Academic literature on the topic 'IMX313P'

Plasmodium falciparum transmission-blocking vaccines (TBVs) targeting the Pfs25 antigen have shown promise in mice but the same efficacy has never been achieved in humans. We have previously published pre-clinical data related to a TBV candidate Pfs25-IMX313 encoded in viral vectors which was very promising and hence progressed to human clinical trials. The results from the clinical trial of this vaccine were very modest. Here we unravel why, contrary to mice, this vaccine has failed to induce robust antibody (Ab) titres in humans to elicit transmission-blocking activity. We examined Pfs25-specific B cell and T follicular helper (Tfh) cell responses in mice and humans after vaccination with Pfs25-IMX313 encoded by replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA) delivered in the heterologous prime-boost regimen via intramuscular route. We found that after vaccination, the Pfs25-IMX313 was immunologically suboptimal in humans compared to mice in terms of serum Ab production and antigen-specific B, CD4+ and Tfh cell responses. We identified that the key determinant for the poor anti-Pfs25 Ab formation in humans was the lack of CD4+ T cell recognition of Pfs25-IMX313 derived peptide epitopes. This is supported by correlations established between the ratio of proliferated antigen-specific CD4+/Tfh-like T cells, CXCL13 sera levels, and the corresponding numbers of circulating Pfs25-specific memory B cells, that consequently reflected on antigen-specific IgG sera levels. These correlations can inform the design of next-generation Pfs25-based vaccines for robust and durable blocking of malaria transmission.

BackgroundTransmission blocking vaccines targeting the sexual-stages of the malaria parasite could play a major role to achieve elimination and eradication of malaria. The Plasmodium falciparum Pfs25 protein (Pfs25) is the most clinically advanced candidate sexual-stage antigen. IMX313, a complement inhibitor C4b-binding protein that forms heptamers with the antigen fused to it, improve antibody responses. This is the first time that viral vectors have been used to induce antibodies in humans against an antigen that is expressed only in the mosquito vector.MethodsClinical trial looking at safety and immunogenicity of two recombinant viral vectored vaccines encoding Pfs25-IMX313 in healthy malaria-naive adults. Replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding Pfs25-IMX313, were delivered by the intramuscular route in a heterologous prime-boost regimen using an 8-week interval. Safety data and samples for immunogenicity assays were taken at various time-points.ResultsThe reactogenicity of the vaccines was similar to that seen in previous trials using the same viral vectors encoding other antigens. The vaccines were immunogenic and induced both antibody and T cell responses against Pfs25, but significant transmission reducing activity (TRA) was not observed in most volunteers by standard membrane feeding assay.ConclusionBoth vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. However, the transmission reducing activity of the antibodies generated were weak, suggesting the need for an alternative vaccine formulation.Trial RegistrationClinicaltrials.gov NCT02532049.

AbstractMalaria control relies heavily on the use of anti-malarial drugs and insecticides against malaria parasites and mosquito vectors. Drug and insecticide resistance threatens the effectiveness of conventional malarial interventions; alternative control approaches are, therefore, needed. The development of malaria transmission-blocking vaccines that target the sexual stages in humans or mosquito vectors is among new approaches being pursued. Here, the immunological mechanisms underlying malaria transmission blocking, status of Pfs25-based vaccines are viewed, as well as approaches and capacity for first in-human evaluation of a transmission-blocking candidate vaccine Pfs25-IMX313/Matrix-M administered to semi-immune healthy individuals in endemic settings. It is concluded that institutions in low and middle income settings should be supported to conduct first-in human vaccine trials in order to stimulate innovative research and reduce the overdependence on developed countries for research and local interventions against many diseases of public health importance.

No vaccines are available for hepatitis C virus (HCV) which infects over 71 million people worldwide. Current therapeutic options are very expensive and as a consequence, only around 1% of those diagnosed with Hepatitis C receive treatment each year. Induction of neutralizing antibody (NAb) by vaccination will be important for the successful prevention of HCV infection. HCV envelope glycoproteins E1 and E2 are required for virus entry into host cells making these proteins attractive targets to prevent virus infection. DNA-based vaccines are appealing candidates for novel vaccine development because they are not infectious and are cost-effective to manufacture on a global scale. However, despite being licensed for veterinary use, DNA vaccine have not been highly immunogenic in large animals. Virus-like particles (VLP), on the other hand, which resemble native viruses but are non-infectious because they lack viral genetic materials, have provided highly encouraging results in clinical trials. In this thesis the immunogenicity of VLPs and the ease of production of plasmid DNA were combined by designing DNA vaccines encoding VLPs consisting of HCV-core, E1 and E2 proteins (which can self-assemble into VLPs following expression). This vaccine also encoded a cytolytic gene perforin (PRF) to cause cell death and ensure the release of the VLPs from vaccine-targeted cells along with damage associated molecular patterns (DAMPs), which act as natural adjuvants. Bicistronic DNA vaccine constructs encoding HCV structural proteins and PRF were successfully generated and validated. Vaccination with the DNA construct encoding CoreE1E2-PRF generated higher adaptive immune responses in mice than vaccination with a construct unable to induce cell death, therefore confirming an adjuvant effect by PRF. However, these responses were weak compared to those reported in the literature. Antigen oligomerisation has been shown to improve vaccine immunogenicity. To improve the immunogenicity of a DNA vaccine encoding HCV-E1E2, a novel strategy that incorporates E1 and E2 into heptamers by fusion with the oligomerisation domain of a chimeric C4 binding protein (namely IMX3133 or IMX313P) was used. As the adjuvanticity of IMX313 or IMX313P requires efficient secretion of the oligomerised protein, the leader sequence of the tissue plasminogen activator (tPA) was introduced upstream of the E1 or E2 proteins (tE1 or tE2) from which the transmembrane domains were removed. The use of tE1 and tE2 proteins as separate immunogens or as a single tE1tE2 polyprotein when fused to IMX313 or IMX313P was assessed in vaccination studies in Balb/c mice using prime-boost intra-dermal DNA immunisations. Vaccination with the DNA construct encoding tE1/tE2 fused to IMX313 or IMX313P resulted in increased antibody and cell mediated immune (CMI) responses compared to the same dose of DNA without IMX313 or IMX313P, while fusion of tE1/tE2 to IMX313P resulted in the highest immune responses. DNA prime/E1E2 protein boost or DNA prime/HCV-VLP boost approaches were then used to further improve the immunogenicity of tE1/tE2-IMX313P DNA constructs. Boosting with E1E2 proteins improved overall antibody responses, compared to boosting with HCV-VLPs or plasmid DNA. However, experiments to examine the neutralisation of binding of labelled VLPs showed that the E1E2 or VLP boost did not improve the neutralising potency of these antibodies or the CMI responses. This thesis demonstrated that expression of heptamerised and secreted tE1/tE2 from DNA vaccine constructs significantly improved the antibody and CMI responses to HCV E1 and E2 proteins. Most importantly, the antibody induced by these constructs possess neutralising properties.
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2018

Background Vaccination is the most cost effective and long-term solution to the global human immunodeficiency virus (HIV) pandemic. The HIV Gag and Tat proteins are attractive components of a HIV vaccine as immune responses targeting these proteins confer protective benefits against HIV infections in humans. This thesis has developed two innovative candidate HIV vaccines viz. a DNA vaccine encoding oligomerised and secreted Tat (pVAXsTat-IMX313), and a recombinant live human rhinovirus serotype A1 (HRV-A1)-based vaccine encoding Gag and Tat (rHRV-Gag/Tat). Methods To construct pVAX-sTat-IMX313, Tat was fused with the oligomerisation domain of IMX313 to form Tat heptamers and linked to the leader sequence of tissue plasminogen activator to ensure that the bulk of oligomerised protein is secreted. To develop the rHRVGag/Tat vaccine, initially, the full length tat gene and 5 discrete overlapping fragments corresponding to the full length gag gene were individually inserted into the junction between the HRV-A1 genes encoding structural and non-structural proteins (P1/P2 junction) to ensure that the exogenous HIV Gag or Tat proteins were separated from the recombinant polyprotein using the HRV encoded 2Aprotease enzyme. Thus, one recombinant HRV encoding Tat (rHRV-Tat) and 5 rHRVs each encoding a unique Gag fragment (rHRV-Gag1-5) were generated. The individual rHRVs were then mixed into a single cocktail vaccine (rHRVGag/Tat), purified and titrated for inoculation in mice. The immunogenicity of these vaccines was evaluated in female BALB/c mice that received up to five intradermal injections of pVAX-sTat-IMX313 (50 μg per dose) at 2 weekly intervals in one study. In another study, mice were vaccinated intranasally with 2 doses (5x106 TCID50/dose) of the rHRV-Gag/Tat followed by a single 50 μg booster dose of a cocktail DNA vaccine containing pVAX-sTat-IMX313 and pVAX-Gag-Perforin. Vaccine-induced immune responses were examined 2 weeks after the last dose by antibody ELISA, in-vitro Tat transactivation neutralization, IFN-γ ELISpot, KdGag197-205 tetramer staining and intracellular cytokine staining assays. Results Data showed that fusing Tat with IMX313 results in complete heptamerisation of Tat. Furthermore, the data suggested that pVAX-sTat-IMX313 vaccination elicited higher titers of serum neutralizing Tat-specific IgG, secretory IgA (sIgA) in the vagina and CMI responses, and showed superior control of ecotropic HIV (EcoHIV) infection, a surrogate murine HIV challenge model, compared with animals vaccinated with other DNA vaccines tested in this study. Human rhinovirus serotype A1 (HRV-A1) was successfully engineered into a replication-competent genetically stable recombinant vector to deliver a mucosally-targeted vaccine, rHRV-Gag/Tat, by inserting exogenous HIV gag and tat sequences into the HRV-A1 genome. Finally, intranasal administration of 2 doses of rHRV-Gag/Tat followed by a single DNA booster dose induced superior poly-functional Gag-specific CD8 T cell responses in the spleen (systemic) and mesenteric lymph nodes (mucosal), higher Tat-specific serum IgG and sIgA in the vagina, and effective control of EcoHIV infection compared to other vaccination regimens tested in this study. Conclusion First, the data support the inclusion of IMX313 as a molecular adjuvant for Tat-based HIV DNA vaccines. Second, the data demonstrated that intranasal vaccination with rHRV-Gag/Tat followed by a single DNA booster dose is effective in eliciting HIV-specific immunity panmucosally and systemically. Collectively, the data support further testing of the pVAX-sTat IMX313 and rHRV-Gag/Tat vaccines in macaques, preferably in a heterologous prime-boost vaccination strategy, and results from these studies might influence future HIV clinical trials.
Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, Adelaide Medical School, 2016.