Malaria Vaccines: The Elements for Success Are Moving into Place
Despite the extraordinary economic and human toll exacted by malaria — and experimental evidence that an effective vaccine could be produced —funds for malaria vaccine development have been meager at best (see Hoffman, 1996, for a history of malaria vaccine development). The explanation for this discrepancy is complex, and includes the lack of a clear, coordinated strategy for vaccine development and the overall diminution of funds for global health activities. Thus, this chapter focuses on the scientific and organizational elements presented at the workshop that provide a basis for action.
Protection against malaria has been demonstrated in several rodent and primate models. Limited immunity against malaria has already been achieved with some vaccines in humans.
Over the past 40 years, numerous studies in man and animal models using different parasite strains have shown that immunity against malaria can be achieved through immunization (Nussenzweig et al., 1967). Radiation-attenuated sporozoites, when injected by mosquitoes or by needle in large numbers, can induce complete protection against malaria infection in animals and in man for a year or more. While this cumbersome method is unsuitable for widespread immunization, synthetic vaccines based on a single antigen derived from this process have successfully protected a small proportion of immunized subjects. Immunity that reduces parasite replication in the liver and in the blood stages of the parasite has been convincingly demonstrated in animal models, and it is reasonable to expect that such immunity could modify infection, and thus prevent or modify disease in humans. Furthermore, an immune response that prevents transmission of the parasite by mosquitoes has also been demonstrated. Research on the molecular biology and immunology of malaria has identified many antigens expressed at different stages of the infection that may contribute to effective immunity. The opportunity now exists to select and combine the best antigens with the most promising vaccine formulation methods to induce effective, multifaceted defenses against the parasite. Workshop participants agreed that such a broad-based approach involving multiple antigens from multiple stages of the parasite will be required for the next generation of malaria vaccines.
Remarkable advances in vaccinology offer great potential for use in malaria vaccines.
Research on both malaria and other infections diseases has generated new approaches to immunization that offer great promise for malaria vaccines. Nucleic acid vaccines, proteosomes, and several new adjuvants are examples of technologies that may be appropriate for the next generation of malaria vaccines.
Market forces for developing malaria vaccines, while not appreciated, are potentially vigorous, and growing on a global scale.
As with the development of any commercial product, a clearly identified market is essential. Remarkably little effort has been directed toward characterizing potential global markets for different malaria vaccines. The traditionally most attractive markets have been thought to be the military and “traveler” markets of North America and Europe—the vast emerging middle classes in South and Central America, Africa, India, and Southeast Asia, where the risk of malaria is widely recognized, have been largely overlooked. Nevertheless, the type of vaccine suitable for travelers, which may be quite expensive, could also find a vigorous and profitable market within these populations. It seemed likely to workshop participants that analyses of potential consumer populations would reveal a market of hundreds of millions of dollars annually, which would render a malaria vaccine an economically sound investment for a pharmaceutical company. The neediest populations, however, still comprise the poor and very large populations of Asia and Sub-Saharan Africa, which suffer disproportionate death and morbidity from malaria, yet have limited ability to pay for vaccines. Workshop participants recognized that a vaccine for reducing mortality in these populations, while potentially more feasible, must also be affordable. Large international agencies such as the World Health Organization, UNICEF, and the bilateral assistance agencies, which would be the most likely purchasers and distributors of vaccines for these populations, would have to do so through pricing and delivery agreements with vaccine manufacturers. Analyses of these markets, including cost-effectiveness studies of vaccine price supports compared with other methods of malaria prevention and control, are essential for informed decision-making by industry and the public sector.
Immunization-challenge studies in humans offer a means of rapid evaluation of efficacy for some types of malaria vaccines.
Obtaining evidence of safety and efficacy in the target population is a critical step for any new vaccine candidate. Early in the development process, preerythrocytic and sexual-stage malaria vaccines can be safely tested for efficacy through experimental challenge of a small number of tightly controlled and monitored volunteers recruited under informed consent procedures. Such small-scale trials ensure that only the most promising vaccine strategies proceed to more elaborate and expensive field trials. The expertise and technical support required to perform this procedure are available in academic centers and in Department of Defense laboratories.
Mechanisms are in place to allow field trials of malaria vaccines to be conducted in an efficient and cost-effective manner.
Proving efficacy in definitive field trials is a critical milestone in the vaccine development process, and it can easily be the most expensive phase, particularly if many thousands of subjects must be studied to achieve sufficient statistical power. This is clearly not the case for malaria—there are numerous areas in which malaria attack rates approach 100 percent yearly. Highly significant results for an effective malaria vaccine can thus be achieved with relatively small, focused field trials. This has been effectively demonstrated by the three field trials of the experimental vaccine, Spf66, in Tanzania, The Gambia, and Thailand (Alonso et al., 1994; D'Alessandro et al., 1995).1 Many promising field sites have already been developed with international funding in anticipation of near-term testing of vaccine candidates. These and other sites in development could be overseen and monitored by an extensive global malaria network of experienced researchers, foundations, and nongovernmental organizations that are anxious to participate in the process and could contribute resources that would greatly diminish the financial risk of taking vaccine candidates to field trials. One such promising example is the African Malaria Vaccine Testing Network, which was assembled in 1995 to strengthen malaria vaccine research capability in Africa and to coordinate and standardize regional field trials of candidate vaccines (Hviid and Jakobsen, 1995).
Clear and important spin-off benefits of malaria vaccine research can be identified.
The inherent complexity of the malaria parasite and the resulting immune response make it a natural target for cutting-edge fundamental and applied research.
As a result, malaria vaccine research has historically been a leader in the development of new technologies with broad applicability to human health. For example, the world's first recombinant vaccine produced in bacteria and the first synthetic peptide vaccine to be tested in humans were malaria vaccines. The most complex vaccine yet devised, an attenuated bioengineered vaccinia vector expressing
The efficacy of SPf66 has been evaluated recently in clinical trials carried out in Sub-Saharan Africa and Thailand. In Tanzanian children aged 1–5, the adjusted efficacy of SPf66 was estimated to be 31 percent (95 percent confidence intervals 0–52 percent; p < 0.05) in preventing clinical malaria (defined as fever and parasite density > 20,000parasites/µL blood) (Alonso et al., 1994). In infants in The Gambia who were 6–11 months of age at the time of first inoculation, the efficacy against first or only episodes of clinical malaria (defined as fever plus parasite density > 6,000 parasites/µL blood) was estimated to be 8 percent (95 percent confidence intervals 18–29 percent; p = 0.50) (D'Alessandro et al., 1995). Estimated efficacy against all episodes of clinical malaria was even lower, at 3 percent. A clinical trial of SPf66 carried out in children in Thailand was recently completed; the results are being analyzed, and should be available by late 1996.
seven malaria genes (NYVAC-P7), is a malaria vaccine now undergoing testing in humans. Malaria vaccine research was also one of the first research domains to incorporate recent technology using plasmid DNA vectors. In addition, some of the most advanced adjuvant work has been driven by malaria vaccine research, and these agents are likely to be important components of vaccines against HIV/AIDS, herpes, cancer, and other diseases.
Development of a malaria vaccine complements other important malaria control measures to limit the burden of disease in endemic regions.
Although malaria vaccines offer the greatest hope for sustained protection for the largest number of people, workshop participants acknowledged that on a global scale, malaria vaccines should be considered as one arm of a multicomponent malaria prevention and control strategy that includes mosquito control programs, the use of bednets and repellents, and chemoprophylaxis as the situation dictates.