THIS DE-WORMED WORLD?

Just as Dr. Armand Kuris’s presidential address (Kuris, 2012) one year ago began with homage to Dr. Norman Stoll’s epic 1947 JP paper, “This Wormy World”, so too does this address. Whereas Dr. Kuris used his talk to provide an authoritative overview of the biology of human parasites, including their origins, infectious strategies and biogeography, my purpose is somewhat different. I intend to highlight that the coming decades are likely to see large reductions in the abundance of many human helminths from the conspicuous levels of per capita infection noted by Stoll in 1947. I am deliberately emphasizing an optimistic point of view throughout this talk, but one that is leavened with plenty of realistic caveats that will surely impede our progress in this endeavor to one extent or another. I am hopeful though that when future historians of science consider the times we live in, among the achievements noted will be, along with documentation of the reality of the Higgs boson, the $1000 genome and the eradication of polio, the elimination of helminth infections as significant human public health concerns. Regardless of the eventual level of success or the rapidity with which it is achieved, this effort will dramatically change our discipline, including how we portray it to the world in both publications and in teaching. Part of my goal is also to point out that the members of ASP have had, and will continue to have, important roles in play in the grand endeavor of bringing human helminthiasis under control.

In 1946, Stoll estimated for 25 different helminth species that there were 2.3 billion helminth infections distributed among 2.2 billion people alive at the time, or 1.04 infections per person. One notable feature of that time was that a significant proportion of the infections still occurred in individuals living within more developed countries (184 million helminth infections in North America and Europe for example). Crompton (1999) provided an update, estimating 5.8 billion people carried in aggregate 4.5 billion helminth infections (0.775 infections per person). Noteworthy here is that even though billions of helminth infections were still present, the overall average rate of infection per person was declining. A 2012 estimate from Lustigman et al. (2012) estimated 4.2 billion helminth infections among a human population of about 7 billion, for 0.606 infections per person (Table 1). The authors note that there is nothing even-handed about the distribution of these infections: they are concentrated among the marginalized, disadvantaged under-resourced poor people who often bear more than one species of helminth per person. It’s clear the world’s “bottom billion” suffer disproportionately from helminths, and in particular, sub-Saharan Africa and tropical Asia are the great remaining redoubts for human helminths.

Although we must bear in mind that all these figures are estimates, even though the number of people in the world has increased dramatically, the overall number of helminth infections has declined, and the proportion of helminth-free people has increased. However, let’s be clear that there are still over 4 billion helminth infections currently afflicting humans. Given this, how can it really be argued that human helminths will anytime soon be relegated to insignificance from a public health point of view?

Some Reasons for Optimism

Several major factors have come together to create optimism: strong leadership from the World Health Organization, donations of needed drugs from several pharmaceutical companies, and innovative new partnerships between governments, companies, non-governmental organizations (NGOs) and private foundations that are often coordinated to attack more than one helminth species at a time. First, consider the leadership role of the WHO, much of which is summarized in the 2013 publication entitled “Sustaining the drive to overcome the global impact of neglected tropical diseases,” borrowed upon heavily in the preparation of this talk. This 2013 document discusses in detail the WHO’s ambitious roadmap for 2020 that was released in 2012 (WHO, 2012). Included are explicit plans and dates for controlling, eliminating or eradicating several neglected tropical diseases (NTDs), including all the major diseases caused by human-infecting helminths: cysticercosis, dracunculiasis, echinococcosis, filariasis, food-transmitted trematodes including Clonorchis, Fasciola, Fascioloides, and Opisthorchis, onchocerciasis, schistosomiasis, soil-transmitted helminths including Ascaris, hookworms and Trichuris, and taeniasis. For any of you teaching parasitology, imagine how your course might change if the goal of eliminating the public health significance of all these parasites is eventually achieved!

Before proceeding further, a clarification of terminology is in order. Following the WHO (2013), control is a reduction of incidence, prevalence, intensity, morbidity or mortality or some combination of these as a result of a deliberate intervention effort. Elimination refers to an interruption of transmission and is the reduction to zero of the incidence of infection for a specific parasite in a defined geographic area, again as a result of a deliberate intervention. Note that re-introduction of the parasite from adjacent regions is possible, requiring continued diligence to prevent re-establishment. Eradication is the permanent reduction to zero of the worldwide incidence of infection caused by a specific parasite, as a result of deliberate control efforts. If the parasite in question is not maintained in any confined settings such as protected laboratories, eradication is equivalent to an extinction event.

Shortly after the issuance of the WHO roadmap, the London Declaration on Neglected Tropical Diseases was launched in January, 2012. With participation from several governments, the WHO, the World Bank, USAID, the Bill and Melinda Gates Foundation, and several pharmaceutical companies, a goal was set to provide $785M to support research and development leading to the elimination or control of 10 major neglected tropical diseases by 2020. Today there are at least 71 organizations including pharmaceutical companies, academic institutes, government agencies and NGOs endorsing the London declaration. Included among the drugs donated are 600 million tablets of albendazole and mebendazole to be donated annually to treat school children. Collectively there are now over 700 million individual treatments being administered annually to control helminths (Bockarie et al., 2013). This amounts to an unprecedented coordinated push to advance the very ambitious agenda outlined in the WHO roadmap for controlling NTDs.

As an aside, prominent among the important drugs being donated is ivermectin (Mectizan), originally discovered by a large interdisciplinary team lead by long-time ASP member Dr. William C. Campbell working at then Merck, Sharp and Dohme (Campbell et al., 1984). This invaluable drug was recovered from a soil bacterium, Streptomyces avermectinius, well recounted by Dr. Campbell on a U tube video called The Story of Ivermectin www.youtube.com/watch?v=t96_xbpXH-M.. The importance of the donation of ivermectin starting in 1987 cannot be overstated as it provided not only a powerful new tool for onchocerciasis control, but also created a new model for partnerships, serving as a forerunner for the many programs in NTD control we see today.

In addition to the forging of new partnerships to provide funding and logistical support for control, another factor aiding global control operations, as reported in the latest U.N. Millennium Development Goals Report (2012), is a decline in both the number of people living in extreme poverty (people living on less than $1.25 per day) and poverty rate in all major regions of the world. Although these reductions have been most dramatic in Asia, a small but steady decline has also been reported in sub-Saharan Africa. As noted in Dr. Kuris’s address, poverty and infection with parasites are strongly linked, and if poverty can be diminished, then there is a greater chance parasite transmission can be diminished as well.

Several other factors come into play and give room for optimism for increased likelihood of achieving helminth control. One is the greatly improved communications that have resulted from the widespread use of cell phones in previously poorly accessible locations, most notably in Africa. It is estimated that mobile cellular penetration has increased to 79% in the developing world, and over 50% in Africa (United Nations, 2012). This obviously greatly facilitates the logistics associated with any kind of complicated control program. Another factor that has important repercussions for control is access to Google Earth and the ability to provide explicit geospatial reference points. This makes it much easier to be sure that even the most remote areas are not overlooked in control programs, a point highlighted by recent attempts to locate nomadic herdsmen in northern Nigeria as part of the polio eradication campaign (Callaway, 2013). Another contributing factor is the slow improvement of road systems in developing countries, and although it doesn’t take long to figure out that we still have a long way to go here, roads are much better developed now than in times past. Finally, another important factor is that we have not suffered any global scale wars for nearly 70 years. There is no shortage of regional conflicts or civil wars to impede progress to control, but nothing of the scale of a confrontation like World War II, when the efforts of so many developed nations were totally given over to wartime needs. Such an environment does not lead to the expenditure of resources to favor parasite control in affected areas, unless of course the particular area is a theatre of war. Our freedom from global-scale conflict, and an unparalleled period of relative global prosperity has created a level of wealth, including among individuals, enabling donation of funds for NTD control in the developing world.

The foundation upon which plans for eradication or elimination of NTDs is largely built is preventive chemotherapy, namely to treat at-risk populations to prevent transmission and morbidity. This is typically achieved with mass drug administration campaigns (WHO, 2006; Bockarie et al., 2013). This is for understandable reasons. Safe, effective and relatively inexpensive drugs are currently available (we all know the dangers and concerns here - see potential pitfalls below) and coordinated distribution networks can be exploited to enable treatment coverage of several NTDs at a time. Although this approach has several advantages, including drastically reducing the number of helminths in existence and thereby inevitably reducing their overall transmission success, it is axiomatic that we also need to tackle some of the root causes favoring helminth transmission in the first place, chief among them being improved sanitation. Provision of sanitation and clean water are of course expensive, but should remain as important fundamental goals facilitating the long term sustainability of control programs. Key to this effort is the development of new toilet technologies (Nature News Blog, 15 Aug 2012), and a growing awareness that human wastes are just too valuable (and plentiful) a source of needed resources to ignore in the future world (Pearce, 2013). As just one example highlighted in Dr. John Hawdon’s Presidential Symposium address, the processing of human wastes in simple low-tech anaerobic digesters, can help solve two huge problems in developing countries (Ding et al., 2013), namely provision of fertilizer for fields and fuel (methane gas, instead of scarce wood) for cooking food. The trees of the world will benefit enormously if technology like this could be broadly implemented!

Where We Stand with Control of Some Major Groups of Human Helminths

For at least one human helminth, the guinea worm, we can legitimately consider the prospect of eradication

The term “eradication” is very much in play for Dracunculus medinensis, the guinea worm, which, thanks to a coalition led since 1986 by the Carter Center with support from the CDC, WHO, UNICEF, ministries from involved countries, thousands of local volunteers and several donors, has reduced the number of cases from about 3.5 million in 1986 to an estimated 542 in 2012 (Hopkins, 2012; Hopkins et al., 2013). According to the Carter Center website, as of July 2, 2013, only 89 cases of Guinea worm disease have been reported thus far this year, in South Sudan, Ethiopia, Chad, and Mali.

Although current political instability in Mali poses a problem, and some surprise outbreaks have occurred in Chad and Ethiopia, assuming no additional major unforeseen developments, cautious optimism for eradication within a decade seems warranted. If so, guinea worm will be only the third infectious agent after smallpox and rinderpest, and the first non-viral pathogen, to be deliberately eradicated by the human hand. The drive to eradicate guinea worm has been greatly facilitated by the apparent lack of reservoir hosts, and by the conspicuous nature of the infection. What is remarkable is that this is the first infectious agent to be eradicated without the benefit of a vaccine, by implementation of very low tech control measures that take advantage of the nematode’s dependency on copepods for its transmission. Simple filtration methods to remove copepods from drinking water, coupled with effective education programs, provision of clean drinking water, use of Abate to kill copepods, and the inherent motivation of the afflicted people to be rid of this horrid parasite have all facilitated the effort.

Lymphatic filariasis is targeted for elimination by an effective global program that is a remarkable public health bargain

Perhaps there is no more feared helminth infection than lymphatic filariasis, caused by the mosquito-borne filarial worms (Wuchereria and Brugia). They cause chronic, disabling infections that can result in elephantiasis, hydrocele and lymphedema. Filariasis is estimated to infect 120 million people living in 83 countries. In response to a call from the World Health Assembly that considered filariasis to be eradicable or potentially eradicable, the WHO launched in 2000 The Global Programme to Eliminate Lymphatic Filariasis (GPELF) with a target global elimination date of 2020. A cornerstone of this program is the donations by GlaxoSmithKline of albendazole and Merck and Co., Inc. of ivermectin for as long as needed to achieve elimination, the project’s final goal. These treatments prevent the spread of new infections, including to infants, prevent existing infections from becoming disabling. The drugs used (albendazole in combination with either ivermectin or diethylcarbamazine citrate), also have beneficial effects on infections of soil-transmitted helminths, onchocerciasis, and even human ectoparasites like lice or scabies, thereby providing add-on benefits to the control program. This has prompted the accolade that the GPELF is a “best buy” among many global health expenditures. Both China and the Republic of Korea have since declared elimination of lymphatic filariasis, and Togo is probably the first sub-Saharan African nation to have interrupted transmission of lymphatic filariasis (Sodahlon et al., 2013). Haiti is close to eliminating filariasis http://www.cdc.gov/media/releases/2013/p0614-haiti-filariasis.html. Of 78 countries still considered endemic, 68 have completed their efforts to map endemic foci. By 2016, all affected countries are slated to be fully scaled up with respect to delivering drug treatment across all geographic regions. Some countries have already scaled back mass drug administration after having achieved 100% geographic coverage (Rebollo and Bockarie, 2013). Although the challenge to eliminate lymphatic filariasis globally is immense, and no doubt certain geographic areas will prove intransigent, it seems undeniable that sustained efforts to diminish transmission and thereby prevent new infections will significantly diminish prevalence of lymphatic filariasis by 2020.

Onchocerciasis is on the ropes in the Neotropics and is under sustained attack in Africa

Again thanks to a leadership role provided by the Carter Center, of 13 known endemic foci of onchocerciasis in the Neotropics, transmission has been eliminated in four, and interrupted in six more (Hopkins, 2013). In 2011, with assistance of the Onchocerciasis Elimination Program of the Americas, WHO, and the Pan American Health Organization (PAHO), Columbia became the first country in the Americs to eliminate onchocerciasis. No new cases of blindness due to Onchocerca volvulis have been reported in the Americas since 1995, and PAHO has pledged to stop transmission in the Western hemisphere by 2012. http://www.globalnetwork.org/colombia-eliminates-onchocerciasis.

In the larger and more intransigent endemic areas in Africa, the Onchocerciasis Control Program, which operated in West Africa from 1974 to 2002 succeeded in eliminating onchocerciasis as a disease of public health importance in 10 countries. The program was initiated with vector control and later supplemented with use of ivermectin. The African Programme for Onchocerciasis Control (APOC) was established in 1995, and includes 19 participating countries not originally targeted by the OCP. It involves Ministries of Health of the involved countries, NGOs, donor countries, UN agencies, and donations of ivermectin (Mectizan) by Merck & Co., Inc. The program features community-directed treatment with ivermectin, thereby empowering local communities to fight river blindness in their own locales. The program is delivering over 80.2 million doses of ivermectin in 19 countries every year, to enable treatment of 90 million people annually, thereby preventing 40,000 cases of blindness per year and reducing prevalence by 73% as compared to pre-APOC levels. APOC will be extended to at least 2025 with the goal of elimination. Onchocerciasis control is synergistic with lymphatic filariasis control as mentioned in the previous paragraph, and as with The Global Programme to Eliminate Lymphatic Filariasis, APOC is one of the most cost-effective large scale public health programs in the world (Coffeng et al., 2013).

Schistosomiasis…dare we say the word….elimination, with 2025 given as a target date for global elimination as a public health problem

Human schistosomiasis has long been recognized as one of the most intractable human helminth diseases. This is because it is hard to achieve sustained control that diminishes the probability of transmission that can lead to elimination. Schistosomiasis has though been eliminated in some island foci or in locations where snail habitats are limited in scope, and an elimination program is currently underway for Zanzibar. Schistosomiasis control has been blessed by the continued efficacy of praziquantel, first implemented on a large scale in 1984. It can now be provided much more inexpensively than in times past, and in 2013 and 2014, it is estimated that between 174–208 million tablets per year will be provided by donors like USAID, DFID, and Merch Germany (WHO Weekly Epidemiological Record, 2013). Largely as a result of sustained use of praziquantel, there have been significant reductions of prevalence in three major endemic countries, China, Egypt and Brazil. Now, >85% of all human cases reside in sub-Saharan Africa. WHO plans call for the elimination of schistosomiasis in the Caribbean, the Eastern Mediterranean Region, Indonesia and the Mekong River Basin by 2015, in selected sub-Saharan African countries by 2020, and globally by 2025. The number of people to be treated and the amount of praziquantel used is projected to peak in 2018, at 235 million people and 645 million tablets (WHO, 2013). One of the significant problems to be overcome is simply to get the pills to the people needing treatment, as shown by a decrease in the number of people treated in 2011 (about 28 million, or about 10.2% of all people estimated to require treatment) as compared to previous years. This drop occurred even though access to praziquantel was not limiting (WHO Weekly Epidemiological Record, 2013).

Although mass drug administration can reduce morbidity and lower prevalence, it is unlikely by itself to interrupt transmission (King et al., 2006) because rates of reinfection originating from infected snails in local snail populations tend to be rapid, and typically not all infected people receive treatment. Ideally, for elimination to succeed, mass drug administration should be supported by education campaigns, improved sanitation and provision of safe water, and efforts to control infections in snail populations. The latter could, for example, interrupt the production of cercariae, and lower the rate at which reinfections occur. I return to this topic later in the talk.

One notable program to mention with respect to achieving the long-term goal of global schistosomiasis elimination is SCORE (The Schistosomiasis Consortium for Operational Research & Evaluation), directed by Dr. Dan Colley, one of our Presidential Symposium speakers. Funded by The Bill and Melinda Gates Foundation, and with a focus on human schistosomiasis in Africa, this program provides a model for how research and operational control can be integrated for the greater good (King et al., 2011). SCORE is devoted to answering key strategic questions about schistosomiasis control that will make control programs more cost-effective, and that will encourage expansion of schistosomiasis control programs and their integration with other control programs. SCORE also provides critical tools and strategies for effective and sustainable global schistosomiasis control and elimination where feasible. For example, SCORE recently sponsored the first meeting of international experts held in decades focused on the topic of snail control. This meeting was held in recognition of the need to supplement chemotherapy with other control approaches, thereby addressing a major gap in schistosomiasis control research.

Other Major Groups of Human Helminths Will Also Be Subjected to Large Control programs in the Next 15 Years

In addition to the helminths mentioned above, plans are also in place (WHO, 2013) to scale up interventions for control of food-borne trematodes (Fasciola, Fasciolopsis, Paragonimus, Clonorchis and Opisthorchis), tapeworms (cysticercosis/taeniasis and echinococcosis) and soil-transmitted helminths (Ascaris, Trichuris, Necator and Ancylostoma). For the food-borne trematodes, the plan is for 75% of people at risk to be treated (praziquantel for clonorchiasis and opisthorchiasis; triclabendazole for Fasciola, and either drug for paragonimiasis) and for morbidity to be controlled in all endemic areas by 2020. For cestodes, validated control projects for taeniasis and cysticercosis will be developed by 2015 and will be scaled up in selected countries by 2020. Control of cysticercosis will require a multifaceted approach involving chemotherapy of pigs and humans, vaccination of pigs, better management of pig farms, and sanitation and health education. For echinococcosis, pilot projects will be initiated by 2015, validated control strategies implemented and coordinated with other programs like rabies control in dogs, and then scaled up and implemented by 2020 in selected countries for control and elimination.

As discussed in Dr. Hawdon’s Presidential Symposium address, it is the soil-transmitted helminths that are both most abundant, and hardest to eventually eliminate. There are more than one billion people infected with soil-transmitted helminths, many of these people with multiple species infections. This total includes 890 million children requiring annual treatment, only about 30% of whom are currently actually covered.

By 2015, the WHO calls for regular treatment of 50% of pre-school and school aged children worldwide, increasing this percentage to 75% in all countries by 2020. The estimated number of treatments required to achieve even 75% coverage from 2011 to 2025 will require about a billion treatments per year over a 10-year stretch. This represents a major financial challenge, and donor fatigue becomes a real concern, especially when the payoffs in improved health are not as obvious as with some of the other human helminths. Also, there is an urgent need to preserve the efficacy of albendazole, one of the few available drugs that is currently effective against all the soil-transmitted helminths. As there is a recurrent problem of rapid rates of reinfection because of the persistence of eggs or larval stages in the soil in many endemic areas, a greater role for improved sanitation as a way to limit transmission and cut down on the acquisition of new infections is urgently needed. As an aside, although pessimism or skepticism are understandable sentiments when it comes to control or especially elimination of soil-transmitted helminths, these sentiments should not lead us to conclude that we cannot achieve elimination of other helminth species. Neither should the optimism engendered by our success in controlling some helminth species blind us to the difficulties of controlling soil-transmitted helminths.

No Shortage of Pitfalls

Plans for global elimination are one thing, but any number of daily realities conspire against successful completion of any and all plans. The best current example is provided by ongoing attempts to eradicate polio (see the Polio Global Eradication Initiative, http://www.polioeradication.org. Our ongoing attempts at polio eradication have recently been foiled by political upheavals in northern Nigeria preventing treatment of all infected people there, some of whom have transferred cases to areas in which eradication had earlier been achieved in the horn of Africa. Political instability in places like Pakistan and Afghanistan have resulted in targeting of polio workers by terrorists, furthering slowing progress. Nonetheless, polio eradication is still likely to be achieved by 2018, but eliminating the last few hundreds of cases will come at a steep price, an estimated $5.5 billion dollars between now and 2018.

With respect to helminth elimination, societal upheavals resulting from natural disasters and violent conflicts are a major impediment to success. In 2013, given ongoing civil conflicts such as occurring in Syria and elsewhere, there are now over 35 million refugees and internally displaced persons scattered around the world (UN Refugee Agency http://www.unhcr.org/pages/49c3646c4b8.html), often living in conditions with marginal health care conducive to helminth transmission. The guinea worm eradication program exemplifies the problem: political upheavals in Mali and insecurity and population movements in South Sudan are obstacles in the final push for eradication but nonetheless case identification and containment activities and heightened surveillance are still proceeding, and reducing transmission (http://www.who.int/neglected_diseases/south_sudan_full_steam_2013/en/).

Climate change, currently estimated to be 1.1–6.4°C above mid-90s level by century’s end is an enormous wild card with which control workers must contend. Accompanying climate change will be droughts and floods and violent weather, all with potentially disruptive effects. Many human helminths subject to control operations have free-living egg or larval stages and/or employ arthropod or molluscan hosts, all of which will be fully exposed to changing climatic regimes and are likely to be affected by them (Mas-Coma et al., 2009). For example, a warming climate in China has been predicted to alter the frequency and transmission dynamics of Schistosoma japonicum, potentially jeopardizing the success of control efforts there (Yang et al., 2006).

Most of the elimination programs are founded on mass drug treatment, and availability of effective drugs is key. Of course everyone realizes that the emergence of drug resistance is an ever-present danger, especially as the treated populations become especially large, and refugia that permit the persistence of drug susceptibility genes become very small. One needs to look no further than the treatment of helminths of domestic animals to be reminded of the problem. Resistance to albendazole, mebendazole, levamisole, pyrantel and ivermectin all are known for helminths of veterinary significance (Besier, 2007). Lack of drug responsiveness is already an important problem with respect to human soil-transmitted helminths because, as Dr. Hawdon noted in his address, mebendazole is not effective against Necator americanus which is responsible for at least three-quarters of human hookworm infections, and neither albendazole nor mebendazole are very effective in a single dose against Trichuris (Keiser and Utzinger, 2008), although these low response rates may not be due to resistance per se. For some diseases, particularly schistosomiasis comes to mind, the available number of drugs in the arsenal is very small. Although we are extremely fortunate that clinically significant resistance to praziquantel has yet to appear, if it does, then the likelihood of meeting the global elimination target would likely quickly fade. This is in part because the reliance on chemotherapy has been so great, that for those helminths using vectors or intermediate hosts (snails), there are still significant problems with attacking the life cycle stages in such hosts. Insecticides are available to check vector populations, but resistance to these too is commonplace (David et al., 2013). Several new innovative vector control strategies are being developed (McGraw and O’Neill, 2013), but it is unclear yet the role they will play in elimination efforts, including for ailments like malaria and dengue.

An additional sobering factor that will complicate control efforts is that the human population growth for the next decade is projected to be highest in Africa, reaching one billion people there by 2020. Africa has 33 of the world’s 49 least developed countries. Another factor that is worrisome for the future is access to freshwater, especially for people living in rural areas in developing countries. This will lead to land degradation and desertification, and this means it will be harder for farmers to raise their crops and to make any kind of profit (Nature, 2013), further relegating them to a lack of food security, and poverty to say nothing about denying them access to clean drinking water and sanitation. The problems posed by burgeoning populations for adequate access to water seem especially problematic.

One last comment here is that much of the success experienced in NTD control has come from the establishment of unique and complex public private partnerships. These are by no means easy to sustain. They require a continuing commitment from the affected countries including provision of the needed human resources to implement and scale up the programs, whether at the central administrative level or at the community level. Maintenance of community enthusiasm for delivering and using drugs can also not be assumed. The programs also require longevity across several phases: initial resolution, development of partnerships, mapping disease distribution, obtaining and maintaining financing, implementation, maintenance of implementation, evaluation and monitoring, and post-intervention monitoring and verification (Bockarie et al., 2013). Our tendency is to focus on the scientific challenges posed by control, but the logistical and practical difficulties are also daunting.

Elimination Efforts Will Bring Plenty of Biological Changes

Elimination Efforts Will Change the Biology of Human Helminths

As noted in the Presidential Symposium address presented by Dr. Joanne Webster, elimination programs are bound to have major impacts on the species being targeted, the most profound impact potentially being extinction. As control efforts expand, populations of targeted helminths will be reduced with likely losses in genetic diversity (Norton et al., 2010), increased fragmentation of subpopulations with concomitant losses of gene flow with implications for spread of traits like drug resistance (Criscione et al., 2005), and of course selection favoring genes conferring resistance (Diawara et al., 2013).

As noted by Basanez et al. (2012), several aspects of our standard conceptions regarding pattern and process in human helminth infections will be altered. For instance, in a pre-control situation, helminth populations tend to exist in an equilibrium state, one in which density dependent regulatory processes predominate, potentially affecting recruitment, level of host immune response, parasite growth and fecundity. Relaxation of such regulation by control could favor otherwise less competitive drug resistant parasites (Churcher and Basanez, 2008). Or, those worms able to initiate re-infections may grow to a larger size with fewer competitors present (Elkins and Haswell-Elkins, 1989). In general, the long-term impacts of the creation of “empty niches” by control programs are very hard to predict. Will other parasites emerge to fill these niches?

Reduced levels of transmission will also shift age-infection profiles, helminth distributions may become even more aggregated and remaining transmission and morbidity may shift to different age groups (Basanez et al., 2012). Also, long-established patterns of co-infections among helminth species will likely be altered such that control targeted towards one species could have unforeseen effects on a co-infecting species. This may be particularly likely when the co-infecting helminth species are responsive to the same drug, but at different does, or when the co-infecting species have different age-infection profiles (Basanez et al., 2012). In general, we know very little about the underlying dynamics of helminth co-infections and how they will impact control operations over the long haul.

Another impact of control targeting human infections may be to favor transmission by alternative hosts in the helminth’s life cycle. Consider S. mansoni which in Africa is mostly transmitted by humans, though other primates like chimpanzees and baboons, and rodents may also serve as definitive hosts. In the face of persistent control, such alternative hosts may come to represent the hosts in which the parasite is more likely to successfully reproduce. If so, this is bound to alter basic life history parameters of the parasite. A relatively small rodent that survives for one year as opposed to a relatively large human that might live for fifty years and be repeatedly exposed to infection obviously present very different environments for the parasite. One might predict different rates of maturation or rates of egg production would be favored in the alternative host species, factors that also affect the parasite’s level of virulence. Although it might be hoped that eventually such parasites would be selected to lose infectiousness for humans, S. mansoni maintained exclusively in mice over a span of decades are still readily infective to people as the occasional lab accident points out. Consequently, unexpected biological changes, including in virulence of the targeted parasite, might accompany our intervention efforts. Similar concerns have been voiced about the deployment of vaccines, with studies of Plasmodium chabaudi in mice suggesting vaccination efforts could unwittingly favor more virulent strains of the parasite (Barclay et al., 2012).

Humans too will be affected in a variety of ways

It is generally considered that children treated for soil-transmitted helminths will benefit by improved growth, cognition and school attendance (Barry et al., 2013), but a recent meta-analysis has challenged this assertion (Taylor-Robinson et al., 2012). Even if children in endemic areas did not benefit from treatment, it is hard to imagine their families would not want their children to be worm-free! Arguably for soil-transmitted helminths, and less arguably for other NTDs, treated individuals will be spared from increased risks of a huge variety of ailments including blindness, disfigurement, bladder cancer or cholangiocarcinoma, reproductive impairment, and portal hypertension to name just a few. These improved health benefits will make it easier for the affected populations to break the poverty-infection cycle.

At the same time, there is a growing awareness in the developed world - where helminths have been relatively rare for some time - that the increasing prevalence of autoimmune diseases like Crohn’s disease, ulcerative colitis, multiple sclerosis, asthma and allergies may be consequences of our freedom from helminth infections. In a recent discussion of this topic in Nature, Weinstock (2012) notes that helminths have three major effects on the immune system: they stimulate regulatory T cells that dampen immune responses; activate regulatory dendritic cells and macrophages that prevent the activation of inflammation-promoting T effector cells; and stimulate “probiotic” bacteria within the microbiome that help maintain intestinal health. This has lead to the establishment of several clinical trials currently underway, mostly to assess the impact of Trichuris suis to ameliorate autoimmune conditions. Preliminary results are encouraging. It will be fascinating to see how the hygiene hypothesis will eventually relate to global programs to eliminate human helminths!

Here I am reminded of one of the very few exposures to helminth antigens experienced either by myself or by many of you in the audience, namely to the skin-penetrating cercariae of avian schistosomes that cause swimmers itch. Will these be one of the few remaining natural sources of exposure to helminth antigens many of us in the developed world will ever experience?

Lastly, although it is certainly hard to argue against the desirability of ridding the world of guinea worm and a variety of other debilitating helminths, certainly it is also the case that a fascinating chapter of the human story will be drawing to an end. Some feel sufficiently strongly about the guinea worm’s imminent demise that they have established a Save the Guinea Worm Foundation http://www.deadlysins.com/guineaworm/. A world in which human helminth infections – including some of the most spectacular of all infections - are but mere historical oddities, will be less interesting, certainly so for parasitologists, and I suspect for poets too.

Once Brought Under Control, NTDs Run the Risk of Really Become Neglected!

Often the stated goal of elimination programs is to lower prevalence or intensity of infection below the level of public health significance. Whenever this level is achieved, however we might define it, there will then be a natural inclination to de-emphasize the study or monitoring of human helminths, and to move on to other health priorities. But the reality is that many, and probably most, of the helminths targeted for elimination will not have been eradicated. They will still be there lurking in the background. It seems inevitable that outbreaks will occur, and without ongoing sensitive monitoring efforts, transmission could potentially return to significant levels, particularly if underlying poverty-associated problems are not addressed. Furthermore, such outbreaks might be accompanied by some unpleasant surprises, such as the emergence of new drug-resistant strains, for example.

For this reason, once a specified level of success has been achieved and pronounced, it is also important we guard against loss of many different kinds of expertise associated with helminth control: ability to mobilize control programs both internationally and locally; basic knowledge of the organisms involved and their epidemiology; ability to diagnose low levels of infection rapidly and accurately; and expertise in research to develop new tools and control strategies. One of the associated goals must be to keep parasitology in the public consciousness and continue to teach and train students in this area. Of course, as an audience like this one very well appreciates, there are many additional reasons to continue to encourage the study of parasitology beyond just the demands imposed by human helminth control.

Also, if the threat of helminth infection diminishes, there may be a tendency to deemphasize remediation of some of the root problems – poverty, inadequate sanitation, drinking water, food, housing or education – that allowed these organisms to thrive in the first place. If we fail to address these fundamental problems, then even if some of the ancient scourges have been successfully dealt with, it would hardly be surprising if new emerging diseases benefitting from the same circumstances would take their place.

Helminth Elimination Efforts Provides Many Opportunities, and ASP Has a Role to Play

The final section of this talk is to emphasize that the efforts to eliminate human helminth infections provide many opportunities - especially for the young and adventuresome - and that the members of ASP have had, and will continue to have, an important role to play.

Mass drug administration plays a central role in almost all of the helminth elimination programs, and the role played by Dr. Bill Campbell in helping to provide ivermectin has already been pointed out. Owing to the problems of emerging drug resistance, or to the present inadequacies of our existing drugs, we need to develop new drugs and ASP members are actively involved in this endeavor. One way is to discover new potential drug targets. The recent tapeworm genome paper published in Nature, with ASP member Dr. Pete Olsen as one of the prominent authors (Tsai et al., 2013), has identified a number of potentially new targets to combat cestodes, including for difficult to treat tapeworm-related ailments like neurocysticercosis or hydatid disease. Similar considerations apply for the S. mansoni genome for which Dr. Phil LoVerde was one of the leading contributors (Berriman et al., 2009). Dr. Tim Geary is currently funded by the Gates Foundation to work with African scientists in South Africa and Botswana, to identify compounds from African botanical and microbial sources that can lead to new drugs to eliminate helminths. This approach is reminiscent of what was followed by Dr. Campbell and colleagues regarding the discovery of ivermectin. Dr. Geary has highlighted the importance of partnerships with scientists from endemic countries for finding new treatment approaches.

Two other ASP contributions deserve mention here. The first is by Dr. David Williams, who along with his colleagues has been developing new approaches to treat helminth infections. For example, reasoning that schistosomes are highly dependent on the production of anti-oxidants to protect themselves from host immune attack, and that schistosomes have a redox network distinctly different from our own, he has pointed out that compounds that target distinctive schistosome redox enzymes may become clinically relevant in the near future (Huang et al., 2012). Also, Dr. LoVerde, at this year’s ASP meeting, pointed out significant advances in identifying a sulfotransferase locus (SmSULT) involved in conferring resistance to the anti-schistosome drug oxamniquine. A change in this gene prevents the enzyme from activating oxamniquine such that it can no longer bind to schistosome DNA and interfere with synthesis or transcription. His studies provide a way forward, not only for how to identify the worm mutations involved in resistance, but also potentially for how to revive this drug so it can be used in the future.

Control programs also inevitably need inexpensive, sensitive, specific, and preferably non-invasive diagnostic techniques that can be read easily and quickly at the point of care. As one example, and as part of his efforts for the SCORE program, Dr. Colley and colleagues have been evaluating a commercially available point-of-care circulating cathodic antigen assay for Schistosoma mansoni, using urine as a test substrate. This technique was found to be more specific than the standard method of Kato-Katz analysis of fecal samples for presence of schistosome eggs, a method that is particularly labor-intensive and is best done on fecal samples from multiple days. Furthermore, urine is easier to collect than fecal samples, results are available in 20 minutes and it is about the same cost as a Kato-Katz diagnosis. Although such a test may not be sufficiently sensitive to detect the low levels of residual infections in the final end stages of elimination programs, it nonetheless will serve as a valuable adjunct to control programs by defining endemic foci, thereby facilitating planning of control strategies and eventual elimination efforts. It also serves to remind us of some simple questions that need to be asked, yet are not trivial to answer: how do we define the end point for elimination efforts, and how do we know we are there?

One of the great strengths of ASP is that it fosters a very broad, biologically grounded approach to parasitism, with an emphasis on the ecology, genetics and evolution of host-parasite relationships (Steinauer et al., 2010). From this will emerge a deeper understanding of the parasites being controlled, with a better ability to predict how control programs will affect their biology. For instance, with schistosomes, Steinauer et al. (2009) have noted that in the absence of water body boundaries, gene flow can occur across large geographic distances, potentially providing for rapid dissemination of resistance genes should they become common. Furthermore, recent studies suggest that even in areas where repeated praziquantel treatment occurs, such that prevalence and intensity of infection are reduced, given that there are typically so many people remaining who have not been treated and rates of reinfection are high, there may be little impact of control on the genetic diversity of the schistosomes being targeted (Steinauer, personal communication). With respect to soil-transmitted helminths like Ascaris, Criscione et al. (2007) have noted that in areas of sympatry, cross transmission can occur between between A. lumbricoides and A. suum, with an apparent greater tendency for pig ascarids to infect humans than vice versa. Furthermore, hybrid worms can be recovered from either host species. Current soil-transmitted helminth control strategies rarely consider the potential involvement of pig ascarids as a source of human infection, suggesting the overall strategy for control needs revision (Peng and Criscione, 2012).

As noted above, one of the current shortcoming in our general approach to control is that it is often uni-dimensional, with lots of reliance placed on drugs: they are available, easy to administer and relatively cheap. But new ways are needed to attack other life cycle stages of the helminths involved, including those occurring in their arthropod vectors or gastropod intermediate hosts. ASP investigators have played an important role in investigating the basic biological interactions between human helminths and their invertebrate hosts. As just some recent examples, Aliota et al. (2010) have shown that distinct transcriptional profiles are generated in mosquitoes following their exposure to filarial worms to which they are susceptible or refractory. This helps not only to understand the complex nature of vector competence and the genes involved, but could lead to new ways to exploit such genes to achieve filariasis control. Taft et al. (2010) have studied the process whereby miracidia of S. mansoni transform into primary sporocysts in snails, and have developed a medium-throughput screen to assess the ability of various compounds to interrupt this process. From this approach they have gained new insights into the role of elevated levels of cAMP in preventing miracidia from initiating the transformation process. Bayne and co-workers have identified particular allelic variants of copper-zinc superoxide dismutase involved in resistance of the snail B. glabrata to S. mansoni infection, and although the results are dependent on the snail’s genetic background, have suggested it may be possible to drive alleles associated with resistance into natural populations of B. glabrata (Bonner et al., 2012).

In addition to studying parasite-vector interactions, ASP investigators have also been actively involved in genome projects for vectors or intermediate hosts. ASP member Dr. Coen Adema is currently spearheading the annotation of the Biomphalaria glabrata genome, the major host for S. mansoni in the Neotropics, and Dr. Christensen has been involved in the genome project for Culex quinquefasciatus, one of the major hosts for human filarial worms (Arensburger et al., 2010). By having complete genome sequences at our disposal, we can better identify new genes that may play roles in either nurturing or combating parasites. They also provide an invaluable comparison against which other vector sequences - now much more rapidly obtained through modern Illumina or 454-based sequencing approaches - can be compared. For example, our current studies of the widespread African intermediate host B. pfeifferi will be greatly aided by the availability of the sequence for the closely-related B. glabrata.

ASP has always fostered studies focused on the biotic interactions occurring among different helminth species, or between helminths and other symbionts within their vectors or intermediate hosts. This has been particularly noteworthy for the study of trematodes in snails. Studies like those of Hechinger et al. (2011) have provided new insights for how trematode species interact within snails, and how some trematode life cycle stages can be viewed as specialized soldier castes to protect their reproductive clone mates from attack. Studies undertaken by Zimmermann et al. (2011) have reawakened interest in nematodes of the genus Daubaylia and their interactions with trematode larvae. Rodgers et al. (2005) have highlighted the interactions occurring between commensal annelids (Chaetogaster) and sporocysts occurring in snails infected with S. mansoni. In each of these cases, important insights are gained about the complex biotic environments that are occupied by helminths targeted for control, and offer suggestions for how these interactions might be exploited to help reduce transmission of schistosome cercariae from snails to humans.

The focus of ASP on basic biological interactions has the potential to provide a unique brand of insight not all that readily available in today’s current research environment, focused as it is on genomics, bioinformatics and approaches relying on vaccines or use of drugs. Again I am reminded here of the simplicity of the guinea worm control program and how it plays off a very basic understanding of guinea worm biology.

Another major potential impediment to control program is the presence of alternative species of definitive hosts (note the case of Ascaris in pigs mentioned above) that will prove difficult if not impossible to treat, and therefore may serve as ongoing sources of eggs that could ultimately, even if indirectly via an intermediate host, serve as a source of new human infections. One of the first things to understand is that there are potentially alternative or reservoir hosts involved with the species being targeted for control. For some helminths like S. japonicum, it is well known that a broad spectrum of mammals can serve as epidemiologically significant hosts and this is built into control strategies from their inception (see Liu et al., 2013 for a discussion of the current Chinese approach to schistosomiasis control). But for other species, like S. mansoni or even S. haematobium, the role of reservoir hosts is less well known. Owing to the experience many ASP members have with searching for and finding parasites in wild animals, this is yet another way our members can play an important role in assisting control programs. The studies of Hanelt et al. (2009) in finding rodents transmitting not only S. mansoni but also a new species of mammalian schistosome in large swampland habitats in Kenya points out the need to be vigilant about the role of such reservoir hosts in initiating new snail infections in locations also used by human hosts.

Several of our members also have a passion for maintaining and using scientific collections of parasites: museums have many roles to play in control efforts. In general, in a fast-changing world, museums provide irreplaceable historical reference points against which all kinds of changes can be measured. First, they can serve as repositories of helminth species that have been relegated to extinction or to near extinction by control programs. Such specimens provide an irreplaceable, tangible historical record for what once existed. Furthermore, assuming sufficient specimens exist for adequate preservation of genetic material, specimens of extinct parasites will provide a wealth of information for future studies, including studies of what made them so successful as to warrant control in the first place. This also raises issues, similar to those that have arisen about the perpetuation of frozen stocks of smallpox, about how accessible such specimens should eventually be. Second, specimens of helminths subjected to control programs should be regularly accessioned into museums, as a means to enable documentation at different time points of how control programs are changing the species being targeted. Again, this provides both historically unique information, but may also eventually prove useful for documenting why a particular control program either succeeded or failed in meeting its objectives. Third, by having museum collections representing the full spectrum of parasite diversity, we can gain a better perspective as to whether currently rare or unheralded species might emerge to fill the helminth niches emptied by control programs.

As a final comment regarding ASP’s involvement in helminth control, one particularly directed towards the younger members of our society who may be looking for positions in parasitology, or ways to make their work more relevant to societal needs, the control program I’ve mentioned offer tremendous opportunities. Contact the people involved - learn more and express your interest. Considering volunteering some of your time as a way to get more familiar with such programs, and as a way to get your foot in the door. Consider undertaking research topics that address some of the critical needs of control programs – develop needed, in-demand skills. Figure out how to use the needs of control programs as a way to help get your grants funded. Lastly, if this is a topic of interest to you, be persistent, because there is a great potential pay-off. Involvement in such programs offers a way to get involved with high-profile projects requiring cutting edge science, and that can help lift the burden of disease quietly suffered by many of the world’s poorest people.

In conclusion, I wish to thank Dr. Christensen for his meticulous preparation of my introduction, and the society for the opportunity to serve as your President. Although the world is still plenty wormy, it is not as wormy as it was in Dr. Stoll’s day, and thanks to many new partnerships, innovative leadership, and the influx of resources, there is more reason than ever for optimism to think we live in the “Age of Human Helminth Control”. This is likely to forever change our view of parasitism and how we teach the subject of parasitology. We must all acknowledge that there are pitfalls aplenty, and particularly for soil-transmitted helminths, the scope of the challenge is daunting. The current emphasis on helminth control creates unique opportunities for our members to make a lasting impact in the world, and your help will be needed if success in this endeavor is to be achieved.