T-cell responses against Malaria: Effect of parasite antigen diversity and relevance for vaccine development

Vaccine ◽  
2018 ◽  
Vol 36 (17) ◽  
pp. 2237-2242 ◽  
Author(s):  
Omarine Nfor Nlinwe ◽  
Kwadwo Asamoah Kusi ◽  
Bright Adu ◽  
Martha Sedegah
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Parasite Antigen ◽  
Cell Responses

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 Immunogenicity and Cross-Reactivity of Rhesus Adenoviral Vectors

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
M. Justin Iampietro ◽  
Rafael A. Larocca ◽  
Nicholas M. Provine ◽  
Peter Abbink ◽  
Zi Han Kang ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Adenoviral Vectors ◽  
Cross Reactivity ◽  
Human Populations ◽  
Humoral Immune ◽  
Cell Responses ◽  
The Impact

ABSTRACT Adenovirus (Ad) vectors are being investigated as vaccine candidates, but baseline antivector immunity exists in human populations to both human Ad (HuAd) and chimpanzee Ad (ChAd) vectors. In this study, we investigated the immunogenicity and cross-reactivity of a panel of recently described rhesus adenoviral (RhAd) vectors. RhAd vectors elicited T cells with low exhaustion markers and robust anamnestic potential. Moreover, RhAd vector immunogenicity was unaffected by high levels of preexisting anti-HuAd immunity. Both HuAd/RhAd and RhAd/RhAd prime-boost vaccine regimens were highly immunogenic, despite a degree of cross-reactive neutralizing antibodies (NAbs) between phylogenetically related RhAd vectors. We observed extensive vector-specific cross-reactive CD4 T cell responses and more limited CD8 T cell responses between RhAd and HuAd vectors, but the impact of vector-specific cellular responses was far less than that of vector-specific NAbs. These data suggest the potential utility of RhAd vectors and define novel heterologous prime-boost strategies for vaccine development. IMPORTANCE To date, most adenoviral vectors developed for vaccination have been HuAds from species B, C, D, and E, and human populations display moderate to high levels of preexisting immunity. There is a clinical need for new adenoviral vectors that are not hindered by preexisting immunity. Moreover, the development of RhAd vector vaccines expands our ability to vaccinate against multiple pathogens in a population that may have received other HuAd or ChAd vectors. We evaluated the immunogenicity and cross-reactivity of RhAd vectors, which belong to the poorly described adenovirus species G. These vectors induced robust cellular and humoral immune responses and were not hampered by preexisting anti-HuAd vector immunity. Such properties make RhAd vectors attractive as potential vaccine vectors.

scholarly journals CD46 Engagement on Human CD4+ T Cells Produces T Regulatory Type 1-Like Regulation of Antimycobacterial T Cell Responses

2010 ◽  
Vol 78 (12) ◽  
pp. 5295-5306 ◽  
Author(s):  
Steven M. Truscott ◽  
Getahun Abate ◽  
Jeffrey D. Price ◽  
Claudia Kemper ◽  
John P. Atkinson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccine Development ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Immune Defense ◽  
Cell Functions ◽  
Cell Responses ◽  
Regulatory Type

ABSTRACT Understanding the regulation of human immune responses is critical for vaccine development and treating infectious diseases. We have previously shown that simultaneous engagement of the T cell receptor (TCR) and complement regulator CD46 on human CD4+ T cells in the presence of interleukin-2 (IL-2) induces potent secretion of the immunomodulatory cytokine IL-10. These T cells mediate IL-10-dependent suppression of bystander CD4+ T cells activated in vitro with anti-CD3 and anti-CD28 costimulation, reflecting a T regulatory type 1 (Tr1)-like phenotype. However, CD46-mediated negative regulation of pathogen-specific T cells has not been described. Therefore, we studied the ability of CD46-activated human CD4+ T cells to suppress T cell responses to Mycobacterium bovis BCG, the live vaccine that provides infants protection against the major human pathogen Mycobacterium tuberculosis. Our results demonstrate that soluble factors secreted by CD46-activated human CD4+ T cells suppress mycobacterium-specific CD4+, CD8+, and γ9δ2 TCR+ T cells. Dendritic cell functions were not downregulated in our experiments, indicating that CD46-triggered factors directly suppress pathogen-specific T cells. Interestingly, IL-10 appeared to play a less pronounced role in our system, especially in the suppression of γ9δ2 TCR+ T cells, suggesting the presence of additional undiscovered soluble immunoregulatory factors. Blocking endogenous CD46 signaling 3 days after mycobacterial infection enhanced BCG-specific T cell responses in a subset of volunteers. Taken together, these results indicate that CD46-dependent negative regulatory mechanisms can impair T cell responses vital for immune defense against mycobacteria. Therefore, modulating CD46-induced immune regulation could be integral to the development of improved tuberculosis therapeutics or vaccines.

scholarly journals Cholera Toxin and Its B Subunit Promote Dendritic Cell Vaccination with Different Influences on Th1 and Th2 Development

2003 ◽  
Vol 71 (4) ◽  
pp. 1740-1747 ◽  
Author(s):  
Kristina Eriksson ◽  
Margareta Fredriksson ◽  
Inger Nordström ◽  
Jan Holmgren
Keyword(s):  
T Cell ◽  
Cholera Toxin ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Dendritic Cell Vaccination ◽  
Th2 Response ◽  
B Subunit ◽  
Cell Responses ◽  
Th2 Responses ◽  
Th1 And Th2

ABSTRACT Cholera toxin (CT) is a strong mucosal adjuvant for codelivered antigens, whereas its nontoxic B subunit (CTB) is an efficient mucosal carrier molecule for the generation of immune responses to linked antigens. We investigated the effects of CT and CTB on the immunogenicity of in vitro-treated antigen-pulsed dendritic cells (DC) following intravenous injection into mice. Prior to infusion, DC were pulsed for 90 min with either free ovalbumin (OVA), OVA mixed with CT or CTB, or chemical conjugates of OVA with CT and CTB (OVA-CT and OVA-CTB). DC pulsed with OVA or with OVA and CTB gave rise to modest antibody and T-cell responses. Conjugation of OVA with CTB enhanced both the subsequent B-cell and T-cell responses to OVA and preferentially induced Th2 responses. CT was shown to be a strong adjuvant when it was coadministered to DC with OVA and was even stronger when it was coadministered with OVA-CTB and primed for a mixed Th1-Th2 response. The antibody and T-cell responses were further enhanced if OVA was coupled to CT, implying that CT can utilize a combined carrier and adjuvant function vis-a-vis linked antigens for DC vaccination. The immunopotentiating capacity of CT- and CTB-linked antigen was associated with both upregulated secretion of interleukin-1β by the pulsed DC and increased expression of CD80 and CD86 on the DC surface. These results imply that CT and CTB can be used to both markedly increase and partially direct the DC vaccine-induced immune response with respect to Th1 and Th2 responses, which has obvious implications for DC-based vaccine development.

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 Kunjin Virus Replicon Vectors for Human Immunodeficiency Virus Vaccine Development

2003 ◽  
Vol 77 (14) ◽  
pp. 7796-7803 ◽  
Author(s):  
Tracey J. Harvey ◽  
Itaru Anraku ◽  
Richard Linedale ◽  
David Harrich ◽  
Jason Mackenzie ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Virus Vaccine ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Recombinant Vaccinia Virus ◽  
Human Immunodeficiency Virus Vaccine ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT We have previously demonstrated the ability of the vaccine vectors based on replicon RNA of the Australian flavivirus Kunjin (KUN) to induce protective antiviral and anticancer CD8+ T-cell responses using murine polyepitope as a model immunogen (I. Anraku, T. J. Harvey, R. Linedale, J. Gardner, D. Harrich, A. Suhrbier, and A. A. Khromykh, J. Virol. 76:3791-3799, 2002). Here we showed that immunization of BALB/c mice with KUN replicons encoding HIV-1 Gag antigen resulted in induction of both Gag-specific antibody and protective Gag-specific CD8+ T-cell responses. Two immunizations with KUNgag replicons in the form of virus-like particles (VLPs) induced anti-Gag antibodies with titers of ≥1:10,000. Immunization with KUNgag replicons delivered as plasmid DNA, naked RNA, or VLPs induced potent Gag-specific CD8+ T-cell responses, with one immunization of KUNgag VLPs inducing 4.5-fold-more CD8+ T cells than the number induced after immunization with recombinant vaccinia virus carrying the gag gene (rVVgag). Two immunizations with KUNgag VLPs also provided significant protection against challenge with rVVgag. Importantly, KUN replicon VLP vaccinations induced long-lasting immune responses with CD8+ T cells able to secrete gamma interferon and to mediate protection 6 to 10 months after immunization. These results illustrate the potential value of the KUN replicon vectors for human immunodeficiency virus vaccine design.

scholarly journals Targeting Antigens to Dendritic Cell Receptors for Vaccine Development

2013 ◽  
Vol 2013 ◽  
pp. 1-22 ◽  
Author(s):  
Vasso Apostolopoulos ◽  
Theresia Thalhammer ◽  
Andreas G. Tzakos ◽  
Lily Stojanovska
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Immune Responses ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Dual Function ◽  
Antigen Delivery ◽  
Surface Receptors ◽  
Mhc Molecules ◽  
Cell Responses

Dendritic cells (DCs) are highly specialized antigen presenting cells of the immune system which play a key role in regulating immune responses. Depending on the method of antigen delivery, DCs stimulate immune responses or induce tolerance. As a consequence of the dual function of DCs, DCs are studied in the context of immunotherapy for both cancer and autoimmune diseases. In vaccine development, a major aim is to induce strong, specific T-cell responses. This is achieved by targeting antigen to cell surface molecules on DCs that efficiently channel the antigen into endocytic compartments for loading onto MHC molecules and stimulation of T-cell responses. The most attractive cell surface receptors, expressed on DCs used as targets for antigen delivery for cancer and other diseases, are discussed.

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.

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