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Repeated dose toxicity study of DNA-Tiantan vaccinia-combined AIDS vaccine in Balb/c mice
Abstract
Objective: A pre-clinical toxicology study of DNA-Tiantan vaccinia-combined AIDS vaccine was conducted to support the design of the phase I trial of the vaccine. Methods: DNA vaccine was initially injected intramuscularly 3 times, and then Tiantan Vaccinia HIV vaccine was boosted by intradermal injection once to Balb/c mice. The parameters of standard toxicology, immunogenicity and immunotoxicity were examined. Results: The strong immunogenicity of DNA-Tiantan vaccinia-combined HIV vaccine was observed after the vaccination. DNA-Tiantan vaccinia-combined HIV vaccine induced a strong and long-period of T cell response. No DNA-Tiantan vaccinia-combined HIV vaccine-related immunotoxicities were found. Conclusion: DNA-Tiantan vaccinia-combined HIV vaccine induces strong humoral and cellular immunoresponses without adverse effect on standard toxicology parameters and DNA-Tiantan vaccinia-combined HIV vaccine-related immunotoxicties.
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In this study, the design and preclinical development of a multigene human immunodeficiency virus type 1 (HIV-1) subtype C DNA vaccine are described, developed as part of the South African AIDS Vaccine Initiative (SAAVI). Genetic variation remains a major obstacle in the development of an HIV-1 vaccine and recent strategies have focused on constructing vaccines based on the subtypes dominant in the developing world, where the epidemic is most severe. The vaccine, SAAVI DNA-C, contains an equimolar mixture of two plasmids, pTHr.grttnC and pTHr.gp150CT, which express a polyprotein derived from Gag, reverse transcriptase (RT), Tat and Nef, and a truncated Env, respectively. Genes included in the vaccine were obtained from individuals within 3 months of infection and selection was based on closeness to a South African subtype C consensus sequence. All genes were codon-optimized for increased expression in humans. The genes have been modified for safety, stability and immunogenicity. Tat was inactivated through shuffling of gene fragments, whilst maintaining all potential epitopes; the active site of RT was mutated; 124 aa were removed from the cytoplasmic tail of gp160; and Nef and Gag myristylation sites were inactivated. Following vaccination of BALB/c mice, high levels of cytotoxic T lymphocytes were induced against multiple epitopes and the vaccine stimulated strong CD8+ gamma interferon responses. In addition, high titres of antibodies to gp120 were induced in guinea pigs. This vaccine is the first component of a prime-boost regimen that is scheduled for clinical trials in humans in the USA and South Africa.
Each year, approximately five million people die worldwide from putatively vaccine-preventable mucosally transmitted diseases. With respect to mass vaccination campaigns, one strategy to cope with this formidable challenge is aerosol vaccine delivery, which offers potential safety, logistical, and cost-saving advantages over traditional vaccination routes. Additionally, aerosol vaccination may elicit pivotal mucosal immune responses that could contain or eliminate mucosally transmitted pathogens in a preventative or therapeutic vaccine context. In this current preclinical non-human primate investigation, we demonstrate the feasibility of aerosol vaccination with the recombinant poxvirus-based vaccine vectors NYVAC and MVA. Real-time in vivo scintigraphy experiments with radiolabeled, aerosol-administered NYVAC-C (Clade C, HIV-1 vaccine) and MVA-HPV vaccines revealed consistent mucosal delivery to the respiratory tract. Furthermore, aerosol delivery of the vaccines was safe, inducing no vaccine-associated pathology, in particular in the brain and lungs, and was immunogenic. Administration of a DNA-C/NYVAC-C prime/boost regime resulted in both systemic and anal-genital HIV-specific immune responses that were still detectable 5 months after immunization. Thus, aerosol vaccination with NYVAC and MVA vectored vaccines constitutes a tool for large-scale vaccine efforts against mucosally transmitted pathogens.
• MVA HPV
• non-human primate
• NYVAC HIV
• preclinical study
• aerosol vaccine assessment
Coordinated interactions between helper and cytotoxic T-lymphocytes (HTL and CTL) are needed for optimal effector cell functions and the establishment of immunological memory. We, therefore, designed a mixed format vaccine based on the use of highly conserved HIV-derived T-lymphocyte epitopes wherein the HTL epitopes were delivered as a recombinant protein and the CTL epitopes which were encoded in a DNA vaccine plasmid. Immunogenicity testing in HLA transgenic mice and GLP preclinical safety testing in rabbits and guinea pigs were used to document the utility of this approach and to support Phase 1 trial clinical testing. Both vaccine components were immunogenic and safely co-administered.
Biotechnology-derived pharmaceuticals are a well established and growing part of the therapeutic armamentarium. Beginning with recombinant versions of products such as insulin that were previously manufactured by extraction from animal and human sources, licensed biotechnology drugs and those in development now span an ever-increasing range of product types and therapeutic categories. As a consequence of this diversity, both general and product class-specific scientific guidelines have been developed on a regional (e.g. EU/US) or international (e.g. ICH - International Conference on Harmonization) basis. The current portfolio of nonclinical guidelines, particularly ICH S6, emphasizes flexibility and adaptability to the specific circumstances of the individual biotechnology product and its intended indication, taking into account factors not generally applicable to small-molecule drugs, such as pharmacodynamic responsiveness of safety and efficacy models, species specificity, and antibody formation. Guidelines developed principally with small-molecule drugs in mind may, nevertheless, have some applicability to biotechnology drugs on issues such as safety pharmacology, as well as on regulatory, procedural and dossier submission requirements. Scientific guidelines, such as those providing nonclinical guidance, are just one, albeit important, component of an increasingly complex legal/scientific environment in drug development.
With a goal of developing a medication for the treatment of MUC1 expressing human cancers, a recombinant heat shock protein 65-MUC1 fusion protein (HSP65-MUC1) between BCG derived heat shock protein 65 (HSP65) and MUC1 derived peptide (MUC1) was developed. To move the HSP65-MUC1 into a phase I clinical trial, a comprehensive non-clinical safety evaluation was conducted. The evaluation comprised of single-dose toxicity and repeat-dose toxicity studies both in mice and rhesus monkeys. The data from the study indicates that the treatment with HSP65-MUC1 is not associated with obvious toxicity in the tested animals. The changes in clinical chemistry and hematology in both the mice and monkeys were considered to be mild because there were no indications of overt toxicity after administering HSP65-MUC1. The data provided here contributed to the approval of initiating a phase I clinical trial with HSP65-MUC1 for the treatment of patients with MUC1-positive breast cancer in China.