- Email: [email protected]
Sm-p80-Based Schistosomiasis Vaccine: Preparation for Human Clinical Trials
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Opinion
Sm-p80-Based Schistosomiasis Vaccine: Preparation for Human Clinical Trials Afzal A. Siddiqui1,* and Sabrina Z. Siddiqui1 Mass antiparasitic drug administration programs and other control strategies have made important contributions in reducing the global prevalence of helminths. Schistosomiasis, however, continues to spread to new geographic areas. The advent of a viable vaccine and its deployment, coupled with existing control efforts, is expected to make[1_TD$IF] significant headway towards[1_TD$IF] sustained schistosomiasis control. In 2016, Science ranked the schistosomiasis vaccine as one of the top 10 vaccines that [9_TD$IF]needs to be urgently developed. A vaccine that is effective against geographically distinct forms of intestinal/hepatic and urinary disease is essential to make a meaningful impact in global reduction of the disease burden. In this [10_TD$IF]opinion article, we focus on salient features of schistosomiasis vaccines in different phases of the clinical development pipeline and highlight the Sm-p80-based vaccine which is now being prepared for human clinical trials. The Heavy Burden of Schistosomiasis Schistosomiasis has remained a persistent human disease since at least 1500 BC [1]. Intestinal/ hepatic schistosomiasis is caused by Schistosoma mansoni which is widespread in Africa, the Eastern Mediterranean, the Caribbean, and South America. Another form of intestinal/hepatic schistosomiasis, mostly reported in central African countries, is caused by Schistosoma intercalatum. A third form of intestinal/hepatic schistosomiasis, known as Oriental or Asiatic, is caused by the Schistosoma japonicum group of zoonotic parasites (including Schistosoma mekongi in the Mekong river basin). S. japonicum is endemic to South-East Asia and the Western Pacific region. Finally, Schistosoma haematobium is responsible for urinary schistosomiasis and is endemic to Africa and the Eastern Mediterranean. Current conservative estimates are that 200 million people are infected with one of the three major schistosome species, and an additional 779 million people are at risk of acquiring this infection [2–4]. However, these estimates are based on insensitive egg-detection techniques and it is now widely believed that for every egg-positive individual with schistosomes, there is an egg-negative infected individual. Using this assumption, the revised estimates are that between 400 million and 600 million people could be infected with schistosomes [4,5]. In addition, this disease carries an estimated yearly mortality rate of 280 000 in 74 countries – 90% of these countries are in Africa [6]. A credible argument has also been made that the figures related to schistosomiasis morbidity and mortality need to be reassessed to include the effects of morbid sequelae such as anemia, growth retardation, and impaired cognitive development as well as rebound morbidity [7–9]. The current estimates of yearly disability adjusted life years (DALYs) for schistosomiasis is 3.3 million [5,10]. However, some of the revised and recent calculations based on health-related quality of life
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Trends There is a widespread agreement among ‘schistosomalogists’ that a sustainable decline in infection transmission and disease morbidity can only be obtained through continual improvement in sanitation and water infrastructures in endemic areas with the addition of vaccination coupled with chemotherapy. A vaccine is expected to help in decreasing the morbidity through induced immune responses leading to reduced worm burdens and decreased egg production that will ultimately result in lower transmission rates. The schistosomiasis vaccine field is now focusing on an immunomics-based approach to antigen discovery, on adjuvant selection to customize vaccinemediated responses, in utilizing efficient protein expression, manufacturing and scale-up platforms, and in employing human surrogates of efficacy. A systems biology approach is now being increasingly applied in the field to identify vaccine-mediated gene signatures and epistatic interactions; protein–protein interactions may also be helpful in predicting vaccine efficacy.
1 Department of Internal Medicine, Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
*Correspondence: [email protected] (A.A. Siddiqui).
http://dx.doi.org/10.1016/j.pt.2016.10.010 © 2016 Elsevier Ltd. All rights reserved.
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(HrQoL) may point to a much higher disease burden of schistosomiasis than has previously been recognized [7]. In addition, pulmonary hypertension associated with schistosomiasis is a substantial global health issue [11]. Over the last several decades, chemotherapy using praziquantel has been a widely used strategy for the control and treatment of schistosomiasis [12]. However, control programs focused solely on chemotherapy [mass drug administration (MDA)] have been challenging because of the rapidity and frequency of reinfection and expense involved in sustaining these programs over a long term [12]. Since praziquantel, a drug developed about 40 years ago, is now the only medicine available to treat schistosomiasis, the possibility that the parasites may develop widespread drug resistance must also be considered [13–16]. Integrated control programs aimed at limiting schistosomiasis by improving education and sanitation, molluscicide treatment programs to reduce the population of the intermediate snail host, and chemotherapy have also had only limited success [12,17,18]. The World Health Organization (WHO), based on the most recent epidemiological data available, reports that 61.6 million people in 52 countries were treated with praziquantel in 2014; this represents 20.7% global coverage of the population that requires preventive drug-therapy [19]. Despite this massive and commendable effort, schistosomiasis is becoming an emerging infection and[1_TD$IF] is gaining footholds in new geographical areas, for example, Corsica [20] (Figure 1). Available data indicate that MDA programs have undoubtedly helped in reducing the global prevalence of some helminth infections, but a major disconcerting fact is that since 1990 there has been no appreciable decrease in the global prevalence of schistosomiasis [10]. To make a meaningful impact in the reduction of disease burden it is evident now that we need to explore
Key: Schistosomiasis-endemic areas Hepac-intesnal
Low risk for urinary
Both hepac-intesnal and urinary
Low risk for hepac-intesnal
Not endemic
Low risk for both hepac-intesnal and urinary
Figure 1. Worldwide Distribution of Schistosomiasis. Reproduced from http://wwwnc.cdc.gov/travel/yellowbook/ 2016/infectious-diseases-related-to-travel/schistosomiasis.
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additional ways of intervention, including more emphasis on developing a vaccine that could supplement the ongoing control effort.
Current Status of Schistosomiasis Vaccines Expert Recommendations and Animal Models Induction of sterile immunity is perhaps unachievable based on the current scientific knowledge and technology at hand, but it is not a prerequisite for a schistosome vaccine to be effective. This somewhat antidogmatic assertion is based on the fact that schistosomes do not replicate within their definitive hosts (e.g., humans, Figure 2), hence, even a partial reduction in worm burden against cercarial infections would be a significant advance. This is because a vaccine that reduces the number of parasites will ultimately reduce egg-induced pathology and transmission rates of the infection [10,21–27]. Over the last 20 years, several different groups of schistosome experts have made recommendations to this effect. For example, in 1999, a Scientific Working Group on Schistosomiasis at the WHO advocated that vaccines that lower adult worm burdens by 50% will be effective in reducing overall morbidity and mortality [21,28,29]. Similarly, a United Nations Development Program/World Bank/WHO's Special Program for Research and Training in Tropical Diseases expert panel (Manila, Philippines, October 2003) again recommended the use of reduction in morbidity as the most relevant endpoint in assessing schistosome vaccines, and that vaccine effectiveness be determined based on the potential for anti-infection, antidisease, and anti-fecundity [30,31]. Additionally, in a gathering of over 70 experts at the Bill and Melinda Gates Foundation (‘Schistosomiasis Elimination Strategy and Potential Role of Vaccine in Achieving Global Health Goals’, March 12–13, 2013, Seattle, WA), a consensus view point had emerged and that was, for a schistosome vaccine to succeed, an ideal vaccine should reduce the adult worm burden by at least 75% in animal models, preferably in baboons, and most importantly the vaccine should be able to significantly reduce egg-induced pathology [32]. Similarly, at another meeting of experts organized by the National Institute of Allergy and Infectious Diseases to develop Preferred Product Characteristics (PPC) for a schistosomiasis vaccine (‘Schistosomiasis Vaccine Clinical Development and Product Characteristics’ in Bethesda, MD; November 13, 2013) [33], it was agreed upon that a prophylactic vaccine to prevent schistosome infection from one of the three major species should reduce the overall worm burden by at least 75%. PPC also emphasizes that the egg excretion should be reduced by close to 75% for a vaccine to be effective (Table 1). During the last two to three decades, many laboratories have attempted to identify schistosome antigens that induce at least a partially protective immune response. Hundreds of antigens have been identified, some of which confer protection of varying degrees and are considered promising, though they do not quite reach the level of immunity elicited following vaccination with irradiated cercariae [34,35]. With the exception of a few antigens, the prophylactic efficacy of these antigens has been evaluated only in the murine model which inherently has an apparent ceiling of 40–50% protection [34]. Recently, it has been argued[2_TD$IF] that the low [12_TD$IF]levels of maturation of penetrating cercariae (32% for Schistosoma mansoni) is a major limitation of the model since 68/100 parasites fail to mature in naïve mice due to natural causes [34]. We believe that[3_TD$IF] baboons, are the most relevant model of human clinical manifestations of both acute and chronic disease. Infection in baboons yields a high rate of cercarial penetration, fast schistosomula migration from the skin to the lungs, and development to adult worms; maturation of infecting larvae exceeds 90% (S. mansoni). Other advantages of this model include similarity to humans in terms of immune response, that is, baboons produce four human-like IgG subclasses [30,34]. Due to these arguments regarding the appropriateness of schistosome vaccine efficacy models outlined above, it is our opinion that, when designing immunization regimens for clinical trials, data obtained through studies in the murine model should be used with caution. A prudent approach in this regard would be that all credible schistosome vaccine candidates should also be tested in a nonhuman primate model, to determine optimal vaccine composition/formulation
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Sm-p80 vaccine efficacy at different levels of infecon, disease, and transmission Therapeuc efficacy (adult worm killing)
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Prophylacc efficacy (worm reducon)
An-pathology efficacy (reducon in ssue egg load)
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Cercaria Eggs
Miracidia Penetrate snail ssue
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the wat er
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Reducon in disease transmission (lessened egg expulsion/reduced snail exposure)
An-egg hatching effect (reducon in egg viability)
Figure 2. Sm-p80 Vaccine Efficacy at Different Levels of Infection, Disease, and Transmission. The Sm-p80 vaccine can lead to a reduction in transmission by decreasing expulsion of eggs into the environment (1). The vaccine also has detrimental effects on eggs and inhibits the hatching of eggs into miracidia (2). The Sm-p80 vaccine has robust prophylactic efficacy due to its effectiveness against schistosomular development into adult worms (5). This vaccine is the only vaccine which has been shown to eliminate already established adult worms, thus exhibiting a therapeutic efficacy (6). The vaccine's effectiveness is also pronounced in reducing the egg retention in tissues (antipathology efficacy) (7).
for use in humans to achieve[13_TD$IF] the highest possible vaccine efficacy clinically. Baboon can serve as an immensely useful bridge between mouse and human studies. Schistosomiasis Vaccines in Human Clinical Trials To date only three schistosome vaccine candidates are in phase I to phase III trials [10,27,36]. These include S. haematobium 28-kD glutathione S-transferase (rSh28GST), S. mansoni
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Table 1. Essential Requirements for Optimal Morbidity-Reducing Schistosomiasis Vaccine Indication
Prevention of infection by the three major human schistosomes thus preventing intestinal/hepatic, Asiatic/oriental and urinary schistosomiasis
Target populations
Population in endemic countries » High-risk school age children (3–12 years of age) » Adults (18–59 years of age) in high-risk occupations or areas
Efficacy
» Reduce at least 75% infection » Efficacy readout – egg output and/or worm burden
Duration of protection
2–3 years after last dosing
Dosage and cost
» Parenteral administration, 2 doses administration » Less than $1 per dose
Product criteria
» The vaccine antigen should not react to IgE from target population » Can be coadministered with local MDA or other disease-control strategies
Manufacturing
Suitability for human trials: purity > 90% (Yield 50 mg/L) Endotoxin levels < 50 EU/mg Non-pyrogenic
14-kDa fatty acid-binding protein (Sm14), and S. mansoni tetraspanin, a 9-kDa surface antigen (Sm-TSP-2) [10,27,36]. Phase I and II clinical data have shown that rSh28GST in alum did not induce any significant toxicity in healthy adults and generated a type 2 (Th2) immune response, and further clinical trials are continuing in humans as a potential vaccine candidate against urinary schistosomiasis [37]. A phase III trial to assess if the combination of rSh28GST and praziquantel would help lower pathologic episodes of S. haematobium infection in infected children was carried out from 2009 to 2012 – the findings of which have not yet been published [10]. Similarly, phase I clinical trial data on tolerability and specific immune responses after vaccination of adult, male volunteers in a nonendemic area for schistosomiasis with rSm14/GLASE has also shown that the vaccine formulation is safe and immunogenic against schistosomiasis (S. mansoni) [38]. A phase I trial for Sm-TSP-2 (S. mansoni) has been initiated in 2014 and is ongoing [10]. The progress thus far on schistosome vaccine human trials has been slow but steady. One important caveat though is that all of these three vaccines target only a single schistosome species [10,27,36].
Essential Features of an Ideal Schistosomiasis Vaccine It is important to note that reduction in morbidity, rather than sterile immunity, is the immediate target for a schistosome vaccine. The PPC developed for a schistosomiasis vaccine in 2013 is an important starting point for developing a prophylactic vaccine [33]. However, we believe that a ‘dream vaccine’ that is expected to reduce the burden of disease in a meaningful fashion should have additional characteristics. It should reduce the overall worm burden by 75% or higher, and the egg retention/excretion should be reduced by close to 100% for a vaccine to be effective in terms of reduction of egg-induced pathology and transmission of infection. Ideally, the vaccine should target, and be effective against, the three major species of schistosomes that cause intestinal/hepatic schistosomiasis (S. mansoni, S. japonicum) and urinary schistosomiasis (S. haematobium), or at minimum be effective against S. mansoni and S. haematobium because in major geographical areas of Africa areas these two species coexist. If a vaccine can be developed that preferentially kills female worms, that should result in reduced egg burdens, ultimately leading to a reduction in egg-induced pathology. [14_TD$IF]This would be considered a major breakthrough: such a vaccine, in addition to inducing adaptive immunity, will also help in preserving natural immunity against schistosomes by maintaining some of the nonpathogenic male worms. This is because, in the absence of a mate, the growth of male worms is stunted and their life-span is significantly shortened, compared to the normal life-span
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of paired worms, which can be anywhere from 5 to 30 years [39–41]. A practical deployment approach could involve first treating schistosome-infected individuals with praziquantel to kill adult worms and then vaccinating them[4_TD$IF]. Since the standard praziquantel regimen would have minimal effect on eggs, reducing existing egg-induced pathology has to be dealt with by other therapeutic means. Subsequent schistosome infection will result in vaccine-mediated preferential killing of female worms. Some males that may escape immune killing will establish themselves as nonpathogenic adults, thus providing concomitant natural immunity.
Sm-p80-[15_TD$IF]Based Vaccine: Effective for Intestinal/Hepatic and Urinary Schistosomiasis Over the last two decades, our group has followed a systematic and methodical approach to develop Sm-p80 as a viable and effective schistosomiasis vaccine. Sm-p80 is the large subunit of the S. mansoni calcium-activated neutral protease calpain. Sm-p80 plays a pivotal role in the surface membrane biogenesis and renewal, which is a mechanism employed by hemo-helminths to evade the host's hostile immune response [42]. Sm-p80 is present in the surface membranes and syncytium of the worm; is the highly immunodominant antigen in the membranes; and exhibits no immunological cross-reactivity with human and other vertebrate calpains [42]. Briefly, Sm-p80 has been tested for its vaccine efficacy in different vaccine formulations and approaches, including naked DNA, recombinant protein and prime/boost in three experimental animal models of infection and disease (mouse, hamster, and baboon) [43–49]. Sm-p80-based vaccine formulation(s) have many effects: (i) prophylactic efficacy against intestinal/hepatic schistosomiasis; (ii) egg-induced pathology resolution both in rodents and baboons; (iii) post-exposure therapeutic effect via killing of established adult worms in chronic infections; (iv) cross-protection against urinary and Asiatic/oriental schistosomiasis; (v) longevity of immune response – robust antibody titers in mice for up to 60 weeks and 5–8 years in baboons; (vi) transplacental transfer of Sm-p80-specific antibodies in baboons. As depicted in Figure 2, the Sm-p80-based vaccine has multifaceted effectiveness against several stages of the parasite's life cycle, including eggs, schistosomula, and adult worms [43–49]. Additionally, Sm-p80specific IgE has not been detected in high-risk or infected populations from Africa [45] and South America [50], thus minimizing the risk of a hypersensitivity reaction following vaccination with Sm-p80-based vaccine in humans. Sm-p80 vaccine will soon move into phase I human trials (Figure 3).
Development roadmap for Sm-p80 vaccine Discovery phase
Nonclinical process development phase
Time period: 10 years Funding need: $10 million
Time period: 5 years Funding need: $5 million
Vaccine efficacy studies in animal models of infecon and disease
Formulaon, opmizaon, characterizaon, mechanisms of acon, immunogenicity
Scale up manufacturing
GMP manufacturing GLP Safety toxicology with lot release data in animal model(s) at Range-finding showing: identy, effecve human toxicology sterility, lack of doses, route of study advenous agents, administraon and purity, potency, general dosing regimen safety, stability
Human clinical trials (Safety, efficacy) Time period: 5 years Funding need: $15 million Correlates of protecon Vaccine immune signature verificaon
Phase I, II, and III, and addional FDA required studies
Figure 3. Development Roadmap for a Schistosomiasis Vaccine. Development of a vaccine entails many different aspects, including identification of appropriate vaccine target; evaluation of the vaccine candidate in efficacy and disease animal models; and vaccine process development for clinical development. This long and arduous process can take decades, and an appreciable amount of funding is needed to develop a vaccine from bench to bedside. Abbreviations: GLP, good laboratory practices; GMP, good manufacturing practices.
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Concluding Remarks and Future Perspectives
Outstanding Questions
Vaccine development is a long process that can take decades (Figure 3). Since funding for vaccine development for neglected tropical parasitic diseases is very limited, a cautious and wellthought-out approach is warranted when moving promising schistosomiasis vaccines forward into human clinical trials. When designing immunization regimens for clinical trials, data solely obtained through studies in the murine model should be used with caution (see Outstanding Questions). The schistosomiasis vaccine field has already suffered a major slowdown in the past when the six ‘priority antigens’ were tested against experimental challenge infection in a potentially flawed murine model [34] resulting in serious dwindling of funding for schistosome vaccine research. A rushed clinical trial, if not successful, carries the potential of negatively affecting the future development of other vaccine candidates. Emphasis should be placed to encourage collaborative partnerships among different laboratories working on schistosome vaccine worldwide, to develop a pipeline of schistosomiasis vaccines through nonprofit Product Development Partnerships with the eventual aim of bringing the cost of the vaccine to less than $1 per dose. We believe that, with sustained efforts, an effective schistosomiasis vaccine will emerge in the next decade. We champion an approach to the control of schistosomiasis – mass drug/vaccine administration or MDVA, a vaccine implementation scheme that would entail treating infected individuals with praziquantel and then vaccinating them with a schistosome vaccine. This integrated approach has the potential for making a meaningful impact in reducing the burden of schistosomiasis. An effective schistosomiasis vaccine could potentially impact up to 1 billion people!
What are the factors influencing the spread of schistosomiasis?
Acknowledgments
How can the efficacy of schistosomiasis vaccine best be evaluated in human populations?
There is no conflict of interest with funding agencies that have supported the research of the authors[16_TD$IF]. We thank Stuart Blalock (The Stuart Blalock Visual Company) for help with graphics. This [17_TD$IF]research was supported by grants from the Bill and
How can we modify existing control measures to make them more efficient in controlling the disease? Can modeling studies predict the impact of vaccine in the field, if combined with other control strategies? How long before there is widespread resistance to praziquantel? Why is widespread resistance to praziquantel not an issue yet? How can existing mouse models for schistosome vaccine research best be used? How sustainable is schistosomiasis vaccine research in baboons? How can immunization regimens best be designed for a schistosomiasis vaccine human trial?
Melinda Gates Foundation[5_TD$IF] (OPP1097535) and from the NIAID/NIH SBIR (R43/R44 AI103983).
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41. Vermund, S.H. et al. (1983) Survival of Schistosoma mansoni in the human host: estimates from a community-based prospective study in Puerto Rico. Am. J. Trop. Med. Hyg. 32, 1040–1048 42. Siddiqui, A.A. et al. (1993) Characterization of Ca2+-dependent neutral protease (calpain) from human blood flukes, Schistosoma mansoni. Biochim. Biophys. Acta 1181, 37–44 43. Ahmad, G. et al. (2009) Prime-boost and recombinant protein vaccination strategies using Sm-p80 protects against Schistosoma mansoni infection in the mouse model to levels previously attainable only by the irradiated cercarial vaccine. Parasitol. Res. 105, 1767–1777 44. Ahmad, G. et al. (2009) Protective and antifecundity effects of Sm-p80-based DNA vaccine formulation against Schistosoma mansoni in a nonhuman primate model. Vaccine 27, 2830–2837 45. Ahmad, G. et al. (2011) Preclinical prophylactic efficacy testing of Sm-p80-based vaccine in a nonhuman primate model of Schistosoma mansoni infection and immunoglobulin G and E responses to Sm-p80 in human serum samples from an area where schistosomiasis is endemic. J. Infect. Dis. 204, 1437–1449 46. Karmakar, S. et al. (2014) Cross-species protection: Schistosoma mansoni Sm-p80 vaccine confers protection against Schistosoma haematobium in hamsters and baboons. Vaccine 2014 32, 1296–1303 47. Karmakar, S. et al. (2014) Use of an Sm-p80-based therapeutic vaccine to kill established adult schistosome parasites in chronically infected baboons. J. Infect. Dis. 209, 1929–1940 48. Zhang, W. et al. (2010) Sm-p80-based DNA vaccine provides baboons with levels of protection against Schistosoma mansoni infection comparable to those achieved by the irradiated cercarial vaccine. J. Infect. Dis. 201, 1105–1112 49. Zhang, W. et al. (2014) Longevity of Sm-p80-specific antibody responses following vaccination with Sm-p80 vaccine in mice and baboons and transplacental transfer of Sm-p80-specific antibodies in a baboon. Parasitol. Res. 113, 2239–2250 50. Gaze, S. et al. (2014) An immunomics approach to schistosome antigen discovery: antibody signatures of naturally resistant and chronically infected individuals from endemic areas. PLoS Pathog. 10, e1004033
Opinion
Sm-p80-Based Schistosomiasis Vaccine: Preparation for Human Clinical Trials Afzal A. Siddiqui1,* and Sabrina Z. Siddiqui1 Mass antiparasitic drug administration programs and other control strategies have made important contributions in reducing the global prevalence of helminths. Schistosomiasis, however, continues to spread to new geographic areas. The advent of a viable vaccine and its deployment, coupled with existing control efforts, is expected to make[1_TD$IF] significant headway towards[1_TD$IF] sustained schistosomiasis control. In 2016, Science ranked the schistosomiasis vaccine as one of the top 10 vaccines that [9_TD$IF]needs to be urgently developed. A vaccine that is effective against geographically distinct forms of intestinal/hepatic and urinary disease is essential to make a meaningful impact in global reduction of the disease burden. In this [10_TD$IF]opinion article, we focus on salient features of schistosomiasis vaccines in different phases of the clinical development pipeline and highlight the Sm-p80-based vaccine which is now being prepared for human clinical trials. The Heavy Burden of Schistosomiasis Schistosomiasis has remained a persistent human disease since at least 1500 BC [1]. Intestinal/ hepatic schistosomiasis is caused by Schistosoma mansoni which is widespread in Africa, the Eastern Mediterranean, the Caribbean, and South America. Another form of intestinal/hepatic schistosomiasis, mostly reported in central African countries, is caused by Schistosoma intercalatum. A third form of intestinal/hepatic schistosomiasis, known as Oriental or Asiatic, is caused by the Schistosoma japonicum group of zoonotic parasites (including Schistosoma mekongi in the Mekong river basin). S. japonicum is endemic to South-East Asia and the Western Pacific region. Finally, Schistosoma haematobium is responsible for urinary schistosomiasis and is endemic to Africa and the Eastern Mediterranean. Current conservative estimates are that 200 million people are infected with one of the three major schistosome species, and an additional 779 million people are at risk of acquiring this infection [2–4]. However, these estimates are based on insensitive egg-detection techniques and it is now widely believed that for every egg-positive individual with schistosomes, there is an egg-negative infected individual. Using this assumption, the revised estimates are that between 400 million and 600 million people could be infected with schistosomes [4,5]. In addition, this disease carries an estimated yearly mortality rate of 280 000 in 74 countries – 90% of these countries are in Africa [6]. A credible argument has also been made that the figures related to schistosomiasis morbidity and mortality need to be reassessed to include the effects of morbid sequelae such as anemia, growth retardation, and impaired cognitive development as well as rebound morbidity [7–9]. The current estimates of yearly disability adjusted life years (DALYs) for schistosomiasis is 3.3 million [5,10]. However, some of the revised and recent calculations based on health-related quality of life
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Trends There is a widespread agreement among ‘schistosomalogists’ that a sustainable decline in infection transmission and disease morbidity can only be obtained through continual improvement in sanitation and water infrastructures in endemic areas with the addition of vaccination coupled with chemotherapy. A vaccine is expected to help in decreasing the morbidity through induced immune responses leading to reduced worm burdens and decreased egg production that will ultimately result in lower transmission rates. The schistosomiasis vaccine field is now focusing on an immunomics-based approach to antigen discovery, on adjuvant selection to customize vaccinemediated responses, in utilizing efficient protein expression, manufacturing and scale-up platforms, and in employing human surrogates of efficacy. A systems biology approach is now being increasingly applied in the field to identify vaccine-mediated gene signatures and epistatic interactions; protein–protein interactions may also be helpful in predicting vaccine efficacy.
1 Department of Internal Medicine, Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
*Correspondence: [email protected] (A.A. Siddiqui).
http://dx.doi.org/10.1016/j.pt.2016.10.010 © 2016 Elsevier Ltd. All rights reserved.
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(HrQoL) may point to a much higher disease burden of schistosomiasis than has previously been recognized [7]. In addition, pulmonary hypertension associated with schistosomiasis is a substantial global health issue [11]. Over the last several decades, chemotherapy using praziquantel has been a widely used strategy for the control and treatment of schistosomiasis [12]. However, control programs focused solely on chemotherapy [mass drug administration (MDA)] have been challenging because of the rapidity and frequency of reinfection and expense involved in sustaining these programs over a long term [12]. Since praziquantel, a drug developed about 40 years ago, is now the only medicine available to treat schistosomiasis, the possibility that the parasites may develop widespread drug resistance must also be considered [13–16]. Integrated control programs aimed at limiting schistosomiasis by improving education and sanitation, molluscicide treatment programs to reduce the population of the intermediate snail host, and chemotherapy have also had only limited success [12,17,18]. The World Health Organization (WHO), based on the most recent epidemiological data available, reports that 61.6 million people in 52 countries were treated with praziquantel in 2014; this represents 20.7% global coverage of the population that requires preventive drug-therapy [19]. Despite this massive and commendable effort, schistosomiasis is becoming an emerging infection and[1_TD$IF] is gaining footholds in new geographical areas, for example, Corsica [20] (Figure 1). Available data indicate that MDA programs have undoubtedly helped in reducing the global prevalence of some helminth infections, but a major disconcerting fact is that since 1990 there has been no appreciable decrease in the global prevalence of schistosomiasis [10]. To make a meaningful impact in the reduction of disease burden it is evident now that we need to explore
Key: Schistosomiasis-endemic areas Hepac-intesnal
Low risk for urinary
Both hepac-intesnal and urinary
Low risk for hepac-intesnal
Not endemic
Low risk for both hepac-intesnal and urinary
Figure 1. Worldwide Distribution of Schistosomiasis. Reproduced from http://wwwnc.cdc.gov/travel/yellowbook/ 2016/infectious-diseases-related-to-travel/schistosomiasis.
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additional ways of intervention, including more emphasis on developing a vaccine that could supplement the ongoing control effort.
Current Status of Schistosomiasis Vaccines Expert Recommendations and Animal Models Induction of sterile immunity is perhaps unachievable based on the current scientific knowledge and technology at hand, but it is not a prerequisite for a schistosome vaccine to be effective. This somewhat antidogmatic assertion is based on the fact that schistosomes do not replicate within their definitive hosts (e.g., humans, Figure 2), hence, even a partial reduction in worm burden against cercarial infections would be a significant advance. This is because a vaccine that reduces the number of parasites will ultimately reduce egg-induced pathology and transmission rates of the infection [10,21–27]. Over the last 20 years, several different groups of schistosome experts have made recommendations to this effect. For example, in 1999, a Scientific Working Group on Schistosomiasis at the WHO advocated that vaccines that lower adult worm burdens by 50% will be effective in reducing overall morbidity and mortality [21,28,29]. Similarly, a United Nations Development Program/World Bank/WHO's Special Program for Research and Training in Tropical Diseases expert panel (Manila, Philippines, October 2003) again recommended the use of reduction in morbidity as the most relevant endpoint in assessing schistosome vaccines, and that vaccine effectiveness be determined based on the potential for anti-infection, antidisease, and anti-fecundity [30,31]. Additionally, in a gathering of over 70 experts at the Bill and Melinda Gates Foundation (‘Schistosomiasis Elimination Strategy and Potential Role of Vaccine in Achieving Global Health Goals’, March 12–13, 2013, Seattle, WA), a consensus view point had emerged and that was, for a schistosome vaccine to succeed, an ideal vaccine should reduce the adult worm burden by at least 75% in animal models, preferably in baboons, and most importantly the vaccine should be able to significantly reduce egg-induced pathology [32]. Similarly, at another meeting of experts organized by the National Institute of Allergy and Infectious Diseases to develop Preferred Product Characteristics (PPC) for a schistosomiasis vaccine (‘Schistosomiasis Vaccine Clinical Development and Product Characteristics’ in Bethesda, MD; November 13, 2013) [33], it was agreed upon that a prophylactic vaccine to prevent schistosome infection from one of the three major species should reduce the overall worm burden by at least 75%. PPC also emphasizes that the egg excretion should be reduced by close to 75% for a vaccine to be effective (Table 1). During the last two to three decades, many laboratories have attempted to identify schistosome antigens that induce at least a partially protective immune response. Hundreds of antigens have been identified, some of which confer protection of varying degrees and are considered promising, though they do not quite reach the level of immunity elicited following vaccination with irradiated cercariae [34,35]. With the exception of a few antigens, the prophylactic efficacy of these antigens has been evaluated only in the murine model which inherently has an apparent ceiling of 40–50% protection [34]. Recently, it has been argued[2_TD$IF] that the low [12_TD$IF]levels of maturation of penetrating cercariae (32% for Schistosoma mansoni) is a major limitation of the model since 68/100 parasites fail to mature in naïve mice due to natural causes [34]. We believe that[3_TD$IF] baboons, are the most relevant model of human clinical manifestations of both acute and chronic disease. Infection in baboons yields a high rate of cercarial penetration, fast schistosomula migration from the skin to the lungs, and development to adult worms; maturation of infecting larvae exceeds 90% (S. mansoni). Other advantages of this model include similarity to humans in terms of immune response, that is, baboons produce four human-like IgG subclasses [30,34]. Due to these arguments regarding the appropriateness of schistosome vaccine efficacy models outlined above, it is our opinion that, when designing immunization regimens for clinical trials, data obtained through studies in the murine model should be used with caution. A prudent approach in this regard would be that all credible schistosome vaccine candidates should also be tested in a nonhuman primate model, to determine optimal vaccine composition/formulation
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Sm-p80 vaccine efficacy at different levels of infecon, disease, and transmission Therapeuc efficacy (adult worm killing)
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Adult w orms in m e or v sente en ric ou v s p en lex u u
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A Adult worm
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B
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C
A um ( rect el/ ) ow r (C f b dde s o la le of b s
po
Prophylacc efficacy (worm reducon)
An-pathology efficacy (reducon in ssue egg load)
Eggs
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Cercaria Eggs
Miracidia Penetrate snail ssue
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ter Wa
4
the wat er
Schistosomula
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3 Snail
Reducon in disease transmission (lessened egg expulsion/reduced snail exposure)
An-egg hatching effect (reducon in egg viability)
Figure 2. Sm-p80 Vaccine Efficacy at Different Levels of Infection, Disease, and Transmission. The Sm-p80 vaccine can lead to a reduction in transmission by decreasing expulsion of eggs into the environment (1). The vaccine also has detrimental effects on eggs and inhibits the hatching of eggs into miracidia (2). The Sm-p80 vaccine has robust prophylactic efficacy due to its effectiveness against schistosomular development into adult worms (5). This vaccine is the only vaccine which has been shown to eliminate already established adult worms, thus exhibiting a therapeutic efficacy (6). The vaccine's effectiveness is also pronounced in reducing the egg retention in tissues (antipathology efficacy) (7).
for use in humans to achieve[13_TD$IF] the highest possible vaccine efficacy clinically. Baboon can serve as an immensely useful bridge between mouse and human studies. Schistosomiasis Vaccines in Human Clinical Trials To date only three schistosome vaccine candidates are in phase I to phase III trials [10,27,36]. These include S. haematobium 28-kD glutathione S-transferase (rSh28GST), S. mansoni
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Table 1. Essential Requirements for Optimal Morbidity-Reducing Schistosomiasis Vaccine Indication
Prevention of infection by the three major human schistosomes thus preventing intestinal/hepatic, Asiatic/oriental and urinary schistosomiasis
Target populations
Population in endemic countries » High-risk school age children (3–12 years of age) » Adults (18–59 years of age) in high-risk occupations or areas
Efficacy
» Reduce at least 75% infection » Efficacy readout – egg output and/or worm burden
Duration of protection
2–3 years after last dosing
Dosage and cost
» Parenteral administration, 2 doses administration » Less than $1 per dose
Product criteria
» The vaccine antigen should not react to IgE from target population » Can be coadministered with local MDA or other disease-control strategies
Manufacturing
Suitability for human trials: purity > 90% (Yield 50 mg/L) Endotoxin levels < 50 EU/mg Non-pyrogenic
14-kDa fatty acid-binding protein (Sm14), and S. mansoni tetraspanin, a 9-kDa surface antigen (Sm-TSP-2) [10,27,36]. Phase I and II clinical data have shown that rSh28GST in alum did not induce any significant toxicity in healthy adults and generated a type 2 (Th2) immune response, and further clinical trials are continuing in humans as a potential vaccine candidate against urinary schistosomiasis [37]. A phase III trial to assess if the combination of rSh28GST and praziquantel would help lower pathologic episodes of S. haematobium infection in infected children was carried out from 2009 to 2012 – the findings of which have not yet been published [10]. Similarly, phase I clinical trial data on tolerability and specific immune responses after vaccination of adult, male volunteers in a nonendemic area for schistosomiasis with rSm14/GLASE has also shown that the vaccine formulation is safe and immunogenic against schistosomiasis (S. mansoni) [38]. A phase I trial for Sm-TSP-2 (S. mansoni) has been initiated in 2014 and is ongoing [10]. The progress thus far on schistosome vaccine human trials has been slow but steady. One important caveat though is that all of these three vaccines target only a single schistosome species [10,27,36].
Essential Features of an Ideal Schistosomiasis Vaccine It is important to note that reduction in morbidity, rather than sterile immunity, is the immediate target for a schistosome vaccine. The PPC developed for a schistosomiasis vaccine in 2013 is an important starting point for developing a prophylactic vaccine [33]. However, we believe that a ‘dream vaccine’ that is expected to reduce the burden of disease in a meaningful fashion should have additional characteristics. It should reduce the overall worm burden by 75% or higher, and the egg retention/excretion should be reduced by close to 100% for a vaccine to be effective in terms of reduction of egg-induced pathology and transmission of infection. Ideally, the vaccine should target, and be effective against, the three major species of schistosomes that cause intestinal/hepatic schistosomiasis (S. mansoni, S. japonicum) and urinary schistosomiasis (S. haematobium), or at minimum be effective against S. mansoni and S. haematobium because in major geographical areas of Africa areas these two species coexist. If a vaccine can be developed that preferentially kills female worms, that should result in reduced egg burdens, ultimately leading to a reduction in egg-induced pathology. [14_TD$IF]This would be considered a major breakthrough: such a vaccine, in addition to inducing adaptive immunity, will also help in preserving natural immunity against schistosomes by maintaining some of the nonpathogenic male worms. This is because, in the absence of a mate, the growth of male worms is stunted and their life-span is significantly shortened, compared to the normal life-span
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of paired worms, which can be anywhere from 5 to 30 years [39–41]. A practical deployment approach could involve first treating schistosome-infected individuals with praziquantel to kill adult worms and then vaccinating them[4_TD$IF]. Since the standard praziquantel regimen would have minimal effect on eggs, reducing existing egg-induced pathology has to be dealt with by other therapeutic means. Subsequent schistosome infection will result in vaccine-mediated preferential killing of female worms. Some males that may escape immune killing will establish themselves as nonpathogenic adults, thus providing concomitant natural immunity.
Sm-p80-[15_TD$IF]Based Vaccine: Effective for Intestinal/Hepatic and Urinary Schistosomiasis Over the last two decades, our group has followed a systematic and methodical approach to develop Sm-p80 as a viable and effective schistosomiasis vaccine. Sm-p80 is the large subunit of the S. mansoni calcium-activated neutral protease calpain. Sm-p80 plays a pivotal role in the surface membrane biogenesis and renewal, which is a mechanism employed by hemo-helminths to evade the host's hostile immune response [42]. Sm-p80 is present in the surface membranes and syncytium of the worm; is the highly immunodominant antigen in the membranes; and exhibits no immunological cross-reactivity with human and other vertebrate calpains [42]. Briefly, Sm-p80 has been tested for its vaccine efficacy in different vaccine formulations and approaches, including naked DNA, recombinant protein and prime/boost in three experimental animal models of infection and disease (mouse, hamster, and baboon) [43–49]. Sm-p80-based vaccine formulation(s) have many effects: (i) prophylactic efficacy against intestinal/hepatic schistosomiasis; (ii) egg-induced pathology resolution both in rodents and baboons; (iii) post-exposure therapeutic effect via killing of established adult worms in chronic infections; (iv) cross-protection against urinary and Asiatic/oriental schistosomiasis; (v) longevity of immune response – robust antibody titers in mice for up to 60 weeks and 5–8 years in baboons; (vi) transplacental transfer of Sm-p80-specific antibodies in baboons. As depicted in Figure 2, the Sm-p80-based vaccine has multifaceted effectiveness against several stages of the parasite's life cycle, including eggs, schistosomula, and adult worms [43–49]. Additionally, Sm-p80specific IgE has not been detected in high-risk or infected populations from Africa [45] and South America [50], thus minimizing the risk of a hypersensitivity reaction following vaccination with Sm-p80-based vaccine in humans. Sm-p80 vaccine will soon move into phase I human trials (Figure 3).
Development roadmap for Sm-p80 vaccine Discovery phase
Nonclinical process development phase
Time period: 10 years Funding need: $10 million
Time period: 5 years Funding need: $5 million
Vaccine efficacy studies in animal models of infecon and disease
Formulaon, opmizaon, characterizaon, mechanisms of acon, immunogenicity
Scale up manufacturing
GMP manufacturing GLP Safety toxicology with lot release data in animal model(s) at Range-finding showing: identy, effecve human toxicology sterility, lack of doses, route of study advenous agents, administraon and purity, potency, general dosing regimen safety, stability
Human clinical trials (Safety, efficacy) Time period: 5 years Funding need: $15 million Correlates of protecon Vaccine immune signature verificaon
Phase I, II, and III, and addional FDA required studies
Figure 3. Development Roadmap for a Schistosomiasis Vaccine. Development of a vaccine entails many different aspects, including identification of appropriate vaccine target; evaluation of the vaccine candidate in efficacy and disease animal models; and vaccine process development for clinical development. This long and arduous process can take decades, and an appreciable amount of funding is needed to develop a vaccine from bench to bedside. Abbreviations: GLP, good laboratory practices; GMP, good manufacturing practices.
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Concluding Remarks and Future Perspectives
Outstanding Questions
Vaccine development is a long process that can take decades (Figure 3). Since funding for vaccine development for neglected tropical parasitic diseases is very limited, a cautious and wellthought-out approach is warranted when moving promising schistosomiasis vaccines forward into human clinical trials. When designing immunization regimens for clinical trials, data solely obtained through studies in the murine model should be used with caution (see Outstanding Questions). The schistosomiasis vaccine field has already suffered a major slowdown in the past when the six ‘priority antigens’ were tested against experimental challenge infection in a potentially flawed murine model [34] resulting in serious dwindling of funding for schistosome vaccine research. A rushed clinical trial, if not successful, carries the potential of negatively affecting the future development of other vaccine candidates. Emphasis should be placed to encourage collaborative partnerships among different laboratories working on schistosome vaccine worldwide, to develop a pipeline of schistosomiasis vaccines through nonprofit Product Development Partnerships with the eventual aim of bringing the cost of the vaccine to less than $1 per dose. We believe that, with sustained efforts, an effective schistosomiasis vaccine will emerge in the next decade. We champion an approach to the control of schistosomiasis – mass drug/vaccine administration or MDVA, a vaccine implementation scheme that would entail treating infected individuals with praziquantel and then vaccinating them with a schistosome vaccine. This integrated approach has the potential for making a meaningful impact in reducing the burden of schistosomiasis. An effective schistosomiasis vaccine could potentially impact up to 1 billion people!
What are the factors influencing the spread of schistosomiasis?
Acknowledgments
How can the efficacy of schistosomiasis vaccine best be evaluated in human populations?
There is no conflict of interest with funding agencies that have supported the research of the authors[16_TD$IF]. We thank Stuart Blalock (The Stuart Blalock Visual Company) for help with graphics. This [17_TD$IF]research was supported by grants from the Bill and
How can we modify existing control measures to make them more efficient in controlling the disease? Can modeling studies predict the impact of vaccine in the field, if combined with other control strategies? How long before there is widespread resistance to praziquantel? Why is widespread resistance to praziquantel not an issue yet? How can existing mouse models for schistosome vaccine research best be used? How sustainable is schistosomiasis vaccine research in baboons? How can immunization regimens best be designed for a schistosomiasis vaccine human trial?
Melinda Gates Foundation[5_TD$IF] (OPP1097535) and from the NIAID/NIH SBIR (R43/R44 AI103983).
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