Early spatiotemporal evolution of the immune response elicited by adenovirus vector vaccination
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ABSTRACT: As the first responders to immunological challenges, the innate immune system has the potential to shape and regulate the ensuing adaptive immune response. Many clinical studies evaluating the role of various innate populations in initiating vaccine-elicited immunity have been largely relegated to blood. It is also largely unknown how the immune response to vaccination is initiating and evolving at the earliest time points post-vaccination. We sought to investigate the spatiotemporal evolution of the earliest immune responses to intramuscular adenovirus serotype 26 (Ad26) vector vaccination in blood and tissues. Using transcriptomic profiling, we show that Ad26 vector vaccination elicits broad transcriptomic changes as early as 1 hour post-vaccination across blood and tissues marked by IL-1, TNF-α, and IL-6 pro-inflammatory pathways. Immunologic data reveals an influx of Ly6C+ myeloid cells into muscle by 1 hour post-vaccination. A Ly6C+CD64+ population emerges in muscle and subsequently in the draining lymph node, suggesting that myeloid cells may be significant drivers of vaccine-elicited immune responses following intramuscular vaccination. Moreover, levels of IL-6, MIG, MIP-1α, and MIP-1β measured in serum at 6 hours post-vaccination positively correlated with the frequency of vaccine-elicited CD8+ T cell responses evaluated at 60 days post-vaccination. Taken together, our data suggests that the immune response to Ad26 vector vaccination commences by 1 hour across compartments and that events at as early as 6 hours post-vaccination can shape vaccine-elicited CD8+ T cell responses at memory time points.
Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines. Splenic CD45.2+ OT-II TCR-Tg CD4 T cells from CD45.1+ B6 mice immunized with Ad5-OVA or Ad26-OVA were purified by FACS on day 10 post-immunization
Project description:Heterologous vaccination regimens are increasingly recommended for their potential benefits, including reduced side effects and enhanced immunogenicity. In this study, we investigated the innate and adaptive immune responses elicited by heterologous prime-boost vaccination using adenoviral vector and mRNA vaccines against SARS-CoV-2 in a mouse model. Our findings show that heterologous vaccination induced superior serum neutralizing and binding antibody titers, as well as enhanced cellular immune responses against the Delta and Omicron (BA.5) variants, compared to homologous vaccination. Single-cell transcriptomic analysis at the injection site, conducted 16 hours post-vaccination, revealed that the lipid nanoparticle (LNP)-based mRNA vaccine—and even empty LNP injection—triggered significant immune cell infiltration, while adenoviral vector vaccination caused minimal changes in injection-site cell composition following the first dose. Notably, spike mRNA was predominantly expressed in fibroblasts and macrophages across both vaccine platforms, suggesting these cells’ role in local immune responses. Further analysis demonstrated that the adenoviral vector booster induced amplified immune responses, marked by increased transcriptional changes, particularly in stromal pro-inflammatory pathways. Heterologous vaccination (adenoviral prime, mRNA boost) further intensified these responses compared to homologous mRNA vaccination, indicating that adenoviral priming enhances inflammatory responses when followed by an mRNA boost. In summary, our results demonstrate that heterologous vaccination strategies elicit stronger innate and adaptive immune responses compared to homologous regimens, supporting their use as an effective approach for enhanced protection against variants.
Project description:Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease, and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 challenge in hamsters stimulates myeloid and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, single-dose immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways such that the gene expression profiles of vaccinated hamsters are comparable to uninfected animals. Furthermore, we validated the protective efficacy of the Ad26.COV2.S against proinflammatory pathways and coagulation cascade in rhesus macaques by proteomics. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses. These data provide further insights into the mechanisms of Ad26.COV2.S based protection against severe COVID-19 in hamsters.
Project description:Here we applied a systems approach to define human innate immune signatures following MRKAd5/HIV immunization and to analyze the effects of pre-existing Ad5 immunity. We defined the global early immune response to MRKAd5/HIV by profiling the PBMC transcriptomes from seven Ad5Neg individuals pre- and post-vaccination in vivo. Since the Step Study results suggested a deleterious effect of pre-existing Ad5 nAb on vaccine immunogenicity, we examined the vaccine-induced transcriptional responses from two Ad5Med and one Ad5Low individual 50 total samples were analyzed. This includes 5 time points post vaccination with MRKAd5/HIV for 10 independent human subjects. The time points were 0hr, 6hrs, 24hrs, 72hrs, and 168hrs. Seven of the subjects did not have pre-existing neutralizing antibodies to the vaccine vector (Ad5Neg). One subject had low level pre-existing neutralizing antibodies to the vaccine vector (Ad5Low). Two subjects had moderate level pre-existing neutralizing antibodies to the vaccine vector (Ad5Low).
Project description:CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. Here we evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality following challenge with a persistent form of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology. Splenic GP66-specific CD4 T cells from mice immunized with either a LMwt vaccine (sham) or LMgp61 vaccine (CD4 vaccine) were purified by FACS on day 8 post-infection with LCMV clone 13
Project description:ChAdOx1 nCoV-19, a chimpanzee adenovirus (ChAd)-vector vaccine expressing the SARS-CoV-2 spike protein, has elicited robust immunological responses in large populations. Despite its proven efficacy and safety, some recipients have reported immediate inflammatory reactions post-vaccination. We comprehensively examined the immune landscape following ChAdOx1 nCoV-19 vaccination based on the epigenomic profiles of monocytes. Glucocorticoids are wildly used as steroid anti-inflammatory drugs to modify acute and chronic inflammation. Recently, dexamethasone is used to modify inflammation in COVID19 and side-effects after COVID19 vaccination. ChAdox1 nCoV-19 induces interferon responses and inflammation in human. In addition to IFNa, TNF and IL1b treatment to mimic inflammatory environment gives general effects of glucocorticoids in complex inflammatory context.
Project description:Thrombosis with thrombocytopenia syndrome (TTS) is an extremely rare but potentially serious adverse event following immunization with the adenovirus vector-based COVID-19 vaccines Ad26.COV2.S (Janssen / Johnson & Johnson) or ChAdOx1 (AstraZeneca). However, no cases of TTS have been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States, suggesting that anti-vector immunity may reduce TTS risk. Here we show robust stimulation of platelet activation and coagulation pathways and innate immune pathways in patients with TTS but only transient activation of these pathways following vaccination. We evaluated proteomic profiles in 2 patients with TTS and transcriptomic and proteomic profiles in 20 people following an initial dose and a booster dose of Ad26.COV2.S and in 14 people who received the mRNA vaccines BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induced transient activation of platelet activation and coagulation pathways and innate proinflammatory pathways that resolved by day 7. TTS patients showed enhanced and sustained upregulation of these pathways, whereas a second immunization with Ad26.COV2.S or a reduced initial dose of Ad26.COV2.S resulted in lower activation of these pathways. These data provide insight into TTS pathogenesis and suggest a potential strategy for reducing TTS risk by lowering the dose of Ad26.COV2.S.
Project description:Ebolavirus disease (EVD) is a severe hemorrhagic fever with a high fatality rate. In this study, we comprehensively investigated transcriptome profiles at 0, 3 hours, 1 and 7 days after vaccination with Ad26.ZEBOV and MVA-BN-Filo. Three hours after Ad26.ZEBOV injection, we observed an increase in gene abundance related to antigen presentation, sensing, and T- and B-cell receptors. The highest response occurred one day after Ad26.ZEBOV injection, with an increase in the expression of genes for interferon-induced antiviral molecules, monocyte activation, and sensing receptors. This response was mainly shaped by the HESX1, ATF3, ANKRD22, and ETV7 transcription factors. A plasma-cell signature was observed on day 7 post-Ad26.ZEBOV vaccination, with an increase of the abundance of CD138, MZB1, CD38, and CD79A, as well as that of immunoglobulin genes. Importantly, we identified early-expressed genes correlated with the magnitude of the antibody response 21 days after the MVA-BN-Filo and 364 days after Ad26.ZEBOV vaccinations. Our results provide early gene signatures that characterize an effective vaccine antibody response against Ebola.
Project description:Ad26.COV2.S has demonstrated durability and clinical efficacy against symptomatic COVID-19 in humans. In this study, we report the correlates of durability of humoral and cellular immune responses in 20 rhesus macaques immunized with single-shot Ad26.COV2.S and the immunogenicity of a booster shot at 8 to 10 months after the initial immunization. Ad26.COV2.S elicited durable binding and neutralizing antibodies as well as memory B cells and long-lived bone marrow plasma cells. Innate immune responses and bone marrow plasma cell responses correlated with durable antibody responses. After Ad26.COV2.S boost immunization, binding and neutralizing antibody responses against multiple SARS-CoV-2 variants increased 31- to 69-fold and 23- to 43-fold, respectively, compared with preboost concentrations. Antigen-specific B cell and T cell responses also increased substantially after the boost immunization. Boosting with a modified Ad26.COV2.S.351 vaccine expressing the SARS-CoV-2 spike protein from the beta variant led to largely comparable responses with slightly higher beta- and omicron-specific humoral immune responses. These data demonstrate that a late boost with Ad26.COV2.S or Ad26.COV2.S.351 resulted in a marked increase in humoral and cellular immune responses that were highly cross-reactive across multiple SARS-CoV-2 variants in rhesus macaques.
Project description:Neoantigens are promising immunogens for cancer vaccines and are traditionally delivered as adjuvanted peptide vaccines. Our goal was to understand how an adenoviral vectored neoantigen vaccine would induce tumor immunity compared to a peptide neoantigen vaccine. We generated adenovirus serotype 26 (Ad26) vaccines encoding MC38-specific neoantigens and compared them to an adjuvanted peptide MC38 neoantigen vaccine. The single-shot Ad26 vaccines induced greater neoantigen specific IFN- CD8+ T cell immune responses than the two-shot adjuvanted peptide vaccine in mice, and Ad26.VP22.7Epi also provided superior protective efficacy compared to the peptide vaccine following tumor challenge. Ad26.VP22.7Epi induced a robust immunodominant CD8+ T cell response against the Adpgk neoantigen, while the peptide vaccine induced lower responses against both Adpgk and Reps1 neoantigens. Tumor infiltrating lymphocytes (TILs) from both vaccine groups were analyzed using scRNA-seq and TCR-seq. Vaccinated mice showed increased CD8+ T cell infiltration, with the peptide vaccine inducing more infiltrating CD8+ T cells than the Ad26.VP22.7Epi vaccine. However, Ad26.VP22.7Epi induced CD8+ T cells showed more upregulation of T cell maturation, activation, and Th1 pathways compared to peptide vaccine induced CD8+ T cells, suggesting improved functional T cell quality. TCR-seq of these TILs also demonstrated that Ad26.VP22.7Epi generated larger T cell hyperexpanded clones compared to the peptide vaccine. These results suggest that the Ad26.VP22.7Epi vaccine led to improved tumor control compared with the peptide vaccine due to increased T cell hyperexpansion and functional activation. Our data suggest that future cancer vaccine development strategies should focus on inducing functional hyperexpanded CD8+ T cell responses and not only maximizing tumor infiltrating CD8+ T cell numbers.