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1.
Cell ; 185(23): 4317-4332.e15, 2022 Nov 10.
Article in English | MEDLINE | ID: mdl-36302380

ABSTRACT

Therapeutic cancer vaccines are designed to increase tumor-specific T cell immunity. However, suppressive mechanisms within the tumor microenvironment (TME) may limit T cell function. Here, we assessed how the route of vaccination alters intratumoral myeloid cells. Using a self-assembling nanoparticle vaccine that links tumor antigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we treated tumor-bearing mice subcutaneously (SNP-SC) or intravenously (SNP-IV). Both routes generated antigen-specific CD8+ T cells that infiltrated tumors. However, only SNP-IV mediated tumor regression, dependent on systemic type I interferon at the time of boost. Single-cell RNA-sequencing revealed that intratumoral monocytes expressing an immunoregulatory gene signature (Chil3, Anxa2, Wfdc17) were reduced after SNP-IV boost. In humans, the Chil3+ monocyte gene signature is enriched in CD16- monocytes and associated with worse outcomes. Our results show that the generation of tumor-specific CD8+ T cells combined with remodeling of the TME is a promising approach for tumor immunotherapy.


Subject(s)
Cancer Vaccines , Tumor Microenvironment , Humans , Mice , Animals , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Immunotherapy/methods , Antigens, Neoplasm , Vaccination/methods , Adjuvants, Immunologic
2.
Cell ; 184(11): 2955-2972.e25, 2021 05 27.
Article in English | MEDLINE | ID: mdl-34019795

ABSTRACT

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.


Subject(s)
Antibodies, Neutralizing/immunology , HIV-1/immunology , Immunoglobulin Fab Fragments/immunology , Polysaccharides/immunology , SARS-CoV-2/immunology , Simian Immunodeficiency Virus/immunology , Spike Glycoprotein, Coronavirus/immunology , env Gene Products, Human Immunodeficiency Virus/immunology , Animals , B-Lymphocytes/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , Dimerization , Epitopes/immunology , Glycosylation , HIV Antibodies/immunology , HIV Infections/immunology , Humans , Immunoglobulin Fab Fragments/chemistry , Macaca mulatta , Polysaccharides/chemistry , Receptors, Antigen, B-Cell/chemistry , Simian Immunodeficiency Virus/genetics , Vaccines/immunology , env Gene Products, Human Immunodeficiency Virus/chemistry , env Gene Products, Human Immunodeficiency Virus/genetics
3.
Neurooncol Adv ; 3(1): vdab027, 2021.
Article in English | MEDLINE | ID: mdl-33860227

ABSTRACT

Though outcomes for pediatric cancer patients have significantly improved over the past several decades, too many children still experience poor outcomes and survivors suffer lifelong, debilitating late effects after conventional chemotherapy, radiation, and surgical treatment. Consequently, there has been a renewed focus on developing novel targeted therapies to improve survival outcomes. Cancer vaccines are a promising type of immunotherapy that leverage the immune system to mediate targeted, tumor-specific killing through recognition of tumor antigens, thereby minimizing off-target toxicity. As such, cancer vaccines are orthogonal to conventional cancer treatments and can therefore be used alone or in combination with other therapeutic modalities to maximize efficacy. To date, cancer vaccination has remained largely understudied in the pediatric population. In this review, we discuss the different types of tumor antigens and vaccine technologies (dendritic cells, peptides, nucleic acids, and viral vectors) evaluated in clinical trials, with a focus on those used in children. We conclude with perspectives on how advances in combination therapies, tumor antigen (eg, neoantigen) selection, and vaccine platform optimization can be translated into clinical practice to improve outcomes for children with cancer.

4.
Nat Immunol ; 22(1): 41-52, 2021 01.
Article in English | MEDLINE | ID: mdl-33139915

ABSTRACT

Personalized cancer vaccines are a promising approach for inducing T cell immunity to tumor neoantigens. Using a self-assembling nanoparticle vaccine that links neoantigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we show how the route and dose alter the magnitude and quality of neoantigen-specific CD8+ T cells. Intravenous vaccination (SNP-IV) induced a higher proportion of TCF1+PD-1+CD8+ T cells as compared to subcutaneous immunization (SNP-SC). Single-cell RNA sequencing showed that SNP-IV induced stem-like genes (Tcf7, Slamf6, Xcl1) whereas SNP-SC enriched for effector genes (Gzmb, Klrg1, Cx3cr1). Stem-like cells generated by SNP-IV proliferated and differentiated into effector cells upon checkpoint blockade, leading to superior antitumor response as compared to SNP-SC in a therapeutic model. The duration of antigen presentation by dendritic cells controlled the magnitude and quality of CD8+ T cells. These data demonstrate how to optimize antitumor immunity by modulating vaccine parameters for specific generation of effector or stem-like CD8+ T cells.


Subject(s)
Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/administration & dosage , Hepatocyte Nuclear Factor 1-alpha/analysis , Nanoparticles , Animals , Antigen Presentation , Cancer Vaccines/immunology , Dendritic Cells/immunology , Female , Immunity, Innate , Mice , Mice, Inbred C57BL , Vaccination
5.
Nat Biotechnol ; 38(3): 320-332, 2020 03.
Article in English | MEDLINE | ID: mdl-31932728

ABSTRACT

Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.


Subject(s)
Adjuvants, Immunologic/chemistry , Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/metabolism , Cancer Vaccines/administration & dosage , Melanoma, Experimental/drug therapy , Animals , Cancer Vaccines/immunology , Cell Line, Tumor , Melanoma, Experimental/immunology , Mice , Nanoparticles , Precision Medicine , Primates , Toll-Like Receptor 7/immunology , Toll-Like Receptor 8/immunology , Vaccination , Vaccines, Conjugate
6.
Oncogene ; 38(34): 6159-6171, 2019 08.
Article in English | MEDLINE | ID: mdl-31289361

ABSTRACT

Malignant tumors of the central nervous system (CNS) continue to be a leading cause of cancer-related mortality in both children and adults. Traditional therapies for malignant brain tumors consist of surgical resection and adjuvant chemoradiation; such approaches are often associated with extreme morbidity. Accordingly, novel, targeted therapeutics for neoplasms of the CNS, such as immunotherapy with oncolytic engineered herpes simplex virus (HSV) therapy, are urgently warranted. Herein, we discuss treatment challenges related to HSV virotherapy delivery, entry, replication, and spread, and in so doing focus on host anti-viral immune responses and the immune microenvironment. Strategies to overcome such challenges including viral re-engineering, modulation of the immunoregulatory microenvironment and combinatorial therapies with virotherapy, such as checkpoint inhibitors, radiation, and vaccination, are also examined in detail.


Subject(s)
Brain Neoplasms/therapy , Drug Resistance, Neoplasm , Herpesvirus 1, Human/physiology , Oncolytic Virotherapy/methods , Therapies, Investigational , Adult , Brain Neoplasms/genetics , Child , Drug Resistance, Neoplasm/immunology , Genetic Therapy/adverse effects , Genetic Therapy/methods , Genetic Vectors , Humans , Immunotherapy/adverse effects , Immunotherapy/methods , Oncolytic Virotherapy/adverse effects , Oncolytic Viruses/physiology , Therapies, Investigational/methods , Therapies, Investigational/trends , Treatment Outcome
7.
PLoS Biol ; 17(6): e3000328, 2019 06.
Article in English | MEDLINE | ID: mdl-31206510

ABSTRACT

Peptide immunogens provide an approach to focus antibody responses to specific neutralizing sites on the HIV envelope protein (Env) trimer or on other pathogens. However, the physical characteristics of peptide immunogens can limit their pharmacokinetic and immunological properties. Here, we have designed synthetic "star" nanoparticles based on biocompatible N-[(2-hydroxypropyl)methacrylamide] (HPMA)-based polymer arms extending from a poly(amidoamine) (PAMAM) dendrimer core. In mice, these star nanoparticles trafficked to lymph nodes (LNs) by 4 hours following vaccination, where they were taken up by subcapsular macrophages and then resident dendritic cells (DCs). Immunogenicity optimization studies revealed a correlation of immunogen density with antibody titers. Furthermore, the co-delivery of Env variable loop 3 (V3) and T-helper peptides induced titers that were 2 logs higher than if the peptides were given in separate nanoparticles. Finally, we performed a nonhuman primate (NHP) study using a V3 glycopeptide minimal immunogen that was structurally optimized to be recognized by Env V3/glycan broadly neutralizing antibodies (bnAbs). When administered with a potent Toll-like receptor (TLR) 7/8 agonist adjuvant, these nanoparticles elicited high antibody binding titers to the V3 site. Similar to human V3/glycan bnAbs, certain monoclonal antibodies (mAbs) elicited by this vaccine were glycan dependent or targeted the GDIR peptide motif. To improve affinity to native Env trimer affinity, nonhuman primates (NHPs) were boosted with various SOSIP Env proteins; however, significant neutralization was not observed. Taken together, this study provides a new vaccine platform for administration of glycopeptide immunogens for focusing immune responses to specific bnAb epitopes.


Subject(s)
AIDS Vaccines/immunology , HIV-1/immunology , Nanoparticles/therapeutic use , Animals , Antibodies, Neutralizing/immunology , Antibody Formation/immunology , Epitopes/immunology , Female , HIV Envelope Protein gp120/chemistry , HIV Infections/immunology , HIV Seropositivity/immunology , Macaca mulatta , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Peptides , Primates
8.
Cancer Lett ; 459: 192-203, 2019 09 10.
Article in English | MEDLINE | ID: mdl-31185250

ABSTRACT

Patients with inadequate anti-cancer T cell responses experience limited benefit from immune checkpoint inhibitors and other immunotherapies that require T cells. Therefore, treatments that induce de novo anti-cancer T cell immunity are needed. One strategy - referred to as in situ vaccination - is to deliver chemotherapeutic or immunostimulatory drugs into tumors to promote cancer cell death and provide a stimulatory environment for priming T cells against antigens already present in the tumor. However, achieving sufficient drug concentrations in tumors without causing dose-limiting toxicities remains a major challenge. To address this challenge, nanomedicines based on nano-sized carriers ('nanocarriers') of chemotherapeutics and immunostimulants are being developed to improve drug accumulation in tumors following systemic (intravenous) administration. Herein, we present the rationale for using systemically administrable nanomedicines to induce anti-cancer T cell immunity via in situ vaccination and provide an overview of synthetic nanomedicines currently used clinically. We also describe general strategies for improving nanomedicine design to increase tumor uptake, including use of micelle- and star polymer-based nanocarriers. We conclude with perspectives for how nanomedicine properties, host factors and treatment combinations can be leveraged to maximize efficacy.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Cancer Vaccines/administration & dosage , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Animals , Cancer Vaccines/immunology , Humans , Immunotherapy/methods , Nanomedicine/methods , Neoplasms/drug therapy
9.
Biomacromolecules ; 20(2): 854-870, 2019 02 11.
Article in English | MEDLINE | ID: mdl-30608149

ABSTRACT

Small molecule Toll-like receptor-7 and -8 agonists (TLR-7/8a) can be used as vaccine adjuvants to induce CD8 T cell immunity but require formulations that prevent systemic toxicity and focus adjuvant activity in lymphoid tissues. Here, we covalently attached TLR-7/8a to polymers of varying composition, chain architecture and hydrodynamic behavior (∼300 nm submicrometer particles, ∼10 nm micelles and ∼4 nm flexible random coils) and evaluated how these parameters of polymer-TLR-7/8a conjugates impact adjuvant activity in vivo. Attachment of TLR-7/8a to any of the polymer compositions resulted in a nearly 10-fold reduction in systemic cytokines (toxicity). Moreover, both lymph node cytokine production and the magnitude of CD8 T cells induced against protein antigen increased with increasing polymer-TLR-7/8a hydrodynamic radius, with the submicrometer particle inducing the highest magnitude responses. Notably, CD8 T cell responses induced by polymer-TLR-7/8a were dependent on CCR2+ monocytes and IL-12, whereas responses by a small molecule TLR-7/8a that unexpectedly persisted in vaccine-site draining lymph nodes (T1/2 = 15 h) had less dependence on monocytes and IL-12 but required Type I IFNs. This study shows how modular properties of synthetic adjuvants can be chemically programmed to alter immunity in vivo through distinct immunological mechanisms.


Subject(s)
Adjuvants, Immunologic/chemistry , CD8-Positive T-Lymphocytes/drug effects , Lymphocyte Activation , Micelles , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/pharmacology , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Line , Cells, Cultured , Cytokines/metabolism , Female , Hydrodynamics , Mice , Mice, Inbred C57BL , Protein Binding
10.
Nat Commun ; 8(1): 1954, 2017 12 05.
Article in English | MEDLINE | ID: mdl-29203865

ABSTRACT

Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/AlbiVax nanocomplexes that self-assemble in vivo from AlbiVax and endogenous albumin for efficient vaccine delivery and potent cancer immunotherapy. PET pharmacoimaging, super-resolution microscopies, and flow cytometry reveal almost 100-fold more efficient co-delivery of CpG and antigens (Ags) to lymph nodes (LNs) by albumin/AlbiVax than benchmark incomplete Freund's adjuvant (IFA). Albumin/AlbiVax elicits ~10 times more frequent peripheral antigen-specific CD8+ cytotoxic T lymphocytes with immune memory than IFA-emulsifying vaccines. Albumin/AlbiVax specifically inhibits progression of established primary or metastatic EG7.OVA, B16F10, and MC38 tumors; combination with anti-PD-1 and/or Abraxane further potentiates immunotherapy and eradicates most MC38 tumors. Albumin/AlbiVax nanocomplexes are thus a robust platform for combination cancer immunotherapy.


Subject(s)
Cancer Vaccines/pharmacology , Lymph Nodes/drug effects , Melanoma, Experimental/pathology , T-Lymphocytes, Cytotoxic/drug effects , Adjuvants, Immunologic/pharmacology , Albumin-Bound Paclitaxel/pharmacology , Albumins , Animals , Antigens, Neoplasm/immunology , Antineoplastic Agents/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Cell Line, Tumor , Drug Delivery Systems , Freund's Adjuvant/pharmacology , Immunotherapy , Lipids/pharmacology , Lymph Nodes/pathology , Mice , Molecular Docking Simulation , Nanostructures , Positron-Emission Tomography
11.
Trends Immunol ; 37(12): 813-815, 2016 12.
Article in English | MEDLINE | ID: mdl-27838188

ABSTRACT

Immunology is an increasingly interdisciplinary field. Here we describe a new model for interinstitutional graduate training as partnerships between complementary laboratories. This collaborative model reduces time to graduation without compromising productivity or alumni outcomes. We offer our experience with one such program and thoughts on the ingredients for their success. Despite tremendous recent advances in technology, communications, and the translation of basic scientific discoveries into new diagnostics and therapies for human diseases, graduate training in immunology and other areas of biomedical research in the United States has remained remarkably unchanged since the early 20th century, with coursework and laboratory rotations taking up much of the first 2 years, and a single mentor shepherding the student through a research project over 3 or more subsequent years. The time to graduation still averages more than 6 years in the biomedical sciences field (http://www.nsf.gov/statistics/2016/nsf16300/), with uncertain benefit of this extended time to research productivity and career advancement.


Subject(s)
Allergy and Immunology/education , Education, Graduate , Models, Educational , Biomedical Research , Career Mobility , Humans , Interdisciplinary Communication , National Institutes of Health (U.S.) , United States , Universities
12.
Bioconjug Chem ; 27(10): 2372-2385, 2016 10 19.
Article in English | MEDLINE | ID: mdl-27583777

ABSTRACT

Structure-based vaccine design has been used to develop immunogens that display conserved neutralization sites on pathogens such as HIV-1, respiratory syncytial virus (RSV), and influenza. Improving the immunogenicity of these designed immunogens with adjuvants will require formulations that do not alter protein antigenicity. Here, we show that nanoparticle-forming thermoresponsive polymers (TRP) allow for co-delivery of RSV fusion (F) protein trimers with Toll-like receptor 7 and 8 agonists (TLR-7/8a) to enhance protective immunity. Although primary amine conjugation of TLR-7/8a to F trimers severely disrupted the recognition of critical neutralizing epitopes, F trimers site-selectively coupled to TRP nanoparticles retained appropriate antigenicity and elicited high titers of prefusion-specific, TH1 isotype anti-RSV F antibodies following vaccination. Moreover, coupling F trimers to TRP delivering TLR-7/8a resulted in ∼3-fold higher binding and neutralizing antibody titers than soluble F trimers admixed with TLR-7/8a and conferred protection from intranasal RSV challenge. Overall, these data show that TRP nanoparticles may provide a broadly applicable platform for eliciting neutralizing antibodies to structure-dependent epitopes on RSV, influenza, HIV-1, or other pathogens.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Nanoparticles/administration & dosage , Polymers/chemistry , Respiratory Syncytial Virus Vaccines/pharmacology , Viral Fusion Proteins/administration & dosage , Animals , Antibodies, Neutralizing , Chemistry Techniques, Synthetic , Drug Delivery Systems/methods , Female , Mice, Inbred Strains , Nanoparticles/chemistry , Respiratory Syncytial Virus Vaccines/administration & dosage , Respiratory Syncytial Virus Vaccines/immunology , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/chemistry , Viral Fusion Proteins/chemistry
14.
Nat Med ; 22(6): 614-23, 2016 06.
Article in English | MEDLINE | ID: mdl-27158907

ABSTRACT

An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10(5) PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21-25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.


Subject(s)
Antibodies, Protozoan/immunology , CD8-Positive T-Lymphocytes/immunology , Immunogenicity, Vaccine/immunology , Liver/immunology , Malaria Vaccines/therapeutic use , Malaria, Falciparum/prevention & control , Parasitemia/prevention & control , Plasmodium falciparum/immunology , Administration, Intravenous , Adolescent , Adult , Animals , Enzyme-Linked Immunosorbent Assay , Female , Healthy Volunteers , Humans , Immunoglobulin G/immunology , Interferon-gamma/immunology , Liver/cytology , Macaca mulatta , Malaria Vaccines/immunology , Male , Middle Aged , Parasitemia/immunology , Sporozoites/immunology , T-Lymphocytes/immunology , Young Adult
15.
Nat Biotechnol ; 33(11): 1201-10, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26501954

ABSTRACT

The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer-TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.


Subject(s)
Adjuvants, Immunologic/chemistry , Toll-Like Receptors/agonists , Vaccines/immunology , Animals , Drug Carriers/chemistry , Female , Male , Mice , Mice, Inbred C57BL , T-Lymphocytes/immunology
16.
J Clin Invest ; 125(3): 1129-46, 2015 Mar 02.
Article in English | MEDLINE | ID: mdl-25642773

ABSTRACT

Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee-derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines.


Subject(s)
Adenoviridae/genetics , Antigens, Viral/biosynthesis , Gene Products, gag/biosynthesis , Interferons/physiology , Membrane Proteins/metabolism , Animals , Antigen Presentation , Antigens, Viral/immunology , CD8-Positive T-Lymphocytes/immunology , Cross-Priming , Dendritic Cells/immunology , Immunity, Innate/genetics , Mice, Inbred C57BL , Mice, Knockout , Receptors, Pattern Recognition/metabolism , Signal Transduction/immunology , Transcriptional Activation , Transcriptome , Vaccination , Vaccines, Synthetic/immunology , Viral Vaccines/immunology
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