Defeating Malaria: A Vision for the Future

by Serena Blacklow

“I was visited by a mother, Tibangwa Sarah, whose daughter had a severe fever. The malaria rapid diagnostic test was negative, so I wrote her a referral to the health centre for more tests. Instead, because she didn’t trust me, she went to the drug shop, bought the wrong drugs and the child died.”

– Katusabe Beatrice, a community health worker in Uganda (25)

About 207 million people were diagnosed with malaria in 2012 (1). An estimated 627,000 deaths occurred that year due to malaria, 90% of which occurred in sub-Saharan Africa (2).  Yet, these numbers mark a 42% decrease in mortality rate since 2000 (1).  Globally, 40% of the population is at risk of contracting malaria (1).  Both the devastation and the global scale of the malaria crisis necessitate that international efforts be expended on conducting research and sending aid to quell the flow of cases.

Malaria thrives in tropical and subtropical environments, especially Sub-Saharan Africa, Asia and South America, where muggy weather allows for ideal mosquito breeding conditions. Children under the age of 5 and pregnant women are the most susceptible subpopulations to contracting the disease.  In Africa, malaria kills one child per minute (1).

Infection

Malaria is caused by a parasitic microorganism from the genus Plasmodium. There are 4 main species that infect humans: P. falciparum, P. vivax, P. ovale, and P. malariae. Mosquitoes successfully infect an individual during a bite by transferring parasites into the bloodstream. The parasites—at this point called sporozoites—travel to the liver, where they mature and reproduce (3).  At this stage, they reenter the bloodstream as merozoites, which further infect red blood cells and reproduce inside them. When these red blood cells burst, usually within 48-72 hours of infection, they release more pathogens into the body, and the cycle continues.
Symptoms range from feverishness to organ failure and commonly include headaches, nausea, vomiting, aches, and an enlarged liver. However, in more severe cases—such as an infection by P. falciparum—other health problems can arise.  Anemia (decreased amount of red blood cells in the bloodstream), respiratory difficulties, low blood pressure, kidney failure, hypoglycemia (low blood sugar levels), and cognitive dysfunction are other potential symptoms.  Malaria can also result in death (4).

Treatments and Resistance

The first effective treatment for malaria was quinine. Quinine remained the primary treatment until the 1920s, when researchers began developing and testing new drugs. By the 1940s, chloroquine replaced quinine as the go-to treatment for a malarial infection. Resistance to chloroquine developed quickly, however, so its use declined, whereas quinine continues to be used as a first- or second-line treatment (5).

More recently, artemisinin derivatives have been incorporated as active ingredients into treatments.  Experts recommend artemisinin-based combination therapy (ACT) as a first-line treatment for malaria when it is available because of fear of rising resistance to pure artemisinin. The four recommended ACTs, according to the World Health Organization, are artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, and artesunate-sulfadoxine-pyrimethamine (6).

There are official, unofficial, and counterfeit drugs distributed as malaria treatments.  Official drugs are those endorsed by institutions such as the CDC and administered by the WHO to the Ministries of Health in countries of need. Unofficial drugs are provided by countries such as China, Brazil, and India in “exchange” for something else in the future (7). On the other hand, locals provide counterfeit drugs, and these drugs are usually composed of a mix of other drugs plus a small amount of active anti-malarial drug such as artemisinin. These low-quality “treatments” can result in health issues due to the other drugs that are mixed in.  Even more significantly, they encourage drug resistance; the small amount of active ingredient is not enough to treat the patient, but it is just enough to expose the parasite for long enough to adapt resistance (7).

Prevention Methods

The most common prevention methods for malaria include indoor residual spraying and mosquito netting.  These relatively inexpensive solutions disincentivize mosquitoes from biting by creating either a chemical or physical barrier between the mosquito and the vulnerable human.  Since a mosquito bite is the primary means of malarial transmission and mosquitoes are most active between dusk and dawn, these methods are among the most successful prevention methods.

In a modern compilation of these methods, Insecticide-Treated Bed Nets (ITNs) are now being endorsed by the Center for Disease Control (CDC) as effective protection for sleeping families in high-risk areas (8). The newest development related to ITNs are long-lasting insecticide-treated bed nets (LLINs).  LLINs are nets that have pyrethroid insecticide woven into their fabric, and they last three to five years before they need to be replaced, with each one costing $2.10 (9, 10). Though the use of these nets has been effective, resistance to pyrethroid is an emerging concern, since other insecticides have not yet been tried with nets and are certain to increase costs (10).

In sub-Saharan Africa, a total of 450 million nets are needed to protect all at-risk households, which corresponds to new net donations of 150 million annually, since they last about three years. In 2004, manufacturers distributed only 6 million nets, but, in 2010, they distributed 145 million. In 2011 and 2012, however, these numbers fell substantially—to 92 and 70 million respectively, though numbers began  to rise again, to 136 million in 2013 and a projected 200 million in 2014 (2).  These delivery numbers need to remain high to ensure continual universal coverage. Any sag in coverage leaves the population vulnerable to malaria resurgence, since the use of nets is one of the most useful forms of protection.

Immunity and Vaccines

Natural immunity provides another form of protection to some individuals. There is remarkable overlap between malaria-dense regions and those populated by sickle-cell heterozygous individuals. Those who are heterozygous for the sickle-cell trait do not have the same symptoms as diseased homozygous individuals, but they have the ability to produce sickled red blood cells, and malarial parasite infection can catalyze this event. Sickled cells are more quickly removed from circulation, and this quick clearing provides natural immunity; the parasites are unable to mature and reproduce in the short time that the sickle red blood cells are in the bloodstream (11). Though fully developed sickle cell anemia has its own health concerns, this temporary response works in an individual’s favor in the case of malaria infection.

Natural immunity is not universal, and the work towards eradication requires more than just administering treatments. Vaccines are also necessary to ensure protection for future generations. There is one malaria vaccine candidate finishing its Phase III clinical trial: RTS,S. The Malaria Vaccine Initiative, run by PATH, reports that “over 18 months of follow-up, RTS,S was shown to almost halve the number of malaria cases in young children (aged 5-17 months at first vaccination) and to reduce by around a quarter the malaria cases in infants (aged 6-12 weeks at first vaccination)” (12). The exact mechanism of RTS,S is unclear, however.  The WHO could recommend RTS,S for use as early as 2015 (12).

Distribution and Reporting

Distribution of bed nets and treatments from the World Health Organization goes through the Ministries of Health. Limitation of this central supply is an obstacle in providing communities with the treatment and protection they need, but there are larger supply chain issues that interfere with efficient distribution. Though treatments are delivered free in many places, the availability of those treatments in the places of need is a focal issue. There are many reasons for this issue. Distributors will not provide treatments until a test has returned positive, and delivery timelines are not always met. Also, since a government may base its distribution on previous data about outbreak patterns in particular areas, if there is in fact a large outbreak somewhere unexpected, redistribution is not efficiently and effectively done (7).

Correct distribution of malarial drugs would be efficiently implemented if there were universal diagnostic testing. Currently, people are so accustomed to encountering malaria in their everyday lives that they sometimes incorrectly assume that anyone with a fever has malaria. Self-diagnosis results in ineffective use of antimalarial agents and unnecessary depletion of resources, undermining long term drug resistance and elimination visions (7). Implementing diagnostic tests, such as the Rapid Diagnostic Test (RDT), and opening their availability to the private sector will help with self-diagnosis and alleviate this strain on already-scarce resources.

Village health care workers ensure compliance and work in delivery teams. They are usually localized grassroots organizations.  Health care workers and volunteers use cell phones to report cases back to clinics using rapid reporting systems. These volunteers are not paid, so the Ministries of Health and partners such as PATH reward them with free cell phones and bikes (13). In the future, rewards should include free cell phone minutes, which will help them make more reporting calls for free.

Costs and Global Initiatives

The World Health Organization estimates total international funding towards malaria in 2012 was the equivalent of 2.5 billion U.S. dollars. Universal malaria control and care would require at least $5.1 billion in global resources per year between 2011 and 2020, so current efforts are falling short by at least 50% (2).

A web of organizations lays the foundation for the international combat against malaria.  Below is a list of initiatives that have been taken to help reduce the threat of malaria worldwide:

Roll Back Malaria: Roll Back Malaria is a global partnership comprising more than 500 foundations, organizations, and institutions from both malaria-endemic countries and their supporters (14). Its overall strategy toward fighting malaria is outlined in the Global Malaria Action Plan, which details goals to reduce malaria mortality and reach elimination, as well strategies and funding needs to reach those goals.

The Global Fund: The Global Fund to Fight AIDS, Tuberculosis, and Malaria is an international nonprofit organization founded in 2002 that has since provided the equivalent of $8.8 billion for malaria programs in 97 countries. It has many partners, including the World Health Organization and Roll Back Malaria (15).

Global Health Initiative: President Obama announced the Global Health Initiative in 2009 in an effort to address gender equity but also to strengthen health systems, encourage partnerships, and promote research (16). The President’s Malaria Initiative is a core component.

The President’s Malaria Initiative (PMI): The President’s Malaria Initiative was established in 2005 with the goal to cut in half the number of malaria cases in 70% of affected places in sub-Saharan Africa from 2000 to 2014 (17).  New goals for 2015-2020 include cutting by 33% the malaria mortality rate in countries of focus (18). From 2000 baseline levels, these goals will result in an 80% reduction of mortality rates by 2020.

The World Health Organization (WHO): The World Health Organization provides Ministries of Health with antimalarial drugs and other prevention methods, such as nets. They provide detailed annual reports on funding; vector control; use of treatments, nets, and diagnostic tests; and case monitoring, among other data.

United States Agency for International Development (USAID): USAID is a U.S. government agency that supports a large spectrum of international investments in humanitarianism. Its malaria programs support Roll Back Malaria’s Global Malaria Action Plan and the President’s Malaria Initiative (19).

Malaria Consortium: The Malaria Consortium has been working against malaria since 2003. The non-profit organization, in collaboration with the Global Fund, local governments, and the President’s Malaria Initiative in Uganda, distributed 10 million LLINs in 2013, trained 13,000 community health workers, and diagnosed and treated over 1 million malaria cases (15). It is funded in part by Comic Relief, a funding source from the U.K.

PATH: PATH is an international non-profit organization that, through the Malaria Vaccine Initiative and The Malaria Control and Elimination Partnership in Africa, collaborates with other partners to come up with innovative ways of developing and delivering malarial treatments and prevention measures, from diagnostic tests to vaccines (12).

Worldwide Antimalarial Resistance Network (WWARN): The Worldwide Antimalarial Resistance Network aims to research antimalarial drug resistance and map its emergence on the world stage. It advocates investment in better surveillance methods and better tracking of the effects of counterfeit or other ineffective drugs (20).

Center for Disease Control (CDC): The CDC helps set standards for malaria policies and also monitors these policies around the world. It collaborates with the World Health Organization, the President’s Malaria Initiative, and Roll Back Malaria (21). In the US, the CDC helps ensure that malaria does not reemerge as a threat and informs travelers of the threat of malaria abroad.

Zambia: a brief case study

The President’s Malaria Initiative has provided Zambia with $127 million since 2005. In 2012, it provided 3 million RDTs, and it will supply 3.5 million more in 2014 (18). Currently, a mass drug administration is being tested in Zambia to see if this mass administration will yield a decrease in malaria cases or a change in the genetics of the parasite population (7). Hopefully, tests such as this one will pave the way for the most efficient distribution of treatments: will administration decrease case counts most effectively if the drugs are distributed en mass, by household if there is at least one infected person, or on a case-by-case basis (7)?

We are so close yet still so far from eliminating malaria as a global public health threat. Complete elimination is a vision for the future, but what we do now will have an enormous impact on that future.

Serena Blacklow ’17 is a sophomore concentrating in Engineering Sciences.

Works Cited

1. World Health Organization (2014). Malaria. Retrieved October 2014 from http://goo.gl/vekhxg
2. World Health Organization (2013). World Malaria Report 2013. Retrieved October 2014 from http://goo.gl/sC4rl9
3. A.D.A.M. Medical Encyclopedia (2013). Malaria. Retrieved October 2014 from http://goo.gl/Ns7dyI
4. Bartoloni, A, et al. (2012). Mediterr. J. Hematol. Infect Dis. 4(1).
5. Achan, J., et. (2011). Malaria Journal. 10(144).
6. World Health Organization (2008). World Malaria Report 2008. Retrieved October 2014 from http://goo.gl/yQp2QB
7. Sarah Volkman (Principal Research Scientist, Dept. of Immunology and Infectious Diseases, Harvard School of Public Health; Director, Malaria Diversity Project, Broad Institute) personal communication, October 16, 2014
8. Centers for Disease Control and Prevention (2014). Insecticide-Treated Bed Nets. Retrieved October 2014 from http://goo.gl/Zdo8NU
9. Global Malaria Programme. Insecticide-Treated Mosquito Nets: a WHO position statement. Retrieved October 2014 from http://goo.gl/0OjlvS
10. Toe, Kobie H., et al. (2014). Emerging Infectious Diseases. 20(10).
11. Hedrick PW (2011). Heredity. 107(4): 283-304.
12. Malaria Vaccine Initiative (2014). Malaria vaccine candidate reduces disease over 18 months of follow-up in late-stage study of more than 15,000 infants and young children. Retrieved October 2014 from http://goo.gl/doRz4h
13. Cheers, Imani M. “How Cell Phones Are Helping Fight Malaria.” PBS NewsHour, Health. April 25, 2013. Retrieved October 2014 from http://goo.gl/Fi4m7Y
14. Roll Back Malaria (2014). RBM Mandate. Retrieved October 2014 fromhttp://goo.gl/nFM1N4
15. The Global Fund to Fight AIDS, Tuberculosis and Malaria (2014). Malaria. Retrieved October 2014 from http://goo.gl/dkQ8HE
16. United States Department of Health and Health Services. Global Health Initiative. Retrieved October 2014 from http://goo.gl/n7hVwZ
17. President’s Malaria Initiative (2014). About. Retrieved October 2014 from http://www.pmi.gov/about
18. President’s Malaria Initiative (2014). President’s Malaria Initiative Malaria Strategy 2015-2020 Draft for External Review. Retrieved October 2014 from http://goo.Sgl/kzkIxF
19. USAID.gov: http://goo.gl/1ePX9n
20. Worldwide Antimalarial Resistance Network (2014). Our Work. Retrieved October 2014 from http://www.wwarn.org/about-us/our-work
21. Centers for Disease Control and Prevention (2012). CDC’s Global Malaria Initiatives. Retrieved October 2014 from http://goo.gl/7AcZAf
22. Kaiser Family Foundation (2013). Estimated Malaria Cases, 2012. Retrieved October 2014 from http://goo.gl/4MTEUE
23. Dondorp, A. M., et al. (20100. Nature Reviews Microbiology. 8: 272-280.
24. Rector and Visitors of the University of Virginia (2007). The Mosquito Net. Retrieved October 2014 from http://goo.gl/j6JwBI
25. Malaria Consortium (2013). 2003-2013: a decade in communicable disease control and child health. Retrieved October 2014 from http://goo.gl/K5R8nX