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Background Malaria is an important parasitic disease that poses a major public health problem. There are approximately 250 million cases of malaria worldwide resulting in almost one million deaths each year (Casares, Brumeanu, and Richie, 2010). The global environmental and climatic changes have caused a change in vector population and distribution, leading to an impact of 35 million disability adjusted life years that is equivalent to loss of 35 million future life years due to premature mortality and disability (Tanner and Vlassoff, 1998).

The control of malaria has been a major global public health challenge. Currently malaria control strategies are based on anti-parasite and anti-mosquito measures (LSHTM Malaria modules, nd. sec 1). Unfortunately, the increasing resistance of malaria parasite, particularly Plasmodium falciparum, to antimalarial drugs and insecticides has raised challenges to current malaria control measures (WHO, 2010). Plasmodium falciparum causes most of the deaths in children under the age of 5 years and pregnant women in sub-Saharan Africa (Targett and Greenwood, 2008).

At this stage an efficacious vaccine could be very useful to reduce the transmission of malaria and concurrently the burden of disease worldwide (Tanner and Vlassoff, 1998). Until today, no reliable vaccine has marketed yet so control measures are mainly focused at drug treatment and mosquito control measures (LSHTM Malaria modules, nd. sec 1).

At present several global organizations are stepping up their efforts with World Health Organization (WHO) malaria control program that ranges from reducing the burden of disease and maintaining it at a reasonably low level, to eliminating the disease from a geographical area, and finally eradicating the disease from the globe (WHO, 2008).

This paper will describe the role of a reliable vaccine in the course of changing epidemiology of malaria worldwide. The prospects of the vaccine in malaria control and its advantages and challenges will also be discussed. Finally a conclusion will be summarised by recommending new approaches to control of malaria.

Introduction Malaria is transmitted with a bite of an infected female Anopheles mosquito. There are five species of human malaria parasite: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi (Warell and Gilles, 2002; pp 8-9).

Plasmodium parasites are highly prevalent in Asia and South America, where individuals can be infected with more than one malaria parasite species simultaneously. Infective foci of Plasmodium knowlesi have been identified in the past decade in South-East Asia, where P. knowlesi is transmitted from simian hosts to humans (Sauerwein, Roestenberg, and Moorthy, 2011).

Public Health Distance learning Program London School of Hygiene & Tropical Medicine

Malaria Control

Mathematical Modles to Control Malaria Abdul Qadeer MBBS, DTM, MSc, CPHI(C), CIC

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Most infections are caused by Plasmodium falciparum, which is particularly dominant in sub-Saharan Africa. Plasmodium vivax infections are also accounts for a major burden of disease worldwide (Gething et al., 2012). Current malaria control strategies are based on anti-parasite and anti-mosquito measures. Anti-parasite measures include early diagnosis and treatment of uncomplicated infections with artemisinin-based combination therapies (LSHTM Malaria modules, nd. sec 1). Anti-mosquito measures are against the adults and larvae of the Anopheles mosquito (vectors) that include widespread indoor residual spraying; use of insecticide-treated mosquito nets; removal of possible mosquito breeding sites, drainage of ditches, the breeding of fish that feed on larvae, and the use of personal protection such as clothing and insect repellents (Warrell and Gilles, 2002; pp107-131).

Since the WHO initiated “Role Back Malaria” campaign, the malaria has been eliminated in much of Europe, US and in most temperate regions by using existing malaria control measures. These successes proved that malaria could be eliminated without the assistance of a vaccine (Casares et al., 2010).

The WHO World Malaria Report 2010 indicates that funding from the international community to fight malaria has increased substantially in recent years that have supported the scaling up of current interventions in malaria endemic regions (Crompton, Pierce, and Miller, 2010). Conversely, the widespread implementations of current malaria control measures in sub-Saharan Africa and other tropical countries may not be able to reduce transmission due to a variety of factors such as poverty, poor health care and political systems (Casares et al., 2010). At this stage the use of an appropriate vaccine could be able to reduce the transmission of malaria in that part of the globe (Crompton et al., 2010).

Mathematical model to describe transmission of malaria The transmission of malaria exhibits a wide range of intensities and diverse epidemiological patterns that are influenced by a number of biological factors such as host, parasite and vector; and environmental factors such as climate, irrigation and house design. The influence of these factors on transmission of malaria can be better understood by using Macdonald mathematical model (LSHTM Malaria modules, nd; sec 3).

The Macdonald model describes the basic case reproduction rate, (R0), which is defined as, “the number of secondary cases arising from one primary case in a fully susceptible human population”. Generally, when each new case gives rise to a single further case (R0=1) during the entire period of infection, the total number of cases remains unchanged. However, if each case gives rise to more than one new case (R0>1), then the number of cases will increase exponentially until the entire population is infected. Conversely, if each case gives rise to less than one new case (R0<1), then the number of cases will decline until the infection disappears (LSHTM Malaria modules, nd; sec 3).

The Macdonald formula provides a quantitative description of all the events that must occur for a transmission to occur, for example:

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R0 = How many people will get malaria directly from the mosquitoes that bite the first case m = Index of mosquito density (female mosquito per person) a = The frequency with which each of the mosquitoes bites a person b = The proportion of infective mosquito bites that actually result in human infection h = The proportion of infected humans that are actually infectious p = The probability that a female mosquito will survive from one day to the next n = The extrinsic incubation period (days) or sporogonic cycle r = The proportion of human cases that recover every day

In the Macdonald model the current control measures such as drug treatment, larviciding, house spraying and use of Insecticide-treated nets will reduce case reproduction rate by reducing the average duration of human infection (1/r), index of female mosquito per person (m), and the probability of daily survival of the vector (p) respectively. These measures will ultimately reduce the burden of disease (LSHTM Malaria modules, nd, sec 3). Targett and Greenwood (2008) analysed that scaling up of the above interventions in certain malaria endemic regions of Africa with low transmission have caused more than 50% reduction in the incidence of malaria. However, in areas of high transmission, vaccine alone may not be able to interrupt the incidence of malaria infection.

Challenges in malaria vaccine development Vaccination is generally a successful method of controlling bacterial and viral diseases and there have been numerous success stories, for example the eradication of smallpox and the virtual elimination of polio (Good, 2001). But to date, no vaccine against a human parasitic disease has ever been licensed yet (Warrell and Gilles, 2002, p 315).

Multiple factors conspire to make the development of a malaria vaccine an incredibly difficult challenge. An important factor is the complex biology of the life cycle of the parasite, which exists in different forms and each form present with a different pattern of antigen expression in different tissues of the body and the mosquito. In these various forms the parasite is susceptible to immune attack, although the type of immune response required is very different for each form. There is evidence that some degree of natural immunity to malaria is acquired by repeated infections. Unfortunately the immunity is incomplete because it cannot eliminate the parasites completely and takes many years of endemic exposure to develop. Theoretically, a vaccine could shortened the period and accelerate this process of immune response (Good, 2001). Therefore, several vaccine strategies need to be adopted to achieve this objective (Chilengi and Gitaka, 2009).

Another factor that impedes vaccine development is the ability of the malaria parasite to alter itself. Antigenic variation and allelic polymorphism are important obstacles to subunit vaccine development, especially given that many of the sequence alterations in malaria proteins occur in regions that are crucial to immunity (Good, 2001).

“The lack of suitably potent adjuvants necessary to induce high-titre antibody responses and immunological non-responsiveness of certain individuals (depending on their human leukocyte antigen and other antigens) to proteins that might comprise a vaccine is also an impeding factor for vaccine development” (Good, 2001).

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Prospects for malaria vaccine development In recent years the development of malaria vaccine has been fuelled by new technology enabling the sequencing of the Plasmodium falciparum genomes and the development of experimentally relevant animal models (Sauerwein et al., 2011). Moreover, there are significant increases in financial resources from funders such as the Bill & Melinda Gates Foundation, the European Union, the US National Institutes of Allergy and Infectious Diseases and the US Agency for International Development (Targett and Greenwood, 2008).

Currently, there are numerous malaria vaccine candidates in the pipeline that are categorized according to the Plasmodium life cycle stages at which the targeted antigen are expressed. The pre-erythrocytic stage vaccines aim to prevent the passage of parasites through the human liver and subsequent blood-stage infection, leading to the induction of sterile immunity. Asexual erythrocytic stage vaccines focus on delaying or decreasing parasite multiplication in red blood cells, thereby decreasing clinical morbidity and preventing mortality (Sauerwein et al., 2011). Transmission blocking vaccines consist of sexual or mosquito-stage antigens that prevent infection passing from humans to mosquitoes, thereby decreasing the spread of malaria in the population (Chilengi and Gitaka, 2009).

How vaccine may affect the transmission of malaria? The pre-erythrocytic stage vaccines would reduce case reproduction rate by reducing both the proportion of infective mosquito bites that actually result in human infection (b) and the proportion of infected humans that are actually infectious (h). This type of vaccine may not be able affect the length of the sporogonic cycle (n) or survival rate in mosquitoes (p) that can be achieved by a synergistic effect from existing control measures. Currently, the RTS,S is the most advanced pre-erythrocytic stage vaccine that recently showed an adjusted efficacy at 53% against malaria infection in Kenyan and Tanzanian children (Chilengi and Gitaka, 2009).

The asexual erythrocytic stage vaccines will reduce the proportion of humans that are actually infectious (h) while the recovery rate (r) would be greatly increased. It is hypothesized that the mosquito bites resulting in human infection (b) would be reduced by the next generation of parasites. The reduction in (b) would substantially contribute lowering case reproduction rate within the vaccinated population. A group of blood stage vaccines such as MSP3 and GLURP may reduce case reproduction rate by inducing antibodies that kill parasites with help from monocytes. Another group of vaccines such as PfEMP1, Rifins, and Pf332 would achieve similar effects by enhancing splenic clearance or complement mediated lysis, or diminish parasite nutrition and growth (Chilengi and Gitaka, 2009).

Transmission blocking vaccines induce antibodies that inhibit fertilization of gametocytes thus renders them non-infectious for the mosquitoes when taken up by mosquito during a blood meal (Sauerwein et al., 2011). These vaccines would disrupt transmission by reducing the survival rate in mosquitoes (p) as well as the proportion of humans actually having the infection (h). However, the key challenge here is that entire populations would have to be immunized and the vaccine effects should last through several transmission cycles to achieve desired effects (Chilengi and Gitaka, 2009).

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Advantages and disadvantages of vaccine The partially effective pre-erythrocytic vaccine may have advantage in countries where health services are not adequate and current vector control methods are not very effective because of the feeding and resting habits of mosquitoes. The mass vaccination of infants could be able to protect children from malaria in an early age. These could also protect pregnant women from malaria and which could replace intermittent preventive treatment (Greenwood and Targett, 2009).

In contrast, in most endemic areas a partially effective vaccine would not be able to replace mosquito nets and house spraying. The nets can provide an added protection against other vector borne diseases such as dengue, leishmaniasis and filariasis as well as provide a sleep free from mosquito bites. The vaccine could also be a cost-effective method of control comparing with house spraying which need more resources and skills in spraying (Greenwood and Targett, 2009).

Greenwood and Targett (2009) also proposes that as partial effective malaria vaccine is directed at prevention of disease at individual level, therefore, the resources should be used for introducing other childhood infections that cause deaths in malaria endemic regions.

Conclusion and Recommendation The evidence suggests that in areas with low transmission, success in malaria control has been achieved with scaling up current control measures. Whereas, it is widely accepted that existing control tools may not be sufficient to interrupt transmission in areas with moderate or high levels of transmission (Targett and Greenwood, 2008). It is concluded that the due to changing epidemiology of malaria and poor health care infrastructure in most part of the word the malaria control programs will not be possible without new antimalarial tool of greater efficacy (WHO 2008).

As there is a shift from malaria control to malaria eradication, more research is focused on malaria vaccine development. The current group of blood stage malaria vaccines are partially effective and primarily targeting disease prevention. At this stage these vaccines may not be able to replace the existing vector control measures. The efficacy of these vaccines needs to be very high to achieve elimination of malaria from a geographical region. On the other hand, the transmission blocking vaccines may have an impact on breaking the life cycle of malaria parasite by mass vaccination of whole population and can be integrated with the existing tool for elimination (WHO 2008).

The development of a vaccine to protect human subjects against malaria is a feasible goal, however, at present multi-pronged approaches should be used. A multi-stage vaccine could be appealing for future research which may have added benefits comparing with current pool of vaccines (Chilengi and Gitaka, 2009). Additionally, WHO malaria report (2008) recommended following new tools for elimination and possible eradication of the malaria.

Search for new longer lasting insecticide for indoor spraying and mosquito nets,

Prevent insecticide resistance by using innovative methods such as, mosaic treatment or combination treatment of insecticidal nets and house spraying,

Introduce new interventions for vector control such as sterile insect technique or transgenic technique,

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Search for new class of highly efficacious antimalarial drugs for both plasmodium falciparum and plasmodium vivax,

Introduce new robust and sensitive diagnostic tool to detect parasite carrier such as latent or asymptomatic infections,

Ensure compliance with medication and use of mosquito nets correctly,

Continuous monitoring and evaluation of these tools by assessing incidence and entomological parameters that may allow targeting of these interventions in high risk areas,

Finally, a social marketing approach should be adopted for successful implementation of the above interventions (Tanner and Vlassoff, 1998).

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