Molecular correlates of vaccine-induced protection against typhoid fever
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ABSTRACT:
PROVIDER: PRJNA899913 | ENA |
REPOSITORIES: ENA
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Project description:Typhoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi. Bulk RNA-sequencing (RNA-seq) data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial involving two vaccines against typhoid fever, a plain polysaccharide vaccine, ViPS and a glycoconjugate vaccine, ViTCV. The participants were then challenged with S. Typhi in a controlled human infection model (CHIM).
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Project description:Crimean-Congo hemorrhagic fever (CCHF), caused by Crimean-Congo hemorrhagic fever virus (CCHFV), is on the World Health Organizations list over emerging pathogens and prioritized diseases. With global distribution, high fatality rate and no approved treatment or vaccine, CCHF constitute a treat against the global health. In the current study we show full protection of mice against lethal CCHFV infection due to mRNA-LNP vaccination. IFNAR-/- mice received two immunizations with either mRNA-LNP encoding for the CCHFV nucleoprotein, glycoproteins or a combination of both. While unvaccinated mice showed clear signs of severe disease, vaccinated mice was significantly protected. Vaccine induced immune responses due to vaccination was evaluated both in IFNAR-/- and immunocompetent mice and a strong humoral and cellular immune response was observed in both mouse models with high titers of neutralizing antibodies and primed T-cells. In addition, we conducted a proteomic analysis on liver samples from vaccinated and unvaccinated mice after CCHFV infection to determine the effect of vaccination on the protein profile. Similar to what has been observed in humans due to vaccination, there was an effect on metabolic pathways. In conclusion, this study shows very promising results regarding development of a vaccine against CCHFV.
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Project description:Lassa fever outbreaks hit West African countries every year and there is still no licensed vaccine to limit the burden of this viral hemorrhagic fever. We previously developed MeV-NP, a single-shot vaccine that induces protective immunity in cynomolgus monkeys one month or more than a year before Lassa virus infection and that is able to protect against divergent viral strains. Given the limited dissemination area of Lassa virus during outbreaks and the high risk of nosocomial transmission, a vaccine that induces rapid protection could be useful to protect exposed people during outbreaks in the absence of preventive vaccination. We tested whether the time to protection could be reduced after immunization by challenging MeV pre-immune cynomolgus monkeys 16 or 8 days after a single shot of MeV-NP. None of the immunized monkeys developed disease and they rapidly controlled viral replication. Animals immunized eight days before the challenge were the best controllers, producing a strong CD8 T-cell response against the viral glycoprotein. A group of animals was also vaccinated an hour after the challenge. These animals did not develop any protective immune responses and presented the same lethal disease as the control animals. This study demonstrates that MeV-NP can induce a rapid protective immune response against Lassa fever in presence of MeV pre-existing immunity but can likely not be used as therapeutic vaccine.
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Project description:Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical against SIV/HIV acquisition. Here, we evaluated the efficacy of a SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded as there was no cross-reactivity between SIV and SHIV Envelope antibodies. After eight low-dose rectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated 83% efficacy, compared to six naïve controls, suggesting protection could be achieved in the absence of anti-Envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for the preventing viral acquisition, as none of the CD8-depleted macaques was infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation, and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 (PF4) on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity and may provide new opportunities for novel HIV vaccines or therapeutic strategy development.
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Project description:Correlates of immune mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of forty volunteers followed for up to one year after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity including complement, the inflammasome and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (Modular IMmune In vitro Construct (MIMIC) system), by the coordinated up-regulation of transcripts for specific transcription factors including STAT1, IRF7 and ETS2 that are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of masters transcription factors, that lead to the development of a broad, polyfunctional and persistent immune response that integrates all effector cells of the immune system.
2008-12-01 | GSE13699 | GEO
Project description:Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical against SIV/HIV acquisition. Here, we evaluated the efficacy of a SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded as there was no cross-reactivity between SIV and SHIV Envelope antibodies. After eight low-dose rectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated 83% efficacy, compared to six naïve controls, suggesting protection could be achieved in the absence of anti-Envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for the preventing viral acquisition, as none of the CD8-depleted macaques were infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation, and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 (PF4) on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity and may provide new opportunities for novel HIV vaccines or therapeutic strategy development.
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Project description:We were able to obtain distinct gene expression profile between children with typhoid fever and other bacteremic infections. Peripheral blood of Nigerian children with typhoid fever and other bacteremic infection were obtained in Paxgene tubes. Total RNa were extracted using Paxgene blood RNA kit and 4x44K (G4112F) human GE array were processed according to standard Agilent procedures
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Project description:Conjugate vaccine against typhoid fever has been shown to be safe and effective in field trials. The mechanism through which the vaccine protects remains elusive. Recent data have implicated antibody glycosylation, and specifically afucosylated antibodies, as an important factor in vaccine-induced effector function for a range of viral infections. Here, we studied IgG glycosylation after conjugate vaccine in a UK cohort, who were then challenged with virulent S.typhi, and among Nepalese children living in a typhoid endemic region. We compared vaccine-induced responses to another licensed typhoid polysaccharide vaccine and correlated these measures with antibody-dependent function to understand if a vaccine against a bacterial infection elicited similar glycosylation/function associations as has been seen for viral infections. Robust antigen-specific IgG Fc galactosylation and sialylation modifications were induced by both polysaccharide and tetanus toxoid-conjugated Salmonella Typhi vaccines in UK adults. These modifications were not able to differentiate controlled human infection model (CHIM) participants who became ill after ingestion of virulent S.typhi from those who remained well after infection. However, among those who did become ill, disease severity was associated with a distinct glycosylation profile. Interestingly, both vaccines induced vaccine-specific IgG1 antibodies that were more fucosylated than total circulating IgG1 and these were not associated with a particular functional profile. While bulk IgG glycosylation was different between Nepalese children and UK adults, vaccination with the Vi-tetanus toxoid-conjugate vaccine resulted in similar Vi-specific IgG glycosylation profiles 28 days after vaccination in both cohorts.
2024-05-30 | PXD037239 | Pride
Project description:Conjugate vaccine against typhoid fever has been shown to be safe and effective in field trials. The mechanism through which the vaccine protects remains elusive. Recent data have implicated antibody glycosylation, and specifically afucosylated antibodies, as an important factor in vaccine-induced effector function for a range of viral infections. Here, we studied IgG glycosylation after conjugate vaccine in a UK cohort, who were then challenged with virulent S.typhi, and among Nepalese children living in a typhoid endemic region. We compared vaccine-induced responses to another licensed typhoid polysaccharide vaccine and correlated these measures with antibody-dependent function to understand if a vaccine against a bacterial infection elicited similar glycosylation/function associations as has been seen for viral infections. Robust antigen-specific IgG Fc galactosylation and sialylation modifications were induced by both polysaccharide and tetanus toxoid-conjugated Salmonella Typhi vaccines in UK adults. These modifications were not able to differentiate controlled human infection model (CHIM) participants who became ill after ingestion of virulent S.typhi from those who remained well after infection. However, among those who did become ill, disease severity was associated with a distinct glycosylation profile. Interestingly, both vaccines induced vaccine-specific IgG1 antibodies that were more fucosylated than total circulating IgG1 and these were not associated with a particular functional profile. While bulk IgG glycosylation was different between Nepalese children and UK adults, vaccination with the Vi-tetanus toxoid-conjugate vaccine resulted in similar Vi-specific IgG glycosylation profiles 28 days after vaccination in both cohorts.
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Project description:Mechanisms of poor responses to vaccines remain unknown. Yellow fever-naïve adults were vaccinated with a yellow fever vaccine (YF-17D, Stamaril). Transcriptomic profilling of blood collected pre-vaccination and post-vaccination (day 3, 7, 14 and 84) was performed in order to identify candidate biomarkers of antibody response to the vaccine.
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