Boosting Vaccine for Tuberculosis

Abstract

An effective new vaccine for the control of tuberculosis is badly needed. While current research attempts to improve vaccination are concentrating on new prophylactic or immunotherapeutic vaccines, virtually no emphasis has been placed on boosting individuals already inoculated with Mycobacterium bovis BCG. It is shown here that mice vaccinated with BCG gradually lose their capacity to resist an aerosol challenge infection as they age. However, if these mice are inoculated with the 30-kDa mycolyl transferase A protein in midlife, after challenge when aged they express levels of protection in the lungs comparable to those of young mice, associated with minimal pathological damage.Currently available epidemiologic data indicate that disease caused by the facultative intracellular bacterial parasite Mycobacterium tuberculosis remains a serious global problem, with around 8 million new cases per year, and there is recent disturbing evidence that the death rate may be increasing (4,7,14,15). For several decades the Mycobacterium bovis-derived bacillus Calmette-Guérin (BCG) has been the only widely used vaccine for tuberculosis, and accumulating data from clinical trials and subsequent meta-analysis (5, 18) have tended to reveal its general ineffectiveness in adults (including those vaccinated with BCG as young children). As a result, many laboratories are now involved in a major effort to develop a new vaccine (12, 13), with virtually all efforts directed towards discovering new candidate vaccines that can be used in a prophylactic or immunotherapeutic mode (1,8,11).The mechanism underlying the gradual loss of effectiveness of BCG as the (neonatally inoculated) individual reaches 10 to 15 years of age is poorly understood. One possible assumption is that memory immunity generated by BCG has disappeared and the individual is now equivalent to a naive host who can be vaccinated with a new candidate vaccine designed to induce primary immunity. An alternate possibility is that memory immunity slowly declines but can be recovered by boosting if a candidate antigen that can be specifically recognized by this immunity is reintroduced. The results of this study support the latter contention.Several laboratories have shown that proteins found in the culture filtrates of M. tuberculosis are highly immunogenic and have promise as candidate vaccines (12). A component of this pool of proteins is the mycolyl transferase A (Ag85A) (3), and we have previously demonstrated that the largest proportion of CD4 T cells accumulating in the lungs of memory-immune mice after challenge infection recognize this antigen (6). Thus, to determine if Ag85A has the potential to boost existing memory immunity in BCG-vaccinated mice, these animals were boosted twice at 9 and 15 months of age and then challenged with virulent M. tuberculosis when elderly. As shown here, this procedure restored the capacity of these mice to express resistance to this infection.Female C57BL/6J mice were purchased from Jackson Laboratories, Bar Harbor, Maine. They were k...

Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guerin mutants that secrete listeriolysin

“…A combination of both strains, therefore, may be considered for replacing conventional BCG for vaccination of newborns. Recently, several subunit vaccine candidates have been described, which can be used to boost immune responses induced by BCG prime (38)(39)(40)(41)(42). It is tempting to assume that a combination of priming with improved BCG such as ∆ureC hly + rBCG and boosting with the most efficacious subunit vaccine would provide more powerful intervention measures against one of the major threats among infectious diseases, tuberculosis.…”

Evaluation of the Mtb72F Polyprotein Vaccine in a Rabbit Model of Tuberculous Meningitis

“…Consequently, new vaccines will be tested and potentially administered in previously BCG-vaccinated individuals. This need is addressed by the prime-boost approach that we have tested (8,32,33). In our experiments, the boosting of BCG with Mtb72FϩAS01B resulted in a significant reduction in the inflammatory response (P was 0.02 for WBC in CSF), less weight loss as well as a reduced bacillary load, and attenuated pathology in the brains of infected rabbits (Table 1).…”

“…Animals boosted with Mtb72F-DNA showed better resolution and earlier healing of lung lesions. One of the current views in TB vaccine design is that existing memory immunity should be targeted with a specific antigen that is recognized by a sufficient number of memory CD4 ϩ T cells (8). Recently, a few prime-boost studies, using Rv3407 DNA (33), Ag85A (8), or MVA85A (modified vaccinia virus Ankara expressing antigen 85A) (32) as a boost, appeared to achieve superior protection compared to that conferred by BCG vaccination alone in mice and improved immunity in humans.…”

“…Consequently, a number of research groups are engaged in developing more effective anti-TB vaccines by utilizing either new attenuated live vaccines (4,12,20,22,39,40,47,49) or subunit protein vaccines (3,6,11,26,34,37,41). While attenuated live vaccines provide prolonged exposure of the host immune system to newly synthesized antigens, the advantage of subunit vaccines is the possibility that their efficacy may not be compromised by exposure to environmental mycobacteria (5) or by prior BCG vaccination (8).…”

The dream of a vaccine against tuberculosis; new vaccines improving or replacing BCG?

“…Experiments using protein subunits in animals previously vaccinated with BCG (BCG+), and using prime-boost protocols give very good results [24]. These experiments used Ag85A, because it was previously demonstrated that most CD4 T cells accumulating in the lungs of memory-immune mice after challenge recognise this antigen.…”