Mucosal Vaccination against Tuberculosis Using Inert Bioparticles

Abstract

c Needle-free, mucosal immunization is a highly desirable strategy for vaccination against many pathogens, especially those entering through the respiratory mucosa, such as Mycobacterium tuberculosis. Unfortunately, mucosal vaccination against tuberculosis (TB) is impeded by a lack of suitable adjuvants and/or delivery platforms that could induce a protective immune response in humans. Here, we report on a novel biotechnological approach for mucosal vaccination against TB that overcomes some of the current limitations. This is achieved by coating protective TB antigens onto the surface of inert bacterial spores, which are then delivered to the respiratory tract. Our data showed that mice immunized nasally with coated spores developed humoral and cellular immune responses and multifunctional T cells and, most importantly, presented significantly reduced bacterial loads in their lungs and spleens following pathogenic challenge. We conclude that this new vaccine delivery platform merits further development as a mucosal vaccine for TB and possibly also other respiratory pathogens. Athird of the world's population is estimated to be infected with Mycobacterium tuberculosis, the causative pathogen of tuberculosis (TB). Although the incidence of TB has been slowly decreasing from year to year, this disease still accounts for over a million deaths per annum, mostly in the developing world. TB, however, is also beginning to have an impact on the more developed nations, for example, because of the increased levels of people movement and international travel, which only serve to disseminate TB. Controlling TB relies on a number of strategies, including vaccination, drug therapy, and improved living standards. However, only improved living standards have been shown to have any real impact, and both the current TB drugs and vaccination strategies carry a number of inherent flaws. With drug therapy, multiresistant strains of M. tuberculosis and, more recently, extensively drug-resistant (XDR) M. tuberculosis variants have emerged, showing that drug development may, at most, produce only a short-term impact. The current vaccine against TB, M. bovis BCG, is generally considered unsatisfactory because of its variable efficacy (in different parts of the world) and the shortlived protection that it confers, especially against the reactivated pulmonary form of the disease. For these reasons, BCG is no longer routinely used in some countries.Bearing in mind these concerns, a better vaccine is now a priority. It should be noted that the results of the first-ever efficacy trial (phase 2b) of a new TB vaccine (MVA85A) that could boost the efficacy of BCG was concluded in early 2013 but with disappointing results (1). Although other trials are planned or are in progress for at least nine other TB vaccines, it is clear that the tasks ahead will be challenging. There are some important issues regarding the design of TB vaccines that might now be reconsidered, for example, the general assumption that cellular responses are of paramount imp...

Epitope‐specific CD4+, but not CD8+, T‐cell responses induced by recombinant influenza A viruses protect against Mycobacterium tuberculosis infection

“…Ag85B‐coated nanoparticles delivered intranasally into mice conferred protective immunity against TB both when administered alone and adjuvanted by CpG . Similarly, M. tuberculosis ‐specific proteins adsorbed to Bacillus subtilis killed spores administered intranasally to mice induced humoral responses and multifunctional T cells and protected against M. tuberculosis challenge . Another strategy is the use of spray‐dried particles containing mycobacterial components for pulmonary delivery.…”

RecombinantBacillus subtilisspores expressing MPT64 evaluated as a vaccine against tuberculosis in the murine model

“…In the nonrecombinant approach, antigens are adsorbed onto the spore surface by a combination of covalent and hydrophobic bonding (Huang et al ., ). Interestingly, this approach has been shown to work well using killed spores of B. subtilis adsorbed with influenza H1N1 virions as well as the MPT64 and Acr‐Ag85B antigens of Mycobacterium tuberculosis (Song et al ., ; Reljic et al ., ). In both cases, nasal administration of adsorbed spores conferred measurable levels of protection in murine models of infection (Song et al ., ; Reljic et al ., ).…”

Mucosal vaccine delivery by non-recombinant spores of

“…As in the previous cases, adsorption of the two M. tuberculosis antigens was pH-dependent. Intranasally administered spores were able to reach the alveoli and to induce both humoral and cellular immune responses [36]. Immunized animals were protected in a challenge experiment and presented reduced mycobacterial loads in their lungs and spleens, confirming that mucosal vaccinations are particularly effective against pathogens entering the animal body through the mucosal surfaces [36].…”

“…Spore-adsorbed pentamers are reacted with the purified receptor (GM1). Spores are visualized by immunofluorescence microscopy with anti-GM1 primary antibody and Texas red conjugated secondary antibody [36]. The same microscopy field is observed by phase contrast and fluorescence microscopy.…”