The Combined CTA1-DD/ISCOMs Vector Is an Effective Intranasal Adjuvant for Boosting PriorMycobacterium bovisBCG Immunity toMycobacterium tuberculosis

Abstract

Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains one of the leading causes of mortality worldwide. The current "gold standard" vaccine Mycobacterium bovis BCG has a limited efficacy that wanes over time. The development of a vaccine to boost BCG-induced immunity is therefore a highly active area of research. Mucosal administration of vaccines is believed to provide better protection against pathogens, such as M. tuberculosis, that invade the host via mucosal surfaces. In this study we demonstrate that an intranasal vaccine, comprising the antigenic fusion protein Ag85B-ESAT-6 and the mucosal combined adjuvant vector CTA1-DD/ISCOMs, strongly promotes a Th1-specific immune response, dominated by gamma interferon-secreting CD4-positive T cells. Mucosal administration of Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs strongly boosted prior BCG immunity, leading to a highly increased recruitment of antigen-specific cells to the site of infection. Most importantly, we observed a significantly (P < 0.001) reduced bacterial burden in the lung compared to nonboosted control animals. Thus, the results demonstrate the effectiveness of mucosal vaccination with Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs as adjuvant for stimulating TB-specific protective immunity in the lung.Tuberculosis (TB) remains one of the leading causes of mortality worldwide, accounting for an estimated 2 to 3 million deaths each year (38). Furthermore, infection with Mycobacterium tuberculosis, the causative agent of TB, is a leading cause of mortality for individuals infected with human immunodeficiency virus (http://www.who.int/mediacenter/factsheets/fs104 /en/). When taken together with the spread of multidrug-resistant mycobacterial strains and the reemergence of the disease in the developed world, it becomes clear why TB remains at the forefront of public health awareness campaigns (32).While the Mycobacterium bovis BCG vaccine for TB remains the most extensively used vaccine worldwide and a large proportion of the population of most counties has already been vaccinated with BCG, the vaccine nonetheless has questionable efficacy. Current indications suggest that BCG does not convey life-long immunity and is of limited value in protecting against adult TB (7, 14, 26). Thus, there has recently been a growing interest in (i) the development of a TB vaccine that can effectively boost preexisting immunity generated by prior BCG vaccination and, hence, the discovery of a suitable adjuvant, or (ii) an improved BCG vaccine (8,15,18,27,33).M. tuberculosis is a pathogen which infects the individual via the mucosal tissue of the respiratory tract following inhalation of infectious droplets. While the majority of approaches to the development of a novel TB vaccine have focused on subcutaneous (s.c.) administration, there is evidence to suggest that mucosal vaccination is an efficient route of administration for vaccines against TB (16, 39); however, an efficient intranasal (i.n.) vaccine against TB requires an efficient mucosa...

Delivery strategies to enhance oral vaccination against enteric infections

“…These results suggest that to improve the oral efficacy of ISCOMs a modification of the immunization protocol such as including an oral/injectable prime-boost regimen or the use of additional coatings or adjuvants may improve efficacy. The inclusion of the mucosal adjuvant CTA1-DD did enhance the ability of nasally delivered ISCOMs to enhance immune responses [164], suggesting that the addition of an additional immune stimulatory component may serve to potentiate the oral efficacy of ISCOMs.…”

What Role Does the Route of Immunization Play in the Generation of Protective Immunity against Mucosal Pathogens?

“…A recent study showed that i.n. administration of the antigenic fusion protein Ag85B-EAST-6 mixed with the mucosal combined adjuvant vector CTA1-DD/ISCOM could significantly boost IFN-␥-secreting CD4 ϩ T cells in the lung elicited by prior BCG immunization and improved protection against M. tuberculosis challenge (25).…”

Primary Activation of Antigen-Specific Naive CD4+and CD8+T Cells following Intranasal Vaccination with Recombinant Bacteria

“…A novel, effective vaccination strategy against adult pulmonary TB has therefore become an international research priority. Nasal TB vaccines have been shown to be capable of inducing both local and systemic responses and to confer protection from infection (1,2,7,10,15,17,20,30,48,52,57). The exact correlates of protection against TB are not yet fully understood; however, CD4 ϩ and CD8 ϩ T cells have been shown to play a crucial role in conferring protection from M. tuberculosis infection (2, 53).…”