Adrian V. S. Hill

“ Nonetheless, the continuing unacceptable impact of malaria morbidity and mortality, amounting to over 800 000 deaths and some 250 million clinical episodes annually [ [5] has led to a variety of sustained efforts to develop effective malaria vaccine candidates. In the last decade in particular, the development of vaccine candidates for malaria has accelerated considerably and one candidate has recently reached the stage of a large-scale phase III trial while other potentially complementary approaches are showing increasing promise. ”

“ Abstract There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. ”

“ The main hurdle has been the concern that deployment of such a transmission-blocking vaccine would prove impractical. Because adults and older children can transmit malaria as well as infants and young children, the target population has to be all residents of an area where transmission reduction is the aim. This type of mass vaccination has been undertaken on occasion for other diseases but may prove logistically challenging. ”

“ Development of an effective malaria vaccine has been a great challenge for medical science but findings and approaches pioneered in efforts to develop a malaria vaccine are proving useful in developing a whole range of vaccines against other difficult diseases. ”

“ By then, the importance of cellular immunity in providing protection against the liver-stage of the parasite had been confirmed in animal models of irradiated sporozoite immunization [ [18] . This led to efforts to induce significant cellular immunity using a new approach—plasmid DNA immunization. The low potency of first generation DNA vaccines [ [19] led to the development of heterologous prime-boost immunization approaches with non-replicating viral vectors that showed some efficacy that could not be attributed to antibody-dependent immunity [ [20] . ”

“ There is substantial stage-specificity of antigen expression by Plasmodium parasites so that candidate vaccines for one stage of the life cycle (figure 1) are unlikely to impact on another stage. Finally, malaria vaccine developers are faced with target species P. falciparum and Plasmodium vivax that will not infect small animals or old world macaques, so excluding the most widely used animal models for straightforward vaccine evaluation. There are many other malaria parasites that infect these species but these differ substantially from human parasites. ”

“ Although natural immunity to malaria develops in most residents of endemic areas, this generally takes some years of exposure and is imperfect. Extensive immunoepidemiological studies have provided limited insight into what the best antigens to include in a vaccine might be: natural immunity predominantly targets a wide variety of blood-stage antigens and no one antigen appears to be especially important in providing protection [9] . ”

“ A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. ”

“ This has proved difficult but possible in some murine models of malaria and this has encouraged many attempts at vaccination against Plasmodium falciparum, the major target species for malaria vaccine development. Parasite vaccines generally face the challenge of generating immunity with an immunogen that reflects only a tiny fraction (less than 1%) of the composition of the organism, a challenge that has been met only rarely in vaccinology. ”

“ In some cases, clear induction of antibodies with activity in impairing parasite growth in a standardized growth inhibitory assay has been achieved [47] but that has not been associated with significant vaccine efficacy. A telling comparator may be that strong adjuvants have generally induced antibody levels comparable to those seen in semi-immune adults living in endemic areas. Such adults have significant protective immunity from natural exposure because they have antibody responses to very large numbers of antigens not just one or two as in vaccinees. ”

“ As described above, the two subunit vaccine strategies that have achieved most efficacy in humans are a protein/adjuvant vaccine, specifically RTS,S, that induces antibodies that clear sporozoites before they can enter the liver, and vectored vaccines that clear infected liver cells. ”

“ A related prime-boost approach is being developed by the US Naval Medical Research Centre, but here the priming vector is plasmid DNA, and a human adenovirus, Ad5, is used to boost the immune response [38] . As in the Oxford programme, several antigenic inserts from both pre-erythrocytic stage and blood stages are under assessment with some encouraging efficacy data in a recent challenge trial (T. Richie 2011, personal communication) . ”

“ In contrast, antibody levels induced to CSP by RTS,S or T cells to TRAP induced by prime-boost vaccination are over a 100-fold higher than levels induced by natural exposure. The third difficulty has been posed by the extensive polymorphism of many leading candidate blood-stage antigens [ [49] : some vaccine candidates include more than one allele to try to overcome this but it remains to be seen how successful this approach will be. ”

“ RTS,S reduces parasite numbers by over 95 per cent and vectored vaccines by over 90 per cent. Viewed in this way, there appears to be a compelling case for testing combinations of leading sporozoite antibody-inducing and liver-stage T cell-inducing vaccines in humans in the near future. This could considerably accelerate the identification of a highly effective deployable malaria vaccine using components that are already in clinical development. ”

“ These systems provide a means of rapidly assessing the likely efficacy of sera from vaccinees participating in phase I trials of mosquito-stage vaccines, a major advantage of this approach to malaria vaccine development. Indeed, in the only reported clinical trial a sexual-stage, Pfs25-based, P. falciparum vaccine generated significant transmission-blocking activity in some vaccinees, even though the trial was not finished owing to safety issues with the protein–adjuvant formulation employed [55] . ”

“ One is difficulty in expressing conformationally correct large antigens and scaling up the methods needed to do this to the extent that would allow large-scale manufacture. A second challenge has been the only modest antibody responses achieved even with a range of new adjuvants. ”

“ Efforts to develop this approach further are ongoing but the major question is whether a means of growing large numbers of parasites in blood or a blood-substitute can be developed which will be acceptable to regulatory authorities, given the tiny risk of unknown infections in any donated human blood. ”

“ Pre-erythrocytic vaccines, which target the sporozoite and the liver-stage parasite are intended to prevent infection as well as disease while blood-stage vaccines are intended to prevent clinical illness and death. Vaccines against parasites 2.
Most of the vaccines that are available today belong to one of three categories—attenuated microbes, killed microbes or protein subunits. Attenuated viruses that protect against a cross-reactive pathogen originate with Jenner's use of a related poxvirus to prevent smallpox. Killed microbes were introduced a century later and several such vaccines, e.g. ”