Advancing a Vaccine to Prevent Human Schistosomiasis

Vaccine 34 (2016) 2988–2991

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Advancing a vaccine to prevent human schistosomiasis

a,b a,b,c,d,e,f,∗ a,c,d

Maureen Merriﬁeld , Peter J. Hotez , Coreen M. Beaumier ,

a,c,d a,c,d b a,b,c,d,e,f

Portia Gillespie , Ulrich Strych , Tara Hayward , Maria Elena Bottazzi

Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development Houston, TX, USA

Sabin Vaccine Institute, Washington, DC, USA

National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA

Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA

Department of Biology, Baylor University, Waco, TX, USA

a r a

t i c l e i n f o b s t r a c t

Article history: Several candidate human schistosomiasis vaccines are in different stages of preclinical and clinical devel-

Available online 29 March 2016

opment. The major targets are Schistosoma haematobium (urogenitial schistosomiasis) and Schistosoma

mansoni (intestinal schistosomiasis) that account for 99% of the world’s 252 million cases, with 90% of

Keywords:

these cases in Africa. Two recombinant S. mansoni vaccines – Sm-TSP-2 and Sm-14 are in Phase 1 trials,

Schistosomiasis

while Smp80 (calpain) is undergoing testing in non-human primates. Sh28GST, also known as Bilhvax is

Vaccine

in advanced clinical development for S. haematobium infection. The possibility remains that some of these

Neglected tropical disease

vaccines may cross-react to target both schistosome species. These vaccines were selected on the basis

of their protective immunity in preclinical challenge models, through human immune-epidemiological

studies or both. They are being advanced through a combination of academic research institutions, non-

proﬁt vaccine product development partnerships, biotechnology companies, and developing country

vaccine manufacturers. In addition, new schistosome candidate vaccines are being identiﬁed through

bioinformatics, OMICs approaches, and moderate throughput screening, although the full potential of

reverse vaccinology for schistosomiasis has not yet been realized. The target product proﬁles of these

vaccines vary but many focus on vaccinating children, in some cases following mass treatment with praz-

iquantel, also known as vaccine-linked chemotherapy. Several regulatory pathways have been proposed,

some of which rely on World Health Organization prequaliﬁcation.

BY license (http://creativecommons.org/licenses/by/3.0/).

Schistosomes are snail-transmitted, water-borne parasitic japonicum or Schistosoma mekongi (the causes of intestinal schis-

platyhelminthes (order Trematoda) that are found in fresh water tosomiasis in East Asia). Schistosomiasis, together with hookworm

bodies in low- and middle-income countries. Current estimates and leishmaniasis, rank as those neglected tropical diseases with

from the Global Burden of Disease Study 2010 (GBD 2010) sug- the highest disease burden as deﬁned by disability-adjusted life

gest that 252 million people are infected with schistosomes, 90% years (DALYs) [1]. While the GBD 2010 estimated that the world lost

of whom live in sub-Saharan Africa [1]. The World Health Orga- 3.3 million DALYs from schistosomiasis in 2010 [1], other estimates

nization (WHO) reports that in 2014 at least 258 million people suggest that DALYs lost may even be an order of magnitude higher if

worldwide required frequent and regular preventive treatment for chronic morbidities such as malnutrition, inﬂammation, and pain

schistosomiasis [2]. Recently though, the disease even emerged in are also taken into consideration [4,5]. In addition, there is some

Europe on the French island of Corsica [3]. Globally two-thirds of evidence that S. haematobium may represent an important risk fac-

the cases are infected with Schistosoma haematobium (the cause tor for HIV/AIDS acquisition because of the mucosal inﬂammation

of urogenital schistosomiasis), one-third with Schistosoma mansoni and ulceration caused by genital schistosomiasis in tens of millions

(the cause of intestinal schistosomiasis), and 1% with Schistosoma of girls and women [6,7]. In addition to S. haematobium-HIV co-

infections, S. mansoni and malaria co-infections are also widespread

in Africa, and may result in synergistic effects [8].

∗ Schistosomes reproduce by asexual reproduction in fresh-

Corresponding author at: Sabin Vaccine Institute and Texas Children’s Hospital

water snails and are released in large numbers as infective

Center for Vaccine Development, Houston, TX, USA.

E-mail addresses: [email protected], [email protected] (P.J. Hotez). larvae. In water, these cercariae penetrate the skin of a human

http://dx.doi.org/10.1016/j.vaccine.2016.03.079

M. Merriﬁeld et al. / Vaccine 34 (2016) 2988–2991 2989

host, transforming into schistosomulae that migrate through the identifying meaningful correlates of immunity, particularly for the

bloodstream and lungs to the liver where they become adult design of a recombinant immunogen.

male-female schistosomes. In the host’s mesenteric or bladder

venules, the adult schistosomes release their eggs into the tissues 2. General approaches to vaccine development for low- and

before some make their way into the feces or urine. Upon contact middle-income country markets

with fresh water, the eggs hatch and give rise to miracidia that

enter the intermediate hosts, snails. Schistosomes do not multiply in the human host, and most of

The pathogenesis of human schistosomiasis begins when eggs the pathology comes as a consequence of the deposition of schisto-

destined for exit out of the body through feces or urine, instead some eggs in the tissues that lead to end-organ damage associated

become embedded in the tissues of the human intestine or bladder. with ﬁbrosis, inﬂammation, and bleeding. Current vaccine develop-

These trapped eggs subsequently induce inﬂammation, granulo- ment strategies aim to prevent schistosome infection and/or reduce

mas, and ﬁbrosis leading to a number of clinical sequelae including ova burden through the interruption of parasite reproduction. Thus,

hepatic ﬁbrosis and hepatosplenomegaly, hematuria, bladder ﬁbro- among the major vaccine targets are the migrating schistosomulum

sis and obstruction, hydronephrosis and chronic renal disease. stages as well as adult females.

S. haematobium ova can also elicit vaginal or cervical inﬂamma- In the 1990s, an independent, WHO/TDR-sponsored evaluation

tion (so-called “sandy patches”) that increases the risk of HIV/AIDS of six S. mansoni vaccine candidates in preclinical development

acquisition, such that schistosomiasis is considered an important found that none achieved better than 40% efﬁcacy in reducing worm

co-factor in Africa’s AIDS epidemic [6]. Moreover, infection with S. load.

haematobium is strongly associated with squamous cell carcinoma Since then the maturing of several new technologies, including

of the bladder [9]. Chronic schistosomiasis, in addition, can lead to OMICs (e.g., genomics, proteomics, transcriptomics), microarrays,

many other sequelae as well, especially in children, including but and immunomic proﬁling, have helped in the identiﬁcation of

not limited to anemia, chronic pain, undernutrition, growth failure promising new target schistosome antigens [22–24]. However,

and cognitive deﬁcits [4,5]. both inadequate funding and infrastructure for vaccine devel-

Strategies to control schistosomiasis center on Mass Drug opment have slowed the translation of these antigen discovery

Administration (MDA) of an acylated quinoline-pyrazine known as technologies to the clinic. Indeed the overall pipeline of human

praziquantel (PZQ). While less than 20% of children who need PZQ schistosomiasis vaccines currently in clinical trials is extremely

MDA actually receive regular treatments, the fact that the preva- modest especially when considering the high disease burden

lence of schistosomiasis may have increased over the last two to of schistosomiasis and its potential role in Africa’s AIDS epi-

three decades [10], suggests that MDA with PZQ alone will not be demic.

adequate for the global elimination of schistosomiasis. Indeed, a For S. haematobium, a single candidate molecule, Sh28GST (Bil-

survey of almost 400 experts on neglected tropical diseases con- hvax), a schistosome glutathione S-transferase common to the

cluded that schistosomiasis may not be eliminated through current schistosomula and adult stages, is believed to currently be under-

approaches [11]. A major reason is that MDA does not interrupt going testing. Early phases 1 and 2 clinical trials conducted in

transmission and does not prevent schistosome reinfection. With Niger and Senegal have demonstrated an acceptable safety proﬁle

the added potential for the emergence of PZQ resistance [12,13], and induction of high IgG3 antibody titers that have neutralized

there is thus an urgent need for vaccines as an alternative approach Sh28GST activity and reduced egg-production, an effect that could

to lower the disease burden, limit transmission and mitigate the lead to decrease urinary tract pathology and transmission [25,26].

morbidity of schistosomiasis [14,15]. A phase 3 trial to evaluate if the vaccine candidate and PZQ admin-

istration would delay pathologic relapses of the S. haematobium

infection in infected children was conducted from 2009 to 2012,

1. Biological feasibility for vaccine development but no results have been reported yet [27].

There are two vaccine candidates for intestinal schistosomiasis

Immunity as a result of natural exposure to a pathogen is often caused by S. mansoni in early stage clinical testing. The ﬁrst com-

taken as evidence of the biological feasibility for vaccine develop- prises the extracellular domain of an integral membrane S. mansoni

ment. In the case of human schistosomiasis, rates and intensity surface protein, Sm-TSP-2, that is bound by IgG1 and IgG3 anti-

of infection tend to diminish with age, especially after puberty. bodies from individuals that have cleared infection [28]. Preclinical

However, it is unclear if acquired immunity is solely responsi- studies in mice have shown that immunization with this protein

ble for this observation. Furthermore, the likelihood that such subunit substantially reduces worm burden. This immunogen has

immunity is partly due to an IgE-mediated mechanism compli- been successfully expressed in yeast (Pichia pastoris) for scale-up

cates strategies that try to mimic natural immunity. The goal of cGMP production [29,30], and is currently in phase 1 trials in Hous-

immunization, therefore, may not be sterilizing immunity but the ton, Texas, USA. A second vaccine candidate in clinical testing is

long-term reduction of both ova burden in the host tissues and based on Sm-14, a fatty acid binding protein from S. mansoni, and

excretion from the host, leading to diminished pathogenicity and it was announced that this vaccine will undergo phase 1 trials in

reduced transmission, respectively. Brazil [31]. While not yet in clinical development, Smp80 (calpain)

The feasibility of schistosomiasis vaccines has been demon- has demonstrated efﬁcacy in NHP challenge studies, and will also

strated in a series of proof-of-concept studies where mice and likely advance to the clinic [32]. As Asian schistosomiasis caused

non-human primates (NHPs) were immunized with radiation- by S. japonicum is an important zoonosis, there is increased inter-

attenuated cercariae, and were found to be protected (with est here in developing a veterinary vaccine for water buffalo, cattle,

efﬁcacies of >80%) against percutaneous schistosomal challenge and pigs as a potential means toward blocking a transmission to

[16–18]. Vaccinated mice exhibited both cellular and humoral humans [33].

immune responses to lung-stage parasites [19], and under some Because several of the antigens under investigation are highly

circumstances, the co-administration of the cercarial vaccine with conserved among different species, there is some optimism for

interleukin-12 adjuvant improved protective immunity [20,21]. advancing a pan-schistosome vaccine, especially for S. mansoni

Although an attenuated cercarial vaccine may not be a viable and S. haematobium co-infection, prevalent in sub-Saharan Africa.

approach in humans due to a number of factors including feasibility In addition, because of the geographic overlap between schis-

of production, quality control, and safety, it represents a model for tosomiasis and hookworm disease, there have also been early

2990 M. Merriﬁeld et al. / Vaccine 34 (2016) 2988–2991

Table 1

Current vaccines in clinical trials (POC = proof of concept trial).

Parasite species targeted Vaccine Major antigens/adjuvants Sponsor Status

Schistosoma haematobium Bilhvax Sh28GST (28-kDa recombinant Institut Pasteur and INSERM Completed Phase 2 and 3 trials

glutathione-S-transferase) in West Africa (results

Alum formulation pending) [15,27].

Schistosoma mansoni Sm-TSP-2 Sm-TSP-2 (9-kDa recombinant Sabin Vaccine Institute Product Initiated Phase 1 trial in 2014

tetraspanin) Development Partnership/NIAID, at Baylor College of Medicine

Alhydrogel ± GLA NIH/Baylor College of Medicine [39].

Vaccine and Treatment Evaluation

Unit

S. mansoni Sm-14 Sm-14 (14-kDa recombinant Oswaldo Cruz Foundation (Fiocruz) Ongoing phase 1 trial [40].

fatty acid binding protein) with Oroﬁno Phase 2 trials are planned for

the adjuvant GLA 2015 in Brazil and Africa.

Table 2

considerations to develop a multivalent vaccine that targets both

Development status of schistosomiasis vaccine candidates (POC = proof of concept

helminths [34]. The general approach would then be to tar-

trial) [12,15].

get school-aged children in hyperendemic areas with broadly

Candidate name/identiﬁer Preclinical Phase I Phase II Phase III

immunogenic and durable vaccines of relatively low cost and

extended shelf-life. An additional potential beneﬁt would be the Sm-TSP-2 X

reduction of HIV/AIDS transmission through the prevention of uro- Sm-TSP-1 X

Sm29 X genital schistosomiasis [7].

Sm23 X

A schistosomiasis vaccine could be developed either as a stand-

Smp80 X

alone technology or used as a companion technology alongside Sh28GST X

MDA. Towards this goal Bergquist and colleagues have made cogent Sm-14 X

Sj97 paramyosin X

arguments for shaping a “vaccine-linked chemotherapy” strategy

CT-SOD X

that would initially implement MDA with PZQ followed by immu-

nization to prevent reinfection [35].

OMICs databases through DNA microarray proﬁling, proteomics,

3. Technical and regulatory assessment

glycomics, and immunomics have helped identify promising

immunogens [22–24,37]. Further signiﬁcant advancement has

The pathway toward regulatory approval of these vaccine can-

been achieved through the successful application of RNA interfer-

didates will likely require at least a 40% reduction of worm burden.

ence (RNAi) technology, which in the case of Sm-TSP-2 allowed

The schistosome antigens and prototype vaccine formulations cur-

investigators to ascribe speciﬁc functions to the molecule and

rently in early clinical testing induce 30–70% reductions in worm

its role in parasite survival [38]. Complexities of advancing true

burden or egg production and have succeeded to increase viabil-

reverse vaccinology approaches (as was successfully done for

ity in laboratory animals. The challenge though remains in the

meningococcus) include large genome sizes, and the requirement

translation of these antigens into humans and maintain a similar

for eukaryotic expression systems, as well as cumbersome labora-

or superior protection through formulation with novel adjuvants,

tory animal model systems.

including the use of Toll-like receptor agonists such as synthetic

lipid A molecules. The immune correlates of protection for a schis-

5. Likelihood for ﬁnancing

tosomiasis vaccine are thought to be observable in IgG1 and IgG3

antibody recognition of the antigens. The standard animal model

According to the public search tool, G-Finder, between 2007

for screening potential antigens has been the mouse model used to

and 2013, approximately $27 million in funding was awarded

test the efﬁcacy of schistosomiasis vaccines, but SmP80 is now also

for schistosomiasis vaccine research and development (R&D), pri-

undergoing extensive testing in NHPs [36].

marily from major public sector funding agencies such as the

Several additional factors must be taken into consideration

Australian National Health and Medical Research Council (NHMRC),

for a successful vaccine development in low- and middle-income

France’s Institut national de la santé et de la recherche médicale

countries including the choice of antigen and target species (e.g.,

(INSERM), the Brazilian Ministry of Health’s Department of Sci-

S. haematobium, S. mansoni or both), production feasibility and

ence and Technology (DECIT), the European Commission, and the

cost per dose. Careful antigen and adjuvant selection, cutting edge

US National Institutes of Health (NIH) [41]. Through a group of

immunogen design based on potential immune correlates, and

philanthropic donors, including the Michelson Medical Research

robust efﬁcacy in laboratory animal models will not be sufﬁcient

Foundation and the Blavatnik Family Foundation the Sabin Vaccine

for a successful vaccine if cGMP manufacturing of the vaccine prod-

Institute Product Development Partnership (Sabin PDP) has also

uct is not feasible [12]. Currently, recombinant vaccines for NTDs

funded schistosomiasis vaccine R&D efforts to a total of approxi-

are thus mostly produced in low-cost bacteria or yeast expression

mately US$1.25 million, with additional NIH support for toxicology

systems. It will also be important to select the appropriate adjuvant

testing and for the phase 1 trial. New and increased ﬁnancing from

and delivery platform to stimulate the correct immune response.

major funders will be critical to advance these candidate vaccines.

An additional challenge here has been the limited availability of

adjuvants with regulatory approval for use in humans.

Conﬂicts of interest

4. Status of vaccine R&D activities

Several of the authors are investigators and patent holders on

vaccines against hookworm and other neglected tropical diseases

The vaccine candidates currently in clinical trials are listed in

and are in part supported by grants to develop these vaccines: and

Tables 1 and 2. Some of the progress in developing these promis-

are in part supported by grants to develop these vaccines.

ing vaccine candidates has come from screening schistosome

M. Merriﬁeld et al. / Vaccine 34 (2016) 2988–2991 2991

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