Report: is a vaccine essential for the control and eradication of malaria

Bevin Clare, MS, RH, LDN

Position Paper: Is a vaccine essential for the control and eradication of malaria?

Table of Contents
1. Overview
2. Malaria as a global burden
2.1 Eradication of malaria in the past 2.2 Challenging factors in Africa 3.1 Emerging resistance 3.2 Financial investments in eradication of malaria 3.3 Promising new genetic methods of understanding 4.1.1 Clinical immunity to malaria in endemic populations 4.1.2 Pharmaceutical treatment 4.1.3 Sociological educational aspects of control 5.1 Criteria for a successful vaccine5.2 Examples in infectious disease 5.3 Current successes and trends in vaccine development 5.4 Vaccines—The best solution? 6. Cost-benefit assessment of the methods of control
7. Current recommendations and identified areas of improvement
1. Overview
The eradication of malaria is a dynamic, integrative process, which will need to incorporate political, sociological, environmental, educational, economical, biomedical and biological aspects of the human parasite relationship. The advent of a successful vaccine would be a major breakthrough in aspects of eradication, but standing alone would not provide the factors necessary for the eradication of the disease. Without a vaccine, it is still possible that through joint collaboration and cooperation of the key players in malaria we may be able to rectify the social, cultural, economic, environmental and medical imbalances which have lead to malaria endemicity. 2. Malaria as a global burden
The human parasite malaria (Plasmodium sp.) causes up to three million deaths per year in addition to greatly impacting the social and economic systems in countries where it remains endemic. Of the approximately five billion cases of malaria each year, the continent of Africa shoulders roughly 90% of this burden (Breman, 2004). Malaria deaths have continued to rise in the last two decades (Malaria Alliance, 2005). According to Berman (2006), 58% of malaria occurs in the poorest 20% of the world’s population, a population which receives the lowest standard of healthcare and therefore suffers the 2.1 Eradication of malaria in the past Historically, malaria occurred throughout much of Europe, Asia, India, China, almost all the Americas, and in most tropical regions (Warrell, 2002). According to Dr. Julius Mannaberg in his 1905 text Malaria, Influenza and Dengue, “The eastern coast of North America…is markedly infected…we find malaria in the Mississippi far into the interior to Missouri.” This perspective delivers both hope and concern. The fact that malaria has been eradicated from much of the world gives us hope that this can extend to Africa with Malaria was eradicated through a number of efforts and concurrent factors. Through modifications of Anopheles habitat by changes in land management and in some places the use of insecticides such as DDT there was a reduction in the biological niches necessary for vector growth. Additionally, improvements in human lifestyle and the introduction of chloroquine eventually led to an overall reduction in the human host and a subsequent eradication of the parasite (Schiff, 2002). 2.2 Challenging factors in Africa The continent of Africa has many unique and compounding factors when it comes to the prevalence of malaria. In addition to the lack of infrastructure in many parts, the deficit of financial resources and the often dismal state of healthcare, there are several biological and sociological reasons that malaria will be a greater challenge to eradicate from Africa than it has been in other area of the globe. From a sociological perspective, a woman’s educational status, awareness and autonomy to take action in the household is essential to the eradication of malaria (Tanner, 1998) as women are the primary household caregivers to those most susceptible to malaria, the children. Additionally, the lack of community members trained in medicine and research is a deficit that cannot be ignored due to its cultural, economic, and long term implications in the overall wellness of a society. Biologically, the primary African vector, Anopheles gambiae, is a most highly efficient host for Plasmodium falciparum (using the MacDonald equation), creating an aggressive and successful pattern of disease transmission unlike anywhere else in the world (Warrell, 2002). While moderate methods of control may be effective in some areas of the globe, the most important area for eradication, Africa, will need more finely honed 3. Current topics in malaria
We are currently in an upswing of interest in malaria with the half-way point in the World Health Organization’s 1993 “Roll Back Malaria” plan coupled with exciting areas As of 2007, there is growing resistance to a number of first line anti-malarial drugs and many insecticides. Both chloroquine and pyrimethamine-sulfadoxine have escalating and widespread resistance, making treatment in many endemic areas increasingly difficult (Warrell, 2002). Fortunately, we have a number of other effective treatments, but careless use of these treatments will most certainly result in resistance. 3.2 Financial investments in eradication of malaria In 2004 the total research and development investment in malaria was over $300 million, with strong investment from both public and private sectors (Malaria Research Alliance, 2005). The interest in malaria research has continued to grow, and despite a seemingly large amount of available research funds, the Malaria Research Alliance (2005) reports that the economic impact malaria makes on humanity is roughly 10 times this amount, accounting for 3.1% of global disease burden. 3.4 Promising new genetic methods of understanding With the completion of the sequencing of the malaria genome, the human genome, and more recently the genome of the most important malaria vector, Anopheles gambiae, we are encountering novel ways of approaching old problems. A comprehensive understanding of the biological and genetic information in the three players involved in malaria (man, mosquito, and protozoa) gives us insight into the development of vaccines, newly targeted drugs, and most importantly, brings us closer to a global solution 4. Current methods of control
Until the advent of a vaccine, human oriented control of malaria will revolve around the many aspects of pharmaceutical prophylaxis and treatment, and the prevention of contact with infected mosquitoes. A vaccine is an important aspect of control of malaria, but it is not essential in a program which incorporates many other areas of control for future 4.1.1 Clinical immunity to malaria in endemic populations In endemic areas of malaria many adults consistently living in the area can develop a clinical immunity to infection with malaria parasites. This is not, however, a true immunity to the parasite, as a sub-clinical infection persists, offering increased chances for community dissemination of the infection. In addition, pregnant woman who have developed this clinical immunity become susceptible to malaria once again during pregnancy, as are their children once born (Warrell, 2002). There are a variety of treatments for malaria which must be selected specifically for the patient depending on their age, pregnancy status, general health and proximity to resistant strains of Plasmodium. Many of the treatments have severe or undesirable side-effects, especially in pregnancy (Warrell, 2002). Quinine became a treatment mainstay after its rise to prominence in the 17th century (Gardiner, 2005), and today continues to be an important treatment in the increasingly large areas of chloroquine resistance (Warrell, 2002). Chloroquine was first produced in the 1930’s and, in combination with vector control, it lead to the eradication of malaria in many areas of the world. Unfortunately, careless use of this effective drug ultimately led to widespread resistance today, and although currently ineffective in many of the most important areas it is still used in up to 84% of malaria infections today (Gardiner, 2005). This pattern of resistance to malaria treatment continued with the implementation of sulfadoxine-pyrimethamine (Fansidar), where resistance was observed within a year of its introduction (Gardiner, 2005). While there are many other available treatments, none are as promising as the artemisinin combination treatments (ACT). ACT uses the compound artemisinin and its derivatives, which comes from the plant Artemisia annua L. (Asteraceae). A. annua is an easy to cultivate, vigorously growing herbaceous plant with a wide growing range. The plant produces varying amounts of artemisinin as well as a number of other anti-malarial compounds in quantity. Development in this area has focused on isolating and chemically reproducing this single constituent; whereas with proper development and application whole plant application may be more suited for preventing resistance and optimizing treatment options (Plant Based Strategies, 2006). Current ACT therapy combines artemisinin, which alone has a high rate of recrudescence, with other effective pharmaceuticals for optimal efficacy and the prevention of resistance to either treatment (Warrell, 2002). Further investigation into the use of A. annua as a treatment for malaria is warranted, as a locally cultivated and processed medicine would have great economic and social benefit. 4.1.3 Sociological and educational aspects of control To eradicate malaria, human nature must be accounted for. There are currently many educational programs to encourage the use of bed-nets, to seek immediate treatment when showing signs or symptoms of malaria infection, and the importance of doing so. In many endemic areas, people are well informed of the cause of malaria and actively participate in reducing vector exposure in the home. This sort of awareness and community participation in prevention and treatment of malaria is essential to the success of any program to eradicate malaria. Additionally, challenges to the social acceptability of a new vaccine must be addressed to avoid issues such as was recently encountered with the polio vaccine in Nigeria (Schiff, 2002). These programs must be continually evaluated, assessed, and updated for newly available therapeutics and advances in Control of the mosquito vector is a pivotal aspect of current treatment programs. Mosquitoes can be controlled by a variety of environmental, chemical, and biological methods. Environmental methods include reducing bodies of water which larvae may develop in, adding screens to homes to prevent the entry of mosquitoes, and reducing uncontrolled development, war, and other environmental disturbances which have been shown to lead to increased transmission (Warrell, 2002). Chemical methods include the application of insecticides in the home and in the environment, another area of malaria control which has met with rising resistance and decreased efficacy. The use of permethrin saturated bed nets is a combination of types of vector control. Biological control methods have been met with some success, particularly the introduction of fish which feed mosquito larvae, and the release of sterile male mosquitoes into the wild In the future, vector control methods coupled with effective treatment and community awareness may lead to eradication if the economic and logistical challenges with these strategies are regularly tended to. While a vaccine might offer a more direct solution in preventing the spread of malaria, the financial and energetic commitment are disproportionate to some of the simpler vector control strategies which are not fully utilized at the present time. Consistency in application of insecticide is essential to prevent resistance, and bed-nets do little good in prevention if they do not reach the people who need them. Programs to ensure to delivery and application of these methods are a necessary part of any eradication program. 5. Vaccination as a solution
5.1 Criteria for a successful vaccine A vaccine for malaria must be safe, effective, affordable, and administrable to the masses. It must also provide lasting immunity, as a vaccine with limited effectiveness is of little use considering the global effort necessary to administer the vaccine. It must be coupled with a comprehensive plan for administration to people in rural areas, under conditions which may not provide refrigeration, and there must be a global solution to offset the massive costs for R&D, production and dissemination. A large and conscious public health plan must be formulated which will allow the people who most need a successful vaccine to receive it. A successful vaccine should also address all four of the Plasmodium species infecting humans. 5.2 Examples of successful vaccines in infectious disease There are many examples of widely successful vaccines, most notably the eradication of smallpox, and the planned eradication of diseases such as hepatitis B and polio. These diseases are candidates for eradication because we have a successful vaccine, and the diseases themselves lack complexity in disease process, reservoirs, and mutation. Malaria, however, does not have such a simple biological and ecological picture. There are several vaccines in development for protozoal diseases including schistosomiasis and leishmaniasis, but there are currently no effective vaccines for use against protozoal disease (New Vaccines, 2005). This is likely due in part to the comparatively large array and expression of surface proteins and antigens in the eukaryotic protozoa in comparison to other more simple microbial pathogens. In addition, the four species of malaria and their great genetic diversity makes a vaccine an even greater challenge. 5.3 Current successes and trends in vaccine development The research arena for the development of a vaccine for malaria is an exciting and busy area of exploration. Despite past failures, in this new era of genetic understanding of man, mosquito, and protozoa there is great hope for an effective vaccine. According to the WHO’s 2006 charts on candidate malaria vaccines in clinical and preclinical development, there are currently 46 vaccines in the pre-clinical stage of development, and 34 vaccines in the clinical stages of investigation (WHO, 2006) . Of note is the diversity in approach to the creation of a successful vaccine. Of the 35 vaccines which are already in the stages of clinical development, 17 target the blood- stage, 15 target the pre-erythrocytic stage, 2 are multi-stage vaccines and one targets transmission. Within each of these areas there are a number of surface proteins in various life stages of the parasite which have been identified as targets. All 15 of the vaccines targeting the pre-erythrocytic stage of the parasite target the circumsporozoite protein (CSP), a cell surface protein of the sporozoite. Within the group targeting the blood-stage ten of the 17 vaccines target surface proteins of the meroziote, five of the vaccines are directed at the merozoite surface protein 1(MSP1), and five of them are directed at the apical membrane antigen (AMA-1) (Alonso, 2006; Bejon, 2006; Collins, 2006). Coupled with the sheer number of vaccines in later stage development, the diversity in targets and the combination of the malaria antigens with more immunogenic proteins demonstrates a hopeful pattern of variety in approach and promising future for a successful vaccine. 5.4 Vaccines—The best solution? A vaccine potentially offers us a permanent solution by providing both individual and herd immunity, therefore reducing the source of hosts for the parasite, eventually creating an enduring interruption in its lifecycle and ultimately eradication of the human infecting Plasmodium. This plan is not, however, without its challenges. To be effective, every man, woman, and child in an endemic area must receive this vaccine. A vaccine with limited effectiveness could result in future disaster as drug development weakens and clinical immunity and in endemic areas falls and a more highly susceptible population Any solution for malaria must have three strong arms. Time has demonstrated that a solution cannot simply target the human, the vector, the parasite or the environment. Clearly, an effective, affordable, safe vaccine is a major step toward a solution for this global crisis, but it must be accompanied by a solid effort in the social, economical and practical aspects of human health, conscious vector control efforts, and health policy which takes into account issues of the environmental, economic, and social structure in the places most affected by malaria. While a vaccine is the best long term solution for malaria, it must be part of a process which addresses the compounding factors which plague the areas most affected by malaria including poverty, war, nutrition, women’s 6. Cost-benefit assessment (CBA) of the methods of control
Previous attempts at treatment strategies which incorporated a seemingly isolated arm of the cause of endemic malaria should be incorporated within a more integrative strategy. Although simple treatment of malaria with chloroquine while ignoring many of the other significant aspects of the disease may have saved money in the short term, we pay the price with continued rise in resistance and mortality (Malaria Alliance, 2005). Any future attempts to approach malaria in a similarly isolated manner will undoubtedly be It is this need for an integrative strategy which makes a CBA particularly difficult, as the employment of one method alone is never the most effective method. The successful eradication of malaria will result from a joint effort between the biomedical, public health, anthropological, epidemiological and economical factions of countries and organizations combining forces and funds. Simple, cost effective measures such as the development and implementation of bed-nets must be coupled with less direct initiatives which seek to provide more gender equality through education. Complex, expensive production and implementation of vaccines must be paired with grassroots efforts to distribute and educate the people of the significance and importance of a vaccination for their children, and the policy makers who disperse great amounts of funds in the fight against malaria must be sure that some of their funds stay in Africa, where it can incite change and development. The development of a vaccine does nothing to eradicate the disease if it is not dispersed appropriately. Any solution, with or without a vaccine should incorporate all of the above listed aspects of control. 7. Current recommendations and identified areas of improvement
While there are many promising possibilities on the horizon, the current situation of malaria endemicity is decidedly bleak. Malaria eradication may be one of the most complex logistical public health problems ever approached, requiring the concurrent commitment and cooperation of all sectors of relevant policy and healthcare players. The project of eradication requires intricate logistical solutions and tremendous financial backing, but the benefits will be far reaching into many aspects of economy and healthcare around the world. Surely a cooperation of this magnitude will serve many areas of health and disease in the future. There are many recommended steps in the process of eradication, the development of a vaccine being an important, but not essential aspect of the eradication of malaria. A vaccine would offer a feasible solution which, while requiring necessary cooperation of many aspects of control, would single-handedly eradicate the parasite malaria given the administration of the vaccination to the entire susceptible population. The failure to produce an effective vaccine will result in the loss of enormous amounts of funds and global effort, as a partially effective vaccine is of little application. Given the extensive logistics of this solution, there still remains the possibility for eradication without a vaccine if the pivotal players in malaria research and policy can join together to create and implement a comprehensive plan which incorporates economic, sociological, cultural, environmental, medical and political solutions. While this plan would be more difficult than the more immediate implementation of a vaccine, the effects would be felt more broadly in areas of economics, gender equality, and general health status, and would affect many of the other concurrent diseases in the endemic areas. A vaccine has the potential to allow us to ignore some of the more central problems associated with the link between socio-economic status and occurrence of malaria, while a more integrated approach to the issue allows up opportunities to increase the quality of life in a population in a variety of ways, offering a brighter and more hopeful future. References
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