A similar approach is being used to generate new vaccines for malaria. Analysis of different stages of Plasmodium falciparum, the major cause of fatal malaria, identified genes that are selectively expressed in sporozoites within the mosquito’s salivary gland, where they first become infectious for human
Fig. 16.26 Genetically attenuated parasites can be engineered sporozoites with targeted disruption of key genes [for example, p52 as live vaccines to provide protective immunity. Top panel: and p36 (p52–/p36–), or uis3 (uis3–)], the sporozoites circulate in the wild-type Plasmodium sporozoites transmitted through the bite of bloodstream and mimic an early infection but cannot establish a an infected mosquito enter the bloodstream and are carried to the productive infection in the liver. The mice do, however, produce an liver, where they infect hepatocytes. Each sporozoite multiplies in the immune response against the sporozoites and are protected against liver, killing the infected cell and releasing thousands of merozoites, a subsequent infection by wild-type sporozoites. the next stage in infection. Bottom panels: in mice immunized with hepatocytes. Deletion of two such genes from the P. falciparum genome rendered sporozoites incapable of establishing a blood-stage infection in mice, yet capable of inducing an immune response that protected mice from subsequent infection by wild-type P. falciparum. This protection was dependent on CD8 T cells, and to some extent on IFN-γ, indicating that cell-mediated immunity is important for protection against this parasite (Fig. 16.26). This highlights once again the importance of being able to generate vaccines that are capable of inducing strong cell-mediated immunity.
16-25 The route of vaccination is an important determinant of success.
The ideal vaccination induces host defense at the point of entry of the infectious agent. Stimulation of mucosal immunity is therefore an important goal for vaccination against the many organisms that enter through mucosal surfaces. Still, most vaccines are given by injection. This route has several disadvantages. Injections are painful and unpopular, reducing vaccine uptake, and they are expensive, requiring needles, syringes, and a trained injector. Mass vaccination by injection is laborious. There is also the immunological drawback that injection may not be the most effective way of stimulating an appropriate immune response because it does not mimic the usual route of entry of the majority of pathogens against which vaccination is directed.
Many important pathogens infect mucosal surfaces or enter the body through mucosal surfaces. Examples include respiratory microorganisms such as
B. pertussis, rhinoviruses, and influenza viruses, and enteric microorganisms such as Vibrio cholerae, Salmonella typhi, enteropathogenic Escherichia coli, and Shigella. Intranasally administered live-attenuated vaccine against influenza virus induces mucosal antibodies, which are more effective than systemic antibodies in the control of upper respiratory tract infection. However, the systemic antibodies induced by injection are effective in controlling lower respiratory tract disease, which is responsible for the severe morbidity and mortality due to this disease. Thus, a realistic goal of any pandemic influenza vaccine is to prevent the lower respiratory tract disease but accept the fact that mild illness will not be prevented.