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Patent
Imaxio Sa and ISIS INNOVATION Ltd | Date: 2010-10-15

There is provided a fusion protein or a polynucleotide sequence encoding said fusion protein that comprises first and second domains, wherein the first domain of the fusion protein comprises an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 1, or a fragment thereof comprising at least 20 consecutive amino acids thereof; and wherein the second domain of the fusion protein comprises a mycobacterial antigen or an antigenic fragment thereof. Also provided are corresponding therapeutic uses thereof for the protection of primates against mycobacterial infections.


Spencer A.J.,University of Oxford | Hill F.,Imaxio SA | Honeycutt J.D.,University of Oxford | Cottingham M.G.,University of Oxford | And 9 more authors.
PLoS ONE | Year: 2012

To prevent important infectious diseases such as tuberculosis, malaria and HIV, vaccines inducing greater T cell responses are required. In this study, we investigated whether fusion of the M. tuberculosis antigen 85A to recently described adjuvant IMX313, a hybrid avian C4bp oligomerization domain, could increase T cell responses in pre-clinical vaccine model species. In mice, the fused antigen 85A showed consistent increases in CD4 + and CD8 + T cell responses after DNA and MVA vaccination. In rhesus macaques, higher IFN-γ responses were observed in animals vaccinated with MVA-Ag85A IMX313 after both primary and secondary immunizations. In both animal models, fusion to IMX313 induced a quantitative enhancement in the response without altering its quality: multifunctional cytokines were uniformly increased and differentiation into effector and memory T cell subsets was augmented rather than skewed. An extensive in vivo characterization suggests that IMX313 improves the initiation of immune responses as an increase in antigen 85A specific cells was observed as early as day 3 after vaccination. This report demonstrates that antigen multimerization using IMX313 is a simple and effective cross-species method to improve vaccine immunogenicity with potentially broad applicability. © 2012 Spencer et al.


Campbell T.A.,Texas A&M University-Kingsville | Garcia M.R.,Texas A&M University-Kingsville | Miller L.A.,National Wildlife Research Center | Ramirez M.A.,Texas A&M University-Kingsville | And 3 more authors.
Journal of Swine Health and Production | Year: 2010

Objective: To determine if a recombinant gonadotropin-releasing hormone (GnRH) vaccine is a potential immunocontraceptive agent for juvenile male feral swine. Materials and methods: At the beginning of the trial (Day 0) we treated animals in Treatment One with a single injection of a sham vaccine containing 1 mL of a buffer-adjuvant emulsion (adjuvant: AdjuVac; National Wildlife Research Center, Fort Collins, Colorado). Treatment Two received 1000 μg of a recombinant GnRH (rGnRH) vaccine (IMX294; Imaxio, Lyon, France). Treatment Three received 500 μg of a rGnRH vaccine. Treatment Four received 1000 μg of a GnRH vaccine (GonaCon; National Wildlife Research Center, Fort Collins, Colorado). On Day 90, Treatment Three received an additional 500-μg boost treatment. All vaccines were emulsified with AdjuVac and injected intramuscularly into the rump. On Day 180, we performed necropsies on swine and compared mass of testes, percent normal seminiferous tubules, numbers of spermatogonia, spermatocytes, and spermatids, serum testosterone levels, and anti-GnRH antibody titers among treatments. Results: As expected, a single dose of GonaCon vaccine reduced testes mass, serum testosterone, and percent normal tubules, and restricted sperm development at each stage. These reductions in reproductive development were associated with elevated GnRH antibodies. The single injection of rGnRH was not as effective in reducing these reproductive parameters; however, the two-dose injection of rGnRH was as effective as the single injection of GonaCon. Implication: Further research and development is needed into oral immunocontraceptive vaccines and oral delivery systems.


Forbes E.K.,University of Oxford | de Cassan S.C.,University of Oxford | Llewellyn D.,University of Oxford | Biswas S.,University of Oxford | And 6 more authors.
PLoS ONE | Year: 2012

Viral vectored vaccines have been shown to induce both T cell and antibody responses in animals and humans. However, the induction of even higher level T cell responses may be crucial in achieving vaccine efficacy against difficult disease targets, especially in humans. Here we investigate the oligomerization domain of the α-chain of C4b-binding protein (C4 bp) as a candidate T cell "molecular adjuvant" when fused to malaria antigens expressed by human adenovirus serotype 5 (AdHu5) vectored vaccines in BALB/c mice. We demonstrate that i) C-terminal fusion of an oligomerization domain can enhance the quantity of antigen-specific CD4+ and CD8+ T cell responses induced in mice after only a single immunization of recombinant AdHu5, and that the T cells maintain similar functional cytokine profiles; ii) an adjuvant effect is observed for AdHu5 vectors expressing either the 42 kDa C-terminal domain of Plasmodium yoelii merozoite surface protein 1 (PyMSP142) or the 83 kDa ectodomain of P. falciparum strain 3D7 apical membrane antigen 1 (PfAMA1), but not a candidate 128kDa P. falciparum MSP1 biallelic fusion antigen; iii) following two homologous immunizations of AdHu5 vaccines, antigen-specific T cell responses are further enhanced, however, in both BALB/c mice and New Zealand White rabbits no enhancement of functional antibody responses is observed; and iv) that the T cell adjuvant activity of C4 bp is not dependent on a functional Fc-receptor γ-chain in the host, but is associated with the oligomerization of small (<80 kDa) antigens expressed by recombinant AdHu5. The oligomerization domain of C4 bp can thus adjuvant T cell responses induced by AdHu5 vectors against selected antigens and its clinical utility as well as mechanism of action warrant further investigation.


Allen E.R.,University of Oxford | Van Diemen P.,University of Oxford | Yamaguchi Y.,University of Oxford | Lindemann C.,University of Oxford | And 5 more authors.
PLoS ONE | Year: 2016

Purpose: To develop and validate a sensitive and specific method of abscess enumeration and quantification in a preclinical model of Staphylococcus aureus infection. Methods: S. aureus infected murine kidneys were fixed in paraformaldehyde, impregnated with gadolinium, and embedded in agar blocks, which were subjected to 3D magnetic resonance microscopy on a 9.4T MRI scanner. Image analysis techniques were developed, which could identify and quantify abscesses. The result of this imaging was compared with histological examination. The impact of a S. aureus Sortase A vaccination regime was assessed using the technique. Results: Up to 32 murine kidneys could be imaged in a single MRI run, yielding images with voxels of about 25 μm3. S. aureus abscesses could be readily identified in blinded analyses of the kidneys after 3 days of infection, with low inter-observer variability. Comparison with histological sections shows a striking correlation between the two techniques: all presumptive abscesses identified by MRI were confirmed histologically, and histology identified no abscesses not evident on MRI. In view of this, simulations were performed assuming that both MRI reconstruction, and histology examining all sections of the tissue, were fully sensitive and specific at abscess detection. This simulation showed that MRI provided more sensitive and precise estimates of abscess numbers and volume than histology, unless at least 5 histological sections are taken through the long axis of the kidney. We used the MRI technique described to investigate the impact of a S. aureus Sortase A vaccine. Conclusion: Post mortem MRI scanning of large batches of fixed organs has application in the preclinical assessment of S. aureus vaccines. © 2016 Allen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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