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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]

Overview

Although some are under development, no vaccine is currently available for malaria. RTS,S malaria vaccine has been proposed in July 2014 and is pending approval by the European Medicines Agency (EMA). Other more recent vaccine, such as PfSPZ malaria vaccine is currently being studied for clinical efficacy.

Preventative drugs must be taken continuously to reduce the risk of infection. Most adults from endemic areas have a degree of long-term recurrent infection and also of partial resistance; the resistance reduces with time and adults may become susceptible to severe malaria if they have spent a significant amount of time in non-endemic areas. Individuals are strongly recommended to take full precautions if they return to an endemic region.

Primary Prevention

Anopheles albimanus mosquito feeding on a human arm. This mosquito is a vector of malaria and mosquito control is a very effective way of reducing the incidence of malaria.

Methods used to prevent the spread of disease, or to protect individuals in areas where malaria is endemic, include prophylactic drugs, mosquito eradication, and the prevention of mosquito bites. Although some are under development, no vaccine is currently available for malaria. RTS,S malaria vaccine has been proposed in July 2014 and is pending approval by the European Medicines Agency (EMA). Other more recent vaccine, such as PfSPZ malaria vaccine is currently being studied for clinical efficacy.

Efforts to eradicate malaria by eliminating mosquitoes have been successful in some areas. Malaria was once common in the United States and southern Europe, but the draining of wetland breeding grounds and better sanitation, in conjunction with the monitoring and treatment of infected humans, eliminated it from affluent regions. In 2002, there were 1,059 cases of malaria reported in the US, including eight deaths. In five of those cases, the disease was contracted in the United States. Malaria was eliminated from the northern parts of the USA in the early twentieth century, and the use of the pesticide DDT eliminated it from the South by 1951. In the 1950s and 1960s, there was a major public health effort to eradicate malaria worldwide by selectively targeting mosquitoes in areas where malaria was rampant.[1] However, these efforts have so far failed to eradicate malaria in many parts of the developing world - the problem is most prevalent in Africa.

Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations, successfully reduced the malaria burden. Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.[2]

The Malaria Control Project is currently using downtime computing power donated by individual volunteers around the world (see Volunteer computing and BOINC) to simulate models of the health effects and transmission dynamics in order to find the best method or combination of methods for malaria control. This modeling is extremely computer intensive due to the simulations of large human populations with a vast range of parameters related to biological and social factors that influence the spread of the disease. It is expected to take a few months using volunteered computing power compared to the 40 years it would have taken with the current resources available to the scientists who developed the program.[3]

Prophylactic Drugs

Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Generally, these drugs are taken daily or weekly, at a lower dose than would be used for treatment of a person who had actually contracted the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative side effects from long-term use, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations.

Quinine was used starting in the seventeenth century as a prophylactic against malaria. The development of more effective alternatives such as quinacrine, chloroquine, and primaquine in the twentieth century reduced the reliance on quinine. Today, quinine is still used to treat chloroquine resistant Plasmodium falciparum, as well as severe and cerebral stages of malaria, but is not generally used for prophylaxis. Of interesting historical note is the observation by Samuel Hahnemann in the late 18th Century that over-dosing of quinine leads to a symptomatic state very similar to that of malaria itself. This lead Hahnemann to develop the medical Law of Similars, and the subsequent medical system of Homeopathy.

Modern drugs used preventively include mefloquine (Lariam®), doxycycline (available generically), and the combination of atovaquone and proguanil hydrochloride (Malarone®). The choice of which drug to use depends on which drugs the parasites in the area are resistant to, as well as side-effects and other considerations. The prophylactic effect does not begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards).

Indoor Residual Spraying

DDT was developed as the first of the modern insecticides early in World War II. While it was initially used to combat malaria, its use spread to agriculture where it was used to eliminate insect pests. In time, pest-control, rather than disease-control, came to dominate DDT use, particularly in the developed world. During the 1960s, awareness of the negative consequences of its indiscriminate use increased, and ultimately led to bans in many countries in the 1970s. By this time, its large-scale use had already led to the evolution of resistant mosquitoes in many regions.

However, given the continuing toll to malaria, particularly in developing countries, there is considerable controversy regarding the restrictions placed on the use of DDT. Though DDT has never been banned for use in malaria control, some advocates claim that bans are responsible for tens of millions of deaths in tropical countries where DDT had previously been effective in controlling malaria. Furthermore, most of the problems associated with DDT use stem specifically from its industrial-scale application in agriculture, rather than its use in public health.[4]

The World Health Organization (WHO) currently advises the use of DDT to combat malaria in endemic areas.[5] For instance, DDT-spraying the interior walls of living spaces, where mosquitoes land, is an effective control. The WHO also recommends a series of alternative insecticides (such as the pyrethroids permethrin and deltamethrin) to both combat malaria in areas where mosquitoes are DDT-resistant, and to slow the evolution of resistance. This public health use of small amounts of DDT is permitted under the Stockholm Convention on Persistent Organic Pollutants (POPs), which prohibits the agricultural use of DDT for large-scale field spraying.[6] However, because of its legacy, many developed countries discourage DDT use even in small quantities.[7]

Mosquito Nets and Bedclothes

Mosquito nets help keep mosquitoes away from people, and thus greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier, so they are often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets (ITN) are estimated to be twice as effective as untreated nets,[8] and offer greater than 70% protection compared with no net.[9] Since the Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and covers the bed completely.

The distribution of mosquito nets impregnated with insecticide (often permethrin or deltamethrin) has been shown to be an extremely effective method of malaria prevention, and it is also one of the most cost-effective methods of prevention. These nets can often be obtained for around US$2.50 - $3.50 (2-3 euros) from the United Nations, the World Health Organization, and others.

For maximum effectiveness, the nets should be re-impregnated with insecticide every six months. This process poses a significant logistical problem in rural areas. New technologies like Olyset or DawaPlus allow for production of long-lasting insecticidal mosquito nets (LLINs), which release insecticide for approximately 5 years,[10] and cost about US$5.50. ITN's have the advantage of protecting people sleeping under the net and simultaneously killing mosquitoes that contact the net. This has the effect of killing the most dangerous mosquitoes. Some protection is also provided to others, including people sleeping in the same room but not under the net.

Unfortunately, the cost of treating malaria is high relative to income, and the illness results in lost wages. Consequently, the financial burden means that the cost of a mosquito net is often unaffordable to people in developing countries, especially for those most at risk. Only 1 out of 20 people in Africa own a bed net.[8] Although shipped into Africa mainly from Europe as free development help, the nets quickly become expensive trade goods. They are mainly used for fishing, and by combining hundreds of donated mosquito nets, whole river sections can be completely shut off, catching even the smallest fish. [11]

A study among Afghan refugees in Pakistan found that treating top-sheets and chaddars (head coverings) with permethrin has similar effectiveness to using a treated net, but is much cheaper.[12]

A new approach, announced in Science on June 10, 2005, uses spores of the fungus Beauveria bassiana, sprayed on walls and bed nets, to kill mosquitoes. While some mosquitoes have developed resistance to chemicals, they have not been found to develop a resistance to fungal infections.[13]

Images

Mosquito nets in Pakistan
Mosquito nets in Pakistan


Vaccination

Vaccines for malaria are under development, with no completely effective vaccine yet available. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live, radiation-attenuated sporozoites, providing protection to about 60% of the mice upon subsequent injection with normal, viable sporozoites.[14] Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans. It was determined that an individual can be protected from a P. falciparum infection if they receive over 1000 bites from infected, irradiated mosquitoes.[15]

It has been generally accepted that it is impractical to provide at-risk individuals with this vaccination strategy, but that has been recently challenged with work being done by Dr. Stephen Hoffman, one of the key researchers who originally sequenced the genome of Plasmodium falciparum. His work most recently has revolved around solving the logistical problem of isolating and preparing the parasites equivalent to a 1000 irradiated mosquitoes for mass storage and inoculation of human beings.

Instead, much work has been performed to try and understand the immunological processes that provide protection after immunization with irradiated sporozoites. After the mouse vaccination study in 1967,[14] it was hypothesized that the injected sporozoites themselves were being recognized by the immune system, which was in turn creating antibodies against the parasite. It was determined that the immune system was creating antibodies against the circumsporozoite protein (CSP) which coated the sporozoite.[16] Moreover, antibodies against CSP prevented the sporozoite from invading hepatocytes.[17] CSP was therefore chosen as the most promising protein on which to develop a vaccine against the malaria sporozoite. It is for these historical reasons that vaccines based on CSP are the most numerous of all malaria vaccines.

Presently, there is a huge variety of vaccine candidates on the table. Pre-erythrocytic vaccines (vaccines that target the parasite before it reaches the blood), in particular vaccines based on CSP, make up the largest group of research for the malaria vaccine. Other vaccine candidates include: those that seek to induce immunity to the blood stages of the infection; those that seek to avoid more severe pathologies of malaria by preventing adherence of the parasite to blood venules and placenta; and transmission-blocking vaccines that would stop the development of the parasite in the mosquito right after the mosquito has taken a bloodmeal from an infected person.[18] It is hoped that the sequencing of the P. falciparum genome will provide targets for new drugs or vaccines.[19]

The first vaccine developed that has undergone field trials, is the SPf66, developed by Manuel Elkin Patarroyo in 1987. It presents a combination of antigens from the sporozoite (using CS repeats) and merozoite parasites. During phase I trials a 75% efficacy rate was demonstrated and the vaccine appeared to be well tolerated by subjects and immunogenic. The phase IIb and III trials were less promising, with the efficacy falling to between 38.8% and 60.2%. A trial was carried out in Tanzania in 1993 demonstrating the efficacy to be 31% after a years follow up, however the most recent (though controversial) study in the Gambia did not show any effect. Despite the relatively long trial periods and the number of studies carried out, it is still not known how the SPf66 vaccine confers immunity; it therefore remains an unlikely solution to malaria. The CSP was the next vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporoziote protein, but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed.

The efficacy of Patarroyo's vaccine has been disputed with some US scientists concluding in The Lancet (1997) that "the vaccine was not effective and should be dropped" while the Colombian accused them of "arrogance" putting down their assertions to the fact that he came from a developing country.

The RTS,S/AS02A vaccine is the candidate furthest along in vaccine trials. It is being developed by a partnership between the PATH Malaria Vaccine Initiative (a grantee of the Gates Foundation), the pharmaceutical company, GlaxoSmithKline, and the Walter Reed Army Institute of Research[20] In the vaccine, a portion of CSP has been fused to the immunogenic "S antigen" of the hepatitis B virus; this recombinant protein is injected alongside the potent AS02A adjuvant.[18] In October 2004, the RTS,S/AS02A researchers announced results of a phase IIb trial, indicating the vaccine reduced infection risk by approximately 30% and severity of infection by over 50%. The study looked at over 2,000 Mozambican children.[21] More recent testing of the RTS,S/AS02A vaccine has focused on the safety and efficacy of administering it earlier in infancy: In October 2007, the researchers announced results of a phase I/IIb trial conducted on 214 Mozambican infants between the ages of 10 and 18 months in which the full three-dose course of the vaccine led to a 62% reduction of infection with no serious side-effects save some pain at the point of injection.[22] Further research will delay this vaccine from commercial release until around 2011.[23]

Other Methods

Sterile insect technique is emerging as a potential mosquito control method. Progress towards transgenic, or genetically modified, insects suggest that wild mosquito populations could be made malaria-resistant. Researchers at Imperial College London created the world's first transgenic malaria mosquito,[24] with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002.[25] Successful replacement of existent populations with genetically modified populations, relies upon a drive mechanism, such as transposable elements to allow for non-Mendelian inheritance of the gene of interest.

Education in recognising the symptoms of Malaria has reduced the number of cases in some areas of the developing world by as much as 20%. Recognising the disease in the early stages can also stop the disease from becoming a killer. Education can also inform people to cover over areas of stangnant, still water eg Water Tanks which are ideal breeding grounds for the parastie and mosquito thus, cutting down the risk of the transmission between people. This is most put in practice in urban areas where there is large centres of population in a confined space and transmission would be most likely in these areas.

Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling or applying oil to places with standing water. These methods have seen little application in Africa for more than half a century.[26]

Secondary Prevention

Malaria transmission can be reduced by preventing mosquito bites with

  • Mosquito nets
  • Insect repellents
  • Mosquito control measures such as
    • Spraying insecticides inside houses
    • Draining standing water where mosquitoes lay their eggs

Policy Implementation and Access to Anti-Malarial Drugs in Developing Countries

The introduction of any anti-malarial therapy requires policies to regulate local distribution, access and guidelines for usage. There are many considerations when implementing the use a newly developed drug.

These include:

  • The known efficacy of the treatment and the adherence levels likely within the constraints of the local health system
  • The economic resources necessary to implement the policy by the health care sector
  • The human and technical resources and the basic primary health care infrastructure
  • Education
  • Training and health promotion schemes for staff and the general population
  • Successful interactions between the public and private sector to ensure that sufficient drugs are supplied
  • Regulation over quality control
  • Distribution and pricing
  • Regular monitoring and a system enabling alteration of the policy

One of the major problems associated with anti-malarial therapy is the inadequate primary health care infrastructure in many of the countries where malaria is endemic. It is estimated that one third of the population at risk of developing the infection has no access to therapy. Access is defined as the availability to pharmaceuticals of quality and can be subdivided in to physical, financial (affordability and equity) and rational-use access. The level of access is determined by many factors from the appropriate knowledge to use the drug effectively, supply management, basic infrastructure for delivery, economic and legislative issues. This is affected by the participation and support of all the stakeholders involved from the government to local private companies. In many countries access is prevented by poor political will and interest, low levels of economic growth and the investment of the majority of financial resources in secondary or tertiary health care. The level of quality control over anti-malarials provided is a key problem in many areas of the world. Poor quality and counterfeit drugs can lead to an increase in the rate of resistance development due to incorrect dosing and can pose a fatal risk if given in acute cases where little or no drug is contained within the given dose. This issue is thought to account, to an unknown degree, to the perceived resistance and treatment failure rates seen. The percentage failure rates in sub-Saharan Africa vary from 20 to 67%. Random content testing has been carried out and demonstrated that, in certain areas up to 100% of this failure is due to poor content. This poses a serious danger to the international campaigns against malaria and therefore cannot be ignored. Suggestions to overcome such problems include international surveillance systems within drug regulatory authorities and supporting pharmaceutical manufacturers.

References

  1. Gladwell, Malcolm. (2001-07-02). "The Mosquito Killer". The New Yorker. Check date values in: |date= (help)
  2. Barat L (2006). "Four malaria success stories: how malaria burden was successfully reduced in Brazil, Eritrea, India, and Vietnam". Am J Trop Med Hyg. 74 (1): 12–6. PMID 16407339.
  3. "What is Malariacontrol.net". AFRICA@home. Retrieved 2007-03-11.
  4. Tia E, Akogbeto M, Koffi A; et al. (2006). "[Pyrethroid and DDT resistance of Anopheles gambiae s.s. (Diptera: Culicidae) in five agricultural ecosystems from Côte-d'Ivoire]". Bulletin de la Société de pathologie exotique (1990) (in French). 99 (4): 278–82. PMID 17111979.
  5. "WHO frequently asked questions on DDT use for disease vector control" (PDF). WHO.
  6. 10 Things You Need to Know about DDT Use under The Stockholm Convention
  7. The Stockholm Convention on persistent organic pollutants
  8. 8.0 8.1 Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary
  9. Bachou H, Tylleskar T, Kaddu-Mulindwa DH, Tumwine JK. (2006). "Bacteraemia among severely malnourished children infected and uninfected with the human immunodeficiency virus-1 in Kampala, Uganda". BMC Infect Dis. 6: 160. doi:10.1186/1471-2334-6-160.
  10. New Mosquito Nets Could Help Fight Malaria in Africa
  11. The Economist (2007). "Traditional Economy of the Kavango". Economist Documentary.
  12. Rowland M, Durrani N, Hewitt S, Mohammed N, Bouma M, Carneiro I, Rozendaal J, Schapira A. "Permethrin-treated chaddars and top-sheets: appropriate technology for protection against malaria in Afghanistan and other complex emergencies". Trans R Soc Trop Med Hyg. 93 (5): 465–72. PMID 10696399.
  13. "Fungus 'may help malaria fight'", BBC News, 2005-06-09
  14. 14.0 14.1 Nussenzweig R, Vanderberg J, Most H, Orton C (1967). "Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei". Nature. 216 (5111): 160–2. PMID 6057225.
  15. Hoffman SL, Goh LM, Luke TC; et al. (2002). "Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites". J. Infect. Dis. 185 (8): 1155–64. PMID 11930326.
  16. Zavala F, Cochrane A, Nardin E, Nussenzweig R, Nussenzweig V (1983). "Circumsporozoite proteins of malaria parasites contain a single immunodominant region with two or more identical epitopes". J Exp Med. 157 (6): 1947–57. Unknown parameter |i pmid= ignored (help)
  17. Hollingdale M, Nardin E, Tharavanij S, Schwartz A, Nussenzweig R (1984). "Inhibition of entry of Plasmodium falciparum and P. vivax sporozoites into cultured cells; an in vitro assay of protective antibodies". J Immunol. 132 (2): 909–13. PMID 6317752.
  18. 18.0 18.1 Matuschewski K (2006). "Vaccine development against malaria". Curr Opin Immunol. 18 (4): 449–57. PMID 16765576.
  19. Gardner M, Hall N, Fung E; et al. (2002). "Genome sequence of the human malaria parasite Plasmodium falciparum". Nature. 419 (6906): 498–511. PMID 12368864.
  20. Heppner DG, Kester KE, Ockenhouse CF; et al. (2005). "Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research". Vaccine. 23 (17–18): 2243–50. doi:10.1016/j.vaccine.2005.01.142. PMID 15755604.
  21. Alonso PL, Sacarlal J, Aponte JJ; et al. (2004). "Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial". Lancet. 364 (9443): 1411–20. doi:10.1016/S0140-6736(04)17223-1. PMID 15488216.
  22. Aponte JJ, Aide P, Renom M; et al. (2007). "Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial". Lancet. doi:10.1016/S0140-6736(07)61542-6.
  23. Africa: Malaria - Vaccine Expected in 2011. Accra Mail. 9 January 2007. Accessed 15 January 2007.
  24. Imperial College, London, "Scientists create first transgenic malaria mosquito", 2000-06-22.
  25. Ito J, Ghosh A, Moreira LA, Wimmer EA, Jacobs-Lorena M (2002). "Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite". Nature. 417: 387–8. PMID 12024215.
  26. Killeen G, Fillinger U, Kiche I, Gouagna L, Knols B (2002). "Eradication of Anopheles gambiae from Brazil: lessons for malaria control in Africa?". Lancet Infect Dis. 2 (10): 618–27. PMID 12383612.




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