Towards a strategy of universally efficacious vaccination against pathogens uniquely susceptible to cell-mediated attack

Infection by some intracellular parasites is contained only by cell-mediated immunity, and yet antibody is produced at the natural infection, leading to chronic or fatal disease. Effective vaccination must therefore generate an immunological imprint ensuring a strong and stable cell-mediated response upon infection. Such diseases include leprosy, tuberculosis, the leishmaniasis and AIDS (Kaplan and Cohn (1986) Int. Rev. Exp. Pathol. 28, 45-78; Surcel et al. (1994) Immunology 81, 171-176; Pearson et al. (1983) Rev. Infect. Dis. 5, 907-927; Clerici and Shearer (1993) Immunol. Today 14, 107-111). BALB/C mice are susceptible to Leishmania major, a protozoan that causes cutaneous leishmaniasis in man, by the criterion that substantial infection results in antibody production and progressive disease (Locksley and Scott (1991) Immunoparasitology Today, A58-A61; J.N. Menon and P.A. Bretscher, unpublished data). Infection of BALB/C mice with very few parasites results in an exclusive cell-mediated, Th1-like response and resistance to an ordinarily pathogenic, high dose challenge. This resistance is associated with a strong and stable cell-mediated response (Bretscher et al. (1992) Science 257, 539-542; J.N. Menon and P.A. Bretscher, unpublished data). The generation of this Th1 imprint by low dose infection has been achieved with three very different strains of the parasite. There is a similar dependency of susceptibility and resistance on relative parasite dose in 'susceptible' and 'resistant' mice and in mice of 'intermediate susceptibility'. For example, 'resistant' mice are resistant to substantial infection but succumb to infection with very high doses of parasites. We therefore propose that infection of a genetically diverse population with a very low dose of viable parasites, that does not induce antibody in any individual, will either induce cell-mediated immunity and contain the parasite, or the parasite will grow until it reaches the threshold required to induce cell-mediated immunity, thereby generating the required imprint. Low dose infection may thus constitute universally efficacious vaccination. The pertinence of these observations to improving the efficacy of BCG vaccination against tuberculosis is discussed.