Extraordinarily few organisms of a live recombinant BCG vaccine against tuberculosis induce maximal cell-mediated and protective immunity

Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis

“…In line with these results is the observation that systemic vaccination with BCG using a wide range of inocula generates similar levels of protection against tuberculosis (27)(28)(29). Finally, intradermal vaccination of guinea pigs with as few as 10 BCG microorganisms induced similar protection to that of a high dose (10 6 BCG microorganisms) vaccination, despite marginal dissemination (30). Thus, it appears that dose and route of application and consequently the dissemination and tissue localization of BCG have minor impact on protective immunity against tuberculosis.…”

A Replication-Limited Recombinant Mycobacterium bovis BCG Vaccine against Tuberculosis Designed for Human Immunodeficiency Virus-Positive Persons Is Safer and More Efficacious than BCG

“…This is in contrast to the case for BCG, where increasing the dose to 10 6 CFU from 10 3 CFU did not increase protective efficacy ( Fig. 7B and D) (nonsignificant differences in the lung and spleen for both experiments), as previously reported (24). rBCG(panCD)30, like rBCG(mbtB)30, was more efficacious when it was administered at a dose of 10 6 CFU than 10 3 CFU (Fig.…”

“…rBCG(mbtB)30 expresses r30 at a similar level to that in rBCG30, the highly potent recombinant BCG vaccine we previously developed (22,(24)(25)(26), and was made safer than BCG for immunocompromised persons by specifically engineering the strain to undergo limited replication in vivo. This was achieved by deletion of mbtB, resulting in a strain that cannot synthesize the mycobactin and exochelin molecules that are needed by mycobacteria for the acquisition of iron under low-iron conditions, such as occurs at sites of mycobacterial replication in the host (10,42).…”

“…The observation that high doses of rBCG(panCD)30 are well tolerated in the guinea pig, a species that is more susceptible than humans to M. bovis and M. tuberculosis infection, bodes well for the safety of high doses of this vaccine in humans. In their dose dependence, these vaccines differ from BCG and rBCG30, which induce cell-mediated and protective immunity independent of dose over 5 orders of magnitude (24). To summarize the impact of increasing the dose of the vaccine on tolerability and protective efficacy, (i) much higher doses of the replicationlimited vaccine rBCG(panCD)30 than of the replication-proficient vaccine BCG are tolerated and (ii) increasing the dose of the replication-limited vaccines rBCG(mbtB)30 and rBCG (panCD)30 enhances their protective efficacy, compensating for their limited replication, whereas increasing the dose of the replication-proficient vaccines BCG and rBCG30 does not enhance their protective efficacy.…”

Scope and Perspectives of New TB Drugs and Vaccines

“…Assessment of safety and efficacy of new vaccines that can replace BCG will require vigorous and careful analyses with assays and trials. rBCG30 rBCG30 is the future vaccine against TB developed by Marcus A Horwitz's team at University of California, Los Angeles (Kaufmann et al, 2010;Horwitz et al, 2006) (Fig. 2).…”