Comparison of different delivery systems of DNA vaccination for the induction of protection against tuberculosis in mice and guinea pigs

Carlos Rz Bladés,Célio L Silva,Fábio Cs Galleti,Daniela Carlos,Edson G Soares,Érika Vg Silva,Camila Matias-Peres,Lúcia H Faccioli,Carlos A Sorgi,Lúcia De Paula,Eduardo Dc Gonçalves,Patrícia Rm Souza,Vânia Ld Bonato

doi:10.1186/1479-0556-5-2

Abstract

The great challenges for researchers working in the field of vaccinology are optimizing DNA vaccines for use in humans or large animals and creating effective single-dose vaccines using appropriated controlled delivery systems. Plasmid DNA encoding the heat-shock protein 65 (hsp65) (DNAhsp65) has been shown to induce protective and therapeutic immune responses in a murine model of tuberculosis (TB). Despite the success of naked DNAhsp65-based vaccine to protect mice against TB, it requires multiple doses of high amounts of DNA for effective immunization. In order to optimize this DNA vaccine and simplify the vaccination schedule, we coencapsulated DNAhsp65 and the adjuvant trehalose dimycolate (TDM) into biodegradable poly (DL-lactide-co-glycolide) (PLGA) microspheres for a single dose administration. Moreover, a single-shot prime-boost vaccine formulation based on a mixture of two different PLGA microspheres, presenting faster and slower release of, respectively, DNAhsp65 and the recombinant hsp65 protein was also developed. These formulations were tested in mice as well as in guinea pigs by comparison with the efficacy and toxicity induced by the naked DNA preparation or BCG. The single-shot prime-boost formulation clearly presented good efficacy and diminished lung pathology in both mice and guinea pigs.

Highlights

Tuberculosis (TB) still remains a major health problem affecting millions of people worldwide [1]
Recombinant BCG strains, DNA-based vaccines, live attenuated M. tuberculosis vaccines and subunit vaccines formulated with novel adjuvants have shown promise in preclinical animal challenge models
In the prevention of TB, the prime-boost strategy of combining DNA priming and boosting with BCG or recombinant proteins has been evaluated by various authors [21,22]. Such protocols typically require more than one high amount of DNA dose for priming, followed by a booster with live vectors, thereby necessitating the use of large quantities of DNA. Taking into account these factors we evaluated both in mice and guinea pigs the use of a new concept in vaccine formulation based on a mixture of two different poly (lactic-co-glycolic acid) microspheres (PLGA) microspheres, presenting faster and slower release of, respectively, DNA encoding hsp65 and the recombinant hsp65 protein [20]

Summary

Introduction

Tuberculosis (TB) still remains a major health problem affecting millions of people worldwide [1]. The only TB vaccine currently available is Mycobacterium bovis BCG. The efficacy of BCG still remains controversial, especially against pulmonary TB in young adults, and development of a better vaccine is urgently required to counteract the global threat of TB [2,3,4]. Over the past 20 years, the technology of vaccine development has changed radically. Several strategies have been employed for generation and evaluation of new TB vaccines. Recombinant BCG strains, DNA-based vaccines, live attenuated M. tuberculosis vaccines and subunit vaccines formulated with novel adjuvants have shown promise in preclinical animal challenge models. The ability of DNA vaccines to elicit Th1 biased CD4+ responses and strong CTL responses make them attractive weapon against M. tuberculosis infection [9,10]

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