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Parasitic Disease Vaccines
Parasitic diseases caused by helminths and unicellular eukaryotes (protozoa) are major causes of human disease in the resource-poor nations of the tropics. The Institute for Health Metrics and Evaluation’s Global Burden of Disease Study for 2019 estimated that 643,000 people die annually from malaria alone, and approximately 10,000 people die annually from either Chagas disease or schistosomiasis, while 5000 from leishmaniasis. It is also important to look beyond the mortality figures, as measuring only deaths fails to provide a complete picture regarding the health and economic consequences of parasitic diseases. These infections represent the most common afflictions of people who live in poverty. More than 100 million people are infected with hookworms (human hookworm infection) or schistosomes (schistosomiasis), according to the GBD 2019. In Africa, 19 million people live with onchocerciasis, a disfiguring skin disease and the cause of river blindness. In Latin America, 6–7 million people live with Chagas disease, a debilitating, chronic cardiac illness. Measured in disability-adjusted life years, the nonmalaria parasitic infections cause a level of illness that parallels better-known infectious disease conditions such as HIV/AIDS, malaria, or tuberculosis. Today, we refer to these conditions as “neglected tropical diseases,” now considered among the most common illnesses of people who live in extreme poverty. Moreover, additional information finds that the neglected tropical diseases can even trap populations in poverty. Several vaccines for these parasitic diseases are in various stages of development. They are sometimes referred to as “antipoverty vaccines” for their potential to improve both health and economic development. However, the scientific, socioeconomic, and geopolitical challenges to advance these technologies to licensure and distribution are formidable.
With regards to the scientific challenges, among the more critical problems in developing vaccines against these pathogens is maintaining them in the laboratory. With a few exceptions, in vitro culture methods cannot be maintained for these pathogens; frequently, laboratory animals are necessary to maintain the complex life cycles of these parasites (e.g., schistosomes). This problem has prevented the production of the large numbers of parasites necessary to develop live attenuated or killed vaccines as used for many of the viral and bacterial pathogens. Moreover, progress in systems biology and bioinformatics has not yet fully translated to success in developing antiparasitic disease vaccines. For example, genome projects have now been completed for most of the neglected parasitic protozoa of global public health importance, , with proteomic, transcriptomic, and metabolomic research increasingly focused on either human parasites or relevant representative species adapted to laboratory animals. However, most of the parasite genomes are not as amenable to reverse vaccinology approaches as bacterial genomes, because of the extensive data mining and bioinformatics required for large parasite genomes, together with the absence of simplified eukaryotic expression systems that can simultaneously express hundreds of properly folded antigens. In addition, there is a dearth of animal models for parasite vaccine testing. ,
Equally formidable are the economic challenges to vaccine development. Antipoverty vaccines for parasitic diseases lack a sustainable financial model and are generally not a priority for multinational pharmaceutical companies. , There has been little commercial interest in the development of human vaccines for neglected tropical diseases. , Private philanthropies such as the Bill & Melinda Gates Foundation were instrumental in helping to launch nonprofit product development partnerships for parasitic disease antipoverty vaccines, but these organizations face ongoing challenges to maintain sustainable funding. Aside from the malaria vaccines (see Chapter 37), fewer than 10 human vaccines are currently undergoing or are about to enter clinical development. These include five anthelmintic vaccines (one each for hookworm infection and onchocerciasis and three for schistosomiasis) and several antiprotozoan vaccines for Chagas disease and leishmaniasis ( Table 44.1 ). There is also an extensive history of first- and second-generation leishmaniasis vaccines composed of live and killed parasites, respectively. , In addition, several veterinary vaccines are under development, which could be used to interrupt zoonotic transmission of several parasites to humans, including vaccines for bovine schistosomiasis, pig cysticercosis, canine echinococcosis, and canine leishmaniasis.
TABLE 44.1
Human Antiparasitic Disease Vaccines Entering or in Clinical Development
| Disease | Parasite Species Targeted | Vaccine | Major Antigens/Adjuvants | Sponsor/Lead Organization (PDP) |
|---|---|---|---|---|
| Hookworm infection | Necator americanus | Human hookworm vaccine | Na-GST-1 (24-kDa recombinant glutathione-S-transferase) Na-APR-1 (45-kDa recombinant inactivated aspartic protease) on Alhydrogel + GLA (IDRI) or other immunostimulant |
Texas Children’s CVD, Human Hookworm Vaccine Initiative with George Washington University and James Cook University HOOKVAC Consortium |
| Onchocerciasis | Onchocerca volvulus | Human Onchocerciasis Vaccine | Ov-RAL-2 and Ov-103 recombinant protein with Alhydrogel in an aqueous formulation of GLA (IDRI) | TOVA (The Onchocerciasis Vaccine for Africa) Initiative with NY Blood Center, PAI Life Sciences, Texas Children’s CVD |
| Schistosomiasis | Schistosoma mansoni | Sm-p80 | Sm-p80 recombinant protein with GLA (IDRI) in a stable emulsion | PAI Life Sciences and Texas Tech University |
| S. mansoni | Sm-TSP-2 schistosomiasis vaccine | Sm-TSP-2 (9-kDa recombinant tetraspanin) Alhydrogel + GLA (IDRI) |
Texas Children’s CVD with George Washington University and James Cook University | |
| S. mansoni | Sm-14 schistosomiasis vaccine | Sm-14 (14-kDa recombinant fatty acid–binding protein) with GLA (IDRI) in a stable emulsion | Oswaldo Cruz Foundation (Fiocruz) | |
| Leishmaniasis | Leishmania spp. | Leish-111f + MPL, or component recombinant antigens | Leishmania recombinant polyprotein MPL |
IDRI |
| Leishmania spp. | LEISHDNAVAX | T-cell epitope-enriched DNA vaccine | European consortium of partners led by London School of Hygiene and Tropical Medicine | |
| Leishmania spp. | Adenovirus-based leishmaniasis vaccine | HASPB and KMP11 | European consortium of partners | |
| Chagas disease | Trypanosoma cruzi | Recombinant protein-based Chagas disease vaccine | Tc24-C4 in a stable emulsion with GLA (IDRI) | Texas Children’s CVD, a PDP with Mexican Consortium of partners, led by Carlos Slim Foundation |
APR, recombinant aspartic protease (hemoglobinase); GLA, glucopyranosyl lipid adjuvant; GST, glutathione- S -transferase; IDRI, Infectious Disease Research Institute (Seattle, WA); MPL, monophosphoryl lipid; PDP, product development partnership.
ANTHELMINTIC VACCINES
Helminth infections are among the most prevalent infections of humans. , Approximately 446 million, 360 million, and 173 million individuals worldwide harbor the soil-transmitted nematodes Ascaris lumbricoides , Trichuris trichiura , and hookworms ( Necator americanus and Ancylostoma duodenale ), respectively, and an additional 140 million or more people are infected with trematodes, especially the schistosomes (primarily Schistosoma mansoni , Schistosoma japonicum , and Schistosoma haematobium ), although the number of individuals infected with these trematodes is thought to be underestimated for a variety of reasons. Another 19 million people suffer from onchocerciasis. Throughout the world’s low- and middle-income countries (LMICs), soil-transmitted helminth infections and schistosomiasis typically exhibit their highest prevalence and intensity of infection (as measured by worm burden) among children and teenagers. Children who are chronically infected with heavy worm burdens develop deficits in physical, intellectual, and cognitive growth. In addition, hookworm and schistosomiasis are important health problems in reproductive health and pregnancy and contribute to increased maternal morbidity and mortality as well as low birth weight and prematurity.
Among the global efforts to control soil-transmitted helminth (STH) infections and schistosomiasis are concerted efforts to administer either albendazole or mebendazole to target the STH infections, together with praziquantel for targeting schistosomiasis, on a yearly or twice-yearly basis. Because STH infections and schistosomiasis primarily affect school-age children, anthelmintic drugs often are administered as part of school-based health and education efforts. However, although albendazole and praziquantel are often effective at removing current infections, children reacquire new helminth infections several months after treatment. This potentially limits the usefulness of anthelmintic agents as a school-based public health control measure, particularly in light of new evidence for the diminished efficacy of anthelmintic drugs with frequent use or the possible emergence of anthelmintic drug resistance. Moreover, single-dose mebendazole is frequently highly ineffective as a treatment for hookworm infection and trichuriasis. A previous survey of experts concluded that mass drug administration alone will not be sufficient to effect elimination either of STH infection or schistosmiasis.
Through support of the Gates Foundation, a Deworm3 project is underway to examine the feasibility of mass drug administration as a means to eliminate STH infections, while a Global Schistosomiasis Alliance advocates for praziquantel mass treatment for schistosomiasis. Both initiatives are evaluating community-based treatments, optimized based on transmission dynamics, for both adults and children as a means to interrupt parasite transmission. The reality, however, is proof-of-concept for this approach remains elusive. As an alternative or complementary approach to helminth control or elimination, efforts continue to develop anthelmintic vaccines. The goals of anthelmintic vaccination are different from those of conventional antiviral and antibacterial vaccination, as it is unlikely that immunization with defined antigens will elicit sterilizing immunity against these complex metazoan organisms, many of which have several life cycle stages in the human host. Instead, the most important goal is to reduce worm burden below a disease-causing threshold; that is, to immunize against the disease rather than the infection. For example, the goal is to reduce hookworm burden to below the threshold that results in significant intestinal blood loss and can lead to anemia, or to reduce the schistosome worm burden below the threshold that results in significant egg deposition and subsequent granuloma formation in the liver, intestines, or bladder. Still another approach to vaccination against helminth disease would be to directly block the action of parasite-induced pathogenic processes. In the case of hookworm, this would require blocking parasite-derived virulence factors that cause blood loss, and for schistosomiasis, blocking egg deposition. It is likely that anthelmintic vaccination will not be used in isolation, but will probably be used in conjunction with other control efforts, including conventional chemotherapy as described above. This concept is sometimes referred to as “vaccine-linked chemotherapy.”
Hookworm Infection
Human hookworm infection is a leading cause of anemia and malnutrition among children in LMICs, with the greatest number of cases in sub-Saharan Africa, Asia, and tropical regions of the Americas. N. americanus is the predominant hookworm worldwide, with A. duodenale responsible for the remaining cases. Humans become infected when third-stage larvae penetrate the skin and undergo extraintestinal migration in the vasculature and reach the heart and lungs. Migration of the hookworm larvae to the lung is associated with a mild pneumonitis, with the larvae ascending the airways and reaching the larynx before they are coughed and swallowed. The larvae molt twice in the intestine to become adult hookworms, which invade tissue and cause blood loss. Unlike other STH infections, high worm burdens with hookworms occur in both children and adults (including pregnant women), so pediatric deworming has no impact on adult populations or on reducing the transmission dynamics of the infection.
Early attempts at developing a hookworm vaccine relied on the observation that numerous small doses of living third-stage infective larvae (L3) of the dog hookworm Ancylostoma caninum could confer resistance against challenge hookworm infections. Protection was measured by reductions in worm burden, worm size, and worm fecundity (as measured by egg counts in feces). Immunity was never sterilizing, but efficacy, based on achieving reductions, was between 60% and 70%. Later it was noted that larger doses of living L3 could be administered over shorter time periods if they were first damaged by ionizing radiation. This provided the basis for commercial radiation-attenuated hookworm L3 vaccines that could be administered to dogs in two doses, with an efficacy of 90%. The canine hookworm vaccine was marketed in the eastern United States during the 1970s, but ultimately it failed as a commercial veterinary product.
Although it is not feasible to produce human antihookworm vaccines using living L3 (damaged or otherwise) at an industrial scale required for mass immunizations, some studies have attempted to identify, isolate, clone, express, and test vaccine antigens from L3 that can reproduce the reduction in worm burdens afforded by the live vaccines. One promising class of antigens to emerge from these investigations is the Ancylostoma -secreted proteins (ASPs), which are released by host-stimulated L3 and contain amino acid sequences homologous to those of the major antigens from insect venoms. , In preclinical studies, it was shown that ASP-2 is an immunodominant antigen associated with the irradiated L3 vaccine, , , and that it is protective against challenge infections with animal hookworms. The ASP-2 from N. americanus ( Na -ASP-2) was expressed in yeast and selected for subsequent process development and pilot manufacture. Na -ASP-2 was formulated with Alhydrogel and underwent Phase I safety and immunogenicity testing in hookworm-naïve individuals in the United States, where it was shown to be safe and immunogenic. However, a subsequent Phase I safety and immunogenicity study in a hookworm-endemic area of Brazil revealed that this vaccine could induce a generalized urticaria among chronically infected individuals with high levels of prevaccination immunoglobulin (Ig) E to the native form of ASP 2. Given these safety concerns, the larval antigen program was halted in favor of the development of a different class of antigens. ,
An alternative approach to hookworm vaccination currently under development by the Human Hookworm Vaccine Initiative, a consortium led by the Texas Children’s Center for Vaccine Development, a Product Development Partnership (PDP) based in the Texas Medical Center located in Houston, which includes The George Washington University and James Cook University takes advantage of the fact that adult hookworms ingest blood. , , Several proteolytic enzymes required for the parasite’s ability to digest hemoglobin have been shown to line the brush-border membrane of the hookworm’s gastrointestinal tract. Vaccination with a recombinant aspartic protease (in this case, a hemoglobinase), aspartic protease (APR)-1 was shown to reduce worm burden, worm fecundity, and host blood loss after hookworm challenge infection in dogs. By site-directed mutagenesis, an enzymatically inactivated hemoglobinase from N. americanus ( Na -APR-1) was also shown to induce neutralizing antibodies against multiple hookworm species and protect dogs against heterologous hookworm infection. In addition, a unique glutathione- S -transferase from N. americanus ( Na -GST-1) was shown to exhibit a unique heme- and hematin-binding function and is hypothesized to be required for parasite heme detoxification. Because heme detoxification follows hemoglobin breakdown, both Na -APR-1 and Na -GST-1 are attractive vaccine targets and could be combined in a bivalent recombinant protein vaccine. A recombinant Na -GST-1 expressed in yeast was shown to be highly protective in laboratory animals. , , , Phase I studies in the United States, nonhookworm-endemic areas of Brazil, and hookworm ( N. americanus )-endemic areas of Brazil show that Na -GST-1/Alhydrogel combined with a toll-like receptor 4 agonist—glucopyranosyl lipid A (GLA)—is safe and immunogenic. GLA was developed by the Infectious Disease Research Institute, a Seattle-based PDP, which was recently renamed the Access to Advanced Health Institute (AAHI). The program is also linked to a vigorous program of supporting assay development. These studies provided the scientific basis of an adult hookworm-vaccine antigen development program for both antigens to be coadministered. Through a HOOKVAC Consortium, supported by the European Commission, both vaccines progressed through Phase I testing in a hookworm-endemic region of West-Central Africa (Gabon). In a Phase I dose-escalation trial of coadministered Na -GST-1 plus Na -APR-1 on Alhydrogel with GLA, this bivalent human hookworm vaccine was shown to be safe and immunogenic. Ultimately, a bivalent human hookworm vaccine may be linked either to the Expanded Programme on Immunization or to anthelmintic chemotherapy in preschool or school-age children. , A cost-effectiveness study in an area of high parasite transmission in Brazil confirms the potential economic value of a hookworm vaccine.
Schistosomiasis
Schistosomes are snail-transmitted, waterborne parasitic platyhelminths (order Trematoda). High rates of infection occur near bodies of fresh water, such as tributaries of the Nile River in Egypt, Lake Victoria in Africa, and the Dongting and Poyang lakes in China. , Approximately two-thirds of the cases result from S. haematobium , the cause of urogenital schistosomiasis, and one-third from S. mansoni , the cause of intestinal schistosomiasis. Africa’s schistosomiasis accounts for more than 90% of the world’s cases, with most of the remainder caused by S. mansoni in Brazil, and elsewhere in Latin America, or| S. haematobium and S. mansoni in the Middle East, and approximately 1% caused by the S. japonicum complex (including S. japonicum and Schistosoma mekongi ) in East Asia. The human schistosomes are typically distinguished by their snail vectors, location in the host vasculature, and egg morphology. Members of the S. japonicum complex also have important domestic animal reservoir hosts (pigs, cattle, water buffaloes). Asexual reproduction of the parasites occurs in the freshwater snail intermediate hosts that release large numbers of free-swimming, infective larval schistosomes (cercariae) into the water ( Fig. 44.1 ). The cercariae invade human skin, lose their tail, and then (now called schistosomula) spend the next few weeks migrating through the bloodstream and lungs until they reach the liver, where they differentiate into male and female schistosomes. Male and female worm pairs migrate through the portal vasculature until they reach their final destination in the mesenteric ( S. mansoni and S. japonicum complex) or bladder venules ( S. haematobium ). The worm pairs release eggs, which exit from the body in feces or urine and then hatch in fresh water. Most of the morbidity associated with schistosomiasis occurs when the eggs fail to exit from the human host and become trapped in the intestinal or bladder wall or in the liver, where they elicit granulomas and host fibrosis. In the liver, fibrosis from chronic S. mansoni or S. japonicum infection (known in the older pathological literature as Symmers’ pipestem fibrosis) leads to portal hypertension and hepatosplenomegaly. In the bladder, S. haematobium eggs stimulate formation of multiple granuloma, resulting in hematuria and an obstructive uropathy leading to chronic urinary tract infections, hydronephrosis, and kidney failure. Chronic bladder fibrosis from the S. haematobium eggs is also associated with squamous cell carcinoma of the bladder. S. haematobium eggs also cause granuloma formation in the uterus and cervix, and lower genital tract leading to female genital schistosomiasis, which is both a leading gynecologic condition on the African continent and an important risk factor for HIV/AIDS in Africa. In addition, chronic schistosomiasis is associated with a wide variety of other sequelae, especially in children, including anemia, chronic pain, undernutrition, growth failure, and cognitive deficits. The full burden of disability-related outcomes in endemic schistosomiasis is only beginning to be fully appreciated.
A number of different approaches have been taken to design antischistosomal vaccines. As in other systems, the administration of radiation-attenuated helminth larvae, known as schistosome cercariae, results in the best protection to date in mice. According to Wilson and Coulson, the major elements of the protective response to irradiated cercariae include direct contact between host dendritic cells and the parasite surface (tegument) thereby highlighting the role of schistosome surface antigens, and a critical role for antibodies and humoral immunity. In addition, Th1 responses linked to IFNγ and tumor necrosis factor alpha (TNFα) are considered essential. One theory, known as the “happy valley hypothesis,” postulates that protective anthelminthic immunity can be acquired either through strong Th1 or Th2 responses, whereas balanced immunity results in diminished protection.
Vigorous attention has been focused on potential vaccine antigens from several schistosomula stages. Schistosomulae represent the larval schistosomes that migrate through mammalian body tissues after initial cercarial entry. Vaccination with stage-specific schistosomula surface antigens has resulted in protection (reductions in worm burden or egg counts) that is usually less than 40%. Somewhat better protection has been achieved using antigens shared between schistosomula and adult schistosomes, including parasite-derived myosin (63 kDa), paramyosin (97 kDa), triose phosphate isomerase (28 kDa), glutathione- S -transferases (GSTs; 26 and 28 kDa), a fatty acid–binding protein (14 kDa), and a 23-kDa surface protein. These vaccines may have the added benefit of reducing female parasite egg production (fecundity). Because schistosome eggs are responsible for the chronic inflammation and end organ damage to the liver, bladder, or female genital tract, such vaccines can reduce host pathology and immunopathogenesis. Moreover, reducing egg production could potentially interrupt parasite transmission.
During the late 1990s, the World Health Organization’s Special Programme for research and Training in Tropical Diseases (WHO/TDR) initiated murine trials of six vaccine candidates for S. mansoni: (1) A 28-kDa GST, as noted earlier , ; (2) a 97-kDa paramyosin ; (3) an irradiated larvae-associated vaccine antigen, the 62-kDa IrV-5, which is a derivative of a 200-kDa molecule with extensive homology with human myosin; (4) a 28-kDa triose phosphate isomerase ; (5) a 23-kDa integral membrane antigen (Sm-23) that is part of a superfamily of proteins that includes CD9 and TAPA-1, first described in hematopoietic cells ; and (6) a 14-kDa fatty acid–binding protein that was thought to also have protective immune cross-reactivity with the liver fluke, Fasciola hepatica. None of these candidate proteins reached a desired target set by WHO/TDR of generating a 40% or better reduction in challenge-derived worm burdens relative to nonimmunized controls. However, it was recommended that work should continue on these antigens, including progression to clinical or veterinary trials, and ultimately led to the first human schistosomiasis vaccine program.
The first human vaccine was developed by a group at the Institut Pasteur in Lille, France, focusing on urogenital schistosomiasis. They produced a 28-kDa GST from S. haematobium (Sh28GST) in yeast under current good manufacturing practices and has embarked on clinical testing. Sh28GST was selected on the basis of protection studies in primates, and studies in humans, which showed that IgG 3 to Sh28GST correlates with an age-dependent decrease in egg output in S. haematobium infection. Among human volunteers, two subcutaneous injections of 100 µg of recombinant Sh28GST at 28-day intervals on alum did not result in any significant toxicity, and resulted in an immune response characterized by antibodies that neutralized the enzymatic activity of Sh28GST. , Studies then advanced in sub-Saharan Africa to evaluate the clinical efficacy of this vaccine, known as Bilhvax. In a Phase III study conducted in Senegal, 250 children received three subcutaneous injections of the recombinant Sh28GST formulated with Alhydrogel, and were compared to a group that received Alhydrogel alone. Microhematuria with the presence of at least one living S. haematobium egg in the urine was considered a primary endpoint. Although the vaccine was well-tolerated and was immunogenic, there was no protective efficacy observed. It was further noted that IgG4 blocking antibodies were induced rather than IgG3 antibodies, which were considered better linked to protection, so that future studies could examine the role of adjuvants that might induce alternative immune responses.
Since then two recombinant protein vaccines for S. mansoni infection have entered clinical trials, with a third vaccine expected to follow. One of the first is a membrane-spanning S. mansoni surface protein (tetraspanin), known as Sm -TSP-2. Sm -TSP-2 results in a 60–70% worm burden reduction in mice and is selectively recognized by IgG 1 and IgG 3 antibodies in putatively resistant individuals, but not in chronically infected individuals living in endemic areas of Brazil. Furthermore, schistosomes treated with double-stranded RNA encoding Sm -TSP-2 display a vacuolated and disrupted tegument and are unable to fully develop in mice. The extracellular domain of Sm -TSP-2 has been expressed in yeast, and was formulated on Alhydrogel together with an aqueous formulation of GLA. Under the auspices of a consortium based at the Texas Children’s Center for Vaccine Development, this antigen advanced to industrial manufacture. In a Phase I clinical trial conducted in Houston, Texas, the vaccine was well tolerated and immunogenic, with coadministration using alterative immunostimulants and vaccine efficacy currently being tested in Brazil and in Uganda. An additional membrane-spanning tegumental antigen now also in Phase I clinical trials is the Sm -14, a fatty acid–binding protein. This vaccine was developed at the Oswaldo Cruz Foundation (FIOCRUZ) using a stable oil-in-water emulsion of GLA, and was shown to be safe and immunogenic among residents of Rio de Janeiro living in a nonendemic area. Based on these results, advanced clinical testing is proceeding in Senegal. In parallel, the Sm-14 vaccine is being developed as a veterinary vaccine for fascioliasis in collaboration with Ourofino Animal Health in Brazil.
A third S. mansoni candidate is also under development by a consortium based at PAI Life Sciences and Texas Tech University. This is another schistosome tegument protein known as Sm -p80, the large subunit of S. mansoni calpain. Vaccine formulations with this molecule have undergone extensive preclinical testing in baboons and has been shown to cross-protect against S. haematobium . , The vaccine formulated in an oil-in-water emulsion of GLA induces substantial reductions in parasite egg count and egg hatching, and therefore its potential for transmission blocking. Studies in baboons have also highlighted the importance of humoral immunity including evidence for the role of host complement and the effectiveness of passive antibody transfer. An S. japonicum version of the vaccine (Sj-p80) is also being developed as a transmission-blocking vaccine for Asian schistosomiasis. Because Asian schistosomiasis is associated with significant animal reservoirs, including cattle, water buffaloes, and pigs, several veterinary vaccine trials have been conducted in China in these reservoir hosts. Multiple S. japonicum protein candidate vaccines have been evaluated in livestock including paramyosin, a triose phosphate isomerase, and glutathione S-transferases. However, none are in widespread use currently.
Onchocerciasis
A program of vaccine-linked chemotherapy is also underway through a new TOVA (The Onchocerciasis Vaccine for Africa) consortium. , Two major recombinant protein candidates have emerged from these preclinical efforts—Ov-103 and OvRAL-2 with a goal to reduce the number of skin microfilariae and skin and eye immunopathology. In so doing vaccination might reduce the time required to eliminate onchocerciasis by annual and semiannual mass drug administration with ivermectin or moxidectin. Studies conducted using sera and other immunological reagents from mice and humans show that in some cases antibodies interfere with parasite molting or operate through cytophilic mechanisms or antibody-dependent cell-mediated cytotoxicity. Processes are being developed for pilot scale manufacturing in anticipation of clinical testing, possibly as alum-adjuvanted recombinant protein vaccines.
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