Malaria over 3 decades: Progress and pessimism

To mark our 30th anniversary, Infectious Disease News will be examining some of the infectious diseases that have defined and changed the field over the past 3 decades.

Drug resistance is considered one of the most important threats hindering the control — and elimination — of malaria. Chloroquine-resistant Plasmodium falciparum malaria first emerged in the 1950s in Southeast Asia and South America; by the 1970s, it had spread to Africa and was a considerable source of malaria morbidity and mortality. The problem continues to threaten progress 30 years later with the emergence of resistance to artemisinin-based combination therapies.

“Until the mid-1980s, we were heavily reliant on chloroquine,” Jo Lines, BSc, MSc, PhD, professor of malaria control and vector biology at the London School of Hygiene & Tropical Medicine, told Infectious Disease News. “Chloroquine is a fantastic drug, for both prevention and treatment. But once resistance developed, it spread quite quickly.”

Philip Rosenthal

The emergence of chloroquine-resistant P. vivax malaria coincided with an unsuccessful campaign for the global eradication of malaria in the 1950s and 1960s. This effort, adopted by the Eighth World Health Assembly in May 1955, was based on the extensive, well-organized use of DDT.

“In the 1950s and 1960s, there was a serious international discussion about eradicating malaria from the world,” Philip Rosenthal, MD, professor of medicine at UCSF School of Medicine, said in an interview. “There were rather optimistic projections and plans. These failed miserably.”

The failure to control malaria, coupled with growing resistance to chloroquine, resulted in a state of “great pessimism” regarding the disease in the 1980s, according to Lines.

Brian D. Foy

“However, it’s worth saying that this period of pessimism and depression was not because we didn’t appreciate the huge burden of malaria,” he said. “We would write, at the beginning of every article, ‘Malaria is, by far, the primary, most important public health problem in Africa. It is, by far, the greatest killer of children under 5 in Africa.’ But we didn’t have good enough tools to suppress it in the long run.”

In 2005, WHO issued a recommendation that artemisinin-based combination regimens (ACT) be used as first-line treatment of P. falciparum malaria. These regimens are now the mainstay of malaria therapy. The combination of insecticide-treated bed nets and ACT have led to a significant reduction in malaria incidence globally. However, that progress is now being threatened.

Sustaining momentum

Malaria has been eliminated from many areas of the world, including the United States and the WHO European Region. In late 2016, Sri Lanka became the second country in the WHO Southeast Asia Region to eliminate malaria.

Currently, the greatest burden of disease is in sub-Saharan Africa, where insecticide-treated mosquito nets are a critical part of control efforts. The nets have decreased the incidence of malaria and disease-related mortality across all ages, but the decline is particularly important among children aged younger than 5 years — the group at greatest risk of dying from the disease. In one study, malaria control interventions in Tanzania were partially responsible for a 45% decline in mortality among children aged younger than 5 years; 11% of this overall decrease correlated with the use of insecticide-treated mosquito nets. In a separate analysis, insecticide-treated mosquito nets reduced the incidence of malaria among children aged 6 to 59 months by 30%.

However, resistance to insecticides used in the nets has also emerged, exacerbated by overuse of the chemicals in agriculture.

“You can easily find the insecticide in rainwater puddles that the mosquito larvae breed in,” associate professor Brian D. Foy, PhD, of the arthropod-borne and infectious diseases laboratory in the department of microbiology, immunology and pathology at Colorado State University, told Infectious Disease News. “The mosquitoes grow in those treated environments. If there are pyrethroid insecticides in the rainwater puddles, resistance develops.”

Infrastructure has helped to decrease or eliminate malaria in developed regions of the world, according to Foy and Lines, where structures like screen doors reduce mosquito bites and, therefore, transmission of malaria. Such infrastructure, however, is lacking in areas where the disease remains endemic.

“African cities can be virtually free of malaria because of increased construction and buildings,” Lines said. “When Africa is paved over, we will not have a malaria problem.”

In addition, an increasing number of reports demonstrate that resistance to ACT is emerging in Southeast Asia, particularly with P. falciparum malaria. Resistance to these regimens was first noted in Western Cambodia between 2008 and 2009; as of 2014, resistance has also been observed in Myanmar, Thailand, Vietnam, China and Laos.

This, according to Rosenthal, is a huge concern.

“We’ve seen resistance in Southeast Asia. It has not yet been seen in most of the world — importantly not in Africa — but we’re very concerned about it,” he said. “There is relatively little malaria in places with drug resistance. If we see ACT resistance spread to areas with very high levels of malaria — notably Africa — it’s going to be a really big problem.”

‘We have the tools’

The development of novel agents, including insecticides and antimalarial drugs, is critical if progress is to be maintained, according to Rosenthal, Lines and Foy. Existing interventions, including indoor residual spraying, must also continue.

A malaria vaccine has been a focus of research for years, according to Rosenthal, although this approach may not be effective enough.

“The highest priority, for me, is the development of next-generation drugs and insecticides. The development of a vaccine is going to be much more challenging,” he said. “One could argue that too much of the available funding for malaria research in the last few decades has gone toward vaccines. That, so far, has not borne fruit, but we can see that the new drugs and new insecticides that we are close to developing could really make a difference in controlling malaria in the future.”

Lines agreed.

“I think people have been trading on the unsure assumption that a malaria vaccine would be like a measles vaccine. The measles vaccine and the polio vaccine changed the whole field,” he said. “With malaria, we are very unlikely ever to get a vaccine that induces lifelong, sterile immunity.”

Further threatening progress against malaria is uncertainty about obtaining the funding needed to sustain these efforts.

Jo Lines

“Development of these new drugs and insecticides takes a lot of money and a lot of effort,” Foy said. “But malaria is a disease of the poor. Companies aren’t spending millions of dollars on the development of these agents. They’re focused on things that would be much more profitable.”

The strategies used to effectively control malaria are “difficult, expensive and hard to implement,” Rosenthal added.

“We have the tools, but they require extensive international funding — for malaria, for tuberculosis, for HIV,” he said. “Funding has, in the last 10 years, been the best it’s ever been, but there is some concern that it is waning. This is worrisome. We need to sustain adequate international funding to really make progress.”

According to Lines, the current rate at which new treatments and prevention tools are being developed may not keep pace with the disease.

“In the villages where I worked in the 1980s, between 50% and 70% of the school-aged children would have parasites. Now, less than 10% have parasites,” he said. “That’s a huge achievement. But that achievement is under threat. We are now committed to an arms race that we are, I think, not sure we can win.” – by Julia Ernst, MS

Disclosures: Foy and Rosenthal report no relevant financial disclosures. Infectious Disease News was unable to confirm Lines’ relevant financial disclosures at the time of publication.

To mark our 30th anniversary, Infectious Disease News will be examining some of the infectious diseases that have defined and changed the field over the past 3 decades.

Drug resistance is considered one of the most important threats hindering the control — and elimination — of malaria. Chloroquine-resistant Plasmodium falciparum malaria first emerged in the 1950s in Southeast Asia and South America; by the 1970s, it had spread to Africa and was a considerable source of malaria morbidity and mortality. The problem continues to threaten progress 30 years later with the emergence of resistance to artemisinin-based combination therapies.

“Until the mid-1980s, we were heavily reliant on chloroquine,” Jo Lines, BSc, MSc, PhD, professor of malaria control and vector biology at the London School of Hygiene & Tropical Medicine, told Infectious Disease News. “Chloroquine is a fantastic drug, for both prevention and treatment. But once resistance developed, it spread quite quickly.”

Philip Rosenthal

The emergence of chloroquine-resistant P. vivax malaria coincided with an unsuccessful campaign for the global eradication of malaria in the 1950s and 1960s. This effort, adopted by the Eighth World Health Assembly in May 1955, was based on the extensive, well-organized use of DDT.

“In the 1950s and 1960s, there was a serious international discussion about eradicating malaria from the world,” Philip Rosenthal, MD, professor of medicine at UCSF School of Medicine, said in an interview. “There were rather optimistic projections and plans. These failed miserably.”

The failure to control malaria, coupled with growing resistance to chloroquine, resulted in a state of “great pessimism” regarding the disease in the 1980s, according to Lines.

Brian D. Foy

“However, it’s worth saying that this period of pessimism and depression was not because we didn’t appreciate the huge burden of malaria,” he said. “We would write, at the beginning of every article, ‘Malaria is, by far, the primary, most important public health problem in Africa. It is, by far, the greatest killer of children under 5 in Africa.’ But we didn’t have good enough tools to suppress it in the long run.”

In 2005, WHO issued a recommendation that artemisinin-based combination regimens (ACT) be used as first-line treatment of P. falciparum malaria. These regimens are now the mainstay of malaria therapy. The combination of insecticide-treated bed nets and ACT have led to a significant reduction in malaria incidence globally. However, that progress is now being threatened.

Sustaining momentum

Malaria has been eliminated from many areas of the world, including the United States and the WHO European Region. In late 2016, Sri Lanka became the second country in the WHO Southeast Asia Region to eliminate malaria.

Currently, the greatest burden of disease is in sub-Saharan Africa, where insecticide-treated mosquito nets are a critical part of control efforts. The nets have decreased the incidence of malaria and disease-related mortality across all ages, but the decline is particularly important among children aged younger than 5 years — the group at greatest risk of dying from the disease. In one study, malaria control interventions in Tanzania were partially responsible for a 45% decline in mortality among children aged younger than 5 years; 11% of this overall decrease correlated with the use of insecticide-treated mosquito nets. In a separate analysis, insecticide-treated mosquito nets reduced the incidence of malaria among children aged 6 to 59 months by 30%.

However, resistance to insecticides used in the nets has also emerged, exacerbated by overuse of the chemicals in agriculture.

“You can easily find the insecticide in rainwater puddles that the mosquito larvae breed in,” associate professor Brian D. Foy, PhD, of the arthropod-borne and infectious diseases laboratory in the department of microbiology, immunology and pathology at Colorado State University, told Infectious Disease News. “The mosquitoes grow in those treated environments. If there are pyrethroid insecticides in the rainwater puddles, resistance develops.”

Infrastructure has helped to decrease or eliminate malaria in developed regions of the world, according to Foy and Lines, where structures like screen doors reduce mosquito bites and, therefore, transmission of malaria. Such infrastructure, however, is lacking in areas where the disease remains endemic.

“African cities can be virtually free of malaria because of increased construction and buildings,” Lines said. “When Africa is paved over, we will not have a malaria problem.”

In addition, an increasing number of reports demonstrate that resistance to ACT is emerging in Southeast Asia, particularly with P. falciparum malaria. Resistance to these regimens was first noted in Western Cambodia between 2008 and 2009; as of 2014, resistance has also been observed in Myanmar, Thailand, Vietnam, China and Laos.

This, according to Rosenthal, is a huge concern.

“We’ve seen resistance in Southeast Asia. It has not yet been seen in most of the world — importantly not in Africa — but we’re very concerned about it,” he said. “There is relatively little malaria in places with drug resistance. If we see ACT resistance spread to areas with very high levels of malaria — notably Africa — it’s going to be a really big problem.”

‘We have the tools’

The development of novel agents, including insecticides and antimalarial drugs, is critical if progress is to be maintained, according to Rosenthal, Lines and Foy. Existing interventions, including indoor residual spraying, must also continue.

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A malaria vaccine has been a focus of research for years, according to Rosenthal, although this approach may not be effective enough.

“The highest priority, for me, is the development of next-generation drugs and insecticides. The development of a vaccine is going to be much more challenging,” he said. “One could argue that too much of the available funding for malaria research in the last few decades has gone toward vaccines. That, so far, has not borne fruit, but we can see that the new drugs and new insecticides that we are close to developing could really make a difference in controlling malaria in the future.”

Lines agreed.

“I think people have been trading on the unsure assumption that a malaria vaccine would be like a measles vaccine. The measles vaccine and the polio vaccine changed the whole field,” he said. “With malaria, we are very unlikely ever to get a vaccine that induces lifelong, sterile immunity.”

Further threatening progress against malaria is uncertainty about obtaining the funding needed to sustain these efforts.

Jo Lines

“Development of these new drugs and insecticides takes a lot of money and a lot of effort,” Foy said. “But malaria is a disease of the poor. Companies aren’t spending millions of dollars on the development of these agents. They’re focused on things that would be much more profitable.”

The strategies used to effectively control malaria are “difficult, expensive and hard to implement,” Rosenthal added.

“We have the tools, but they require extensive international funding — for malaria, for tuberculosis, for HIV,” he said. “Funding has, in the last 10 years, been the best it’s ever been, but there is some concern that it is waning. This is worrisome. We need to sustain adequate international funding to really make progress.”

According to Lines, the current rate at which new treatments and prevention tools are being developed may not keep pace with the disease.

“In the villages where I worked in the 1980s, between 50% and 70% of the school-aged children would have parasites. Now, less than 10% have parasites,” he said. “That’s a huge achievement. But that achievement is under threat. We are now committed to an arms race that we are, I think, not sure we can win.” – by Julia Ernst, MS

Disclosures: Foy and Rosenthal report no relevant financial disclosures. Infectious Disease News was unable to confirm Lines’ relevant financial disclosures at the time of publication.