12 World Health • SlstYeor, No. 3, Moy-June 1998 A vaccine for malaria? Howard Engers & Nina Mattock

constitute a powerful addition to severe and life-threatening con­ these tools. sequences of malaria in non­ Natural exposure to malaria leads immune individuals. About 20 to the development of partial immu­ human clinical trials with various nity in humans, but repeated re­ Plasmodiumfalciparum pre­ infection is required to maintain this erythrocytic vaccine candidates immunity. Inactivated sporozoites have been conducted to date. (parasite forms living in the mos­ One highly promising candidate, quito which are infective to humans) "RTS,S", is currently in field have been shown to be highly effec­ trials in the Gambia. tive at inducing immunity in hu­ • Asexual blood-stage vaccines mans. Unfortunately, it is not prevent the parasite merozoite possible to produce inactivated stage from entering or develop­ sporozoites in the enormous num­ ing within red blood cells. bers required to make this a feasible Immunity against the asexual method of vaccination. However, blood stages of the parasite, we now have new technologies at which are responsible for the our disposal. Nucleic acid-based symptoms of malaria, would DNA vaccine technology, for exam­ have a direct impact on disease ple, allows us to identify promising morbidity and death in the indi­ A child receives the third and final dose of a immunogenic molecules much more vidual but would not necessarily malaria vaccine as part of a field trial to test its rapidly, and this considerably ex­ prevent people from getting efficacy under African conditions. African children stand to gain most from an effective pands the number of potential infected. At least six asexual malaria vaccine. Photo WHO/TOR/A Crump vaccines. Novel adjuvants - neutral blood stage vaccines have been substances that enhance the body's tested clinically or are currently immune response to antigens - are undergoing human trials. Improved knowledge and becoming available for clinical use. • Transmission-blocking vaccines Other delivery systems (live vectors inhibit development of the sexual the availability of new such as salmonella or vaccinia which stages of the parasite within the incorporate antigen gene sequences, mosquito. The sexual forms of technologies give us reason and DNA vaccines) are under devel­ the malaria parasite develop in to believe that vaccination opment and starting to be evaluated the red blood cells a few weeks in humans. after infection, and are infective against malaria is possible. This improved knowledge and for mosquitos biting infected the availability of new technologies individuals. With wide coverage give us reason to believe that vacci­ these vaccines could reduce n the last decade, considerable nation against malaria is possible. transmission of the disease in progress has been made in the endemic regions by reducing the I search for a malaria vaccine, and number of mosquitos infected. the tum of the century is expected to Several transmission-blocking see one or more such vaccines being What sort of vaccines are candidate vaccines are already actively developed by the pharma­ being developed? undergoing clinical trials for ceutical industry. safety and immunogenicity in the Globally, malaria is a major The malaria parasite has a number of USA. public health problem. The story of different stages in its life cycle (see mosquito resistance to insecticides figure on page 13). Candidate vac­ Vaccines currently under develop­ and parasite resistance to drugs cines are based on various antigens ment include: impeding malaria control is a famil­ derived from these different stages: • Vaccines based on cocktails of iar one. And while there are re­ • Pre-erythrocytic vaccines pre­ antigens (multicomponent vac­ newed efforts to combat malaria vent the malaria parasite sporo­ cines). The first multicomponent both through conventional and novel zoite stage from entering or synthetic peptide vaccine SPf66, drugs and through vector control developing within liver cell s. developed by Dr Manuel activities, an effective vaccine would Such vaccines would prevent the Patarroyo in Colombia (repre- World Health • SlstYear, No. 3, May-June 1998 13

senting three asexual blood stage malaria, there is the problem of not strains or isolates of the parasite can antigens and a sporozoite anti­ being able to grow malaria parasites also express different forms of the gen), is the most widely tested in large enough quantities to make same antigens. A multicomponent vaccine to date. It has given vaccines in the traditional way, vaccine, aimed at covering several mixed results in field trials in either from live but weakened organ­ of the antigens, could overcome this South America, Africa and isms or from crude antigen prepara­ problem but would be highly com­ South-East Asia. tions. Hence the focus on synthetic plex and difficult to develop. And • Another multicomponent vaccine, peptides, recombinant proteins or finally, there is the complexity of engineered in attenuated vaccinia DNA vaccines. One difficulty is conducting the clinical and field virus and expressing three pre­ that, in clinical trials so far, most trials themselves, when researchers erythrocytic proteins, three asex­ vaccines have failed to live up to the are confronted with measuring the ual blood-stage an tigens and a potential they have shown experi­ reduction of morbidity and mortality transmission-blocking candidate, mentally in animal models. This following vaccination with a candi­ gave limited protection in a situation may be overcome when date vaccine. human clinical trial in the USA. novel, more powerful adjuvants for Research on vaccines against • A third multicomponent asexual human use become available. malaria is mainly supported by a blood-stage vaccine under devel­ Then there is the difficulty of variety of international agencies, opment by Australian scientists is evaluation. The fact that there are organizations, foundations and currently undergoing clinical trial no good in vitro surrogate screening national funding agencies, including in Papua New Guinea. systems to assess the efficacy of the governments of some countries different vaccines in the laboratory and various research institutes. Second-generation vaccines include is a significant limitation, and means There is also greater involvement of those that contain modified malarial that vaccines have to be tested ex­ the private sector when vaccine peptides or novel adjuvants; DNA perimentally, often in expensive, candidates have reached advanced · vaccines (nucleotide sequences time-consuming animal model stages of development. encoding the antigen in question), systems, including monkeys. which have shown promising results Another problem is that, unlike in rodent models; and antitoxic or less complex organisms, parasites Where do we go from here? anti-disease vaccines. have developed ingenious ways of avoiding the host's immune There is no guarantee that the cur­ response. For instance, the malaria rent promising approaches to Why is a vaccine for malaria parasite expresses different antigens malaria vaccine development will proving so elusive? at each stage of its life cycle, and is result in a cost-effective malaria often able to change these antigens vaccine. Nevertheless, new tech­ We don't yet have a vaccine for any when the host mounts an immune nologies are becoming available and human parasitic disease. For response towards them. Different there is intensified political and financial support for research on malaria. The UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Di seases (TDR) is committed to evaluating the currently available Antibodies and cell­ leading P. f alciparum malaria vac­ mcdiatcd immunity cine candidates in clinical trials by can inhibit liver stage development 2005. If all goes well, a malaria vaccine could be ready for use Multi-component sometime in the next decade. • vaccine

+- Antibodies and cytokines can block infection of RB C and inhibit malaria pathogenesis development into sporozoites Asexual blood-stage vaccine Transmission-blocking vaccine

Dr Howard Engers and Dr Nino Mattock are with the Special Programme for Research and Training in Tropical Diseases, W orld Health Different stages (in red circles) in the malaria parasite life cycle provide a range of targets for the Organization, I 2 I I Geneva 27, vaccines. Graphic by WHO/ TOR Switzerland.