Preclinical study and clinical trial of a novel therapeutic vaccine against multi-drug resistant tuberculosis

Abstract

ABSTRACT[Purpose] Multi-drug resistant (MDR), Mycobacterium tuberculosis (TB) is a big problem in the world. We have developed novel TB therapeutic vaccine (HVJ-E/HSP65 DNA CIL-12 DNA).[Methods and Results] DNA vaccine expressing TB heat shock protein 65 and IL-12 was delivered by the hemagglutinating virus of Japan (HVJ)-envelope. This vaccine provided remarkable protective efficacy and strong therapeutic efficacy against MDR-TB and XDR-TB in murine models. Furthermore, this vaccine provided therapeutic efficacy of prolongation of survival time of TB infected monkeys and augmented the immune responses. Therefore, the preclinical tests were studied for clinical trial. The injection of 100 mg of the vaccine /mouse i.m. three times in two weeks induced significantly strong production of IFN-g and IL-2. 100 mg and 200 mg DNA vaccine/mouse i.m. augmented the production of these cytokines compared with 25 mg DNA vaccine/mouse i. m.. The ratio of 100 mg pDNA to 1AU HVJ-E enhanced the production of IFN-g and IL-2. The decrease in the number of M. tuberculosis in liver of mice was observed by the vaccination of 100mg pDNA. By using these conditions, safety pharmacology study and toxicology test is being studied in monkeys administered by GMP level DNA vaccines. By the toxicology test using monkeys, high dose GMP level vaccine/ monkey is administrated. Safety pharmacological study of repeated administration is also being investigated in GLP level. Furthermore, we have planned to do clinical phase I trial. Targets are human patients with MDR-TB. The safety and tolerability of the vaccine will be evaluated.[Conclusion and recommendations] These data indicate that our novel vaccine might be useful against tuberculosis including XDR-TB and MDR-TB for human therapeutic clinical applications.

Advance in strategies to build efficient vaccines against tuberculosis

“…Okada et al developed a DNA vaccine expressing tuberculosis antigen HSP65 and cytokine IL-12, which was encapsulated by Japanese hemagglutination virus (HVJ). The study found that the ability to induce IFN-γ and IL-12 is stronger when using 100 μg DNA, which was better than the PDD control group ( 156 ). Mangalakumari Jeyanathan et al developed an adenovirus-based tuberculosis vaccine for respiratory inoculation, which provided a valuable reference of aerosol vaccine strategies.…”

Mechanisms of ag85a/b DNA vaccine conferred immunotherapy and recovery from Mycobacterium tuberculosis‐induced injury

“…(2) Subunit vaccine: Of the subunit vaccines prepared from some cell components of the MTB complex, BCG polysaccharide and nucleic acid injection (trade name Siqikang) has obtained a new drug certificate in China 18 ; RUTI (prepared from MTB H37Rv cultured under low oxygen, low pH and low nutrient conditions by crushing, detoxification and then embedding in liposomes), 18 and four recombinant protein vaccines (M72/AS01E, H56/IC31, ID93/GLA‐SE, and AEC/BC02) have entered phase I or II clinical trials 20–22 ; (3) DNA vaccine: Of the DNA vaccines constructed from the genes encoding MTB antigen and eukaryotic expression vectors, only Korean GX‐70 (composed of four MTB antigen plasmids and Flt3 ligand) has obtained the approval for phase I clinical trial (http://ClinicalTrials.gov Identifier: NCT03159975), but this study has been withdrawn because of unconfirmed research expenses. Although no TB DNA vaccine has entered the clinical trial status, many results of animal experiments proved that DNA vaccine could provide remarkable protective efficacy and strong therapeutic effect on mouse TB models 23–25 …”

“…Although no TB DNA vaccine has entered the clinical trial status, many results of animal experiments proved that DNA vaccine could provide remarkable protective efficacy and strong therapeutic effect on mouse TB models. 23 , 24 , 25 …”

“…Although no TB DNA vaccine has entered the clinical trial status, many results of animal experiments proved that DNA vaccine could provide remarkable protective efficacy and strong therapeutic effect on mouse TB models. [23][24][25] MTB Ag85A and Ag85B are secreted proteins and antigens recognized by host innate immune cells at an early stage, with good immunogenicity. However, the adaptive immune response in the mouse lungs arrests the proliferation of MTB and results in a 10 to 20-fold reduction in the messenger RNA (mRNA) expression of the secreted Ag85 complex.…”

Antigens for DNA Vaccines Against Tuberculosis

“…The first experimental DNA vaccine against TB was developed by Lowrie et al in 1994 by cloning the cross-reactive mycobacterial antigen HSP65 in a plasmid [10]. The recombinant plasmid-based DNA vaccines expressing HSP65 have been shown to provide protection against M. tuberculosis challenge in preventive studies in mice [11], and have also shown therapeutic potential in mouse and monkey models of TB [12,13]. A number of DNA vaccines providing protection against TB in animal models have been developed using other cross-reactive antigens of M. tuberculosis, e.g.…”