**3.1** *Plasmodium falciparum*

234 Malaria Parasites

garnered much support from funding organisations [35]. As both subunit and whole parasite approaches are valid approaches [35, 36], they are being pursued in parallel. This

Malaria vaccines fall into three main classes based on the lifecycle stage that they target and

i. Pre-erythrocytic vaccines – based on antigens on the surface of the sporozoite or liver stage parasites or whole parasite (sporozoite approaches). These vaccines are designed to target the pre-erythrocytic stages of the parasite lifecycle and therefore inhibit

ii. Blood stage vaccines – based on antigens on the surface of the blood stages such as the merozoite or intraerythrocytic stages or whole blood stage parasites. These diseaseblocking vaccines are designed to control parasitaemia by preventing invasion of uninfected erythrocytes (merozoite targets) or to control disease by preventing

iii. Transmission blocking vaccines – based on antigens on the surface of the sexual stages, expressed either within the human host or anopheline vector. Known as transmissionblocking vaccines because they are designed to elicit antibodies within the human host that will target gametocytes (transmission forms) or to be taken up in the mosquito

Vaccine approaches currently being tested include individual candidates from a single lifecycle stage as well as combination vaccines formulated with targets from multiple

The advent of recombinant DNA technology has greatly facilitated the development of subunit malaria vaccines by providing the tools with which to synthesise large amounts of parasite protein, and to disrupt gene expression for detailed functional characterisation [40- 42]. Preclinical development for many candidate antigens has been successful and Phase II clinical trials have proceeded for at least eight candidate antigens, with evidence of

The release of the first full malaria genome sequence in 2002 allowed the systematic identification of novel malaria vaccine candidates amongst approximately 5300 genes. Genome wide screening for single nucleotide polymorphisms (SNPs) has been used to reveal loci under positive selection and therefore encoding proteins that may be targeted by the immune response [4, 47]. Proteomics approaches have characterised the "immunome" [48], and measured the abundance of parasite proteins on the parasite surface [49]. A pipeline of bioinformatic screens has also been used to identify surface proteins, gene knockouts and high-throughput immunological assays to identify novel surface antigens (e.g. [50]). In the last 10 years, the list of potential malaria vaccine candidates has rapidly expanded to encompass many antigens about which there is still much to be learnt. Targets that were discovered first are therefore further down the development pipeline rather than

cytoadhesion (intraerythrocyte targets), which leads to pathogenesis.

blood meal to target parasite proteins within the mosquito midgut.

antimalarial efficacy for MSP2 [6], CSP [43, 44], MSP3 [45] and AMA1 [46].

review focuses primarily on the former approach.

their expected biological effects [37-39]. These include:

**3. Subunit vaccine candidate antigens** 

novel proteins that may ultimately be more successful.

**2.4 Malaria vaccine subclasses** 

infection.

lifecycle stages.

*P. falciparum* is responsible for most of the mortality and morbidity associated with malaria, with up to 1 million deaths and around 225 million clinical cases caused by this species [52]. It is the only major human malaria parasite for which an *in vitro* culture system is available thus making it more tractable for investigations to characterise molecular structure and function and interactions with its human and anophelene hosts. As a result, malaria research has focused on developing ways to combat this particular species with less focus on other human infecting malaria parasites. The number of well-developed *P. falciparum* vaccine candidates in advanced stages of clinical development reflects this bias and there are strong candidates for every stage of the *P. falciparum* lifecycle within the human host. Some of these are described in detail below.
