A Background About Malaria History Of The Disease Biology Essay

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The aim of this project is to analyse the possibility and impact of a future vaccine against malaria. With a number of different potential vaccines in trial stages, focussing on several different mechanisms to control the disease, is a useful and efficient vaccine far away? Are we looking at a vaccine that will help to completely eradicate malaria in certain regions, or worldwide? Or will a vaccine just add another string to our bow for controlling the disease and ultimately reducing the worldwide burden of morbidity? Or perhaps we would be better diverting our attention and resources away from vaccination and add to the efforts of vector control, prophylaxis and treatment?



A background about malaria, history of the disease

How malaria affects the host

Epidemiology and impact on the world

Lifecycle of the parasite - particularly P.falciparum

Overview of how malaria is currently prevented/treated and the success to date

Include discussion of resistance

Who is involved with malaria prevention - and the kind of money involved

Why is it important


Explanation of how vaccines work and how they are developed

Examples of vaccines

Stories of eradication

Small pox

Polio - and why it has not been eradicated yet worldwide

Challenges of making vaccination successful

Malaria vaccine

Potential target sites

How would a vaccine work/be rolled out/administered

Current vaccines in progress development

Overview of recent trials

Successful trials

Failed trials

Outcome of trials

Political views


Does a vaccine look likely?

How does a vaccine fit in with the other methods of malaria control?

What future trials are expecting to see


A background about malaria, history of the disease

Malaria is one of the oldest recognised diseases in the world. It is thought to have affected our ancestors long before even the origins of homo sapiens around 250,000 years ago. Throughout history references have been made to malaria-like illnesses, with descriptions of "paroxysmal fevers associated with enlarged spleens and a tendency to epidemic occurrences" as far back as 4,700 years ago in China [1] . Further references in Indian, Egyptian and Greeks texts from between 4,000 years ago and 500BC suggest that the spread of malaria had been historically global.

Despite the parasite responsible for malaria (genus Plasmodium) being discovered as recently as 1880 by Alphonse Leveran [2] and the anopheles mosquito vector in 1897 by Major Ronald Ross, malaria-like disease had historically been associated with marshy areas, stagnant waters and swampland for over 2,500 years. This led the Romans to undertake drainage of standing water in urban areas and in the 11th century a Royal decree was outlined prohibiting the planting of rice fields too close to village areas. The link with mosquito bites and disease has also long been suspected - Roman officials would prohibit habitation in mosquito infested districts and shepherds would furnish their quarters with livestock to provide a non-human alternative blood-meal. Perhaps unbeknownst to them at the time, these were the first examples of malaria control.

The discovery of the infective organism and its vector led to a raft of new malaria control methods. One such method was the implementation of sanitation drives in areas such as England, India and Sierra Leone, led by the likes of Major Ross and others, from which success was limited. Oiling, netting, insecticides and even the introduction of larvivorous fish into Californian water collections were used to varying degrees of success.

In the early to middle 20th century many countries were employing a broad range of malarial control techniques, including the use of DDT insecticide, quinine, personal protection with bednets and anti larval measures that included drainage, soil modification, proscription of urban agriculture. By 1945 malaria had been eradicated from Egypt and Brazil. By 1951 it had been eradicated from the USA. Following the launch of the WHO Global Malaria Eradication Programme in 1955, European countries followed suit, with the last endemic cases in the UK during the 1950s and many countries such as Hungary, Bulgaria, Romania, Yugoslavia, Spain, Poland, Italy, Netherlands and Portugal free of malaria by 1969. However, by this time many other countries had made little progress and despite its success, the WHO admitted the failure of the campaign in 1969.


Malaria is one of the leading causes of morbidity and mortality in the developing world, with approximately half of the world's population at risk [34]. In 2009 there were 225 million cases (169 - 294, p = 0.05) of malaria worldwide [3]. This is down by 7%, from 244 million cases in 2005, with large decreases in incidence in Europe (86% decrease) and the Americas (42% decrease). However, less progress has been made in Africa and South East Asia, which accounted for 78% and 15% of cases respectively, as shown in Figure and Figure .

Of the 781,000 deaths (628,000 - 968,000, p=0.05) reported, Africa had by far the greatest burden, accounting for 91% of world malaria deaths. Approximately 85% of deaths occurred in under 5's and 93% were due to P. falciparum and the majority of the remaining to P. vivax. [32] Malaria accounts for approximately 1.5% of worldwide deaths and 7% of all deaths in Africa, including 15% of all deaths ages 0 - 4 and 11% of deaths age 5 - 14 [33].

Figure - Number of cases of malaria by WHO region

Figure - Number of deaths due to malaria by WHO region

The WHO has identified a number of specific populations that are at risk [34]. These are:

Young children who have not yet developed protective immunity

Non-immune pregnant women, leading to higher rates of miscarriage and maternal death

Semi-immune pregnant women in high transmission zones

Semi-immune HIV infected pregnant women who are at higher risk of vertical transmission

People with HIV or AIDS

International travellers from non-endemic areas

Immigrants from endemic areas and their children, who on returning to area of origin, have lost acquired immunity

Public health impact of malaria

In 2004 there were 109 countries in the world with endemic malaria, mostly affecting Sub-Saharan Africa, Central and South America and Central and South-East Asia [42]. However, in 2010 both Morocco and Turkmenistan were certified by the WHO Director General as free from Malaria, with Armenia soon too follow. Despite these successes, the struggle to control and eliminate malaria is enormous and it continues to have substantial public health, political and economic impacts. The WHO estimates that in endemic countries, malaria accounts for 40% of public health expenditure, 30 - 50% of inpatient admissions and 60% of health clinic visits [WHO Website]. Of course, it is the poor that are most affected due to their limited access to health services, prevention methods, treatment and information, as well as inability to move away from high risk areas. Furthermore, studies reported by Gallup and Sachs [43] looking at economic growth between 1965 and 1990, suggested that countries with substantial amounts of malaria grew 1.3% less per year, whilst a 10% reduction was associated with 0.3% growth. In the most affected countries, malaria control and treatment accounts for 15% of the national budget [Abuja Declaration]. This not only indicates a significant economic effect, but also shows that this effect can be reversed by improving malaria control and reducing its incidence.

These impacts manifest themselves in several ways. Loss of life and hence output has wide ranging effects from the family level, to local economies and the macro-economy. Similarly, illness due to infection, be it uncomplicated malaria or severe malaria, leads to loss of output, as well as the cost of treatment and time caring for sick individuals. For families, the cost of prevention in the form of bednets, sprays and repellants is estimated at US$0.05 - US$2.05 per person per month and the cost of treatment US$0.39 - US$3.84 [46]. Hence, malaria can cost a average family of five around $150 per year, over 15% of the average annual income, a substantial economic burden.

Malaria also heavily affects intellectual development, be it from the neurological sequelae of cerebral malaria, or from school absenteeism [45]. Leighton and Foster [44] found that primary school children in Kenya and Tanzania were absent for up to 11% of their school year due to illness from malaria, a figure which decreases with age, but even teachers lost up to 2% of their school year due to the disease. In countries where many children do not receive education beyond primary school, such a level of absenteeism clearly impacts their future prospects and productivity.

With such a significant and worldwide impact, the case for working to control and eliminate malaria is clear and is being tackled by the "Roll Back Malaria" initiative, launched by the WHO in 1998, combined with resources from numerous other organisations, including the Global Fund to fight AIDS Tuberculosis and Malaria, the World Bank's Booster Program, the US President's Malaria Initiative and the Bill & Melinda Gates Foundation.

Millennium Development Goals (MDGs)


Eradicate extreme poverty and hunger


Achieve universal primary education


Promote gender equality and empower women


Reduce child mortality


Improve maternal health


Combat HIV/AIDS, malaria and other diseases


Ensure environmental sustainability


Develop a Global Partnership for development

Table - United Nations Development ProgrammeMalaria control is also an important factor in achieving the Millennium Development Goals (Table ), with MDG6 specifying a decrease in incidence of malaria, as well as increase in the numbers of children under 5 having access to ITNs and appropriate treatment. With the increasing prevalence of insect-repellent resistant mosquitoes and treatment resistant parasite strains, these goals are becoming more difficult to meet, and it is widely recognised that a vaccine will play a significant role in the battle against malaria, particularly in the high risk groups such as young children. Indeed the Malaria Vaccine Technology Roadmap had set a target of creating a vaccine that confers 80% protection versus infection lasting >4 years by 2025, with an intermediate of 50% protection lasting >1 year by 2015 [47]. If this is achieved it will significantly help to reduce the public health and economic worldwide burden of malaria.


Figure - Map of malaria cases (WHO, 2004)

Lifecycle of the parasite - particularly P.falciparum

In terms of the history of the disease, the vector for malaria has only recently been identified. Malaria-like illness has long been associated with marshland and areas of standing water, however it was not until 1880 that the malaria parasite was discovered by Alphonse Laveran and subsequently the female anopheles mosquito as a vector by Major Ronald Ross in 1987 [8]. The lifecycle of the parasite is complex but is now well understood and fundamental to the understanding and development of potential vaccines. It is similar for all 5 human-infective species of Plasmodium. Figure - Life cycle of malaria parasite showing key areas for vaccines (adapted from "Malaria - a handbook for health professionals"[48]) and Table below detail the lifecycle and the potential target areas for vaccines.











lifecycle - Malaria - a Handbook for Health Professionals.jpg

Figure - Life cycle of malaria parasite showing key areas for vaccines (adapted from "Malaria - a handbook for health professionals"[48])




Female anopheles mosquito bites human and injects sporozoites from salivary glands into blood


Sporozoites infect blood for about 30 minutes before disappearing. Many are phagocytosed but some enter hepatocytes (with and without help from Kupffer cells).


Sporozoites undergo pre-erythrocytic schizogony, developing and multiplying to form pre-erythrocytic schizonts. In P.vivax and P.ovale, some form into hypnozoites (involved with relapsing infections).


6 - 16 days after infection, schizont ruptures and releases merozoites into blood stream. No infective symptoms or signs occur before this point.


Merozoites invade erythrocytes and form trophozoites, before undergoing an asexual dividing process of erythrocytic schizogony, forming schizonts containing merozoites.


Erythrocyte ruptures, releasing merozoites which infect other erythrocytes. This occurs every 24 - 72 hours, depending on species, leading to an exponential expansion of parasite population in the blood.


Some merozoites differentiate into gametocytes (macrogametocytes - female, microgametocytes - male).


Female anopheles mosquito bites infected host and gametocytes enter mosquito's gut. Here male gametocytes fertilise female gametocytes, creating a zygote which becomes an ookinete.


Ookinete migrates to stomach lining and exits via stomach wall to form oocyst, which matures with sporozoites inside.


Oocyst ruptures and released sporozoites migrate to the salivary glands of the mosquito.

Table - Explanation of the life cycle of Plasmodium

How malaria affects the host

Malaria is a disease caused by parasites of the genus Plasmodium. It is generally considered that there are 4 species which affect humans: P. falciparum, P. Vivax, P. ovale and P. malariae, however a fifth species, P. knowlesi, has been attributed to up to 70% of cases in some areas and may be an emerging health problem [35]. Infection with the malaria parasite causes an acute febrile illness, with periodic febrile paroxysms every 48 - 72 hours and afebrile, asymptomatic intervals. The exact incubation period, course and severity all depend on the species, and are also affected by the host's age, genetics, immunity, health, nutritional status and prophylaxis.

Although there are large gaps in the understanding of how malaria invades cells and causes disease, the clinical features can be understood well against the lifecycle.

After inoculation by the mosquito, there is an incubation phase when the merozoites are reproducing in the hepatocytes. Towards the end of this phase, the patient may begin to look ill, with jaundice and hepatosplenomegaly, and suffer from malaise, fatigue, headaches, dizziness, joint and back ache, anorexia, nausea, vomiting and a low grade fever. The first paroxysm then develops with a "cold stage" of shivering, chattering, vomiting, increased core temperature and increased pulse rate. This lasts 15 - 60 minutes before developing to a "hot stage", during which the patient becomes very hot (core temperature 40 - 410C) with severe headache, increased respiratory rate, palpitations, postural syncope, epigastric discomfort, a rapid and full bounding pulse, and splenic enlargement. After 2 - 6 hours the patient enters the "sweating stage" and the fever declines over 2 - 4 hours [27].

These paroxysms coincide with the rupture of the schizonts, initially from the hepatocytes and subsequently from the erythrocytes, releasing the merozoites into the blood stream. It is thought that the "malaria toxin" lipid, glycosyl phosphotidyl inositol (GPI), part of the parasite membrane protein (MSP-1), combined with macrophage cytokine release, precipitate the symptoms. The paroxysms thus occur roughly every 48 hours in P. ovale and P. vivax and hence they are referred to as tertian (occurring on the third day). P.malariae fever is referred to as quartan as the paroxysms occur every 72 hours (Manifestations of severe malaria). P.falciparum does not cause such defined spiking fevers, but rather causes daily fevers with short interval periods occurring on the third day. P.falciparum is responsible for the most severe disease and can progress very rapidly, even causing death within 24 hours.


Manifestations of severe malaria

Cerebral malaria

Severe anaemia

Renal failure

Pulmonary oedema & ARDS


Circulatory collapse (algid malaria)

Abnormal bleeding or DIC

Repeated generalized convulsions

Acidaemia <pH7.25

Macroscopic haemoglobinuria

Impaired consciousness

Prostration or weakness




Figure - Clinical course of malarial fevers

Table - Complications of malaria

Severe malaria is almost exclusively caused by P. falciparum and is defined by the presence of certain clinical presentations identified by the WHO in 1990 (revised 2000) (Table ). Associated with poor prognosis, relapses and death, cerebral malaria and severe anaemia are the two most common forms of severe malaria, however pulmonary oedema and respiratory distress is the most dangerous [22].

Cerebral malaria manifests itself in decreased consciousness, coma, convulsions, nystagmus, delirium, psychosis and cerebellar syndrome. It can develop very rapidly, particularly in children, and left untreated has a mortality rate of 25 - 50% [ref needed]. 10% of those who survive cerebral malaria have neurological sequelae [26].

Severe anaemia….

Resp distress….

Naturally acquired immunity

Although the lifecycle is well documented, the way the body's immune system reacts to the parasite is very poorly understood. Results from genome sequencing suggest there are over 5,300 potential P.falciparum antigens [23], many of which show high degrees of polymorphism, but only 1% of which how been studied so far [38]. Single parasite clones can also have up to 50 copies of a single gene encoding the same protein, expressing different versions with each wave of parasitaemia [15]. This great diversity of the phenotypes and genotypes of the malaria parasite [49] not only make the clinical presentations of malaria so variable, but also are responsible for the ability of the parasite to avoid the body's immune response. This is partly why our understanding of the body's immune response to malaria is so limited and hence why producing a vaccine so difficult. Gaining a deeper understanding of this immune response is critical to designing a suitable vaccine.

Figure - Development of immunity to malaria [38]The human body is usually able to mount an effective immune response to malaria - more than 99% of cases do not cause death [49]. Immunity to malaria can also be developed, and was recognized in people who had been deliberately exposed to malaria in order to treat neurosyphilis. Natural history studies also show that those living in endemic areas and are frequently exposed to malaria parasite develop natural immunity. This immunity is not sterile immunity [38], but protects the person from severe manifestations of the disease, such that a person may have a high parasitaemia but experience little or no clinical symptoms. Immunity is progressively acquired during the lifetime of the person through repeated exposure. Initially rapid immunity to severe malaria develops and then as immunity builds, rates of infection, parasitaemia and clinical disease decrease (Figure ). Furthermore, children born to immune mothers appear to have immunity for 3 - 6 months, particularly to severe malaria [27]. This is why cases of severe malaria and fatal malaria are far less common in adults and death after 5 years of age is rare [27]. Conversely, humans with no previous exposure to the malaria parasite, such as children or travellers from non-endemic areas, are particularly vulnerable and become ill on the first exposure. immunity.jpg

This immunity does not last if a person leaves an endemic area and is no longer repeatedly exposed to the parasite challenge. Hence those with previous immunity returning to an endemic area after a period of absence are at increased risk. Genetics also appear to play an important role, with some individuals appearing to have non-specific innate resistance. In particular, red cell polymorphisms such as sickle-cell trait (HbS), HbS/HbC, HbE, hereditary ovalocytosis, β-thalassaemia and G6PD deficiency appear to be protective [27].

The knowledge that humans can mount a lasting immune response has encouraged researchers to believe that a vaccine is feasible. Furthermore, passive immunity has been demonstrated by administering purified immunoglobulins from immune patients to non-immune patients, and in the 1970s it was shown that exposure to UV irradiated sporozoites could produce 90% immunity, albeit short lived [15]. In recent years a number of candidate vaccines have shown varying degrees of results, however the immunological basis upon which they work is still unconfirmed.

The immune response to malaria is both cell mediated and humoral and could occur at any or all of the three stages - pre-erythrocytic, erythrocytic and sexual stages. Langthorne et al. [38] describes a number of different mechanisms involved in the immune response, these include:



Pre- erythrocytic

Antibodies to sporozoites - neutralizing, opsonising sporozoites or blocking hepatocyte invasion

Interferon-gamma (IFN-γ), CD4+ dependent CD8+ cells, Natural killer cells (NK), Natural Killer T cells (NKT), γδT-cells - killing intrahepatic schizonts


Antibodies to merozoites - blocking erythrocyte (RBC) invasion

Antibodies to infected erythrocytes (RBCi) - opsonise RBCi's for phagocytosis by complement and block adhesion of RBCi's to endothelium

Antibodies to RBCi's - prevent schizont rupture


Antibodies to RBCi's to prevent maturation of gametocytes

Antibody and complement taken up in blood meal - prevent parasite development in mosquito

Table - Immune mechanisms vs. Plasmodium

Which particular aspect of this immune response that is most important in developing lasting immunity is not clear, however studies have shown that the pre-erythrocytic phase has limited involvement in its development [38]. It is clear though repeated infection is needed to boost and maintain both antibody levels (which are often very short lived) through memory B cells and cell mediated response by memory T-cells (both CD4+ and CD8+) to both pre-erythrocytic and erythrocytic stages.

This understanding is perhaps contradicted by the fact that the most successful vaccines to date (RTS,S) target the pre-erythocytic phase.

Current control of malaria and the need for a vaccine

Figure - Overview of the control of malaria and where a vaccine fits in. IRS - insecticide residual spraying; ITN - insecticide treated betnet; PEV - pre-erythrocytic vaccine; ESV - erythrocytic stage vaccine; SSV - sexual stage vaccine; PCR - polymerase chain reaction; ACTs - artemisinin-based combination therapy; NACTs - non-artemisinin based combination therapies; Malarone - atovaquone/proguanil; Lariam - mefloquineThroughout malaria endemic regions, control of the disease is being attempted through vector control, reliable diagnosis and effective treatment (Figure ). Successful elimination of malaria has occurred in Europe and most recently in Turkmenistan and Morocco, with other countries soon to follow. The WHO estimate that if full coverage of these methods could be met, 4.2 million lives could be saved by 2015 [42]. There are however a number of barriers to further success, which support the need for a vaccine.control of malaria.jpg

Vector control

Vector control through the use of insecticide-treated nets (ITNs) and insecticide residual spraying (IRS) is highly efficacious, in particular ITNs have consistently been shown to reduce child mortality and morbidity [22]. However, the effective life of ITNs is limited and resistance to the insecticides used is threatening their usage. Similar issues threaten IRS, which is leading to insecticide resistance [19], as well as the increased prevalence of exophilic [3] (over endophilic) anopheles mosquitoes.


Chemoprophylaxis is effective in reducing morbidity and mortality from malaria. Suppressive prophylaxis such as doxycycline and mefloquine (Lariam) work on the erythrocytic phase of the parasite cycle, whilst causal prophylaxis such as Malarone act on the pre-erythrocytic phase. When used over short periods these drugs have high efficacy. However, reliably taking regular medications over long periods is difficult and costly, can interfere with the development of natural immunity and could contribute to the development of drug resistance [50]. As such it is not suitable for ongoing prevention in people living in endemic areas.


For many years chloroquine has been the first-line treatment of malaria, but most strains now show full resistance. Current best treatments use artemisinin-based therapies, derived from the artemesia anua plant. These are combined with drugs such as amodiaquine and mefloquine - ACTs. ACTs have shown high efficacy, however at ten times the cost of mono-therapy [22], are prohibitively expensive for poor people living in endemic areas. Furthermore, the sub-optimal use of artemisinin compounds as a mono-therapy in areas such as Cambodia has been linked to developing resistance to P.falciparum [51].


With current control methods struggling to meet the enormous burden of malaria, compounded by the decreasing efficacy of our most advanced control methods, the case for incorporating a vaccine as part of the control programme is strong. Such a vaccine may look to reduce clinical cases of malaria, or potentially look to eliminate the disease [1]. Either way, vaccines will be used in combination with existing control strategies, rather than as an alternative.

Malaria Vaccines

Vaccines are currently being developed for both P.falciparum and P.vivax, although the majority are targeted against P.falciparum. The ideal vaccine would be safe, highly efficacious, widely available, cheap, stable in hot climates, compliment natural immunity and induce long-lasting sterile immunity [28]. This is yet to be achieved and may never be for malaria, however there are a number of vaccines in development, classified by the stage of the lifecycle they are acting on - pre-erythrocytic, erythrocytic and sexual (or transmission) stage (see Figure - Life cycle of malaria parasite showing key areas for vaccines (adapted from "Malaria - a handbook for health professionals"[48]) on page 9). Pre-erythocytic stage vaccines (PEV) aim to induce an immune response against the invasion of hepatocytes by sporozoites and the subsequent development of merozoites. Erythrocytic stage vaccines (ESV) act on the asexual-reproduction stage, aiming to block the invasion of erythrocytes and destroy blood stage merozoites. Sexual stage vaccines, also called transmission blocking vaccines, target antigens on the gametes or oocytes in order to interfere with the sexual reproduction stage in the anopheles mosquito.

Table xx and table xx in the appendices list the current and inactive trials for malaria vaccines. Despite the huge number of antigens that could be targeted, 50% of the 75 vaccines currently in clinical trials focus on just three proteins [15], indicating a focussed research effort as well as broad scope for future development. These proteins are:

Circumsporozoite protein (CSP) - expressed on pre-erythrocytic sporozoites and liver stage schizonts.

Merozoite surface protein (MSP) - expressed on blood stage merozoites.

Apical membrane antigen 1 (AMA 1) - expressed on blood stage merozoites.

Other target proteins include: liver-stage antigen (LSA) [54], thrombospondin-related anonymous protein (TRAP), falciparum malaria protein (FMP), glutamate-rich protein (GLURP), plasmodium falciparum surface protein-25 (Pfs-25) and plasmodium vivax surface protein-25 (Pvs-25) [62].

Measuring vaccine immunogenicity and efficacy

The majority of trials have been phase I and phase II trials investigating the safety of vaccine candidates in malaria naïve adults in non-endemic areas, as well as immunogenicity through sporozoite challenge (see Table ). Several candidates have also been tested in adults and children in malaria endemic areas, allowing for analysis of vaccine protection by natural infection. Immunogenicity and vaccine efficacy (VE) is measured in a number of ways. Humoral and cell mediated immune responses are primarily measured by production of antibodies against the target antigens, CD4+ and CD8+ T-cell response and cytokine induction (such as IL-2 and IFN-gamma) [53,54,55,58]. Immune response can also be measured by testing for inhibition of parasite growth in vitro [60,61]. Vaccine efficacy can be measured by the time to develop parasitaemia, particularly in trials where sporozoite challenges are used [56], as well as the level of parasitaemia which is also measured in field trials [57]. The efficacy of more advanced vaccine candidates, such as the RTS,S vaccine, has been assessed not only by the aforementioned measures, but also by looking at its effect on reducing episodes of clinical and severe disease [52].

It is important to note though that some vaccines that have shown good immunogenicity have not subsequently shown protection against parasitaemia, such as the pre-erythrocytic CSP long synthetic peptide vaccine, which induced high levels of antibodies in all vacinees but no difference in parasitaemia between vacinees and controls [63]. This may be because the vaccines are not targeting the correct antigens or that the immune response is not strong enough. It should be remembered, however, that even in individuals that have naturally acquired immunity parasitaemia can occur without clinical disease and so these vaccines may still offer come level of protection.


Details of phase

Length of phase


Identify antigens, conduct initial animal testing and develop manufacturing process

3-4 years


Safety and immunogenicity in healthy volunteers from non-endemic countries

1-2 years


As above in malaria exposed populations

1-2 years


Safety, immunogenicity and efficacy in larger groups in non-endemic countries, including dosing regimens and natural exposure.

2+ years


As above in malaria endemic regions

2+ years


Monitor efficacy, safety and side effects in much larger population to evaluate overall benefit.

3 - 5 years


Ongoing monitoring of efficacy and safety

4 - 6 years

Table - Details of clinical trial phases (adapted from [5])

Pre-erythrocytic vaccines

People who have acquired natural immunity still develop asymptomatic parasitaemias, so it appears that complete immunity to the pre-erythrocytic stage does not occur naturally. It therefore seems something of a paradox that the only vaccine to consistently show protection against clinical disease in adults and children [64] acts on this stage of the parasite life cycle.

To date the vaccine RTS,S, acting on the circumsporozoite protein (CSP), has shown to be the most promising and is the only candidate to have progressed to phase III trials. CSP was first identified as a potential vaccine target in the 1980s when irradiated sporozoites, which were able to enter hepatocytes but not produce merozoites, were shown to induce immunity in rodents, and subsequently in humans [64]. CSP is the predominant antigen on the surface of sporozoites and plays an important role in allowing the sporozoite to sequester in the liver sinusoids and invade hepatocytes. Hence, it is an excellent candidate antigen against which to mount an immune response.

after phase II challenge studies and phase II field trials both showed 30 - 50% efficacy against clinical disease [19]. Other vaccines have not shown such promise or have not progressed so far through trials, however a number are currently in phase II studies and have been shown to be safe and immunogenic.

Data has also shown that RTS,S can be coadministered with other vaccines [64], meaning it can be easily integrated into current vaccination programmes without effecting its, or other vaccines, efficacy.