May 9, 2019 0 By S Harachand

The latest numbers pertaining to malaria have raised the fear that the disease may be on a comeback trail in several regions of the world, wiping out the hard-earned gains of yesteryears.

Since 2010, fresh cases of malaria had been declining steadily, reflecting the high efficacy of the new artemisinin-based combination therapy (ACT) and other interventional strategies like vector control.

The trend, however, started showing a reversal since 2016.

As many as 219 million cases of malaria occurred worldwide in 2017, compared with 217 million cases in 2016. The ten highest burden African countries saw an estimated 3.5 million more malaria cases in 2017 than a year ago. While the African region claimed 92% of the cases, the South East Asian Region shared 5% and 2% of the disease burden respectively, according to The World Malaria Report 2018 by the WHO.

Children aged under 5 years accounted for 61% of the number of 435,000 deaths from malaria globally.

Evidently, the human toll of malaria, and the global risk it still poses, remains unacceptably high.

Experts cite several reasons for the stalled progress in eliminating the mosquito-borne disease in spite of the fact that the parasitic infection is completely curable and preventable.


Resistance or ‘partial’ resistance?
The threat of pathogens emerging resistant to artemisinin is one of the most challenging issues faced by some of the high-burden countries today. Artemisinin, a plant-derived lactone, is the cornerstone of global efforts to control malaria. Drug combinations with artemisinin as the anchor drug have shown over 95% efficacy in malaria caused by Plasmodium falciparum — the most commonly found infectious agent.

The WHO recommends ACTs as the first and second-line treatment for uncomplicated P. falciparum malaria as well as for chloroquine-resistant P. vivax malaria. There are many advantages to using ACTs. The artemisinin quickly and drastically reduces the majority of malaria parasites by killing the protozoan at all stages of its life-cycle within the host, while the partner drugs in the combo clear the small number of parasites that remain. Tackling in different ways, ACTs, which are considered the most effective anti-malarial treatment today, ensure that no trace of the pathogen remains in the system post-therapy.

The resilience of the malarial parasite is well known. In the late 1950s and 1960s, the emergence of P. falciparum strains resistant to chloroquine and sulfadoxine–pyrimethamine was reported on the Thai–Cambodian border and spread across Asia and Africa, resulting in millions of deaths from malaria.

Resistance to artemisinin class of drugs was first documented in Southeast Asia in 2008 and has been particularly menacing in the Greater Mekong Subregion (GMS) comprising Cambodia, China, Lao People’s Democratic Republic, Myanmar, Thailand and Vietnam.

GMS has already gained notoriety as the epicentre of antimalarial drug resistance. After generating resistant strains to chloroquine, sulfadoxine, pyrimethamine, quinine and mefloquine, this region has now spawned parasites resistant to artemisinins, researchers say.

Though artemisinins have, relatively, been a new introduction in many parts of the world, the compound has been in use as monotherapies in western Cambodia for more than 30 years. It was during the early 2010s that public health authorities discovered that artemisinin resistance had emerged independently in multiple areas, along with resistance to ACT partner drugs.

Signs of artemisinin resistance have developed in the African continent as well. A study carried out in 2010 at the Carlos III Hospital and the Network of Tropical Diseases Research Centres on the blood samples collected from 200 patients with P. falciparum infection, who had come to Spain from eighteen African countries, suggested the appearance of strains related with resistance to ACT.

Similarly, another study published by Centers of Disease Control and Prevention (CDC), US, to assess the emergence of artemisinin-resistant parasites in Uganda during 2014–2016 using a newly developed ex vivo ring-stage survival assay (RSA) concluded that survival rates of parasites in some isolates were more than 10% higher. Similar rates have been closely associated with delayed parasite clearance after drug treatment and are considered to be a proxy for the artemisinin-resistant phenotype.

Since India sits with Africa and SE Asia on either sides, the spread of resistant strains of the parasite is somewhat an imminent possibility. Already, sporadic cases of artemisinin resistance have been reported from the eastern region of India, the country’s malaria hotspot. A study conducted in West Bengal in isolates from 136 patients with P. falciparum infection obtained from April 2013 through March 2014 using ex-vivo RSA observed increased parasite clearance half-lives in 14% of the patients.

Artemisinin resistance is defined as a delay in the clearance of malaria parasites from the bloodstream following ACT. The artemisinin combo is considered less effective if it fails in clearing all parasites within a 3-day period.

The WHO, however, describes the delayed clearance of the parasites as only “partial resistance” as the mechanisms of resistance developed by the parasites against artemisinin compounds affect only one stage of its cycle in humans, the ring stage. Hence, it is more appropriate to call the delayed clearance “partial resistance”, to highlight this time-limited and cycle-specific feature.

Also, drug resistance, per se, did not contribute to the rising numbers of cases in GMS and Africa. “Between 2012 and 2017, the reported number of malaria cases in GMS fell by 75% despite confirmed partial artemisinin resistance in 5 countries and multidrug resistance in 4 countries. Malaria deaths fell by 93% over the same period. In Africa, artemisinin resistance has not yet been confirmed. The ACTs used as first and second line treatments are highly efficacious in all African countries,” says a spokesperson from RBM Partnership to End Malaria, which coordinates with the WHO in the ‘High Burden to High Impact’ initiative launched in November 2018 to bring malaria control on track. P. vivax resistance to artemisinin is yet to be reported.


Asymptomatic malaria and POC detection
P. falciparum is the most prevalent malaria parasite in Africa, accounting for 99.7% of the estimated cases in 2017, as it is in South-East Asia (62.8%), the Eastern Mediterranean (69%) and the Western Pacific (71.9%).

P. vivax is predominant in the Americas, representing 74.1% of malaria cases.

In places like India, where both P. falciparum and P. vivax are present, the burden of disease due to P. vivax is more difficult to be addressed because the parasite transfers to a dormant hypnozoite stage in the liver, which is currently undetectable and leads to relapses.

Many people who are infected with malaria parasites remain asymptomatic or undiagnosed. The density of parasitaemia in many such cases will be so low that it cannot be detected with current routine diagnostic tools. Though they manifest no symptoms, they can transmit the infection to others. These so-called “infectious parasite reservoirs” pose yet another threat to bring the numbers down effectively.

The lack of point of care (POC) diagnostic methods in endemic areas for detecting parasites in asymptomatic individuals, who are the reservoirs for transmission, forms another hurdle to the efforts towards the global elimination of malaria.

Microscopy and rapid diagnostic tests (RDTs) continue to be the mainstay even though they have low sensitivity and specificity for the malarial parasite. Molecular techniques, as well as biosensing-based methods for a more accurate detection, quantitation and POC application, are urgently warranted. Nucleic acid-based detection methods with a high degree of sensitivity are yet to be put for routine applications. Biosensing technology has the advantage of suitability for off-lab situations.

Studies call for a multiplexed approach, in conjunction with biosensors, for malaria diagnosis, considering the high fatality rates associated with mixed infections. Besides better detection rates, multiplexed testing strategies reduce the risk of outbreaks.

“Understanding trends in Plasmodium falciparum helps inform global policy and malaria control planning and implementation and surveillance initiatives,” says Dr Daniel Weiss, Director of Global Epidemiology at the Malaria Atlas Project, University of Oxford, UK.

There are regions where progress against P. falciparum has stalled or reversed in recent years, underscoring the need for persistence in control efforts and efficient resource targeting.


Complexities of malaria vaccine
Lack of an effective vaccine to prevent malaria infection is also hampering efforts to eliminate the parasitic disease. The only approved vaccine as of today is RTS,S, a recombinant protein-based vaccine developed by PATH’s Malaria Vaccine Initiative and GSK. RTS,S, which targets P. falciparum, requires four injections. The use of the vaccine is not recommended in babies between 6 and 12 weeks of age due to its relatively low efficacy.

More than 20 other vaccine constructs are currently being evaluated in clinical trials or are in advanced preclinical development, according to WHO. These candidate malaria vaccines target the different phases of the parasite’s life cycle such as pre-erythrocytic stage and erythrocytic stage, or are transmission blocking vaccines and anti-disease vaccination.

Other than circumsporozoite protein (CSP) as used in RTS,S, the candidate vaccines are being worked under several technological formats including attenuated whole parasites, sub-unit vaccines, whole cell sporozoite vaccine, long synthetic peptide, adenovirus, plasmid DNA, merozoite surface proteins, apical membrane antigens, chimeric fusion proteins etc.

The development of a vaccine for malaria has turned out to be a highly complex exercise owing to a host of challenges. Like other infectious agents, a natural malaria infection does not induce much immune protection. Only a partially effective immunity is acquired after repeated and prolonged exposure to malaria parasite over several years. This short-lived and highly stage- and strain-specific immunity does not provide complete protection against future challenge.

“Malaria is caused by a different kind of pathogen – a parasite as opposed to a virus or bacterium. You have to take into account a more complex lifecycle. We don’t have any vaccines in human use against parasites. They transit between two organisms—humans and mosquitoes,” says Dr Ashley Birkett, Director of PATH’s Malaria Vaccine Initiative.

The scientific community now understands that the magnitude of the immune response needed to protect against malaria is higher than that required for gaining immunity against other infectious agents such as bacteria. A related challenge is the induction of durably protective responses. Vaccine-induced immunity wanes over time, falling below the very high protective threshold more rapidly than observed with typical pathogens, resulting in renewed susceptibility. So, it is important to know how very high, or more potent, immune responses can be induced and provide protective immunity over the long term, he adds.

Insecticides turn ineffective
Vector resistance to insecticides further jeopardises efforts to contain the spread of the infection. The WHO Global Report on Insecticide Resistance in Malaria Vectors: 2010–2016 showed widespread resistance by all major Anopheles species to pyrethroids, organochlorines, carbamates and organophosphates, the commonly used insecticide classes, across Africa, the Americas, South-East Asia, the Eastern Mediterranean and the Western Pacific.

Of the 80 malaria endemic countries, resistance to one of the insecticide classes in one malaria vector was detected in 68 countries.

Pyrethroids are the only insecticide class currently used in insecticide-treated bed nets (ITNs). Resistance to pyrethroids was detected in more than two-thirds of the sites tested and was highest in Africa and the Eastern Mediterranean. ITNs continue to be an effective tool for malaria prevention.

Inadequacies in funding; poor health systems
One of the most challenging aspects of the long-haul fight against malaria is sustained financing. Efforts to counter the disease have been kept alive with steady and robust funding by international donors since 2010. With population growth and the emergence of resilient transmission patterns, existing levels of funding proved inadequate in recent years, especially in highest burden countries. Global funding for malaria control fell short of the estimated US$ 4.4 billion needed in 2017, with total funding estimated at US$ 3.1 billion, representing a yearly shortfall of US$ 1.3 billion. Investment in malaria R&D too fell in 2016. At a total of US$ 588 million, it represented about 85% of the US$ 693 million needed every year for malaria basic research and product development R&D, as estimated in the Global Technical Strategy (GTS) for malaria 2016-2030.

Investment in malaria vaccine development too is limited. Most financing into the development of vaccines to combat malaria comes from the public sector.

The fact that malaria affects some of the world’s poorest means that there is a limited ‘market’ for investment from the private sector.

In the meantime, financing for vector control products and diagnostics have significantly increased.

Among the systemic and technical measures identified by the WHO to accelerate malaria control are inadequate performance of health systems, weak management of supply chains, an unregulated private health sector in countries like India, a lack of surveillance systems, monitoring and evaluation, a dearth of adequate technical and human resource capacities to scale up efforts, and insufficient tools to diagnose and treat effectively infections due to P. vivax and other non-falciparum malaria parasites.

India: Declining numbers
Compared to 2016, India reported 3 million fewer cases in 2017, marking a 24% decrease. Yet, fifteen countries in sub-Saharan Africa and India carried almost 80% of the global malaria burden. India, again, figures in the seven countries which accounted for 53% of all global malaria deaths. It has a share of 4%, after Nigeria (19%), Congo (11%), Burkina Faso (6%), Tanzania (5%), Sierra Leone (4%) and Niger (4%). India has shown a reduction of about 53% in malaria incidence since 2015.

In India, malaria is a public health problem. The government launched the National Strategic Plan for Malaria Elimination (2017-22) under the National Vector Borne Disease Control Programme in 2017. The programme aims to eliminate malaria with a target to eradicate the vector-borne disease by 2027. The strategy outlines year-wise elimination targets in various parts of the country, depending upon the endemicity of the disease in the five-year period.

The majority of malaria cases are reported from the eastern and central part of the country and from states which have the forest, hilly and tribal areas. These states include Odisha, Chhattisgarh, Jharkhand, Madhya Pradesh, Maharashtra and some north-eastern states like Tripura, Meghalaya and Mizoram.


Poorest still missed out?
It remains a fact that malaria is preventable and treatable, despite the limitations of the current tools available. The bigger issue, however, is making these advancements reach the remotest hinterlands where the most deprived live with the least access to any form of interventions.
“A large number of people in the high burden countries, such as Nigeria, Democratic Republic of Congo and Mozambique, still miss coverage of key interventions. Often, it is the hard-to-reach, the poorest and marginalized populations that are missing out. It is time to focus on countries that have stubbornly high numbers of malaria deaths and ensure that prevention and treatment is available to those in greatest need,” says the RBM Partnership spokesperson.