Evaluation of vaccine development against
the human pathogen, Schistosoma mansoni

Introduction

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Human Schistosomiasis
is among the neglected tropical disease acknowledged by the World Health
Organization (WHO) (Fuaad et al., 2015). Estimated by WHO in 2016, at least
206.5 million people have required treatment for schistosomiasis out of which
more than 88 million people were reported to have been treated worldwide.
(World Health Organization, 2017).  

Human
schistosomiasis (acute or chronic), is a parasitic disease caused by three main
species of genus Schistosoma, Schistosoma mansoni, S. japonicum (causes
of intestinal/hepatic schistosomiasis) and S.
haematobium, results in urogenital schistosomiasis (Merrifield et al., 2016;
Walker 2011). The main focus of the systematic review will be on S. mansoni. Schistosoma mansoni, which is transmitted by Biomphalaria snails, which leads to intestinal and hepatic
schistosomiasis in Africa, the Arabian peninsula, and South America (Figure 1) (Merrifield
et al., 2016; WHO, 2017)

Life Cycle
and Transmission

The
blood-dwelling fluke worms has a cylindrical body, a complex tegument and
mature into separate sex adults. The adult worms live within the vein of their
human host (Colley et al., 2014). This complex life cycle has given the
parasites a co-evolution in intricate interplay between the parasite and the
snail or vertebrate host, also between the adult and female worms (Walker
2011).

The
life cycle of schistosomes, at fresh water with excreted eggs from infected
human urine, faeces or vaginal discharge. On contact with fresh water, the eggs
release a miracidum. The ciliated miracidium then swims and are in look for an
intermediate host snail to start their next stage in their life cycle. Once the
miracidium have penetrated the snails they replicate due to asexual
reproduction, through this #process the mother and daughter sporocyst stage
occur and finally produce thousands of cercariae (approximately 4-6 weeks after
infection) (Walker 2011, and Colley et al., 2014). The cercariae then leave the
snail host seeking a suitable final host. Human infection occur due to cercariae
penetration thought the skin, after infecting the parasite starts to travel by
transforming into parasitic schistosomula by shedding its tail (Walker 2011).
The schistosomula slowly migrate in the skin travelling along the pulmonary
capillaries (lung schistosomula) and entering the circulation to migrate to
designated location, S. manosni reside in the mesenteric venules (Walker 2011,
Alberto-Silva et al., 2015). Rapid growth begins when the parasite reaches the
blood vessels, where the parasite begins the develop into an adolescent stage
to sperate sex adults. S. mansoni, the
first schistosomula that arrives around day 7, the gut caeca join posteriorly
around day 15, sex organs develop after approximately 21 days. Around 4 – 5
weeks after skin penetration the adult worms start the egg production, where
the female releases hundreds of eggs per day and continues for up to 15 years
(Walker 2011).

The
tegument (Figure 2), the outermost surface of intra-mammalian stages of the
parasite is the major contributor to the parasite’s survival but is it also a
vulnerable target for vaccines and drugs. This is the location where the
host-parasite interface occurs (Githui et al., 2009). Adult worms resided in
human veins import sugar directly across from the bloodstream to their internal
tissues using their tegument and transport proteins located on them. Molecular
characterization techniques have been used to determine the composition and
abundance of proteins located on the tegument for have a better understanding
of the tegument. This would help when looking for new drug and possible vaccine
targets in the parasite.

Figure 2. Proteins exposed on the outer tegument of adult S.mansoni. The
tegument of male worm (left) and female worm(right). t. tubercles. ep- excretory
pore. (Claudineide
Nascimento Fernandes de Oliveira et al., 2013).  Adaptation of Brachi, Borges and Wilson, 2006
diagram representing the S. mansoni tegument
and associated cell body- not to scale. The tegument of adult worm consists of
cytoplasmic syncytium with an exclusive double outer tegument membrane. The S.mansoni outer tegument contains two
closely apposed lipid bilayers, extend over the pitted surface of the tegument,
inclusion the spine (Xavier et al., 1998). The nullity layered vesicles travel
from the cell body and discoid bodies though the cytoplasmic channels to the
tegument. (Brachi, Borges and Wilson, 2006).

As the
current treatment for Human Schistosomiasis, praziquantel (PZQ) is the drug being
used widely due to high cure rate and no significant side effect (Pinto-Almedia
et al., 2015), though it is safe and a simple drug to use, the effect against
immature worms or eggs and preventing of re-infection is negative. There is
also a huge problem relating to the resistance to drugs. PZQ have been
co-administered with albendazole and ivermectin, in areas where these drugs
have been used separately for preventive chemotherapy. Recent study conducted
by Pinto-Almeida et al., (2015) highlights the involvement of effiux pumps, for
instance members of ATP-binding cassette transport proteins, including
P-glyvcoprotein (P-gp) and multiple drug resistant associate proteins in S. mansoni resisting to PZQ. Some
studies have shown increased tolerance to PZQ in male worm (Kasinathan et al.,
2009 and Kasinathan and Greenberg. 2012), however the results are not replicated
to the female worms, this suggests that the resistance mechanism may be
different in the adult worms (Pinto-Almeida et al., 2015).

This
factor alone is alarming and pushes forward the need for vaccine, whether to
prevent or as therapeutic against human schistosomiasis. Even though there are
no vaccines available for human schistosomiasis so far, the number of studies
conducted up to now are showing possible targets and vaccine candidates with great
potential.

Tretraspanin (an example as
possible candidate)

There
are over 100 possible vaccine candidates that have been identified. However
only hand few of molecules, S.mansoni fatty
acid binding protein (Sm14), S. mansoni tetrspanin
(Sm-TSP-2) have entered human clinical trials with Smp80 (calpain) undergoing
testing in non-human primates. (Tebeje et al., 2016)

The
tetranspanin family of integral membrane proteins seems to be in abundant in
the tegument of schistosomes, and studies done on mouse vaccine models suggests
that this gamily of membrane proteins offer promising results of possible schistosomiasis
vaccine (Loukas, Tran and Pearson, 2007)

Tetrapsnains
engage in wide range of specific molecular interactions that occur though the
formation of tetraspanin-enriched microdomains. They are family of membrane
proteins found in all multicellular eukaryotes. Tetraspanins are superfamily of
proteins with four transmembrane domains with characteristic of structural
features (Andreu and Yáñez-Mó, 2014).