Intranasal Mucosal Boosting with an Adenovirus-Vectored Vaccine Markedly Enhances the Protection of BCG-Primed Guinea Pigs against Pulmonary Tuberculosis
Background Recombinant adenovirus-vectored (Ad) tuberculosis (TB) vaccine platform has demonstrated great potential to be used either as a stand-alone or a boost vaccine in murine models. However, Ad TB vaccine remains to be evaluated in a more relevant and sensitive guinea pig model of pulmonary TB. Many vaccine candidates shown to be effective in murine models have subsequently failed to pass the test in guinea pig models. Methods and Findings Specific pathogen-free guinea pigs were immunized with BCG, AdAg85A intranasally (i.n), AdAg85A intramuscularly (i.m), BCG boosted with AdAg85A i.n, BCG boosted with AdAg85A i.m, or treated only with saline. The animals were then infected by a low-dose aerosol of M. tuberculosis (M.tb). At the specified times, the animals were sacrificed and the levels of infection in the lung and spleen were assessed. In separate studies, the long-term disease outcome of infected animals was monitored until the termination of this study. Immunization with Ad vaccine alone had minimal beneficial effects. Immunization with BCG alone and BCG prime-Ad vaccine boost regimens significantly reduced the level of M.tb infection in the tissues to a similar extent. However, while BCG alone prolonged the survival of infected guinea pigs, the majority of BCG-immunized animals succumbed by 53 weeks post-M.tb challenge. In contrast, intranasal or intramuscular Ad vaccine boosting of BCG-primed animals markedly improved the survival rate with 60% of BCG/Ad i.n- and 40% of BCG/Ad i.m-immunized guinea pigs still surviving by 74 weeks post-aerosol challenge. Conclusions Boosting, particularly via the intranasal mucosal route, with AdAg85A vaccine is able to significantly enhance the long-term survival of BCG-primed guinea pigs following pulmonary M.tb challenge. Our results thus support further evaluation of this viral-vectored TB vaccine in clinical trials.
References
[1]
L？nnroth K, Raviglione M (2008) Global epidemiology of tuberculosis: prospects for control. Semin Respir Crit Care Med 29: 481–491.
[2]
Xing Z, Charters ThomasJ (2007) Heterologous boost vaccines for BCG prime immunization. Expert Rev Vaccines 6: 539–546.
[3]
Ly LH, McMurray DN (2008) Tuberculosis: vaccines in the pipeline. Expert Rev Vaccines 7: 635–650.
[4]
McShane H, Hill A (2005) Prime-boost immunisation strategies for tuberculosis. Microbes Infect 7: 962–967.
[5]
Karonga Prevention Trial Group (1996) Randomized controlled trial of single BCG, repeated BCG or combined BCG and killed Mycobacteium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Lancet 348: 17–24.
[6]
Rodrigues LC, Pereira SM, Cunha SS, Genser B, Ichihara MY, et al. (2005) Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial. Lancet 366: 1290–1295.
[7]
Basaraba RJ, Izzo AA, Brandt L, Orme IM (2006) Decreased survival of guinea pigs infected with Mycobacterium tuberculosis after multiple BCG vaccinations. Vaccine 24: 280–286.
[8]
Buddle BM, Wedlock DN, Parlane NA, Corner LA, De Lisle GW, et al. (2003) Revaccination of neonatal calves with Mycobacterium bovis BCG reduces the level of protection against bovine tuberculosis induced by a single vaccination. Infect Immun 71: 6411–6419.
[9]
Izzo A, Brandt L, Lasco T, Kipnis AP, Orme I (2005) NIH pre-clinical screening program: overview and current status. Tuberculosis (Edinb) 85: 25–28.
[10]
Wang J, Thorson L, Stokes RW, Santosuosso M, Huygen K, et al. (2004) Single mucosal, but not parenteral, immunization with recombinant adenoviral-based vaccine provides potent protection from pulmonary tuberculosis. J Immunol 173: 6357–6365.
[11]
Xing Z, Santosuosso M, McCormick S, Yang TC, Millar J, et al. (2005) Recent advances in the development of adenovirus- and poxvirus-vectored tuberculosis vaccines. Curr Gene Ther 5: 485–492.
[12]
Santosuosso M, Zhang X, McCormick S, Wang J, Hitt M, et al. (2005) Mechanisms of mucosal and parenteral tuberculosis vaccinations: adenoviral-based mucosal immunization preferentially elicits sustained accumulation of immune protective CD4 and CD8 T cells within the airway lumen. J Immunol 174: 7986–7994.
[13]
Santosuosso M, McCormick S, Roediger E, Zhang X, Zganiacz A, et al. (2007) Mucosal luminal manipulation of T cell geography switches on protective efficacy by otherwise ineffective parenteral genetic immunization. J Immunol 178: 2387–2395.
[14]
Santosuosso M, McCormick S, Zhang X, Zganiacz A, Xing Z (2006) Intranasal boosting with an adenovirus-vectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG immunization against pulmonary tuberculosis. Infect Immun 74: 4634–4643.
[15]
Vordermeier HM, Huygen K, Singh M, Hewinson RG, Xing Z (2006) Immune responses induced in cattle by vaccination with a recombinant adenovirus expressing mycobacterial antigen 85A and BCG. Infect Immun 74: 1416–1418.
[16]
Mu J, Jeyanathan M, Small CL, Zhang X, Roediger E, et al. (March 24 2009) Immunization with a bivalent adenovirus-vectored tuberculosis vaccine provides markedly improved protection over its monovalent counterpart against pulmonary tuberculosis. Mol Ther (e-pub ahead of print).
[17]
Yamamoto T, Lasco TM, Uchida K, Goto Y, Jeevan A, et al. (2007) Mycobacterium bovis BCG vaccination modulates TNF-alpha production after pulmonary challenge with virulent Mycobacterium tuberculosis in guinea pigs. Tuberculosis (Edinb) 87: 155–165.
[18]
Ly LH, Russell MI, McMurray DN (2008) Cytokine profiles in primary and secondary pulmonary granulomas of Guinea pigs with tuberculosis. Am J Respir Cell Mol Biol 38: 455–462.
[19]
Williams A, Hatch GJ, Clark SO, Gooch KE, Hatch KA, et al. (2005) Evaluation of vaccines in the EU TB Vaccine Cluster using a guinea pig aerosol infection model of tuberculosis. Tuberculosis (Edinb) 85: 29–38.
[20]
Tatsis N, Ertl HC (2004) Adenoviruses as vaccine vectors. Mol Ther 10: 616–21.
[21]
Santosuosso M, McCormick S, Xing Z (2005) Adenoviral vectors for mucosal vaccination against infectious diseases. Viral Immunol 18: 283–291.
[22]
Williams A, Goonetilleke NP, McShane H, Clark SO, Hatch G, et al. (2005) Boosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigs. Infect Immun 73: 3814–3816.
[23]
Brandt L, Skeiky YA, Alderson MR, Lobet Y, Dalemans W, et al. (2004) The protective effect of the Mycobacterium bovis BCG vaccine is increased by coadministration with the Mycobacterium tuberculosis 72-kilodalton fusion polyprotein Mtb72F in M. tuberculosis-infected guinea pigs. Infect Immun 72: 6622–6632.
[24]
Brennan MJ, Fruth U, Milstien J, Tiernan R, de Andrade Nishioka S, et al. (2007) Developing Countries Vaccine Regulatory Network and the Ad Hoc Regulatory and TB Expert Panel. Development of new tuberculosis vaccines: a global perspective on regulatory issues. PLoS Med 4: e252.
[25]
Horwitz MA, Harth G, Dillon BJ, Maslesa-Galic S (2005) Enhancing the protective efficacy of Mycobacterium bovis BCG vaccination against tuberculosis by boosting with the Mycobacterium tuberculosis major secretory protein. Infect Immun 73: 4676–4683.
[26]
Lei XF, Ohkawara Y, St？mpfli MR, Gauldie J, Croitoru K, et al. (1998) Compartmentalized transgene expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mouse lung enhances allergic airways inflammation. Clin Exp Immunol 113: 157–165.
[27]
Damjanovic D, Zhang X, Mu J, Fe Medina M, Xing Z (2008) Organ distribution of transgene expression following intranasal mucosal delivery of recombinant replication-defective adenovirus gene transfer vector. Genet Vaccines Ther 6: 5.
[28]
Kugathasan K, Roediger EK, Small CL, McCormick S, Yang P, et al. (2008) CD11c+ antigen presenting cells from the alveolar space, lung parenchyma and spleen differ in their phenotype and capabilities to activate na？ve and antigen-primed T cells. BMC Immunol 9: 48.
[29]
Ibanga HB, Brookes RH, Hill PC, Owiafe PK, Fletcher HA, et al. (2006) Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design. Lancet Infect Dis 6: 522–528.
[30]
(Mar 19 2009) EUREKALERT TB vaccine developed at McMaster University in Canada. Genetic Engineering & Biotechnology News. 2.
