Intracellular pathogens: the role of antibody-mediated protection in Salmonella infection

The recent review in this journal by Dr Casadevall[1xCasadevall, A. Trends Microbiol. 1998; 6: 102–107Abstract | Full Text | Full Text PDF | PubMed | Scopus (73)See all References[1]is not only timely, but its message also illustrates the resultant pitfalls when scientists succumb to a bandwagon mentality and fail to review the literature in a scholarly way.The new paradigm put forward so brilliantly in 1964 by Dr George Mackaness proposed that host defense to intracellular pathogens of macrophages was dependent on cellular rather than humoral immunity[2xMackaness, G.B. J. Exp. Med. 1964; 120: 105–120Crossref | PubMedSee all References[2]. In the early 1960s, the concept of a thymus-dependent arm of the immune system that controlled both delayed-type hypersensitivity reactions and resistance to intracellular pathogens, and induced the `angry macrophage', was totally novel and captured everyone's imagination[3xMackaness, G.B. J. Infect. Dis. 1971; 123: 439–445Crossref | PubMed | Scopus (120)See all References[3]. Unfortunately, the paradigm was applied not only to mycobacteria and Listeria, where antibodies seem to play a limited role, but also to murine models of typhoid fever using infection with Salmonella typhimurium[4xMackaness, G.B., Blanden, R.V., and Collins, F.M. J. Exp. Med. 1966; 124: 573–583Crossref | PubMedSee all References, 5xBlanden, R.V., Mackaness, G.B., and Collins, F.M. J. Exp. Med. 1966; 124: 585–600Crossref | PubMedSee all References, 6xCollins, F.M., Mackaness, G.B., and Blanden, R.V. J. Exp. Med. 1966; 124: 601–619Crossref | PubMedSee all References]. The conclusion from these studies was that the only type of vaccine that would be truly effective against typhoid fever was live attenuated Salmonella, because live, but not killed, vaccines could induce cellular immunity[7xCollins, F.M. and Mackaness, G.B. J. Immunol. 1968; 101: 830–845PubMedSee all References[7].This conclusion, although theoretically appealing, disregarded at least half a century of empirical evidence: killed typhoid vaccine was introduced in 1897 and had excellent efficacy in British and American soldiers[8xWright, A. and Semple, D. Br. Med. J. 1897; 1: 256Crossref | PubMed | Scopus (21)See all References, 9xSee all References]. In addition, extensive field trials under the auspices of the World Health Organization demonstrated beyond question that nonviable vaccines were effective, with levels of protection as high as 85% for up to 7 years[10xSee all References[10]. Studies in many laboratories using mouse models of typhoid fever showed that killed vaccines, purified antigens and even semisynthetic O antigens protected mice against 100 LD50 doses of virulent Salmonella[11xLindberg, A.A. et al. Infect. Immun. 1974; 10: 541–545PubMedSee all References, 12xHerzberg, M., Nash, P., and Hino, S. Infect. Immun. 1972; 5: 83–90PubMedSee all References, 13xKuusi, N. et al. Infect. Immun. 1981; 34: 328–332PubMedSee all References, 14xJenkin, C.R., Rowley, D., and Auzins, I. Aust. J. Exp. Biol. Med. Sci. 1965; 42: 215–228CrossrefSee all References]. Nonviable extracts were assumed to work by induction of protective antibody, and several studies showed that passive immune serum protected mice against murine typhoid[15xOrnellas, E.P., Roantree, R.J., and Steward, J.P. J. Infect. Dis. 1970; 121: 113–123Crossref | PubMed | Scopus (29)See all References[15]. Several investigators, however, could not demonstrate protection with killed vaccines or with passive serum in mice[16xCollins, F.M. J. Bacteriol. 1969; 97: 667–675PubMedSee all References, 17xHobson, D. J. Hyg. 1957; 55: 334–343Crossref | PubMed | Scopus (13)See all References].Our laboratory reconciled these disparate results. We showed that nonviable vaccines and passive immune serum protected mouse strains that are inherently resistant to Salmonella infection, but not strains that are inherently hypersusceptible[18xEisenstein, T.K., Killar, L.M., and Sultzer, B.M. J. Infect. Dis. 1984; 150: 425–435Crossref | PubMedSee all References[18]. A retrospective review of the literature revealed that in studies in which nonviable vaccines or passive immune serum failed, hypersusceptible mice had been used, whereas in studies in which protection was achieved, inherently resistant mice had been used[18xEisenstein, T.K., Killar, L.M., and Sultzer, B.M. J. Infect. Dis. 1984; 150: 425–435Crossref | PubMedSee all References[18]. Consequently, the question we posed was whether the human is more like the inherently resistant or the inherently susceptible mouse[19xEisenstein, T.K. and Sultzer, B.M. Adv. Exp. Med. Biol. 1983; 162: 261–296Crossref | PubMedSee all References[19]. Based on the evidence showing that killed-cell vaccines protect, we concluded that the human is more like the resistant mouse, in which antibodies alone should be protective[19xEisenstein, T.K. and Sultzer, B.M. Adv. Exp. Med. Biol. 1983; 162: 261–296Crossref | PubMedSee all References[19].However, the attractiveness of the new theory of cellular immunity, which favored the use of live vaccines, led to a dismissal of the value of nonviable vaccines. Application of the cellular immunity theory spurred development of an oral attenuated strain of Salmonella as a vaccine. Strain Ty21a showed high levels of protection in initial trials in Egypt[20xWahdan, M.H. et al. Bull. WHO. 1980; 58: 469–474PubMedSee all References[20]but, when tested in Chile, showed levels of efficacy that were comparable with the killed vaccines[21xSee all References[21]. Dr John Robbins and co-workers, convinced of the power of antibody in host defense to Salmonella, developed a vaccine for typhoid fever composed only of the purified polysaccharide Vi antigen and showed that it was as protective as Ty21a in field trials[22xAcharya, I.L. et al. New Engl. J. Med. 1987; 317: 1101–1104Crossref | PubMedSee all References[22]. Thus, the human vaccine trials have shown that the live vaccine that induces cellular immunity is not superior to a microbial extract that only induces anti-Vi antibody.It is clear from laboratory studies and vaccine trials that, for Salmonella, both antibody and cellular immunity are effective in host defense[23xSee all References[23]. Salmonella is a paradigm for an organism that stands between the poles of mycobacteria and pneumococci, the former being held in check only by cellular immunity and the latter by humoral immunity. Dr Casadevall's elegant work suggests that cryptococci occupy a similar niche to that of Salmonella. The time has now come to modify our thinking to accommodate the possibility that, for some organisms that parasitize macrophages, both antibody and cellular immunity can be protective.