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MALARIA: Obstacles and Opportunities 9 Vaccines WHERE WE WANT TO BE IN THE YEAR 2010 After years of research, several different malaria vaccines will be available and licensed for use in humans. For infants and children in highly endemic regions of the world, an inexpensive, safe, and stable vaccine that gives long-lasting protection from death and severe clinical illness will be integrated into existing immunization programs. For nonimmune visitors to malarious areas and for the control of epidemics, there will be a vaccine that gives complete short-term protection against malaria with few side effects. Finally, a vaccine that confers no individual protection, but prevents the development of the parasite in the mosquito, will be used in combination with the other vaccines and control measures to reduce, and in some areas even interrupt, malaria transmission. WHERE WE ARE TODAY Prospects for a Vaccine Vaccination is an exceptionally attractive strategy for preventing and controlling malaria. Clinical and experimental data support the feasibility of developing effective malaria vaccines. For example, experimental vacci-
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MALARIA: Obstacles and Opportunities nation with irradiated sporozoites can protect humans against malaria, suggesting that immunization with appropriate sporozoite and liver-stage antigens can prevent infection in individuals bitten by malaria-infected mosquitoes. In addition, repeated natural infections with the malaria parasite induce immune responses that can prevent disease and death in infected individuals, and the administration of serum antibodies obtained from repeatedly infected adults can control malaria infections in children who have not yet acquired protective immunity. These data suggest that immunization with appropriate blood-stage antigens can drastically reduce the consequences of malaria infection. Finally, experimental evidence shows that immunization with sexual-stage antigens can generate an immune response that prevents parasite development in the vector, offering a strategy for interrupting malaria transmission. Prospects for the development of malaria vaccines are enhanced by the availability of suitable methods for evaluating candidate antigens. These include protocols that allow human volunteers to be safely infected with malaria, and the identification of many areas in the world where more than 75 percent of individuals can be expected to become infected with malaria during a three-month period. In contrast to vaccines for diseases of low incidence, for which tens of thousands of immunized and nonimmunized controls must be studied over several years, malaria vaccines could be evaluated in selected areas in fewer than 200 volunteers in less than a year. Developments in molecular and cellular biology, peptide chemistry, and immunology provide the technological base for engineering subunit vaccines composed of different parts of the malaria parasite, an approach that was not possible 10 years ago. During the last 5 years, more than 15 experimental malaria vaccines have undergone preliminary testing in human volunteers. Although none of these vaccines has proven suitable for clinical implementation, progress has been made in defining the parameters of a successful vaccine and the stage has been set for further advancement. Despite the inherent attractiveness and promise of this approach, there remain a number of obstacles to vaccine development. With the exception of the erythrocytic (blood) stages of P. falciparum, human malaria parasites cannot be readily cultured in vitro, limiting the ability of researchers to study other stages of this parasite and all stages of the other three human malaria parasite species. In vitro assays, potentially useful for screening candidate vaccines for effectiveness, do not consistently predict the level of protective immunity seen in vivo. The only laboratory animals that can be infected with human malaria parasites are certain species of nonhuman primates, which are not naturally susceptible to these organisms. This makes it difficult to com-
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MALARIA: Obstacles and Opportunities pare the results of many studies done in animals with what happens in human malaria infection. The promises of modern vaccinology, while potentially revolutionary, have so far proved elusive. Few commercially available vaccines have been produced by this technology, for both scientific and economic reasons. Scientists have not yet been able to assemble defined synthetic peptides and recombinant proteins and combine them with new adjuvants and delivery systems into a practical human malaria vaccine. However, as discussed above and in the remainder of this chapter, there are good reasons to believe that this approach will ultimately succeed. Approaches to Vaccine Development The complex life cycle of the malaria parasite provides a number of potential targets for vaccination (Figure 9-1). Under investigation are vaccines that would be effective against the extracellular sporozoite, during the short period it spends in the bloodstream; the exoerythrocytic (or liver-stage) parasite, during the roughly seven days it develops within liver cells; the extracellular merozoite, released from liver cells or infected erythrcytes and FIGURE 9-1 Host defense against malaria. (Adapted, with permission, from Rickman, L. S., and S. L. Hoffman. 1991. Malaria. Pg. 1039 in Medical Microbiology, 3rd Ed., S. Baron, ed. New York: Churchill Livingstone)
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MALARIA: Obstacles and Opportunities free in the circulation prior to invading other erythrocytes; the asexual parasite that develops within red blood cells; exogenous parasite material released from infected erythrocytes; and the sexual-stage parasite, which occurs both inside erythrocytes and in mosquitoes. The optimal vaccine would include antigens from the sporozoite, asexual, and sexual stages of the parasite, thus providing multiple levels of control, but vaccines effective against individual stages could also prove highly useful. In addition, a vaccine against the Anopheles mosquito itself, which reduced the insect's life span and prevented complete development of the parasite, could be valuable. Regardless of the stage of parasite targeted for vaccine development, a similar strategy is envisioned. Based on knowledge of the mechanisms of protective immunity, specific parasite antigens (immunogens) are identified that induce a protective immune response, and synthetic or recombinant vaccines that accurately mimic the structure of that antigen are prepared. In the subunit approach to vaccine development, this is done by combining the immunogen with carrier proteins, adjuvants, and live vectors or other delivery systems. This approach is being pursued throughout the world in laboratories studying infectious diseases. Clinical utility has yet to be demonstrated for the majority of these efforts, and barriers to obtaining satisfactory immunization by the subunit approach remain. Nevertheless, research on malaria subunit vaccines will continue to be at the cutting edge of this innovative and important approach to vaccine development. Pre-Erythrocytic Vaccines A pre-erythrocytic vaccine is designed to prevent malaria infection. If all sporozoites and liver stages of the parasite are destroyed before they can mature to cause blood-stage infection, all clinical manifestations of malaria will be prevented. Such a vaccine, even if it induced protection that lasted for only a few months, would be especially useful for tourists, diplomats, businessmen, military personnel, and other short-term visitors to malarious areas, since nonimmune individuals are highly susceptible to the rapid development of severe and fatal malaria. A pre-erythrocytic vaccine could be useful for long-term residents of malarious areas if it induced long-lasting protection, or if immunity could be boosted by natural exposure to malaria. Mechanisms of Immunity In the 1960s and 1970s a number of researchers showed that immunization with live sporozoites that were treated in such a way as to be noninfective
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MALARIA: Obstacles and Opportunities (attenuated) confers protection against subsequent sporozoite-induced malaria infection in mice, monkeys, and humans (Nussenzweig et al., 1967; Clyde et al., 1973a,b, 1975; Rieckmann et al., 1974, 1979; Gwadz et al., 1979). In the human studies, mosquitoes infected with malaria sporozoites were exposed to x-rays, and the resulting radiation-attenuated sporozoites were introduced into human volunteers during the mosquitoes ' blood meal. Immunization with radiation-attenuated sporozoites induces protection unlike that found after natural infection. Naturally acquired immunity seems to be directed primarily against the erythrocytic stages of the parasite, so that infection per se is not prevented, but people are protected from severe disease and death. Individuals who have lived for 20 or more years in endemic regions still become infected, although they may have few or no symptoms (Hoffman et al., 1987). In contrast, volunteers immunized with irradiated sporozoites do not develop any detectable blood-stage infection. The differences may be due in part to the fact that even in areas of the highest malaria transmission, naturally exposed individuals are bitten by relatively few infective mosquitoes (fewer than 50 per month) (Beier et al., 1990). Thus they may not receive sufficient stimulation by sporozoite antigens to induce the protective immune responses achieved by repeated exposure to many hundreds of irradiated, infected mosquitoes over a few weeks or months (Clyde et al., 1973a,b, 1975; Rieckmann et al., 1974, 1979). Vaccinating people with irradiated sporozoites cannot be routinely done. No culture system capable of producing large numbers of sporozoites is available or perhaps even feasible. Dissecting sporozoites from infected mosquitoes is far too labor intensive, and exposing people to mosquitoes containing irradiated sporozoites is not a tenable strategy. Given these limitations, the only hope for a pre-erythrocytic vaccine lies in the construction of a subunit vaccine, and researchers have been focusing on this objective. Identifying the mechanisms of protective immunity and the parasite antigens against which these protective immune responses are directed is a prerequisite to the development of this type of vaccine. Both antibodies and cellular immune responses contribute to this protection. Antibody-Mediated Immunity Mice and humans immunized with irradiated sporozoites develop antibodies directed against sporozoites. When administered to animals, some of these antisporozoite antibodies can protect against sporozoite-induced malaria infection (Potocnjak et al., 1980; Egan et al., 1987; Charoenvit et al., 1991a,b). Protective antisporozoite antibodies generally react with only a single species of malaria parasite and thus confer protection only against that species. This is similar to the species-specific immunity induced by immunization with irradiated sporozoites (Clyde et al., 1975).
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MALARIA: Obstacles and Opportunities The mechanisms by which antibodies confer protection are not certain. Antibodies can prevent the invasion of sporozoites into liver cells in culture (Hollingdale et al., 1984; Mazier et al., 1986), and it is likely these antibodies inhibit parasite binding to or invasion of liver cells. Antibodies appear to have other damaging effects on sporozoites, since those that successfully invade liver cells in the presence of antisporozoite antibodies often do not develop normally and fail to release merozoites that can initiate a blood-stage infection (Mazier et al., 1986). Conceivably, antibodies might also kill sporozoites directly or make them more susceptible to phagocytosis. Cell-Mediated Immunity Cell-mediated immunity is a broad classification that includes all immune responses that involve antigen-primed white blood cells (lymphocytes) or their products, other than antibodies. These are produced by B lymphocytes (so called because their maturation occurs in the bone marrow). The site on an antigen recognized by an antibody is known as a B-cell epitope. The cellular portion of the immune response includes T lymphocytes (so called because their maturation occurs in the thymus), natural killer cells, and monocytes. T lymphocytes have been further subdivided into helper cells (which enhance the production of antibody or stimulate other lymphocytes), suppressor cells (which suppress the production of antibody or inhibit other lymphocytes), and cytotoxic T lymphocytes (which directly kill other cells, including malaria-infected cells). The site on an antigen recognized by a T cell is known as a T-cell epitope. Both lymphocytes and monocytes secrete proteins, called cytokines, that affect the function of other cells. Some of these cytokines regulate the function of lymphocytes. Other cytokines act to destroy cells, including those that contain infectious agents such as malaria parasites. Cell-mediated immunity is an important part of the protection induced by immunization with irradiated sporozoites. For example, mice that are unable to produce antibodies can be successfully immunized with irradiated sporozoites (Chen et al., 1977). In addition, administration of immune lymphocytes to normal mice can protect them from sporozoite-induced malaria infection in the absence of anti-sporozoite antibodies (Egan et al., 1987). Experimental subunit sporozoite vaccines that elicit cell-mediated immunity without inducing antisporozoite antibodies also can protect mice against sporozoite-induced malaria (Sadoff et al., 1988). These studies suggest the presence of protective cell-mediated immune responses. There are a number of mechanisms by which cell-mediated immunity could protect against sporozoite-induced malaria. Cytokines such as gammainterferon may play a role. Gamma-interferon inhibits the development of malaria parasites in cultured liver cells (Ferreira et al., 1986; Mellouk et al., 1987). Treatment with agents that induce interferon production (Jahiel,
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MALARIA: Obstacles and Opportunities 1968a,b), or administration of purified gamma-interferon (Maheshwari et al., 1986; Schofield et al., 1987a) will protect animals from sporozoite-induced malaria. Cytotoxic T lymphocytes are also important. In some mouse strains, these cells appear to be the principal mechanism of protective immunity, since treatment of immunized mice with antibodies that destroy cytotoxic T lymphocytes renders them susceptible to sporozoite-induced malaria (Schofield et al., 1987b; Weiss et al., 1988). Some cytotoxic T lymphocytes recognize malaria-infected liver cells (Hoffman et al., 1989b; Weiss et al., 1990); administration of these cells can protect mice from sporozoite-induced malaria infection (Romero et al., 1989; Tsuji et al., 1990). A general feature of T lymphocytes is that they do not recognize whole antigens directly. Instead, they recognize fragments of antigens presented as a complex with certain host proteins (the major histocompatibility complex, or MHC, proteins) on the surface of cells. Thus, cell-mediated immune responses will not be directed against extracellular sporozoites in the circulation, but will instead be directed against malaria-infected liver cells (Hoffman et al., 1989b). Because sporozoites invade liver cells within a few minutes or hours but parasite maturation within liver cells takes many days, protective cell-mediated immune responses directed against infected liver cells may be more effective than antisporozoite antibodies. Targets of Pre-Erythrocytic Immunity In both humans and laboratory animals, immunity induced by irradiated sporozoites is both stage specific and species specific; that is, immunization with sporozoites does not protect against infection with blood-stage parasites, and immunization with P. falciparum sporozoites does not protect against infection with P. vivax (and vice versa). This suggests that the immune response is directed against species-specific antigens on the sporozoite or the host' s infected liver cells. Significantly, the protection is not strain specific; immunization with one P. falciparum isolate elicits protective immunity against isolates from other regions of the world (Clyde et al., 1973b). Circumsporozoite Protein For a number of reasons, initial efforts to develop a pre-erythrocytic vaccine have focused heavily on one protein found on the surface of the sporozoite, the circumsporozoite (CS) protein. The CS protein is a target of both protective antibody and cell-mediated immune responses. The gene encoding the CS protein was one of the first malaria genes to be cloned by using molecular biology techniques, and CS genes have been cloned from a large number of human and animal malaria
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MALARIA: Obstacles and Opportunities parasites (Chulay, 1989), which facilitates the testing of vaccines in various animal model systems. The CS proteins of all malaria parasites studied thus far are similar in size and overall structure but vary considerably in specific composition. All have a central region consisting of tandem repeats of species-specific amino acids (Dame et al., 1984). After immunization with irradiated sporozoites, most of the antibodies that develop are directed against the repetitive region of the CS protein (Zavala et al., 1983). Antibodies directed against the CS repetitive region inhibit sporozoite invasion into cultured liver cells (Mazier et al., 1986), and administration of such antibodies can completely protect against sporozoite-induced malaria in mouse and monkey model systems (Potocnjak et al., 1980; Egan et al., 1987; Charoenvit et al., 1991a,b). In P. falciparum, the repetitive region contains a series of four amino acids (asparagine-alanine-asparagine-proline) that has been detected in all isolates analyzed (Zavala et al., 1985). Thus, protective immunity directed against the repetitive region of P. falciparum would be expected to be species specific but not isolate specific. Antibodies against non-repetitive regions of the CS protein have also been shown to inhibit sporozoite invasion into cultured liver cells (Aley et al., 1986; D. M. Gordon, Department of Immunology, Walter Reed Army Institute of Research, personal communication, 1990). The CS protein is also a target of cell-mediated immunity. Mice and humans immunized with irradiated sporozoites develop cytotoxic T lymphocytes directed against portions of the CS protein (Kumar et al., 1988; Romero et al., 1989; Weiss et al., 1990; Malik et al., 1991). Such cytotoxic T lymphocytes can destroy malaria-infected liver cells in culture (Weiss et al., 1990), and administration of cloned T lymphocytes specific for portions of the CS protein can protect mice against sporozoite-induced malaria (Romero et al., 1989; Del Giudice et al., 1990). The CS protein also contains epitopes recognized by helper T lymphocytes. These T helper epitopes are present in both the repetitive and flanking non-repetitive regions of the CS protein (Good et al., 1987). Sporozoite Surface Protein 2 A second sporozoite surface protein (SSP2) that is a target of protective immunity has recently been identified in P. yoelii (Charoenvit et al., 1987; Hedstrom et al., 1990). Antibodies against SSP2 partially inhibit sporozoite invasion into liver cells in culture (S. Mellouk, unpublished), and administration of a cloned T lymphocyte that recognizes SSP2 can protect mice against sporozoite-induced malaria (S. Khusmith, unpublished). Immunization of mice with either a CS protein vaccine alone or an SSP2 vaccine alone can protect a proportion of mice against sporozoite-induced malaria, while concurrent immunization with both vaccines protects all mice (Khusmith et al., 1991). This synergistic effect emphasizes one of the advantages of including multiple antigens from a single parasite stage in a multicomponent malaria vaccine.
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MALARIA: Obstacles and Opportunities Other Sporozoite Proteins Antibodies directed against other sporozoite antigens can inhibit sporozoite invasion into liver cells in culture, and when administered to mice can protect them from sporozoite-induced malaria (Hollingdale et al., 1990). Administration of a cloned T lymphocyte that recognizes another sporozoite antigen, that is also expressed by infected erythrocytes, can also protect mice against sporozoite-induced malaria (Tsuji et al., 1990). Liver-Stage Antigens CS protein and other sporozoite antigens are expressed in malaria-infected liver cells. There are other antigens not found on sporozoites that are first produced by parasites developing within liver cells (Guerin-Marchand et al., 1987; Hollingdale et al., 1990). It is likely that some of these liver-stage antigens contain epitopes that are targets for protective cell-mediated immune responses. Impediments to Pre-Erythrocytic Vaccine Development Production of Antigen Sporozoites, like other stages of malaria parasites, cannot be produced in sufficient quantity or purity to be used to immunize humans. Malaria vaccine development has therefore relied on subunit vaccines. A subunit vaccine is generally constructed in three parts: the target of the desired protective immune response (e.g., B-cell epitopes as targets for antibodies and T-cell epitopes as targets for cytotoxic T lymphocytes); carrier peptide(s) to stimulate helper T lymphocytes; and an adjuvant or other delivery system to improve the magnitude and quality of the immune response. The first malaria sporozoite vaccines tested in humans contained the repetitive B-cell epitope of the CS protein plus T-cell epitopes from nonmalaria proteins and were constructed by using recombinant DNA technology or synthetic peptide chemistry (Ballou et al., 1987; Herrington et al., 1987). Other approaches have utilized entirely synthetic vaccines consisting of B- and T-cell epitopes from the CS protein (Tam et al., 1990) or malaria B-cell epitopes coupled to selected proteins or peptides that have helper but not suppressor epitopes. A peptide from tetanus toxoid with these latter properties has been described (Etlinger et al., 1990). In mice primed with bacillus Calmette-Guerin (BCG), a live, avirulent strain of tuberculosis bacterium, immunization with a vaccine consisting of the B-cell epitope of the P. falciparum CS protein coupled to a purified tuberculosis protein produced high titers of antibodies to sporozoites without the use of any other adjuvant (Lussow et al., 1990). Given the widespread sensitization of humans to tuberculosis proteins and BCG, this vaccine, or a recombinant BCG expressing the CS protein, might be effective. Recombinant live attenuated vaccines might also be used. For example,
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MALARIA: Obstacles and Opportunities insertion of the CS protein gene into attenuated strains of Salmonella creates a vaccine that can protect mice from sporozoite-induced malaria (Sadoff et al., 1988; Aggarwal et al., 1990). Although it is relatively easy to produce vaccines for animal immunization studies, production of subunit vaccine antigens of sufficient purity for trials in human volunteers is more difficult and expensive. Research laboratories studying malaria immunity are not equipped to produce these high-quality vaccines, and collaboration with pharmaceutical or biotechnology companies is generally necessary. Induction of the Appropriate Immune Response ANTIBODIES Administration of monoclonal antibodies directed against specific sporozoite B-cell epitopes can protect animals against sporozoite-induced malaria. Inducing high levels of antibody is thus one objective of immunization with sporozoite vaccines. Early subunit vaccines conferred complete protection from sporozoite-induced malaria in a small number of immunized volunteers who were experimentally exposed to the bites of infected mosquitoes, and they delayed the onset of blood-stage infection in other volunteers who had antibodies (Ballou et al., 1987; Herrington et al., 1987). Overall, however, these vaccines induced relatively low levels of antibody (Chulay, 1989). These antibody levels were lower than those to the same vaccine in mice and rabbits. They were also lower than the highest antibody levels induced by natural exposure to the bites of sporozoite-infected mosquitoes (Hoffman et al., 1987), and such levels of antibody are not protective. One way to increase the level of antibody induced by sporozoite vaccines is to change the carrier protein and the adjuvant. Early results suggest this approach can increase the level of antibody 10-fold (Rickman et al., 1991). The quantity of antibody is not the only determinant of protection, however. High levels of antisporozoite antibodies were achieved after immunization with the P. falciparum repetitive B-cell epitope coupled to a bacterial protein, but only one of eight volunteers was protected against malaria, and that individual did not have one of the highest levels of antibody (L. Fries, Associate Professor of International Health, Center for Immunization Research, Johns Hopkins School of Hygiene and Public Health, personal communication, 1990). The specificity of the antibody response is also important. For example, monkeys can be protected from sporozoite-induced P. vivax malaria by administration of a monoclonal antibody directed against the CS protein (Charoenvit et al., 1991b). This monoclonal antibody recognizes a four-amino-acid B-cell epitope contained within the nine amino acids of the repetitive portion of the CS protein (Charoenvit et al., 1991b). A recombinant P. vivax sporozoite vaccine containing all
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MALARIA: Obstacles and Opportunities nine amino acids of the CS repeat section that contained only the repetitive amino acids of the CS protein induced high levels of antisporozoite antibodies in monkeys and humans (Collins et al., 1989; Gordon et al., 1990), but these antibodies were not directed against the four-amino-acid B-cell epitope recognized by the protective monoclonal antibody (Charoenvit et al., 1991b). Protection does not appear to be a function of the specific immunoglobulin G (IgG) subclass of antibodies, since monoclonal antibodies of the IgG1, IgG2b, and IgG3 subclasses, as well as Fab fragments (antibodies lacking their subclass-specific portion), have all been shown to transfer protection passively in mice (Potocnjak et al., 1980; Egan et al., 1987; Charoenvit et al., 1991a,b). Protection also does not appear to be explained by differences between the structure of the native sporozoite protein and the synthetic and recombinant peptide subunit vaccines, since monoclonal antibodies produced by immunization with short peptides can also confer protection when administered to animals. Immunization undoubtedly produces polyclonal antibodies of varying affinities and specificities. To achieve consistent antibody-mediated protection, a vaccine may have to focus the immune response, or dramatically increase the overall production of antibody, to achieve appropriate concentrations of the “correct” antibodies. PASSIVE IMMUNIZATION Because passive transfer of monoclonal antibodies is so effective in protecting against sporozoite-induced malaria in animals, some researchers are working to develop human monoclonal antibodies against the repeat regions of the human malaria CS protein. These antibodies could be used to passively immunize short-term visitors to malarious areas in the same way that gamma globulin is used to prevent hepatitis A. CELL-MEDIATED IMMUNE RESPONSE Little is known about how to induce protective cell-mediated immune responses with subunit vaccines. Cytotoxic T lymphocytes generally are not induced by immunization with standard preparations of inactivated microbial antigens. Cytolytic T lymphocytes can be induced by immunization with recombinant live attenuated vaccines, such as those for salmonella, BCG, and vaccinia (smallpox vaccine). Work is in progress to construct recombinant live attenuated vaccines that express malaria genes and that might induce protective cell-mediated immune responses in humans. Cytotoxic T lymphocytes can also be induced by immunization with antigens contained within liposomes (small lipid-bound vesicles that can interact with cells of the immune system), immunostimulatory complexes (particles formed by antigen complexed with the detergent saponin) (Takahashi et al., 1990), and peptides containing a cytotoxic T-lymphocyte epitope
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Representative terms from entire chapter: