(ANALYSIS)
In this section, we present our analysis of the six major categories of candidate malaria vaccines:
PRE-ERYTHROCYTIC VACCINES – Feasibility
Inoculation with only one sporozoite is capable of causing malaria. Therefore, in order to entirely prevent the disease from developing in the human host, a vaccine solely targeting sporozoites would need to be 100% effective (1). While the goal of pre-erythrocytic vaccines is to achieve complete protection, it may still be valuable to produce a vaccine that eliminates a large number of the sporozoites present upon infection. The discovery that immunization with irradiated sporozoites elicits some protective immunity was cause for encouragement among researchers. Clinical trials for pre-erythrocytic vaccines, and the RTS,S vaccine in particular, have been promising. Many patients have achieved partial protection, however, efforts to increase the efficacy of pre-erythrocytic vaccines must continue.
The sporozoite stage of the parasite’s life cycle is particularly difficult to target, as the sporozoites only remain in the bloodstream of the human host for 30 to 40 minutes before invading the liver. The body only has a very short time to mount an immune response against the sporozoites and ensure that the development of disease does not occur. However, targeting parasites in the liver stage may be advantageous as there is a relatively low burden of parasites at this stage of infection. While improvements must be made, pre-erythrocytic vaccines hold particular promise.
Blood-Stage Vaccines – Feasibility
There is huge potential for blood-stage vaccines to reduce the disease burden of malaria in endemic areas by preventing the characteristic symptoms manifested during the blood-stage of the Plasmodium life cycle. However, while blood-stage vaccines show some efficacy in studies using mice and monkeys, little protection from disease in cases of infection by more virulent strains of Plasmodium, specifically P. falciparum, has been observed (2).
Results from human clinical trials show marked decreases in parasitic load and enhanced immune responses to merzoite and ring-infected eryrthocytic antigens, but little protection against disease symptoms. For example, the MSP/RESA vaccine, also known as Combination B, has proven effective for reducing parasitic density in the blood in clinical trials conducting in Australia and Papua New Guinea, but does not seem to be protective against incidence of malaria disease (3). Thus, while blood-stage vaccine development has made marked progress in reducing parasitic load after infection, increased focus must be placed on development of a blood-stage vaccine that is protective against the malaria-associated morbidity and mortality that occurs during erythrocytic infection.
Transmission-Blocking Vaccines – Feasibility
As is the case in the development of malaria vaccines targeting other stages of the Plasmodium life cycle, antigenic variation makes it extremely difficult to effectively target or inhibit any stage of parasitic development (4). However, a promising factor of transmission-blocking vaccine development is that the molecules targeting by the vaccine are expressed by the parasite in its ookinete stage – that is, once it has been ingested by the mosquito. Targeting ookinete surface proteins expressed in the mosquito, then, avoids the problem of immune selective pressure in the human host, a major cause for increased or more rapid antigenic variation (4).
The feasibility of transmission-blocking vaccines as an effective barrier against onward transmission appears promising at this stage in development. However, although inhibition of infection in mosquitoes has been complete in trials in mice and other mammals, no clinical trials have yet been conducted in humans (5). Thus, the efficacy of such vaccines has not yet been evaluated in transmission from humans to mosquitoes (5). Furthermore, the efficacy of transmission-blocking vaccines in clinical trials is relatively difficult to quantify, due to the fact that protection is not conferred to the individual that receives the vaccine, but rather to the prevention of infection of other members of the surrounding community. The implications of widespread transmission-blocking vaccination in endemic communities are extremely exciting. However, much progress must be made before transmission-blocking vaccines can be widely distributed.
Vaccine for Malaria During Pregnancy – Feasibility:
A vaccine for placental malaria is currently one of the most promising candidates for a malarial vaccine. The discovery that women can acquire lasting natural resistance to the disease over the course of several pregnancies was cause for great optimism among vaccine researchers. In general, the inadequacy of natural immunity is one of the major barriers to developing an effective malaria vaccine. However in the particular case of placental vaccine, natural immunity appears quite effective. Researchers have already made significant progress towards identifying molecules that will mimic natural immunity by inhibiting the binding of infected erythrocytes to the placental endothelium (5).
A vaccine that targets the placental will, of course, only be effective in pregnant women. However, considering the fact that pregnant women are among the most likely to die from malaria, a placental malaria vaccine could save many thousands of maternal lives. In addition, it is estimated that 75,000-200,000 annual infant deaths are related to malaria in pregnancy, and many of these lives would be saved by a placental malaria vaccine (6).
DNA Vaccine – Feasibility:
DNA vaccines appear to be the best hope for the development of a broad-spectrum malaria vaccine in the near future. Because DNA vaccines can contain several segments of parasite DNA, they can deliver multiple different forms of protection against malaria infection. DNA vaccines seem to have the best prospects for overcoming the major biological barriers to malaria vaccine development, including antigenic variation, strain-specific immunity, and the complex parasite life-cycle (7).
In addition, DNA vaccines are far less expensive to produce than synthetic vaccines, making them the most cost-effective candidates for a malaria vaccine. DNA vaccines are generally stable and can withstand transportation, harsh temperatures, and storage (8).
Synthetic vaccines have dominated the research scene for much of the last 20 years, but DNA vaccines are now rapidly drawing attention and funding. The versatility of DNA vaccines, combined with their low cost and stability, are great causes for optimism among malaria vaccine researchers.
MALARIA CONTROL: ALTERNATIVES TO A VACCINE
In the absence of effective malaria vaccines, public health programs in malaria-endemic areas have focused their resources on other malaria control strategies, which aim to minimize the mortality and morbidity associated with malaria. Although elimination of malaria infection and disease has been achieved in some previously endemic areas, eradication of malaria is not considered feasible in the majority of malaria-endemic regions. However, public health strategies can nevertheless make huge impacts on reducing incidence of malaria infection and disease, and have been extremely effective at controlling transmission even in lieu of an effective protective vaccine.
While it is certainly important to continue supporting the research and development of malaria vaccines, international health organizations, national health programs and other organizations involved in the global effort to control malaria must strive to develop more cohesive, feasible and cost-effective control programs in malaria-endemic areas using available methods.
Effective malaria control incorporates a variety of strategies to prevent infection, transmission, and the negative health impacts associated with clinical disease. This requires the implementation of a wide variety of control measures, including prompt detection and appropriate treatment of malaria victims, prevention of infection through a wide variety of vector control strategies, and prevention of disease through the distribution of antimalarial drugs in high-risk populations such as pregnant women and children under 5 years old.
Furthermore, widespread education about the effects of malaria, diagnosis, treatment and prevention of transmission is necessary in every comprehensive malaria control program. Social marketing of bed nets, campaigns for environmental control of malaria breeding grounds, and awareness campaigns highlighting high-risk groups such as pregnant women and young children have been highly effective in increasing community support and involvement in public health interventions (9).
Case Management:
Effective malaria control programs must include effective programs for detection, diagnosis and distribution of appropriate treatment to patients with clinical disease caused by malaria. Although early detection and treatment can be extremely difficult in resource-poor settings that lack the necessary health infrastructure, such as hospitals, clinics, trained health personnel, or adequate access to antimalarial drugs, the importance of appropriate and effective case management in endemic regions is two-fold: first, prompt detection and treatment greatly reduces the morbidity and mortality associated with clinical disease; additionally, treatment is an effective way to prevent onwards transmission by eliminating the possibility of mosquitoes becoming infected from the patient and further spreading infection (9).
Preventative Treatment:
Administration of antimalarial drugs can be a cost-effective measure for prevention of clinical disease in especially vulnerable populations. Most commonly, preventative treatment with antimalarial drugs such as chloroquine and sulfadoxine-pyrimethamine chemoprophylaxis is used to protect pregnant women, who are at particularly high risk for severe disease (10). Preventive antimalarial chemoprophylaxis has also been used successfully for preventing incidence of disease in children under 5 years old.
Vector Control:
A major component of any effective malaria control program is vector control, with the goal of preventing contact between competent malaria vectors and humans. There are many effective methods of vector control that are currently used to prevent infection, ranging from environmental control measures such as the elimination of mosquito breeding grounds to personal protective measures such as the use of insecticide-treated bed nets.
Insecticide-Treated Bed Nets:
Insecticide-treated bed nets (ITNs), which have become a major component of malaria control strategies worldwide, aid in the prevention of malaria transmission and also reduce risk of death and severe morbidity due to malaria in two ways: first, they act as a physical barrier separating the humans that sleep under them from mosquitoes; ITNs also have the effect of killing large amounts of mosquitoes that enter the home and land on the net. Thus, ITNs are effective not only for preventing mosquito contact with humans, but also for directly killing or repelling many mosquitoes.
A major advantage of ITNs is this so-called community effect that has been observed: because ITNs not only repel, but also kill mosquitoes, ITNs actually confer protection from malaria infection within a 300-meter radius of the nets (Phillips-Howard). Thus, the efficacy of ITNs as a control measure extends to neighbors in the community, even if all members do not have access to ITNs (11).
The efficacy of ITNs as a physical barrier for transmission depends on correct use and upkeep of the nets, which requires education and creative social marketing campaigns informing the public about the efficacy and proper use of bed nets. However, when used correctly, ITNs are effective in not only reducing incidence of severe disease, but also have dramatic impacts on all cause mortality in children under 5 years old (11). Studies of bed nets dipped in pyrethroid insecticides such as permethrin have show over 95% reductions in bites by Anopheline mosquitoes in users of bed nets versus those who slept without ITNs (13). A comprehensive study conducted in Western Kenya collaborates the efficacy of ITNs in the prevention of infant mortality, showing a nearly 20% reduction in all-cause mortality in children under 5 years old who consistently slept under ITNs (11).
One of the major barriers to the widespread feasibility of ITNs is the need for periodic re-treatment with insecticides, usually every 6 months. Vector control programs aiming for widespread distribution of ITNs must account for this need for re-treatment, which can be difficult in areas with little health infrastructure.
Indoor Residual Spraying:
Indoor residual spraying (IRS) is the process of coating the walls of a dwelling with insecticide. IRS can use a wide variety of insecticides, ranging from DDT, which is now banned in most developed countries, to a wide variety of pyrethroids and other synthetic insecticides. As in the case of ITNs, the goal of IRS is to reduce the number of mosquitoes present within dwellings by either directly killing or repelling the malaria vectors (9).
Although fears over growing insecticide resistance in the 1960s and 1970s led to the decreased use of IRS as a widespread control measure, IRS remains an effective method for reducing severe diseases and has been revived in recent years due to the huge success of IRS campaigns in South Africa, where high coverage of IRS reduced clinical malaria cases by over 80% (14).
Several barriers to widespread implementation of IRS include the need for trained personnel to apply insecticides and maintain equipment, as well as the necessity of periodic re-spraying, all of which may be difficult in regions that lack adequate financial support for health intervention programs, appropriate infrastructure and other resources (15) Finally, IRS is only effective when applied to a high proportion of houses in a community, thus requiring significant resources, organization, and community cooperation (14).
Environmental Management:
Environmental vector control encompasses a wide variety of methods for eliminating mosquito larva populations. Also called source reduction, larval control campaigns have been extremely successful at eliminating vector breeding grounds and controlling larval densities through application of insecticides and other biological insecticidal control agents, such as bacterial toxins. Introduction of predatory species such as “mosquito fish,” or Gambusia affinis, has also been shown to be effective at reducing larval densities in some areas (14).
Innovative environmental management programs in Oaxaca, Mexico, have galvanized community support and leadership in malaria control programs. In one such program, members of the community were trained in identifying and filling in potential larval breeding grounds such as potholes and other standing pools of water, cleaning algae and other debris from bodies of water, as well as other environmental control measures for preventing larval development (16).
Insecticide Resistance:
The efficacy of many effective vector control methods to date relies heavily on the use of a wide variety on insecticides. However, widespread insecticide resistance poses a major threat to the continued efficacy of such measures, particularly due to the over-reliance on widespread DDT and other insecticide use during the global malaria eradication campaign of the 1950s and 1960s (17). Currently, more than 100 mosquito species, many of them competent malaria vectors, show resistance to one or more pesticides (17). Furthermore, insecticide-resistant vectors are not limited to a particular region, but rather are present in all malaria-endemic areas (13).
Whereas insecticides were once widely used agriculturally, current control measures incorporating insecticides – from insecticide-treated bed nets to indoor residual spraying – limit as much as possible the volume of insecticide used (17). Restrictions on insecticide use, as well as increased focus on alternative environmental management control strategies, increase the likelihood of the long-term sustainability and efficacy of malaria control programs worldwide.
Requirements for Effective Malaria Control:
Effective malaria control requires the involvement and cooperation of organizations, groups, and resources from the community to the international level. The most effective malaria control efforts are based on not only coordination with national and international guidelines and policies, but also meaningfully involve members of the community. Training community workers to apply indoor residual spraying, distribute, hang and re-treat bed nets, and identify and eliminate vector breeding grounds are all sustainable and effective measures to ensuring long-term malaria control (18).
Insecticide-treated bed nets, in particular, are a promising intervention because they are easily administered by community-based organizations, and are a cost-effective and sustainable way of providing protection for high-risk populations such as pregnant women and young children (12).
Continued development of effective local health infrastructure, trained personnel, and other resources to strengthen current malaria control programs is important not only for continued control of malaria-associated morbidity and mortality through current measures, but also lays in place an effective framework for widespread distribution in the event of the development of an effective malaria vaccine. Whether in the form of a vaccine, vector control, or preventative chemoprophylaxis, coordination between local health providers and community workers and international organizations is imperative for the effective control of one of the most devastating diseases worldwide.
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