp120 DNA vaccine. In addition, a single dose of the Shigella gp120 DNA vaccine vector afforded significant protection against a vaccinia-env challenge. Moreover, the number of vaccinia-env PFU recovered in mice vaccinated intranasally with the Shigella vector was about fivefold less than the number recovered from mice vaccinated intramuscularly with the gp120 DNA vaccine. Since theShigella vector did not express detectable levels of gp120, this report confirms that Shigella vectors are capable of delivering passenger DNA vaccines to host cells and inducing robust CD8+ T-cell responses to antigens expressed by the DNA vaccines. Furthermore, to our knowledge, this is the first documentation of antiviral protective immunity following vaccination with a live Shigella DNA vaccine vector.

scholarly journals Sustained Specific and Cross-Reactive T Cell Responses to Zika and Dengue Virus NS3 in West Africa

2018 ◽  
Vol 92 (7) ◽  
Author(s):  
Bobby Brooke Herrera ◽  
Wen-Yang Tsai ◽  
Charlotte A. Chang ◽  
Donald J. Hamel ◽  
Wei-Kung Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Dengue Virus ◽  
Zika Virus ◽  
Cell Response ◽  
Vaccine Development ◽  
T Cell Responses ◽  
T Cell Response ◽  
Zikv Infection ◽  
Cell Responses

ABSTRACT Recent studies on the role of T cells in Zika virus (ZIKV) infection have shown that T cell responses to Asian ZIKV infection are important for protection, and that previous dengue virus (DENV) exposure amplifies the protective T cell response to Asian ZIKV. Human T cell responses to African ZIKV infection, however, remain unexplored. Here, we utilized the modified anthrax toxin delivery system to develop a flavivirus enzyme-linked immunosorbent spot (ELISPOT) assay. Using human ZIKV and DENV samples from Senegal, West Africa, our results demonstrate specific and cross-reactive T cell responses to nonstructural protein 3 (NS3). Specifically, we found that T cell responses to NS3 protease are ZIKV and DENV specific, but responses to NS3 helicase are cross-reactive. Sequential sample analyses revealed immune responses sustained many years after infection. These results have important implications for African ZIKV/DENV vaccine development, as well as for potential flavivirus diagnostics based on T cell responses. IMPORTANCE The recent Zika virus (ZIKV) epidemic in Latin America and the associated congenital microcephaly and Guillain-Barré syndrome have raised questions as to why we have not recognized these distinct clinical diseases in Africa. The human immunologic response to ZIKV and related flaviviruses in Africa represents a research gap that may shed light on the mechanisms contributing to protection. The goal of our study was to develop an inexpensive assay to detect and characterize the T cell response to African ZIKV and DENV. Our data show long-term specific and cross-reactive human immune responses against African ZIKV and DENV, suggesting the usefulness of a diagnostic based on the T cell response. Additionally, we show that prior flavivirus exposure influences the magnitude of the T cell response. The identification of immune responses to African ZIKV and DENV is of relevance to vaccine development.

scholarly journals CD8 T Cell Responses to an Immunodominant Epitope within the Nonstructural Protein NS1 Provide Wide Immunoprotection against Bluetongue Virus in IFNAR−/−Mice

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Alejandro Marín-López ◽  
Eva Calvo-Pinilla ◽  
Diego Barriales ◽  
Gema Lorenzo ◽  
Alejandro Brun ◽  
...  
Keyword(s):  
T Cell ◽  
Bluetongue Virus ◽  
Neutralizing Antibodies ◽  
Nonstructural Protein ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
N Terminus

ABSTRACTThe development of vaccines against bluetongue, a prevalent livestock disease, has been focused on surface antigens that induce strong neutralizing antibody responses. Because of their antigenic variability, these vaccines are usually serotype restricted. We now show that a single highly conserved nonstructural protein, NS1, expressed in a modified vaccinia Ankara virus (MVA) vector can provide multiserotype protection in IFNAR−/−129 mice against bluetongue virus (BTV) that is largely dependent on CD8 T cell responses. We found that the protective antigenic capacity of NS1 resides within the N terminus of the protein and is provided in the absence of neutralizing antibodies. The protective CD8 T cell response requires the presence of a specific peptide within the N terminus of NS1, since its deletion ablates the efficacy of the vaccine formulation. These data reveal the importance of the nonstructural protein NS1 in CD8 T cell-mediated protection against multiple BTV serotypes when vectorized as a recombinant MVA vaccine.IMPORTANCEConventional vaccines have controlled or limited BTV expansion in the past, but they cannot address the need for cross-protection among serotypes and do not allow distinguishing between infected and vaccinated animals (DIVA strategy). There is a need to develop universal vaccines that induce effective protection against multiple BTV serotypes. In this work we have shown the importance of the nonstructural protein NS1, conserved among all the BTV serotypes, in CD8 T cell-mediated protection against multiple BTV serotypes when vectorized as a recombinant MVA vaccine.

scholarly journals T cell responses to nonstructural protein 3 distinguish infections by Dengue and Zika viruses

2018 ◽  
Author(s):  
Bobby Brooke Herrera ◽  
Wen-Yang Tsai ◽  
Carlos Brites ◽  
Estela Luz ◽  
Celia Pedroso ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Vaccine Development ◽  
Nonstructural Protein ◽  
Sequence Similarity ◽  
T Cell Responses ◽  
T Cell Response ◽  
Endemic Region ◽  
Cell Responses ◽  
Nonstructural Protein 1

ABSTRACTThe 2015-16 Zika virus (ZIKV) epidemic in the Americas and the Caribbean demonstrates that clinical assays to detect, distinguish, and characterize immune responses to flaviviral infections are needed. ZIKV and dengue virus (DENV) are mosquito-transmitted flaviviruses sharing overlapping geographical distribution and have significant sequence similarity that can increase the potential for antibody and T cell cross-reaction. Using nonstructural protein 1-based enzyme-linked immunosorbent assays (ELISAs), we determine the serostatus of individuals living in a DENV- and ZIKV-endemic region in Brazil, identifying individuals with primary DENV (pDENV) and ZIKV (pZIKV), ZIKV with primary DENV (ZIKVwpDENV), and secondary DENV (sDENV) infections; pDENV and pZIKV were further confirmed by neutralization tests. Development of an enzyme-linked immunospot (ELISPOT) assay for DENV and ZIKV structural and nonstructural (NS) protein antigens enables us to distinguish infections by these viruses based on T cells and to characterize those responses. We find that IFN-γ and TNF-α T cell responses to NS3 differentiates DENV and ZIKV infections with 94% sensitivity and 92% specificity. In general, we also show that pDENV and sDENV cases and pZIKV and ZIKVwpDENV cases elicit similar T cell response patterns, and that HIV-infected individuals have T cell responses that are lower in magnitude compared to HIV-negative individuals. These results have important implications for DENV and ZIKV diagnostic and vaccine development and provide critical insights into the T cell response in individuals with multiple flaviviral infections.

scholarly journals CD4+ T Cells Induced by a DNA Vaccine: Immunological Consequences of Epitope-Specific Lysosomal Targeting

2001 ◽  
Vol 75 (21) ◽  
pp. 10421-10430 ◽  
Author(s):  
Fernando Rodriguez ◽  
Stephanie Harkins ◽  
Jeffrey M. Redwine ◽  
Jose M. de Pereda ◽  
J. Lindsay Whitton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Vaccine ◽  
Cell Response ◽  
T Cell Responses ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Cell Responses ◽  
Lysosomal Targeting

ABSTRACT Our previous studies have shown that targeting DNA vaccine-encoded major histocompatibility complex class I epitopes to the proteasome enhanced CD8+ T-cell induction and protection against lymphocytic choriomeningitis virus (LCMV) challenge. Here, we expand these studies to evaluate CD4+ T-cell responses induced by DNA immunization and describe a system for targeting proteins and minigenes to lysosomes. Full-length proteins can be targeted to the lysosomal compartment by covalent attachment to the 20-amino-acid C-terminal tail of lysosomal integral membrane protein-II (LIMP-II). Using minigenes encoding defined T-helper epitopes from lymphocytic choriomeningitis virus, we show that the CD4+T-cell response induced by the NP309–328 epitope of LCMV was greatly enhanced by addition of the LIMP-II tail. However, the immunological consequence of lysosomal targeting is not invariably positive; the CD4+ T-cell response induced by the GP61–80 epitope was almost abolished when attached to the LIMP-II tail. We identify the mechanism which underlies this marked difference in outcome. The GP61–80 epitope is highly susceptible to cleavage by cathepsin D, an aspartic endopeptidase found almost exclusively in lysosomes. We show, using mass spectrometry, that the GP61–80 peptide is cleaved between residues F74 and K75 and that this destroys its ability to stimulate virus-specific CD4+ T cells. Thus, the immunological result of lysosomal targeting varies, depending upon the primary sequence of the encoded antigen. We analyze the effects of CD4+ T-cell priming on the virus-specific antibody and CD8+ T-cell responses which are mounted after virus infection and show that neither response appears to be accelerated or enhanced. Finally, we evaluate the protective benefits of CD4+ T-cell vaccination in the LCMV model system; in contrast to DNA vaccine-induced CD8+ T cells, which can confer solid protection against LCMV challenge, DNA vaccine-mediated priming of CD4+ T cells does not appear to enhance the vaccinee's ability to combat viral challenge.

scholarly journals Virus-Specific CD4+ and CD8+ Cytotoxic T-Cell Responses and Long-Term T-Cell Memory in Individuals Vaccinated against Polio

2005 ◽  
Vol 79 (10) ◽  
pp. 5988-5995 ◽  
Author(s):  
Rahnuma Wahid ◽  
Martin J. Cannon ◽  
Marie Chow
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses

ABSTRACT The presence of poliovirus (PV)-specific CD4+ T cells in individuals vaccinated against polio has been shown, but CD8+ T-cell responses have not been described. Here, we functionally characterize the CD4+ T-cell response and show for the first time that dendritic cells and macrophages can stimulate PV-specific CD8+ T-cell responses in vitro from vaccinees. Both CD4+ T and CD8+ T cells secrete gamma interferon in response to PV antigens and are cytotoxic via the perforin/granzyme B-mediated pathway. Furthermore, the T cells also recognize and kill Sabin 1 vaccine-infected targets. The macrophage-stimulated CD4+ T and CD8+ T cells most likely represent memory T cells that persist for long periods in vaccinated individuals. Thus, immunity to PV vaccination involves not only an effective neutralizing antibody titer but also long-term CD4+ and CD8+ cytotoxic T-cell responses.

scholarly journals Making a Cold Tumor Hot: The Role of Vaccines in the Treatment of Glioblastoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Stephen C. Frederico ◽  
John C. Hancock ◽  
Emily E. S. Brettschneider ◽  
Nivedita M. Ratnam ◽  
Mark R. Gilbert ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Immune Monitoring ◽  
T Cell Response ◽  
Cell Responses

The use of immunotherapies for the treatment of brain tumors is a topic that has garnered considerable excitement in recent years. Discoveries such as the presence of a glymphatic system and immune surveillance in the central nervous system (CNS) have shattered the theory of immune privilege and opened up the possibility of treating CNS malignancies with immunotherapies. However, despite many immunotherapy clinical trials aimed at treating glioblastoma (GBM), very few have demonstrated a significant survival benefit. Several factors for this have been identified, one of which is that GBMs are immunologically “cold,” implying that the cancer does not induce a strong T cell response. It is postulated that this is why clinical trials using an immune checkpoint inhibitor alone have not demonstrated efficacy. While it is well established that anti-cancer T cell responses can be facilitated by the presentation of tumor-specific antigens to the immune system, treatment-related death of GBM cells and subsequent release of molecules have not been shown to be sufficient to evoke an anti-tumor immune response effective enough to have a significant impact. To overcome this limitation, vaccines can be used to introduce exogenous antigens at higher concentrations to the immune system to induce strong tumor antigen-specific T cell responses. In this review, we will describe vaccination strategies that are under investigation to treat GBM; categorizing them based on their target antigens, form of antigens, vehicles used, and pairing with specific adjuvants. We will review the concept of vaccine therapy in combination with immune checkpoint inhibitors, as it is hypothesized that this approach may be more effective in overcoming the immunosuppressive milieu of GBM. Clinical trial design and the need for incorporating robust immune monitoring into future studies will also be discussed here. We believe that the integration of evolving technologies of vaccine development, delivery, and immune monitoring will further enhance the role of these therapies and will likely remain an important area of investigation for future treatment strategies for GBM patients.

scholarly journals Immunization with a Mixture of HIV Env DNA and VLP Vaccines Augments Induction of CD8 T Cell Responses

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Ling Ye ◽  
Zhiyuan Wen ◽  
Ke Dong ◽  
Lei Pan ◽  
Zhigao Bu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Dna Vaccine ◽  
Cell Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Antibody Responses ◽  
Cell Responses ◽  
Virus Like Particle

The immune response induced by immunization with HIV Env DNA and virus-like particle (VLP) vaccines was investigated. Immunization with the HIV Env DNA vaccine induced a strong CD8 T cell response but relatively weak antibody response against the HIV Env whereas immunization with VLPs induced higher levels of antibody responses but little CD8 T cell response. Interestingly, immunization with a mixture the HIV Env DNA and VLP vaccines induced enhanced CD8 T cell and antibody responses. Further, it was observed that the mixing of DNA and VLP vaccines during immunization is necessary for augmenting induction of CD8 T cell responses and such augmentation of CD8 T cell responses was also observed by mixing the HIV Env DNA vaccine with control VLPs. These results show that immunization with a mixture of DNA and VLP vaccines combines advantages of both vaccine platforms for eliciting high levels of both antibody and CD8 T cell responses.

scholarly journals Comparative analysis of human immune responses following SARS-CoV-2 vaccination with BNT162b2, mRNA-1273, or Ad26.COV2.S

2021 ◽  
Author(s):  
Dominique J. Barbeau ◽  
Judith M. Martin ◽  
Emily Carney ◽  
Emily Dougherty ◽  
Joshua D. Doyle ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Cell Response ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
T Cell Response ◽  
Virus Neutralization ◽  
Cell Responses ◽  
Humoral Responses ◽  
Prospective Longitudinal

AbstractBackgroundThree SARS-CoV-2 vaccines, two based on mRNA, BNT162b2 and mRNA-1273, and one based on an adenovirus platform, Ad26.COV2.S, received emergency use authorization by the U.S. Food and Drug Administration in 2020/2021. These vaccines displayed clinical efficacy in initial studies against confirmed COVID-19 of 95.0%, 94.1%, and 66.9%, respectively.MethodsIndividuals receiving one of these vaccines were invited to participate in a prospective longitudinal comparative study of immune responses elicited by the three vaccines. In this observational cohort study, humoral responses were evaluated using a SARS-CoV-2 receptor-binding domain (RBD) ELISA and a SARS-CoV-2 virus neutralization assay at mean of 21-31 days and 45-63 days following each initial vaccination. IFN-γ ELISPOT assays were conducted with peripheral blood mononuclear cells obtained at a median of 45-63 days after each initial vaccination.ResultsThe two mRNA-based platforms elicited similar RBD ELISA responses and neutralizing antibody responses. The adenovirus-based vaccine elicited significantly lower RBD ELISA and SARS-CoV-2 virus neutralization activity. The mRNA-1273 vaccine elicited significantly higher spike glycoprotein-specific T cell responses than either the BNT162b2 or the Ad26.COV2.S vaccines.ConclusionsBoth mRNA based vaccines elicited higher magnitude humoral responses than Ad26.COV2.S and mRNA1273 elicited the highest magnitude of T cell response. Neutralizing antibody titers correlated with reported estimates of vaccine efficacy.Summary of key pointsWe compared antigen specific humoral and T cell responses following vaccination with BNT162b2, mRNA-1273, or Ad26.COV2.S. Both mRNA based vaccines elicited higher magnitude humoral responses than Ad26.COV2.S and mRNA1273 elicited the highest magnitude of T cell response.

scholarly journals Resolution of Chlamydia trachomatis Infection Is Associated with a Distinct T Cell Response Profile

2015 ◽  
Vol 22 (11) ◽  
pp. 1206-1218 ◽  
Author(s):  
Michele D. Picard ◽  
Jean-Luc Bodmer ◽  
Todd M. Gierahn ◽  
Alexander Lee ◽  
Jessica Price ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Vaccine Development ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Mediated Immunity ◽  
Transmitted Infection ◽  
Content Type ◽  
Cell Responses

ABSTRACTChlamydia trachomatisis the causative agent of the most frequently reported bacterial sexually transmitted infection, the total burden of which is underestimated due to the asymptomatic nature of the infection. UntreatedC. trachomatisinfections can cause significant morbidities, including pelvic inflammatory disease and tubal factor infertility (TFI). The human immune response againstC. trachomatis, an obligate intracellular bacterium, is poorly characterized but is thought to rely on cell-mediated immunity, with CD4+and CD8+T cells implicated in protection. In this report, we present immune profiling data of subjects enrolled in a multicenter study ofC. trachomatisgenital infection. CD4+and CD8+T cells from subjects grouped into disease-specific cohorts were screened using aC. trachomatisproteomic library to identify the antigen specificities of recall T cell responses after natural exposure by measuring interferon gamma (IFN-γ) levels. We identified specific T cell responses associated with the resolution of infection, including unique antigens identified in subjects who spontaneously cleared infection and different antigens associated withC. trachomatis-related sequelae, such as TFI. These data suggest that novel and uniqueC. trachomatisT cell antigens identified in individuals with effective immune responses can be considered as targets for vaccine development, and by excluding antigens associated with deleterious sequelae, immune-mediated pathologies may be circumvented.

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