Onchocerciasis in the Tropics
Onchocerciasis in the Tropics – River blindness (Human onchocerciasis) is a serious neglected tropical disease caused by the filarial nematode parasite Onchocerca volvulus and an important cause of blindness and chronic disability in the developing world. Presently, it is estimated that 37 million people carry O. volvulus, with 90 million at risk in Africa. Morbidity at present is estimated at 987,000 disability-adjusted life-years and there are 46,000 new cases of blindness annually. Through mass drug administration of the donated drug ivermectin (Mectizan) onchocerciasis has been recognized by the World Health Organization as a potential candidate for global elimination, with a World Health Assembly goal to establish community based sustainable treatments in areas of meson and hyperendemicity by 2010 ( www.apoc.bf/en). However, formidable technical and logistical obstacles must be overcome before the goal of elimination can be attained, and additional tools are critically needed to support the control measures and thus potentially eliminate this infection as a public health problem. These new control tool requirements include a need for a vaccine against onchocerciasis to “complement” the present Control measures and further the goals of the existing control programs (Cook et al., 2001; Dadzie et al. 2003; Hoerauf and Steel, 2004). The rationale for why a vaccine is in critical need includes the observations that:
(a) The present control measures are not going to succeed in the elimination of O. volvulus infection by themselves (Dadzie et al., 2003 )
(b) Evidence for emerging resistance to ivermectin, the only drug used for mass treatment of onchocerciasis (Osei-Atweneboana et al., 2007); and
(c) Practical considerations in treating people for 14 – 35 Years (Winnen et al., 2002; Boat in and Richards, 2006).
Importantly, protective immunity against Onchocerca Infective larval stages, also known as third-stage larvae or L3, has now been definitively demonstrated in humans, cattle, and mice, thereby proving the conceptual underpinnings that a vaccine can be produced against this infection (Abraham et al., 2002; Lustigman et al., 2003; Tchakoute et al.,2006). The value of developing a vaccine against O. volvulus infection was recognized by the Edna McConnell Clark Foundation. Their 15 years of support (1985–1999) provided the research foundation for antigen discovery and development of animal models for testing the efficacy of vaccine candidates. This chapter will highlight the current status of vaccine development against onchocerciasis and the potential for being able to accelerate vaccine development to provide this crucial element required for the successful elimination of onchocerciasis. Reduction in worm burden after vaccination, even if not absolute, will reduce the number of microfilariae produced by the adult female worms, and thereby reduce both pathology and the rates of transmission within endemic regions.
EPIDEMIOLOGY OF RIVER BLINDNESS IN THE TROPICS
Onchocerciasis is endemic in 27 countries in Africa, (Basanez , Pion , Churcher , et al., 2006). Approximately 90 million people are at risk, with 37 million people infected. About 270, 000 individuals developed blindness from onchocerciasis and another 500 000 have severe visual disability. (Hoerauf , Büttner , Adjei , et al., 2003) Global disease burden in 2002 was 0.95 million disability-adjusted life years (Remme, 2004) Over 99% of cases occur in sub-Saharan Africa. In hyper endemic villages of Africa, infection rates commonly approach 100%.In Latin America, distribution is focal and vector transmission is at least 10-fold less intense. Thus, infected individuals in Latin America have low worm burdens and consequently few people develop blindness. Forest-strain O.volvulus, found in rainforest coastal regions of sub-Saharan Africa are genetically different from the savanna strain, (Flockhart , Cibulskis , Karam , et al., 1986) only causes mild ocular diseases but rarely blindness, even in heavily infected persons. (Dadzie , Remme , Rolland , et al., 1989). In contrast, in endemic savanna regions of Africa, a linear relationship between a derived parameter, the community microfilarial load, and the incidence of blindness in that community exists (Remme , Dadzie , Rolland , et al., 1989). On an individual basis, the likelihood of blindness is positively associated with increasing microfilarial burden (Little , Basanez , et al., 2004). Other factors influencing the epidemiology of onchocerciasis are less well defined. Host immunity seems to play a role in limiting total worm loads with increasing age. Also, children of O. volvulus infected mothers have a higher risk of infection and become infected at a younger age and with increased microfilaria intensity, suggesting intrauterine O. volvulus specific immunosuppressant (Kirch , Duerr , Boatin , et al., 2003). In regions outside the savanna, skin manifestations are the main complications of disease. The profound psychosocial implications of unremitting pruritus and disfiguring skin lesions make onchocercal skin disease a major public health problem and more than 50% of Daly’s lost due to onchocerciasis are due not to blindness but to skin disease (Murdoch , Asuzu , Hagan , et al., 2002). On a community basis, there is a strong correlation between prevalence of pruritus and O. volvulus endemicity in the community. In communities hyper endemic for O. volvulus (defined as >60% of people with microfilardermia and >30% with palpable nodules (onchocercomas), 30 –40% have symptomatic skin disease and 50% of children aged 5–9 are already infected. Adult persons may harbor up to 50 adult worms and >100 microfilariae/mg skin. In mesoendemic areas, 30 –60% of people and in hypoendemic areas <30% have microfilardermia.
SOCIOECONOMIC TOLL
In the 1970s, when investigations of onchocerciasis in the endemic villages and districts of West Africa began, Scientist made astonishing and disturbing discoveries. More than 60 percent of the savanna population carried the parasite; 10 percent of the adult population and half of the males over 40 years of age were blind, 30 percent of the people were visually impaired. And early signs of onchocerciasis were common among children (WHO 1973, 1987, 1995a). Scientists revealed the huge socioeconomic consequences of the high infection rates they had found. As village blindness reached epidemic proportion, it left too few able-bodied people to work in fields. Food shortages and economic collapse forced residents to abandon homelands in fertile river valleys. The socioeconomic consequences of onchocerciasis are profound O. volvulus -induced blindness is associated with a life expectancy 10 years shorter than that of no blinded persons in the same area (Kirkwood , Smith , Marshall , etal.,1983). Microfilarial burden is the single most significant parameter associated with mortality. (Little , Breitling , Basanez , et al., 2004) Consequences of onchocerciasis extend beyond the individual and affect family, community, and country .The observation of young boys holding sticks to guide blind, unproductive men in their twenties and thirties attests to why entire villages, within otherwise fully arable river zones, become economically nonviable and have been deserted when blindness rates reach about 10%.
ONCHOCERCIASIS IN NIGERIA
Onchocerciasis is perhaps the most studied filarial infection in Nigeria. It is estimated that 7-10 million Nigerians are infected with onchocerca volvulus, approximately 40 million are at risk of disease (WHO,1996), and 120,000 cases of onchocerciasis related blindness (WHO,1987), with many thousand suffering from disabling complications of the disease (Anosike , onwuliri , 1995). New foci of onchocerciasis are still be discovered and therefore its distribution could be far more expensive than has be assumed (Akogun and Onwuliri , 1991).
In southeastern Nigeria, there are pockets of endemic foci, although there is gross under reporting of the scourge. The most significant area in the sub region is the hilly and undulating Udi Enugu- Okigwe axis from where some rivers or their tributaries, supporting blackfly vector breeding, have their origin. These include rivers such as:
1) Oji river
2) Ajali river
3) Mamu river
4) Adada river
5) Imo river (the biggest of them.)
Unfortunately, studies in the subregion have be largely cross- sectional. There has not been any comprehensive study on all aspects of infection: parasitological, clinical and epidemiological.
The life of the parasite can be traced through the black fly and the human hosts in the following steps.
(a) A simulium female black fly takes a blood meal on infected human hosts. And ingests microfilaria.
(b) The microfilaria enters the gut and thoracic fight muscles of the black fly. Progressing into the first larval stages (JI).
(c) The larvae mature into the second larval stage (J2.). And move to the proboscis and into the saliva in its third larval stage (J3.).Maturation takes about 7 days.
(d) The black fly takes another blood meal. Passing the larvae into the next human host’s blood.
(e) The larvae migrate to the subcutaneous tissue and undergo two more molts. They form nodules as they mature into adult worms over six to twelve months.
(f) After maturing. Adult male worms mate with female worms in the subcutaneous tissue to produce between 700 and 1.500 microfilaria per day.
(g) The microfilaria migrates to the skin during the day and the black flies only feed in the day, so the parasite is in a prime position for the female fly to ingest it. Black flies take blood meals to ingest this microfilaria to restart the cycle.
THE DISEASE
In symptomatic persons, inflammatory responses to microfilaria cause the following:-
I. dermatitis,
2 keratinize
3 chorioretinitis
These are the cardinal manifestations of infection. The subcutaneous nodules containing adult worms evoke no inflammatory response and hence few, if any, clinical symptoms. Of importance to clinicians in non-onchocerciasis endemic areas is that nonspecific dermatitis is usually the sole clinical disease manifestation in short-term visitors to endemic areas.
SUBCUTANEOUS NODULE
Asymptomatic 0.5–3.0 cm subcutaneous onchocercomas usually occurring over bony prominences are freely movable encapsulated nodules that contain coiled masses of adult worms. In Latin America, where the vector .ochraceum bites high, nodules are often located on the head and upper body. In Africa where S. damnosum bites lower, nodules are most often over the hips, over the os sacrum and lower limbs, but also on the thorax and near the knee; in children they are often found on the head. Palpable subcutaneous nodules are uncommonly found in lightly infected expatriates.
DERMATITIS
The especially intractable pruritus of onchocerciasis is secondary to reactions to microfilariae. In heavily affected persons, scratching and excoriation to the point of bleeding occurs. Episodes of localized rash, erythema, and angioedema may be superimposed on ongoing dermatologic manifestations at essentially any stage of the disease
CATEGORIES OF SKIN DISEASE:
Acute papular onchodermatitis: Small pruritic papules may be scattered on limbs, shoulders, and trunk. Lesions may progress to become vesicular or pustular and may be spontaneous or occur as a reaction to microfilaricidal treatment.
Chronic papular onchodermatitis: Papules, often flat-topped, are larger but more variable in size than in the acute papular eruption. Dermatitis is usually symmetrical over buttocks, waist, and shoulder areas and less pruritic than in the acute eruption. Clinical hyperpigmentation and hyperkeratosis correlate histologically with epidermal acanthosis and incontinence of pigment. This is the most common skin manifestation in hyperendemic areas.
Lichenified onchodermatitis: Due to pruritus and scratching, the epidermis becomes hypertrophied, resulting in thickening of the skin and exaggeration of normal skin markings.
Atrophy: Premature atrophy, due to degeneration of the structural elements of the skin with chronic infection, is most common over the buttocks but can occur over limbs. Clinically, fine wrinkles will appear after pushing along the skin surface with one finger. Loss of elasticity can be demonstrated by slow return to position of skin pinched between two fingers. Histologic stains reveal loss of elastic fibers. The diagnosis of onchocercal atrophy should only be made in those under 50 years.
Depigmentation: Areas of depigmentation over the anterior shin with islands of normally pigmented skin around hair follicles, commonly called “leopard skin,” are seen in advanced onchodermatitis.
LYMPHADENOPATHY
Dead microfilariae, eliminated via the lymphatics, can cause lymphadenitis leading to atrophy of the lymphatic tissue with fibrosis. The so-called hanging groin results when large fibrotic inguinofemoral lymph node conglomerates build up in a sling of stretched-out atrophic skin.
EYE
Involvement of all tissues of the eye has been described.Host reactions to microfilariae of O.volvulus as they migrate through the eye initially present as punctate keratitis or as snow lake corneal opacities. Individual opacities clear spontaneously to be followed by others. Free microfilariae may be visible by slit-lamp examination in the anterior chamber or aqueous humor. Long-standing infection in particular with savanna-strain O.volvulus leads to sclerosing keratitis and eventually to blindness. Sclerosing keratitis is characterized by a fibrovascular pannus and an inflammatory infiltrate at the level of Bowman’s membrane. The opacity develops around the edge of the cornea and as it becomes vascularized advances toward the center. Iridocyclitis with flare and cells in the anterior chamber leads to development of synechiae, raised intraocular pressure, and secondary glaucoma. Adult O.volvulus do not migrate through the subconjunctiva, in contrast to the occasional subconjunctival migration of the adult worm of Loa loa confusingly called the eye worm, that is visible to the naked eye of both patient and observer Inflammatory disturbances of the retinal pigment epithelium leading to chorioretinitis, chorioretinal atrophy ,and posterior ocular disease occur in up to 10% of the population of savanna regions. The acute phase can last for a year or more. A postneuritic optic atrophy associated with scarring and retinal pigment disturbance or with vascular sheathing of retinal vessels then ensues. Visual field loss may progress to keyhole vision or even total loss of light perception.
DIAGNOSIS
CLINICAL EXAMINATION
O.volvulus has a well-defined distribution, but because of its geographic overlap with other filarial parasites, a well-taken travel or residence history by an epidemiologically cognizant physician will reduce unnecessary diagnostic investigations in those with no possible exposure. O. volvulus, Loa loa ,Mansonella perstans, M. ozzardi ,and M. streptocerca all may cause overlapping clinical syndromes.In suspected onchocerciasis, the history should focus on duration and intensity of exposure.
A physical examination with the patient completely disrobed is necessary to detect:
(1) Localized dermatitis, preferentially occurring where the onchocercomas and thus the emigrating microfilariae are present (e.g., in the buttock region in adults from Africa), associated with either O. volvulus or M. streptocerca ;
(2) subcutaneous nodules; or
(3) Calabar swellings of loiasis. A thorough palpation of all lymph node groups, including those in the inguinal region, will aid in the diagnosis of Wuchereria bancrofti , O. volvulus , or M. streptocerca . Slit-lamp examination of the eye is required to work up possible ocular onchocerciasis, although the yield is so low in lightly infected expatriates that it is likely unnecessary. The patient should first sit for 10 minutes with the head forward and bowed to allow microfilariae located posteriorly and inferiorly to become visible. Fluorescein angiography is the most sensitive detector of early chorio retinal lesions.
LABORATORY DIAGNOSIS
Definitive diagnosis is often dependent on the parasitologic demonstration of microfilariae from skin snips. In well-equipped clinical settings, biopsy or ultrasound demonstration of adult parasites in nodules may be diagnostic.
Skin Snips
Microfilariae are detected utilizing skin snips taken down to the level of the dermal papillae. This type of limited skin biopsy employs either a razor blade to slice a thin piece of skin which has been tented up with a needle, or a corneoscleral biopsy instrument to obtain 1–2 mg of skin bloodlessly(Taylor , Munoz , Keyvan-Larijani , et al.,1989). A microscopic count of highly motile microfilaria migrating out of two to six biopsies, one from over each scapula, iliac crest, and lateral aspect of each calf, is performed after incubation of the skin snips with saline in micro plate wells at 37 °C .In heavier infections, motile microfilaria will be visible emerging from the skin snip under low-power microscopy in 10 –60 minutes, but initially negative snips should be covered to prevent evaporation and checked periodically for at least 24 hours. Sensitivity can be increased if skin snips are put in a 1% collagenase solution. A heavily infected person may have more than 100 microfilaria/mg of skin.
Blood Examination
Because of geographic overlaps in distributions of filarial parasites that may cause overlapping clinical syndromes, examination for circulating microfilaremia is often necessary.
Urine and Other Fluids
Microfilariae of O.volvulus have been found in the urine of some infected persons during mass epidemiologic studies in hyperendemic regions, with microfilarial counts being correlated with skin counts. Examination of the urine, however, has no utility as a general diagnostic technique and is no substitute for skin snips in the diagnostic workup of a single patient. Cerebrospinal fluid microfilariae can be seen in severe O.volvulus infection.
Demonstration of the Adult Parasite
A coil of hair like white worms discovered in an excised nodule in the appropriate epidemiologic setting is diagnostic of onchocerciasis on visual inspection. Most nodules have only three to five adults in them (less in hypoendemic areas), though nodules containing as many as 50 have been found, which can be liberated from tissue by collagenase digestion
Serology
Serologic testing for O.volvulus IgG is not generally available and when done usually utilizes a crude antigenic preparation of a non-onchocercal filarial parasite.A positive result cannot differentiate between the eight filarial species and may cross-react, albeit at lower titers, with other nematode infections such as strongyloidiasis. Despite the lack of specificity, the sensitivity of this type of serology is almost 100%.Most people resident in endemic areas will have antibodies whether or not they are currently infected. Thus, serologic evaluation in filarial disease is helpful only in two situations: in persons exposed to or infected with filarial parasites who are originally from nonendemic areas and were presumably seronegative initially; and (Remme, 2004) to detect a quantitative decrease in antibody levels that may occur as a response to definitive therapy.
Eosinophil Count
The total eosinophil count is not helpful diagnostically as it is often but inconstantly elevated in onchocerciasis.
IgE Levels
Serum IgE levels are usually elevated in onchocerciasis, with highest levels in sowda patients.
Ultrasound Examination
Adult worms in suspected onchocercomas will produce a central, relatively homogeneous echogenic area containing echo-dense particles with a lateral acoustic shadow. Within the onchocercomas, calcifications or fluid may be identified. Occasionally, worm movements are observed, regularly so in cystic nodules. Particularly in these nodules, sequential ultrasonographic monitoring of nodules after macrofilaricidal therapy can provide information on drug effects.
Mazzotti Test
A 50 mg dose of diethylcarbamazine (DEC), the Mazzotti test, can be given to patients suspected of harboring O.volvulus but in whom no microfilariae can be detected. Since severe reactions in the skin and eye are not totally avoidable, the systemic test has now been replaced by a patch test performed by applying topical DEC (10% in body solutions such as Nivea) to a small area of skin (10 × 10 cm) in order to provoke a localized Mazzotti reaction. This is a highly sensitive and specific diagnostic test (pruritus and pustular onchodermatitis develop after 24–48hrs) and is considered for detecting recrudescence of O.volvulus infection in a sentinel population of children and young adults within the onchocerciasis-free zone created by the control programs. (Toe, Adjami , Boatin , et al., 2000).
DNA Diagnosis of Individual Patients
Detection of parasite DNA in routine skin snips by PCR amplification of O-150, an O.volvulus -specific 150 bp repeated genomic DNA family ,is more sensitive for detecting low-level infection in individual patients than classical skin snipping, and similar in sensitivity to the DEC patch test. (Boatin, Toe, Alley, et al., 2002) PCR assays, available in research settings, are of importance in diagnosing expatriates. Several methods (standard qualitative protocols followed by gel electrophoresis, PCR-ELISA, (Pischke , Buttner , Liebau , et al., 2002) quantitative PCR with probes) are applied to DNA extracted from skin snips or less painful skin scratches that are fresh, frozen, or preserved in ethanol. PCR is the method of choice in the detection of O.volvulus in the Simulium vector in large pooled samples. (Yameogo , Toe , Hougard, et al., 1999).
DIAGNOSTIC DIFFICULTIES
Scabies, insect bites, hypersensitivity reactions, miliaria rubra, and contact dermatitis enter the differential diagnosis of acute pruritic disease. In expatriates, Calabar swellings, clinically similar episodes of localized rash, and mild angioedema can mimic onchodermatitis. Tuberculoid leprosy and eczema should be considered if there are chronic skin changes. Dermatomycoses, previous trauma, and yaws can also cause hypopigmented skin lesions. The differential diagnosis of onchocercomas comprises lipomas, fibromas,lymph nodes, cysticerci, dermoid cysts,foreign body granulomas, exostosis, and ganglia. Onchocercal chorioretinitis must be differentiated from choroiditis due to syphilis,tuberculosis, or toxoplasmosis.Optic neuropathy in endemic areas may be due to nutritional optic atrophy, syphilis, or primary glaucoma. In expatriates with a suggestive history (i.e. being a travel partner of a skin snip positive patient) but with negative skin snips and no nodules, presumptive diagnosis can be made by Mazzotti test and/ or serology.
TREATMENT AND PROGNOSIS
Because the pathologic sequelae of O.volvulus infection are due to microfilariae in skin and ocular tissues, a treatment leading to sustained absence of microfilariae is necessary for morbidity reduction. This can be achieved either by repeated treatment with drugs active against microfilariae for the lifetime of adult worms (up to 14 years), or by killing or removing the adult worms. In principle there are two modes of treatment available for onchocerciasis: nodulectom, and microfilaricidal or macrofilaricidaldrugs.
Ivermectin
Ivermectin (Campbell, 1991) elicits receptor-mediated hyperpolarization of cells after an influx of negatively charged ions occurs utilizing a novel glutamate sensitive chloride channel presentin nematodes. (Cully, Vassilatis, Liu, et al.,1994). Ivermectin is well absorbed oral, excretion is almost entirely in the feces, and its serum half-life is 12 hours. Large field trials in Africa in the 1980s established ivermectin as the treatment of choice in a single oral microfilaricidal dose of 150 µ g/kg administered every 6–12 months. Skin microfilariae are decreased within days though maximum reduction may not occur for up to 2 weeks. Because drug effects are so much longer than its half-life, and because histologically, immune effector cells attack the damaged microfilariae microfilariae for identification.In contrast to M. streptocerca ,O.volvulus microfilariae are longer and thicker (55–9 µ m in contrast to 3–5 µ m width and a maximum length of 260 µ m for M. streptocerca ),have anterior nuclei that are side by side, a caudal space free of nuclei, and a tail tapered to a fine point. M. streptocerca is most often found in snips taken from the upper trunk.
Moxidectin
This drug, currently in phase II efficacy studies, is structurally similar to ivermectin and has shown more sustained diminution of microfilariae in animal models. The hope is therefore that moxidectin may reduce microfilarial loads and thus transmission better than does ivermectin. Since the drug has the same mode of action and binds to the same sites, it is uncertain whether it could act as a replacement for ivermectin were ivermectin resistance to spread.
Doxycycline
Doxycycline 100 mg/day for 6 weeks leads to depletion of the endosymbiotic Wolbachia in O.volvulus, followed by long-term or even permanent cessation of early embryogenesis and thus production of transmissible microfilaria. (Cully, Vassilatis, Liu, et al., 2000) This contrasts with ivermectin, which kills larvae only at the later stage of intrauterine microfilariae production (Hoerauf , Mand , Adjei , et al., 2001) with the result that early embryos survive to develop again into microfilariae. In place be controlled trials, doxycycline at 200 mg/day for 6 weeks killed 60 –7 0% of adult female worms and sterilized the remaining ones.
The same dose for 4 weeks has equivalent sterilizing and about 50% macrofilaricidal activity. If followed up for a longer period of over 2 years, the 100 mg daily dose also has 50% macrofilaricidal effects and shows complete sterilization in the remaining female worms. This makes doxycycline the only safe macrofilaricidal drug against O.volvulus. Due to the length of treatment and restrictions of its use in pregnant and Breast feeding women and children below age 9, doxycycline is currently not suitable for mass chemotherapy but has its advantages in the treatment of individual patients, for example expatriates and others who leave in an endemic region for longer,or patients with severe hyperreactive onchodermatitis whose symptoms would not be controlled with repeated ivermectin therapy .A recommended current regimen comprises 200 mg/day doxycycline for 6 weeks plus 1–2 additional standard doses of ivermectin (1150 µ g/kg) toward the end of the doxycycline cycle and for 3–4 months thereafter
Diethylcarbamazine
DEC has microfilaricidal but not adulticidal activity and was used before the introduction of ivermectin. Due to frequent unacceptable DEC elicited reactions to dying microfilariae, ranging from urticaria and angioedema to hypotension and death, and ocular damage, DEC is no longer used for microfilaricidal treatment of onchocerciasis. Pruritus in lightly infected expatriates may be refractory to annual or 6-month therapy and repeated treatments with standard doses may be needed for the first 2 years or so.
Suramin
Before doxycycline, suramin was the only agent adulticidal to O.volvulus. Suramin is extremely toxic, necessitating hospitalization for several days with each dose; and its original regimen of weekly 1 g doses given for 6 weeks is clearly unsafe. Toxicity includes a fatal progressive wasting syndrome, exfoliative dermatitis, progression of chorioretinitis, and development of optic atrophy .Better-tolerated weekly escalating dose regimens, which deliver 4 or 5 g total, are still not without risk and have the disadvantage that at least 34% of adult worms are viable 1year later. Because of this, and the alternatives available, suramin treatment is rarely if ever used nowadays.
Nodulectomy
Periodic removal of palpable nodules to reduce microfilarial loads and the ensuing pathologies has been successfully pursued in Latin America. In Africa, where many nodules are deeper, and less accessible, and where reinfection is more frequent, this strategy is less effective. Removal of a single nodule in an expatriate with no further exposure anticipated may be considered.
PREVENTION AND CONTROL
Prophylaxis
At present, there are no effective vaccines or approved chemoprophylactic drugs. Since doxycycline was shown, in several animal models, to block the development from infective larvae (L3) to adult worms (Casiraghi, McCall,Simoncinil, et al.,2002 and Arumugan , Pfarr, Hoerauf ,2008 ), doxycycline likely also has an equivalent blocking effect on L3 to adult maturation in onchocerciasis and thus might be prophylactic. As onchocerciasis transmission areas often overlap with those of malaria endemicity, travelers may consider using doxycycline as malaria chemoprophylaxis for the added benefit of protection against onchocerciasis.For expatriates or others with sufficient resources, personal mosquito protection using repellents is likely of benefit. As Simulium spp. are daytime biters, bednet programs for malaria control have no effect on onchocerciasis transmission. Protective immunity is induced after inoculation with live radiation attenuated L3 in animal models (Allen, Adjei ,Bain ,et al.,2008) that are not naturally permissive hosts for O.volvulus, as well as under natural exposure conditions in bovine onchocerciasis with O. ochengi, the species most closely related to O. volvulus(Tchkoute). Similar degrees of protection, however, could not be achieved following immunization with single recombinant antigens (Lustigman, James, Tawe,et al.,2002). It is hoped that in the post-genomics and proteomics era better vaccine candidates may be identified.
Vector Control
The Onchocerciasis Control Program (OOCP) by the WHO extended from 1974 to 2002 over 11 countries of West Africa most affected by blinding savanna-strain O. volvulus. (Thylefors , 2004) A strategy of aggressive vector control using aerial larviciding of 50,000 km of rivers combined with annual ivermectin treatments (added in 1988) essentially interrupted transmission in the area under control. It is estimated that 35 million people were prevented from infection, and about 200,000 people have been prevented from going blind.
PROSPECTS FOR THE FUTURE
Although it was previously considered that O. volvulus infection was on the cusp of being controlled using ivermectin distribution, it is becoming increasingly clear that without additional modalities, such as drugs which kill or permanently sterilize the adult worms or a vaccine, elimination of onchocerciasis from sub-Saharan Africa will remain an unfulfilled goal. A vaccine aimed at preventing infection (anti-L3) or blocking transmission and/or pathology (antimicrofilariae) could be the essential supplement for the successful control or elimination of onchocerciasis. The process would be to link the vaccine with drug treatments in a program of vaccine-linked chemotherapy (Hotez and Ferris, 2006; Hotez, 2007). Although the ultimate goal of a vaccine against onchocerciasis has not yet been achieved, fortunately, through the commitment of the Edna McConnell Clark Foundation and researchers in the field of filariasis, appropriate scientific infrastructure is now in place to meet this challenge. Research on vaccine development has provided the foundation for antigen discovery and development of animal models for testing the efficacy of vaccine candidates, and consequently resulted with at least 15 vaccine candidates that were shown to induce partial but significant protection against an L3 challenge using an experimental mouse model. Moreover, protective immunity against O. volvulus L3 has now been definitively demonstratedin humans, cattle, and mice thereby proving the concespt that a vaccine can be produced against this infection (Abraham et al., 2002; Lustigman et al., 2003).
Future steps for vaccine development would initially use the O. volvulus L3 mouse model to select a subset of highly immunogenic antigens from the 15 recombinant vaccine candidates for further development and assessment. This subset of r Ov Ags would be then moved to product development and scale up applicable for human use. The bovine O. ochengi model has proven the feasibility of immunoprophy-laxis against Onchocerca using irradiated L3 ( Tchakoute et al., 2006) and would therefore be a superb secondary screen to verify the potency of recombinant vaccines developed in the mouse model. The availability of the O. volvulus EST data-base ( Williams et al., 2002 ), the complete sequencing of the Brugia genome ( Ghedin et al., 2004 ) and Caenorhabditis elegans (www.wormbase ), as well as the rapidly expanding technologies in proteomics, functional genomics, and bioinformatics could provide the
needed tools for integrated comparative functional genomics and result in the identification of additional Onchocerca larval proteins that could be used as potential vaccine candidates (Hashmi et al., 2001 ). For example, 47 essential C. elegans molting genes ( þ 90% reduction in molting due to gene-specific RNA interference) belonging to the categories: novel, proteases, protease inhibitors, peroxidases, extracellular matrix,sterol-sensing domain, DNA binding, nucleic acid interacting, signaling, WD domains, and others have been identified (Frand et al., 2005). It appears that 46 of them are also potentially encoded by filarial transcripts (Lustigman, unpublished), and may prove to be excellent vaccine antigens. An alternative approach that could be taken would be to develop a vaccine targeting the microfilaria stage. The microfilaria is responsible for the development of pathology and for transmission of the disease. Therefore, a vaccine against this stage would be a terrific asset for control of the infection. A caveat for this vaccine is the possibility that vaccination against microfilariae would exacerbate disease development caused by microfilariae. A possible way to circumvent this issue would be to immunize people with parasite antigens and not with Wolbachia derived antigens.
It is anticipated that the vaccine against onchocerciasis will be administered to populations that may have been treated for many years with ivermectin. Therefore, longitudinal studies examining the immune responses following long-standing ivermectin treatment need to be performed. Attempts to define the nature of the targets of the post treatment responses should be undertaken by surveying all possible avail-able antigens. With the advent of antibiotic therapy against Wolbachia, studies following the changes in immune responses following this treatment should also be executed. In conclusion, the human studies of onchocerciasis patients have suggested that protective immunity can develop in humans. The experimental and natural infections of animals have demonstrated that protective immunity does develop and that vaccines can protect animals from infection under natural conditions.
The foundation studies on antigen screening have been accomplished and now the challenge is to optimize and formulate vaccines suitable for human usage. The development of drug resistance to the only treatment available for control of onchocerciasis has rejuvenated the impending critical need for a vaccine against onchocerciasis.
CONCLUSION
River blindness which is a serious neglected disease in tropics has caused many disabilities in people living the tropics. Serious measures should be taken into consideration to eradicate the etiology agent of this disease in tropics and to prevent further damages.
