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Trends Parasitol. Author manuscript; available in PMC 2018 March 01.
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Trends Parasitol. 2017 March ; 33(3): 194–201. doi:10.1016/j.pt.2016.10.010.

Sm-p80-based schistosomiasis vaccine: Preparation for human

clinical trials
Afzal A. Siddiqui and Sabrina Z. Siddiqui
Department of Internal Medicine, Center for Tropical Medicine and Infectious Diseases, Texas
Tech University Health Sciences Center, Lubbock, TX 79430, USA
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Abstract
Mass anti-parasitic 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. Advent of a viable vaccine and its deployment coupled with
existing control efforts is expected to make a significant headway towards a sustained
schistosomiasis control. In 2016, Science ranked schistosomiasis vaccine as one of the top 10
vaccines that need 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 disease burden. In this review 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.
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Keywords
Schistosomiasis; Vaccine; Schistosoma mansoni; Schistosoma haematobium; Schistosoma
japonicum; Protective immunity; Neglected tropical disease (NTD)

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
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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

Corresponding Author: Afzal A. Siddiqui, Ph.D., Department of Internal Medicine, Center for Tropical Medicine & Infectious
Diseases, Texas Tech University Health Sciences Center, 3601 4th Street, Mail Stop 9410, Lubbock, TX 79430, (806) 743-2638
(Office) | (806) 743-4030 (Fax), afzal.siddiqui@ttuhsc.edu.
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 Siddiqui and Siddiqui Page 2

Mediterranean. Current conservative estimates are that 200 million people are infected with
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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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(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 re-infection 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;14] [15;16].
Integrated control programs aimed at limiting schistosomiasis by improving education and
sanitation, molluscicide treatment programs to reduce the population of the intermediate
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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 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 additional ways of interventions including more
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emphasis on developing a vaccine that could supplement 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 anti-dogmatic assertion is based on the fact that schistosomes

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do not replicate within their definitive hosts (e.g. humans, Figure 2), hence, even a partial
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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 to use 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, anti-disease, and anti-
fecundity [30;31]. Additionally, in a gathering of over 70 experts at the Bill and Melinda
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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 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 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).
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During the last 2-3 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
with convincing arguments that the low level 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 the natural hosts of
schistosomes, 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,
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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 i.e., 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

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schistosome vaccine candidates should also be tested in a nonhuman primate model, to

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determine optimal vaccine composition/formulation for use in humans to achieve 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 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 has 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
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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
non-endemic area for schistosomiasis with rSm14/GLA-SE has also shown that the vaccine
formulation is safe and immunogenic against schistosomiasis (S. mansoni)[38]. 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
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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 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
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reduced egg burdens, ultimately leading to lessened egg-induced pathology. That would be a
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 non-pathogenic 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 normal
life-span 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

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 Siddiqui and Siddiqui Page 5

praziquantel to kill adult worms and then vaccinating them with the vaccine. Since standard
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praziquantel regimen would have minimal effect on eggs, reducing existing egg-induced
pathology has to be dealt with 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 non-pathogenic adults, thus providing
concomitant natural immunity.

Sm-p80-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
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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
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effectiveness against several stages of the parasite’s life cycle, including eggs, schistosomula
and adult worms [43-49]. Additionally, Sm-p80-specific IgE has not been detected in high
risk or infected populations from Africa [45] and South America [50], thus minimizing the
risk of hypersensitivity reaction following vaccination with Sm-p80-based vaccine in
humans. Sm-p80 vaccine will soon move into phase I human trials (Figure 3).

Concluding Remarks and Future Perspectives

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
well-thought-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
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(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

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 Siddiqui and Siddiqui Page 6

schistosomiasis vaccines through non-profit Product Development Partnerships with the

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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!

Acknowledgements
There is no conflict of interest with funding agencies that have supported the research of the authors. This work was
supported by grants from the Bill and Melinda Gates Foundation grant (OPP1097535) and from the NIAID/NIH
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SBIR (R43/R44 AI103983).

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irradiated cercarial vaccine. J Infect Dis. Apr 1; 2010 201(7):1105–12. [PubMed: 20187746]
[49]. Zhang W, Ahmad G, Le L, et al. 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. Jun; 2014 113(6):2239–50. [PubMed: 24728521]
[50]. Gaze S, Driguez P, Pearson MS, et al. An immunomics approach to schistosome antigen
discovery: antibody signatures of naturally resistant and chronically infected individuals from
endemic areas. PLoS Pathog. Mar.2014 10(3):e1004033. [PubMed: 24675823]
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Outstanding Questions
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• What are the factors influencing in the spread of schistosomiasis?

• 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?
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• How can immunization regimens best be designed for a schistosomiasis

vaccine human trial?

• How can the efficacy of schistosomiasis vaccine best be evaluated in human

populations?
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Trends Box
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• There is a widespread agreement among ‘schistosomalogists’ that 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 vaccine-
mediated responses, in utilizing efficient protein expression, manufacturing
and scale up platforms, and in employing human surrogates of efficacy.
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• A systems biology approach is now being increasingly been applied in the

field to identify vaccine-mediated gene signatures and epistatic interactions;
protein-protein interactions may also be helpful in predicting vaccine efficacy.
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Figure 1.
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Worldwide distribution of schistosomiasis. Reproduced from http://wwwnc.cdc.gov/travel/

yellowbook/2016/infectious-diseases-related-to-travel/schistosomiasis.
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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
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pronounced in reducing the egg retention in tissues (anti-pathology efficacy) (7).

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Figure 3.
Development Roadmap for a Schistosomiasis Vaccine. Development of a vaccine entails
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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
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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Table 1

Essential Requirements for Optimal Morbidity Reducing Schistosomiasis Vaccine.

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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 (18-59years 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
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Product Criteria » The vaccine antigen should not react to IgE from target population
» Can be co-administered 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
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