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Two vaccine formulations previously shown to induce protective immunity in mice and prevention of longterm necrosis in guinea pigs were tested as potential immunotherapeutic vaccines in mice earlier infected by aerosol with Mycobacterium tuberculosis. Neither vaccine had any effect on the course of the infection in the lungs, but both reduced the bacterial load in the spleen. Similarly, inoculation with Mycobacterium bovis BCG had no effect whatsoever and, if given more than once, appeared to induce an increasingly severe pyogranulomatous response in the lungs of these mice.

This study was undertaken to define the antigens in culture filtrates of actively replicating Mycobacterium tuberculosis that are recognized by antibodies from tuberculosis (TB) patients. Two-dimensional Western blots were probed with sera from healthy controls and TB patients that were preabsorbed with Escherichia coli lysates to deplete cross-reactive antibodies. Antibodies from TB patients recognized 26 of the >100 culture filtrate proteins, and the repertoire changed with disease progression. Only 12 of 26 antigens, including 3 proteins implicated in colonization and invasion by mycobacteria (MPT51, MPT32, and 85C), and 9 (as yet undefined proteins) were reactive with sera from TB patients with early noncavitary or cavitary disease. Eight additional antigens, including 4 undefined proteins, were recognized only by sera from a subset of patients with advanced cavitary disease. Studies suggest that 3 of the antigens recognized by sera from patients with early TB (85C, MPT32, and a 88-kDa protein) have strong serodiagnostic potential.

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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...