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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 90, Num. 2, 1995, pp. 217-220
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Memorias Instituto Oswaldo Cruz, Vol. 90(2):217-220
mar./apr. 1995
Opportunitites and Constraints in Schistosomiasis Vaccine
Development: Infection Characteristics and Industry
Realities
Graham F Mitchell
R&D Division, CSL Limited, Parkville, Victoria 3052,
Australia
Code Number: OC95044
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Text: 18K
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[TABLES AT END OF TEXT]
The notes provided in this article relate to two components
of the development of vaccines against schistosomiasis: (1)
The characteristics of schistosome infections (eg. features of
the schistosome life cycle), and the parasite itself, that
have implications for vaccination strategies; (2) The
characteristics of the biopharmaceutical industry that have
implications for product development. As will be seen, these
two topic areas are not vastly disparate.
Key words: schistosomiasis - vaccines - life cycle -
immunopathology - pharmaceutical industry
Various aspects of the schistosome life cycle (attention here
being restricted to Schistosoma mansoni and S.
japonicum) are relevant to the approaches taken to
vaccination in mammalian hosts. These include skin
penetration by cercariae, migration of schistosomules through
the lungs, residency of adult worms in the portal system, and
tissue location of maturing eggs and the immunopathologic
responses elicited. In addition, much has been written about
the fact that worms do not proliferate in their vertebrate
hosts and, since the severity of disease is related to worm
burden, a schistosomiasis vaccine need not be 100% effective
to be a useful adjunct control measure.
Cercarial dermatitis in humans provoked by bird schistosomes
raises some concerns that vaccination with cercarial antigens
may sensitize for undesirable skin reactions on challenge.
Such reactions are not a prominent recorded feature of
schistosome-related pathology in endemic areas but, depending
on the type and magnitude of responses induced by vaccination
and subsequent skin exposure to cercariae, some cutaneous side
effects may become apparent.
Studies on life cycle characteristics of Philippines isolates
of S. japonicum in the mouse have raised the
possibility that this schistosome in mammalian hosts may
differ from others in transiting the lungs very rapidly
(Mitchell et al. 1991). Petechiae are prominent on the lung
surface of mice infected a few days previously with cercariae
of S. japonicum (Philippines) and the number matches
the number of adult worms found in the portal system at later
times. However, finding schistosomules in lungs is very
difficult. Moreover, young schistosomes can be found readily
in the liver at one week, compared with two weeks in S.
mansoni infection. If this is true in human infections
with S. japonicum (Philippines) then the lung stage of
the schistosome life cycle may not be an attractive target for
immune intervention. Schistosomules are something of a "moving
target" but those of S. japonicum (Philippines) may be
a "speeding target". Inflammatory responses (including
subsequent expulsion into airways) and IFN-g production by
sensitised T cells in lungs have been implicated in expression
of resistance to infection with S. mansoni in mice
exposed previously to irradiated cercariae (see Wilson RA,
this Symposium). It is of some interest that no demonstration
of resistance to infection in mice has been made using
irradiated cercariae of S. japonicum (Philippines)
[c.f. S. mansoni and S. japonicum (Chinese)].
Moreover, mice that are exposed to irradiated S.
japonicum (Chinese) and that are protected against
homologous challenge, are not resistant to infection with
S. japonicum (Philippines) (Moloney et al. 1985).
The mouse model of chronic schistosomiasis has been used to
demonstrate unequivocally that portal system changes that
follow granuloma formation, fibrosis and subsequent portal
hypertension can militate against incoming parasites remaining
in the portal system. The collateral blood flow presumably
transports them back to the lungs continuously and
demonstrations of resistance to reinfection in the mouse can
be ascribed readily to these (immuno) pathological events
rather than to anti-worm immune responses. Not surprisingly,
no candidate vaccine molecules have been identified through
analysis of apparent resistance to reinfection in the mouse
host. Interestingly, a similar phenomenon of high resistance
to first infection in a mouse strain studied at The Walter &
Eliza Hall Institute (WEHI) in Melbourne, namely the WEHI
129/J mouse (and to a lesser extent in the related C57Bl/6
strain), can be ascribed to portal system peculiarities that
result in young schistosomes being shunted to the lungs. The
basis of this peculiarity may be nutritional, though this has
not been demonstrated. Yet through analysis of immune
responses differentially expressed in resistant WEHI 129/J
mice compared with other susceptible (permissive) mouse
strains such a BALB/c, the glutathione S-transferases (GSTs)
were first identified as vaccine candidates! (Smith et al.
1986). The 26 kDa GST (Sj26) forms the basis of the useful
pGEX expression system developed by Donald Smith at WEHI, but
the molecule has proven not to induce consistent host-
protective immunity to S. japonicum (Philippines) in
various mouse strains. [On the question of a nutritional
contribution to portal system peculiarities in 129/J ñ C57Bl/6
mice on which we have speculated (Mitchell et al. 1990), it is
possible that hypervitaminosis A may lead to accumulation of
fat droplets in Ito cells in the Space of Disse (with or
without differentiation into myofibroblasts and fibroblasts)
and occlusive events in the liver (see Almeida Barbosa,
Pfeifer and Andrade this Symposium). The 129/J mouse could be
genetically prone to respond to any subsequent changes, such
as an increase in portal pressure, by formation of
intrahepatic portal shunts. It must be remembered that 129/J
mice purchased from the Jackson Laboratories are entirely
permissive hosts of schistosomes and their "resistance"
develops subsequent to breeding in the WEHI mouse rooms. At
the time, mouse foods were being supplemented with a vitamin
mix.]
The most obvious feature of schistosomiasis that should be
amenable to vaccine-induced modification is the
immunopathologic response to eggs that underlies the severe
pathology of chronic infection. Clear demonstrations of
granuloma modulation ("endogenous desensitization") following
prolonged exposure to egg antigens (eg. chronic infection)
sparked a flurry of activity throughout the 70s and 80s on
immunomodulation and the search for immune mediators and cells
responsible for this apparent down-regulation phenomenon.
During this period, an alternative explanation - that of
antibody-mediated anti-embryonation immunity and accelerated
destruction of immature eggs - was propounded to account for
the phenomenon in S. japonicum (Philippines) - infected
mice. This is discussed in a separate presentation at this
conference. Essentially, the hypothesis is that destructive
immune responses to antigens of maturing eggs destroy the eggs
before the miracidium matures. These responses thus reduce
production of immunopathologic antigens by the egg. Presen-
sitization with defined antigen (i.e. use of a molecular
vaccine) should inhibit the severe pathologic consequences of
infection. No molecules (or immune mechanisms) have yet been
identified that would form the basis of such an anti-disease
vaccine (see Mitchell et al., this Symposium).
Another means to reduce the overall intensity of disease
processes in schistosomiasis would be to induce anti-fecundity
responses resulting in reduced egg production by the female
worms. Fewer eggs in tissues should lead to reduced pathology
and reduced clinical manifestations (see Capron, this
Symposium).
Clearly, the complexity of the schistosome life cycle in
mammalian hosts provides difficulties as well as additional
opportunities for the vaccine developer (Table I). Whilst
similarities in the life cycle are obvious between the various
schistosomes, differences can be pronounced particularly in
infection of mice with S. japonicum (Philippines)
(see Mitchell et al., this Symposium).
The second topic area embraces issues far more relevant to
parasite vaccine development than parasitological issues.
An opportunity for new product development will be evaluated
by a potential manufacturer and commercializing organization
according to technical feasibility (ie risk) and a combination
of commercial attractiveness of the eventual product and
strategic fit of the project to corporate objectives (ie
value). This risk-value analysis can be quantitated and
plotted and will take into account the difference between an
idea with limited supporting data, a product concept, and a
clearly-defined prototype product, the latter obviously being
the most attractive. The intellectual property position (ie.
patents and licences but also proprietary information, secret
know-how, etc) and market size influence commercial
attractiveness with strategic fit embracing opportunities for
co-development and joint ventures, introduction of new
technologies into the in-house R&D department, and
establishment of strategic alliances and long-term linkages
with particular research groups. The reality is that any
attractions of human parasite vaccines are virtually confined
to opportunities for alliances with high-tech research groups
or, equally importantly, those able to undertake clinical
studies. Another reality - the extent and quality of the
documentation required for biologicals taken through the
regulatory and registration process - is quite extraordinary
and difficult for an academic, laboratory-based scientist to
comprehend. The under-resourced or faint-hearted will not
embark on this process! In Table II are listed some
deterrents to a vaccine developer, manufacturer and marketer
taking up a schisto vaccine opportunity.
Studies in Australia by Spithill and colleagues (Sexton et al.
1991), and Hillyer and Tendler et al. (this Symposium) offer
what might be an attractive approach to schistosomiasis
vaccines through a veterinary pathway. A trematode molecule
(eg GST or FABP) that induces a high level of protective
immunity against both Fasciola hepatica and
Schistosoma spp. could be developed as a (profitable)
fascioliasis vaccine in the first instance for use in sheep
and cattle. There should be little difficulty in attracting
the necessary development dollars for this product. In a
sense, the schisto vaccine could emerge as a "spin off" with
comprehensive investigations on the use of the vaccine in a
variety of hosts being important information for further
development of the product for use in humans as a schisto
vaccine.
The issue of autoimmunity and immunopathology is a major one
in schisto vaccine development. A disease that is known to be
associated with immunopathology -"schisto is a classical
immunopathologic disease" - and parasite vaccine candidates
that are related to host molecules (closely in some cases) are
definite negatives. Despite painstaking efforts to exclude
self-like epitopes and to exclude immunopathologic responses
induced to eggs through laboratory-based studies, the
relevance of autoimmunity and immunopathology is likely to
only become evident in late-stage, comprehensive and thus
expensive phase III and IV trials. The costs and effort to
even get to that stage and having the program clouded by the
ogre of immunopathology and autoimmunity (regardless of how
difficult it is to induce untoward autoimmune reactions in
short-lived laboratory animals) will be enough to dissuade
even an organization with an impeccable record in global
health endeavours and an altruistic component to its corporate
objectives.
The options available in parasite vaccine development are
decreasing rather than increasing even when viewed through the
eyes of an optimist and long-term advocate of the human
parasite vaccine objective. There are definite requirements
for full-blooded involvement by tropical countries themselves
which will have to take vaccine candidates through the D phase
of R&D and into manufacturing and clinical trials. The role of
local manufacturers (eg. FIOCRUZ in Brazil) becomes critical
with a facilitating role played by WHO and AID agencies of the
industrially-developed countries. Most important will be a
transfer of knowledge on process development as well as
clinical and regulatory affairs from the Western biopharma-
ceutical industry to counterparts in the developing world with
due recognition of infrastructural deficiencies, cultural
differences and technological limitations. The need is for
"assisted initiative" on the part of endemic countries if the
quest for new control measures for parasitic diseases
including vaccines (and the quest for improved global health,
that must be relentless) are to be successful.
TABLE I
Schistosomiasis vaccines: infection, parasite and epidemiological
characteristics that provide opportunities and difficulties
and uncertainties
Opportunities
Antigenically different life cycle stages :
multiple sites for immune attack with multiple immune effeetor
mechanisms to be exploited.
Non-proliferating parasite in vertebrate hosts :
population antigenie changes in the host unlikely.
Disease severity related to number of worm pairs :
partially effective vaccine still useful in endemic areas.
Disease abatement in chronic infection is immunologically based:
vaccination against disease is feasible.
Good epidemiological evidence for age-related resistance to infection
as well as disease.
Clear demonstrations of immune-facilitated drug action :
vaccine component to increase drug potency or useful life time
a possibility.
Identified as a priority disease for vaccine development by WHO-TDR
and other AID agencies.
Difficulties and Uncertainties
Complex organism - moving target for immune responses;
antigenie repertoire and polymorphisms ill defined;
multiple immune evasion mechanisms; potential for repair of
immune-mediated damage unknown.
Immunopathology - chronic schisto is a classical immunopathologic
disease; cutaneous hypersensitivity in vaccines possible
("cercarial dermatitis"); many protective antigens related to self
molecules - autoimmune possibilities.
Uncertainties about relevance of the immunology of infection in
animal models - what is basis of resistance in humans; relevant
model critical for defining a product to be developed (c.f. testing
a product concept in early clinical trials). Resistance in some
instances known not to be immunologically based - anatomical
peculiarities, hormones, etc.
Reinfection common after drug cure - what will be the duration of
memory in vaccinees constantly exposed or not'?
TABLE II
Deterrents to schistosomiasis vaccine developer
1. Immunopathology/autoimmunity/hypersensitivities
2. Expectations on efficacy - especially travellers
(+ endemic populations in some instances)
(Will an anti-disease or partially-effective vaccine
actually be acceptable'?)
3. Profitability and value of the product (technical
feasibility [risk] versus commereial attractiveness
+ strategic fit [value])
4. The costs and logistics of clinical trials for a prophylactic
in endemic countries (attractiveness of therapeutic vaccines
in clinical trials)
5. Regulatory requirements and ethical considerations
(Is the vaccine likely to be better and/or cheaper than
"the best current therapy?")
6. Vaccination risks in previously exposed individuals in endemic
countries
7. The adjuvant dilemma
"Most attractive to the vaccine developer are new, patentprotected products
for the treatment of illnesses that affect large numbers of affluent
people and for which current therapies are inadequate". N.B. Global markets
for several veterinary parasite vaccines are also very attractive.
References
Mitchell GF, Tiu WU, Garcia EG 1991. Infection
characteristics of Schistosoma japonicum in mice and
relevance to the assessment of schistosome vaccines. Adv
Parasitol 30: 167-200.
Mitchell GF, Wright MD, Wood SM, Tiu WU 1990. Further studies
on variable resistance of 129/J and C57BL/6 mice to infection
with Schistosoma japonicum and Schistosoma
mansoni. Parasite Immunol 12: 559-567.
Moloney NA, Garcia EG, Webbe G 1985. The strain specificity
of vaccination with ultra violet attenuated cercariae of the
Chinese strain of Schistosoma japonicum. Trans R Soc
Trop Hyg 79: 245-247.
Sexton JL, Milner AR, Panaccio M, Waddington J, Wijffels G,
Chandler D, Thompson C, Wilson L, Spithill TW, Mitchell GF,
Campbell NJ 1991. Glutathione S-transferases: novel vaccine
against Fasciola hepatica infection in sheep. J
Immunol 145: 3905-3910.
Smith DB, Davern KM, Board PG, Tiu WU, Garcia EG, Mitchell GF
1986. Mr26,000 antigen of Schistosoma japonicum
recognised by resistant WEHI 129/J mice is a parasite
glutathione S-transferase. Proc Natl Acad Sci USA
83: 8703-8707.
Copyright 1995 Fundacao Oswaldo Cruz (Fiocruz)
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