Nobel prize for the artemisinin and ivermectin discoveries: a great boost towards elimination of the global infectious diseases of poverty

This year’s Nobel Prize in Physiology or Medicine, awarded for the discovery of artemisinin
and ivermectin, was divided between Youyou Tu “for her discoveries concerning a novel
therapy against malaria” and William C. Campbell together with Satoshi ?mura “for
their discoveries concerning a novel therapy against roundworm infections” (Fig. 1). These parasitic infections have endangered human existence disproportionately,
impeding productivity and economic growth due to major public health and societal
burdens in developing and semi-industrialized countries in Sub-Saharan Africa, Southeast
Asia and South America 1], 2]., For example, approximately 25 million people in Africa are still infected by onchocerciasis
with more than 300,000 suffering from blindness, which explains the disease’s alternative
name ‘river blindness’. It is estimated that the population at risk of just this one
disease in the 31 endemic countries will be 250 million by 2016 2], 3].

Fig. 1. Nobel Prize Laureate Scientists in Physiology or Medicine, 2015

The burden of persisting and threatening infectious diseases in most developing countries
is a complex affair, a fact recognized by The United Nations’ Millennium Development
Goals (MDGs) 4] that represent one of the most successful anti-poverty movements ever undertaken.
This 15-year effort to achieve eight goals, set out in the Millennium Declaration
of the year 2000, has provided invaluable insights how governments, business and civil
society can work together and achieve transformational breakthroughs in many areas,
not the least in dealing with long-term, endemic diseases. Ours is a pivotal time
for the international development sector with massive implications for global co-operation
to control and eliminate endemic diseases and promote transformative social change
to end poverty. The new 17 Sustainable Development Goals (SDGs) constitute a continuation
and expansion of all aspects of the original eight MDGs and inclusion of neglected
tropical disease (NTDs) in the Sustainable Development Goals. With respect to health,
the MDG goal number 6 (to combat HIV/AIDS, malaria and other diseases) has been replaced
by the SDG goal number 3 (to ensure healthy lives and promote well-being for all at
all ages). Goal number one remains the same, i.e. to end poverty everywhere.

The root cause of the infectious diseases of poverty (IDoPs) is the ubiquitous presence
of infectious agents. However, social and economic issues play a large role in their
transmission and persistence, a fact recognized in both the MDGs and the follow-up
SDGs. Still, the transformation of the endemic landscape is almost entirely due to
large-scale distribution of the three novel ‘wonder drugs’ artemisinin, ivermectin
and praziquantel, mainly used against malaria, lymphatic filariasis (LF)/river blindness
and schistosomiasis, respectively. All three, discovered and developed in the 1970s
(though extracts of the plant Artemisia – qinghaosu – has a long history in Chinese traditional medicine), are broad-spectrum
drugs that can be used to cure many more infections than mentioned above; amazingly,
the artemisinins have even effect against immature schistosomes, while ivermectin
seems to limit the behaviour of the malaria vector. However, it was not evident that
a new era had begun until the new drugs were in general use. Trying to pinpoint this
historic shift exactly is of course futile, but it can be said that after the large-scale
introduction of modern chemotherapy in the 1980s and 1990s, the first decade of the
new millennium marks the time that world-wide implementation of mass drug administration
(MDA) occurred 9], 12]. Thanks to market price reductions and broad-scale interventions by international
donor programmes, it did not take long until major endemic diseases had become manageable.
Indeed, disease control programmes in the endemic countries were not only showing
clear progress, but it was also possible to sustain the reduced morbidity and mortality
achieved making it realistic to start planning for elimination of many of the endemic
IDoPs, a momentous revolution 10], 12].

The discovery of artemisinin and ivermectin have had, and will continue to have, a
long-lasting, strong impact on the IDoPs, the former due to its effect on the parasites
causing malaria; the latter because its effect on the different nematodes that cause
river blindness (Onchocerca volvulus), LF (Brugia and Wuchereria), hookworm infection (Ancylostoma, Necator) and other soil-transmitted helminthic (STH) infections 1]–4]. With the presentation of a road map for the battle against the NTDs in January 2012,
the World Health Organization (WHO) inspired the international community to engage
into coordinated action involving policy-makers and implementers as well as international
donors and the pharmaceutical industry 4]. While it was evident that many of these diseases could realistically be targeted
for elimination, it was equally clear that novel drugs, sensitive diagnostics and
sustainable approaches for effective surveillance and response together with effective
and coordinated, preventive vector control programmes also must be in place 5], 6]. The new drugs, already developed, licensed and used for public health , have decisively
demonstrated that malaria, river blindness and LF are preventable diseases whose control
would particularly benefit the most vulnerable sectors of the endemic populations
4]–8]. Progress has been achieved in all these areas, but greatest impact so far has been
with respect to chemotherapy rather than vaccines that will be needed to complement
chemotherapy in the longer perspective 7]–10].

Youyou Tu’s landmark work, documented by increasing access to life-saving, effective
artemisinin-based combination therapies (ACTs) against acute and severe malaria, intermittent
preventive treatment and curative with respect also to the asexual plasmodium stages,
has provided relief and hope for a large proportion of vulnerable populations in the
endemic areas 9]–11]. Importantly, in the face of increasing resistance of malaria parasites to 4-aminoquinolines
(chloroquine) and antifolate drugs (sulphadoxine-pyrimethamine), thanks to the advent
of the ACTs that the Global Malaria Action Plan (GMAP) managed to reduce malaria morbidity
and mortality by 75 per cent in comparison to the situation in 2005, particularly
among the poorest groups across all affected countries aggregately 12], 13]. Moreover, the new chemotherapy approach has made it possible to scale up national
malaria control and elimination programmes enhancing interventions and universal health
coverage to achieve WHO’s Roll Back Malaria (RBM) initiatives and those of the MDGs
13], 14]. For example, by the end of 2012, the United Nations Children’s Fund (UNICEF) had
procured about 25 million ACTs treatments for 28 countries; however the proportion
of children in sub-Saharan Africa with access to ACT is still variable and in many
cases despairingly low (range 7 % to 90 % with the latter level only reached in
a few countries) 10], 15], 16]. ACT is the drug of choice against acute and severe infection by Plasmodium falciparum and P. vivax, the most deadly malaria species, which are now resistant to chloroquine and antifolate
drugs 10], 11], 16] in most endemic areas. Hence the call for innovative and integrated community-based
packages 16], 17] in strengthening implementation and management has executed by the Malaria Eradication
Research Agenda (malERA) and the Malaria Eradication Scientific Alliance (MESA) in
the most highly endemic developing and semi-industrialized countries 18].

Both acute and severe malaria continues to exert a deep-rooted impact in 109 countries
and territories around the world and still constitute a leading risk factor for infant
mortality and sub-optimal growth and development in spite of the global malaria elimination
campaign programmes (GMECPs) that were in effect in the 1950s to the 1970s 10], 19]. By 2000, there was an estimated 350–500 million cases of malaria and more than one
million deaths, most of them in children under 5 years, pregnant women and non-immune
travelers in Africa and Asia-Pacific 19]. The saying “One child dying of malaria every second” remains true to this day, and
the disease still has a serious economic impact in Africa, retarding economic growth
and development and perpetuating the vicious cycle of poverty 15], 18]–20].

In 1971, at the Pharmaceutical Institute of the Academy of Traditional Chinese Medicine,
Youyou Tu showed that Artemisia plant extracts could kill P. berghei, a rodent malaria parasite laboratory model. The following year, she succeeded in
isolating the active ingredient (qinghaosu), now part of ACT, the most important class
of anti-malaria medications 9], 20], 21]. Artermisinin derivatives are postulated to act by inhibiting the major metabolic
processes of the malaria parasite, such as glycolysis, nucleic acid and protein synthesis,
thus exercising a broad- based activity extending to impeding the development of gametocytes
that promises future development of transmission-blocking, sexual-stage drugs and
vaccine discovery 5], 6], 11], 15], 22], 23]. Still, years after the original discovery of the drug, the complete mechanism of
artemisinin is not fully elucidated, though recent evidence suggest that is based
on the activity of 13 proteins, some of which shown to be involved in the emergence
of resistance in Southeast Asia, e.g. the Thai-Cambodia borders areas 24]. Impressive progress has been achieved in product development, manufacturing, procurement
as well as financial accessibility to treatment (the latter regarding the ACTs in
particular) even if prompt, affordable and widespread coverage is still not achieved
in many public health facilities in remote, hard-to-reach endemic settings 12], 24], 25]. From 2004 to 2006, the annual global procurement of ACT increased from 4 million
to ~100 million doses (~125 million doses in 2007), around 70 % of which were used
in Africa, resulting in a significant reduction of morbidity and mortality in children
and trimmed-down numbers of acute and severe cases of malaria overall 12], 14], 25], 26].

The latest decades have witnessed substantial progress in raising awareness and increasing
the production, adoption and distribution of existing effective interventions besides
the use of ACTs, e.g. indoor residual spraying (IRS) and large-scale distribution
of long-lasting insecticidal nets (LLINs) as prescribed by the RBM’s universal coverage
partnership 12], 27], 28]. The latest available worldwide report of malaria cases concerns the year 2013, in
which WHO reports that about 3.2 billion people are at risk of this infection with
more than 132 million confirmed cases; however, the real level of incidence must be
higher since the number of suspected cases has surpassed 367 million 29]. Africa still has the heaviest burden with children less than 5 years old making
up 90 % of the malaria-related deaths, which accounts for 78 % of the total mortality
29], 30]. In addition to the high local healthcare burden in Africa, malaria illness and mortality
affect crop production and decrease tourism, which is estimated to cost approximately
USD12 billion each year due to increased school and work absenteeism, lost productivity
and constraints to foreign investment 10], 30]. Hence, although the impact of malaria in the endemic countries has abated to some
extent in some areas, transmission continues at a high level assuring that the global
ACTs demand will remain robust over the coming years as treatment-adherence and compliance
remain vital in the struggle to substantially reduce malaria morbidity and mortality
supporting the hope of eventually reaching sustained control, elimination and subsequent
eradication of the disease 29], 31].

William C. Campbell and Satoshi ?mura discoveries proved to be a breakthrough in the
tenacious fight against infections caused by roundworm parasites, mainly onchocerciasis
and LF, dreaded health scourges of the most vulnerable groups of affected populations.
The discovery, industrial development and implementation of the active avermectin
derivative ivermectin (best known under the brand name Mectizan) led to a significant
reduction of onchocerciasis in the endemic areas in central Africa and Latin America
as well as of LF and scabies that are also endemic in India and Southeast Asia, thus
improving the situation in vulnerable communities in low- and middle-income countries
(LIMCs) 1], 3]. In an unusual move, the manufacturer of ivermectin, Merck Co., Inc. declared it
would donate ivermectin free of charge for as long as it would be needed through its
Mectizan Donation Program, which works with governments (Ministries of Health) and
various partners with national onchocerciasis control programmes to scale up distribution
and coverage of the drug locally 9], 32]. Its impact on mosquitoe control in malaria is debatable and the drug is not donated
for this purpose.

Onchocerciasis, transmitted by the filarial worm O. volvulus, is transmitted to humans through bites of infected female blackflies (Simulium spp.). Adult worms can live up to 18 years in infected human hosts and release up
to 1,000 microfilariae daily causing a variety of ailments including skin lesions
due to chronic dermatitis, , rashes, intense itching, depigmentation as well as visual
impairment due to eye inflammation causing corneal scars eventually leading to irreversible
blindness 3], 32]. The disease is endemic in 35 countries, including 28 African countries, Yemen in
the Middle East and six Latin American countries resulting in an estimated 17.7 million
people infected, approximately 500,000 with visual impairment, 270,000 of whom are
blind; about 99 % of all cases, however, are found in Africa according to WHO 2], 32], 33]. The Onchocerciasis Control Programme (OCP) operated in West Africa from 1974 to
2002 2]–33] and its work is being continued by the larger African Programme for Onchocerciasis
Control (APOC) that coordinates annual community-wide treatment regimens with ivermectin
in 16 countries. An estimated 8.2 million disability-adjusted life years (DALYs) 4], 13] at a nominal cost of about USD257 million was averted between 1995 and 2010 and APOC
estimates to have warded off another 9.2 million DALYs between 2011 and 2015 at a
nominal cost of USD 221 million 2], 4]. Interventions in countries in West Africa employed large-scale, community-directed
treatment with ivermectin (CDTI) and ONCHOSIM, a computer-based software developed
to model the transmission and control of onchocerciasis allowing the continuous annual
treatment of more than 30 million people 34]. As of 2012, over 200 million people have received ivermectin; 118 million a combination
of ivermectin and albendazole and more than 100 million people have been treated in
26 countries in 2013 alone 35].

The Onchocerciasis Elimination Program of the Americas (OEPA) was launched in 1992
under the Pan American Health Organization (PAHO) with the goal of interrupting onchocerciasis
transmission in six endemic Latin American countries by 2015 36]. The WHO’s regional NTDs elimination agenda includes fostering coalition and partnerships
in resource mobilization aimed at increasing free availability and accessibility of
ivermectin to needy populations. Since 2007, WHO also engaged in activities ensuring
periodic sustainability of treatment activities and feasibility studies of foci and
ongoing regional eradication 36], 37]. Columbia became the first country achieving elimination of onchocerciasis; Ecuador
and Mexico have also been verified as free from transmission (verified by WHO in 2013).
Likewise, Brazil and the Bolivarian Republic of Venezuela have embarked on reciprocal,
cross-border interventions finding ivermectin very effective in controlling the disease
36]–38]. Ivermectin is provided as MDA once or twice annually to millions of the most vulnerable
children and adults populations in most LMICs 3], 4], 39], 40]. Interruption of transmission of O. volvulus and reduction of the burden of visual impairment and blindness have been achieved
41], 42]. However, repeated ivermectin treatment showed reduced susceptibility in the India
and South East Asia LF control to elimination programmes. This has led to the call
for novel alternative approaches in accelerating and sustaining the transmission-free
status once achieved to avoid the risk for re-introduction or resistance of the disease
in the process of elimination and eventual eradication in Africa and others areas
(e.g.: Yemen) with disease co-endemicity 33], 35], 43].

Though not recognized for this year’s Nobel Prize, the story would not be complete
without mentioning praziquantel. Praziquantel, a drug that has modernized the control
of schistosomiasis and many other helminth infections in the same way the ACTs and
ivermectin worked for malaria and LF/onchocerciasis, respectively 44], 45]. Praziquantel was developed by the German pharmaceutical companies Merck KGaA, Darmstadt
and Bayer AG, Leverkusen in the early 1970s 46]–48] and the drug currently figures on WHO’s list of essential medicines 49]. The drug’s good safety profile and broad therapeutic efficacy extend its therapeutic
efficacy from the five Schistosoma spp. species capable of infecting humans 47], 50]–52] to cestodes (tapeworms) such as Echinococcus spp. 49], whose larval stages infects various organs, Taenia spp. that can infect the brain and muscles with its eggs and larvae (cystocercosis)
and food-borne trematodes (FBTs), such as Paragonimus spp., Opistorchis spp. and Clonorchis spp. 50].

FBT transmission is linked to traditional customs, e.g. consumption of dishes containing
raw fish, crustaceans and plants in countries where these diseases are sustained by
entrenched cultural practices, which are difficult to change. FBTs affect over 56
million people infected in over 70 countries 51]; this figure, however, includes Fasciola spp., a parasitic worm preferably treated with triclabendazole (sold under trade
names Egaten and Fasinex) 52].

Schistosomiasis is acquired through contact with water infested with cercariae, the
free-swimming larval forms emanating from the intermediate snail host when infected.
The microscopic adult worms live in the veins of abdominal organs, where large amounts
of eggs are produced for excretion via faces or urine aimed at hatching and infecting
fresh-water snails thus closing the parasite’s lifecycle. Large numbers of the eggs
are, however, trapped in the tissues and where immune reactions cause damage that
varies from subtle to serious. Millions of people suffer from severe schistosomiasis
2], 44], 53], a type of injury that can be suppressed by regular treatment preventing reinfection
giving rise to morbidity. The current WHO chemotherapy-based strategy controls the
morbidity in poor and marginalized communities in conjunction with interventions against
cestode and nematode infections with albendazole and ivermectin. Severe morbidity
due to schistosomiasis can be prevented by regular treatment of risk groups targeted
based on community diagnosis at sentinel sites. Like malaria, LF and river blindness,
schistosomiasis is prevalent in tropical and sub-tropical areas, in poor communities
without potable water and adequate sanitation. Like the other infections discussed
here, schistosomiasis is one of IDoPs. It affects about 240 million people worldwide,
and more than 700 million people live in endemic areas 53], 54]. In contrast to FBT infections, cysticercosis and echinococcosis, there has been
strong progress on the schistosomiasis agenda, mainly thanks to long-term, national
control programmes that in some countries, notably Brazil, China and Egypt, have been
highly successful in driving prevalence and morbidity down. In 2013, more than 39
million people were treated for this disease with praziquantel. However, this represents
only about 13 % of the population requiring treatment globally 2], 44], 46], 55], 56].

The global IDoP elimination agenda will require strengthening community, national
and regional leadership and commitment to rapidly increase funding and fostering integrated
multidisciplinary and inter-sectorial policies. Furthermore, scaling-up of high-impact
MDA coverage of available drugs, development and implementation of new, effective
vaccines and other novel approaches and tools are needed in addressing the geographical
complexity of the panoply of different diseases including malaria, river blindness,
LF and schistosomiasis 56], 57]. This would mean enlarging the use of geographical information systems (GIS) and
other advanced cutting-edge technologies for general surveillance and monitoring,
including risk mapping of vector and parasite hotspots and studying reservoir resurgence
and drug resistance. Improving local and cross-border malaria early-warning signals
and surveillance systems is imperative in providing new information on potential epidemiologic
transitions, crucial for quick response to any potential resurgence of vector density
and competence potentially leading to disease outbreaks. These approaches will contribute
to new evidence-based information needed in adapting effective health financing and
programming to effective local and national programmes and interventions. Hence, consolidating
and refining the laudable gains and lessons learnt from cost-effective therapeutic
discoveries should contribute to the continuous pharmacovigilance associated with
adverse reactions (ADR) of existing therapies leading to improved access to quality
care services, procurement and supply of quality medicines and supplies needed in
boosting the momentum of the elimination of IDoP.

The pharmacological and therapeutic paradigm shift discussed here calls for further,
strong investments in research and development in the field of drugs and vaccines
creating pipelines of new products capable of tackling the challenge of rapid emergence
and spread of vectors, parasites and drug resistance. Timely, evidence-based and cost-effective
operational approaches and solutions for IDoPs and NTDs are required for dealing with
the rise and spread of insecticide resistance, and the environmental impact of climate
change. Likewise, development of diagnostics with improved sensitivity and specificity
as well as preventive therapeutics and efficient information communication/dissemination
mechanisms underscore the quest for novel and innovative approaches. Leveraging on
lessons learnt, efficient and integrated intersectoral partnerships as well as collaboration
in the development of needed, new diagnostics, drugs and vaccines are much needed.
So are also proven and innovative community-based programmes with respect to ownership
in health systems, surveillance and new opportunities in elimination interventions
packages and eventually in moving forward eradication of IDoP worldwide.