Parasite Vaccines in Trials and in Use

Current ParasitiC
VaCCine : in use and in
trial
Presenter:
DrAnjanSarma, PGT
Deptt. Of Microbiology, GMCH

# Classification &# Classification &
DefinationsDefinations
# Currently used Vaccines# Currently used Vaccines
# Parasite Vaccines and# Parasite Vaccines and
their Problemstheir Problems
#NTP & Major Human#NTP & Major Human
parasitic diseasesparasitic diseases
# Protozoan vaccines :# Protozoan vaccines :
Malaria VaccineMalaria Vaccine
# RTS,S : The Leading# RTS,S : The Leading
Malaria vaccine candidateMalaria vaccine candidate
# Leishmania & other# Leishmania & other
protozoan Vaccinesprotozoan Vaccines
# Helminthic Vaccine# Helminthic Vaccine
:Hookworm & Schistosoma:Hookworm & Schistosoma
# Conclusion# Conclusion

introduCtionintroduCtion
What does a vaccine do ?
Stimulates normal protective immune response of host to
fight invading pathogen.
Exposure to pathogens allows vertebrate hosts to mount
pathogen-specific acquired immune responses that
sometimes protect against subsequent infection, forming
the basis of vaccinology.

What knowledge is needed to produce a vaccine?
1. Understand life–cycle of parasite → find best target stage.
2. Understand immune mechanisms stimulated by parasite.
→ humoral /cellular response.
What does a vaccine needs to do to work?
 Vaccines contain antigens that serve as targets for the
immune system.
 Antigens must produce protective response: ideally
sustained protection.

 Vaccine must stimulate good response → without adjuvant
is best.
 Good level of protection without boosting→ using simple
delivery system.
 Safe: Vaccine must not itself cause illness or death
PRACTICAL CONSIDERATIONS:
i. Low cost per dose.
ii. Biological stability.
iii.Ease of administration.
iv.Minimal side-effects.

HistoriCal asPeCts…HistoriCal asPeCts…

Year Event
1000 AD :Chinese employed smallpox inoculation (or variolation, as such use of smallpox
material was called) . Powdered scabs from infected people were used to
protect against the disease.
1721 Lady Mary Wortley brought the knowledge of these tecniques from
Constanstinople (now Istanbul) to England. 2 to 3 % of all smallpox vacinees
died from the vaccination itself.
1796 Edward Jenner’s innovations, begun with his successful use of cowpox material
to create immunity to smallpox. The term “vaccine” was coined from the latin
word “vacca” meaning cow.
1879 Louis Pasteur showed that chicken cholera weakened by growing it in the
laboratory could protect against infection against more virulent strains.
1881 Louis Pasteur showed in a public experiment in Pouilly-Le-Fort that his anthrax
vaccine was efficient in protecting sheep, goat, cows.
1885 Pasteur developed a rabies vaccine based on live attenuated virus.
1886 Edmund Salmon and Theobold Smith developed a (heat) killed cholera vaccine.
1927 Over the next 20 yrs, killed typhoid and plague are developed.
The bacille Calmette-Guerin (BCG vaccine) aginst tuberculosis vaccine was
developed.

ClassifiCation of VaCCinesClassifiCation of VaCCines

some definations…some definations…
Subunit vaccine:
A vaccine made up of only the antigens that best
stimulate the immune system. They are made in one
of two ways: either by chemical extraction of the
native antigen, the whole organism, or as
recombinant proteins expressed in other organisms
(e.g., bacteria), in which case they would be termed
‘recombinant subunit vaccines’.

some definations…some definations…
• Live attenuated vaccine: a vaccine made from the living
microbe that has been weakened in the laboratory so it
cannot cause disease but may still be able to replicate in
the host.
• Inactivated vaccine: a vaccine made by killing the disease-
causing microbe with chemicals, heat, or radiation.
• Conjugate vaccine: a vaccine created by covalently
attaching a poorly immunogenic antigen (e.g., a
polysaccharide) to a carrier protein thereby conferring the
immunological attributes of the carrier to the attached
antigen. This type of vaccine is a special type of subunit
vaccine.

Currently liCensed Human VaCCinesCurrently liCensed Human VaCCines
Vaccine Common
name/combinatio
n vaccine
Pathogen Type of vaccine
Anthrax Bacteria Subunit
Chicken pox Varicella Virus Live, attenuated
Cholera Bacteria Inactivated
Diptheria DPT Bacteria Inactivated toxin
Haemophilus influenza
type B
Hib Conjugate
Hepatitis A Virus Inactivated
Hepatitis B Virus Subunit
Human papilloma virus HPV Virus Subunit
Influenza vaccine Virus Live, attenuated
Japanese encephalitis
vaccine
Virus Inactivated

Vaccine Common
name/combination
vaccine
Measles MMR Virus Live, attenuated
Mumps MMR Virus Live, attenuated
Rubella MMR Virus Live, attenuated
Pertusis Whooping cough (DPT) Subunit
Pneumococcal
infections
Meningitis and
pneumonia
Meningococcus
Subunit
Polio Virus Attenuated (Sabin polio
vaccine)
Inactivated (Salk polio
vaccine
Rabies Virus Inactivated

Vaccine Common
name/combination
vaccine
Rotavirus Virus Live, attenuated
Small pox Dryvax Virus Live, attenuated
Shingles Herpes zooster Virus Live, attenuated
Tetanus DPT Bacterial toxin Inactivated toxin
Tuberculosis Bacilli Calmette–Ge
´urin (BCG)
Bacteria Live, attenuated
Typhoid Bacteria Inactivated
Yellow fever Virus Live, attenuated

Parasite VaCCinesParasite VaCCines
Why limited success in parasite vaccine
development ?
 Parasites avoid, deflect & confuse host immune system.
 Right parasite antigens not identified yet: complicated life
cycles (maybe 20,000 proteins in nematodes).
 Protective host responses not understood in target species
: multi-responses (most research in rodent models).

Problems related to Parasite VaCCinesProblems related to Parasite VaCCines
Significant :
• The Protective Immune Response
• Antigen Expression and Variation
• Animal models
• Single/Multiple antigens
• Adjuvants
Others :
• Antigen discovery
• Process development
• Preclinical development
• Clinical development

The Protective Immune Response:
 Lack of definition of the exact immune effectors and
responsible parasitic antigens.
 Lack of consensus on the type of immune response
required to eliminate infections.
Antigen Expression and Variation:
 Parasites present a variety of temporally expressed
antigens to the host immune system, which also shows
stage-specificity.
 Some may be associated with protective immune response,
and not all.
 Most parasites also show great antigenic variation of
surface proteins.

Animal models :
 Animal models are essential to define immune response,
protective efficacy, and safety prior to clinical trials.
 Candidate antigens may show efficacy in animals but not in
humans.
 Animals may not be fully permissive so that infection
outcomes may be different from those in humans.

Single/Multiple antigens:
 Parasites are complex organisms and protective response
may not be elicited by a single protein antigen.
 Antigen combinations are generally more effective, and
possibly targeting more than one stage of the parasite.
Adjuvants :
 Wrong choice of adjuvant may lead to misleading
experimental outcomes.
 Thus good candidate antigens may be rejected.

FEW OthEr PrOblEms …FEW OthEr PrOblEms …
Antigen discovery:
 Complicated genetic structures of pathogens
 Absence of genome databases or bioinformatic algorithms
for selecting candidate antigens of promise.
Process development:
 Necessity to scale up production of vaccine at adequate
yields and at low cost.
 Failure of many bacterial expression systems to produce
properly folded recombinant proteins .

FEW OthEr PrOblEms …FEW OthEr PrOblEms …
Preclinical development :
 Difficulty in maintaining different life cycle stages of
parasites in vitro.
 Paucity of laboratory animal models permissive to the
parasites.
Clinical development :
 Clinical trials in resource-poor setting difficult.
 Highly modulated immune response from infection with
many parasites, especially helminths , present some
dangers for vaccination.

NEglEctEd trOPical disEasEsNEglEctEd trOPical disEasEs
Helminth Infections Protozoan Infections Bacterial Infections
Ascariasis Chagas Disease Trachoma
Trichuriasis Human African
Trypanosomiasis
Leprosy
Hookworm Leishmaniasis Buruli Ulcer
Lymphatic Filariasis
Onchcocerciasis
Dracunculiasis
Schistosomiasis
The core group of 13 neglected tropical diseases
includes the following :

NEglEctEd trOPical disEasEsNEglEctEd trOPical disEasEs
• These are ancient conditions that have plagued humankind
for centuries, and are sometimes also referred to as the
“biblical diseases.
• Most are confined to economically deprived countries.
• Anti-poverty vaccines.

maJOr hUmaN Parasitic disEasEsmaJOr hUmaN Parasitic disEasEs
DISEASE Population at Risk
(106
)
Cases
(106
)
Mortality
(106
)
MALARIA > 2100 270-400 1120
Sleeping Sickness >60 0.3-0.5 49
Chagas Disease 120 17 13
Leishmaniasis 350 12 57
Intestinal Protozoa 3500 450 65
Schistosomiasis 600 >200 15
Onchocerciasis 120 18 0
Lymphatic filariasis 1000 120 0
Geohelminths 4500 3000 17

PrOtOzOaN VacciNEsPrOtOzOaN VacciNEs
STAGE Mode of Action
The Pre-erythrocytic stage Better known as the liver stage, or the stage before
the parasite infects human red blood cells
The Erythrocytic stage The blood stage when the parasite is infecting the red
blood cells
The Sexual stage The stage when the parasite has been taken up by a
mosquito and is sexually reproducing in the mosquito
gut.
MALARIA VACCINE: Before we go into detail on how a
vaccine could prevent malaria, it’s helpful to review
the stages of the parasite’s life cycle.
The three stages of the Plasmodium life cycle are :

immUNitY & malariaimmUNitY & malaria
The starting point in our understanding of immunity to malaria is that
from epidemiological studies it is known that:
 malaria infections are long-lived, 1–2 years in the case P. falciparum
and 3–50 years for P. Malariae
 individuals can be reinfected after natural recovery or cure
 there is a gradual build up of immunity over a period of many years
 any immunity fades quickly
 immunity is largely strain-specific
 children born to immune mothers are themselves resistant to that
particular strain of malaria.
In summary, immunity to malaria can be considered to be the rule, although it is
often incomplete and may take many years and numerous exposures to the bite
of infected mosquitoes to develop. Thus, there is evidence of some immunity
and the real challenge is to try to understand the mechanisms involved in order
to develop effective vaccines.

immUNitY & malariaimmUNitY & malaria
 Each stage in this complex life cycle is antigenically distinct and a
potential target for immune attack.
 In addition, malaria parasites have evolved a number of ways to
evade the immune response so some of the antigens identified could
be counter-protective.
 The malaria parasite is most susceptible when the sporozoite is
circulating in the blood, when merozoites are liberated from the liver
into the bloodstream before they invade the red blood cells, and
when merozoites have been released from red blood cells.
 The sporozoite is the obvious first target for immune attack. It is the
first stage in the infection and the parasites are free in the blood for
up to 30_45 min.

liFE cYclE OFliFE cYclE OF PlasmOdiUm sP.PlasmOdiUm sP.

malaria VacciNEsmalaria VacciNEs
Main Challenge : Does not confer so-called sterile
immunity.
This means that if you become ill from malaria and recover,
you can be infected over and over again. The fact that your
immune system responded to malaria in the past will not
prevent future infection.
Most people who are re-infected with malaria experience
only mild symptoms due to this partial acquired immunity.
But, naturally acquired partial immunity does not last long.

So, one approach to developing a malaria vaccine would be
to understand the mechanism of partial immunity and
develop a vaccine based on that principle.
1967: Nussenzweig et al. immunized mice with radiation
attenuated Plasmodium berghei (a non-human form of
malaria) sporozoites.
2002: Hoffman et al. showed that they could use gamma
radiation to attenuate the sporozoites inside infected
Anopheles mosquitoes.

• This irradiation approach had two major flaws:
I. It was not cost effective and
II. Not practical on a large scale.
• Nevertheless it served as a proof of principle, giving
scientists hope for the future and helping to stimulate a
great deal of research into the field.
Current Research :
• Scientists have expanded on what was learned in the 2002
study to develop many potential malaria vaccines.
• And because the parasite has three different life stages,
there are three distinct vaccines approaches being
investigated.

malaria aNtigENsmalaria aNtigENs
Antigen Target How it works
Circumsporozoite Protein (CSP) An immunodominant 40–60 kda protein surface coat of the
sporozoite.
Thrombospondin Related
Adhesion Protein (TRAP)
Involved in sporozoite motility (sultan et al. 1997).
(LS-A), LS-A1, and LS-A3 Liver-stage antigens
Merozoite Surface Protein (MSP)-1 It is a glycoprotein with a molecular weight of c. 190–195
kda. Found in all the malaria parasites . Antibodies against
MSP-1 block red blood cell invasion
Apical Membrane Antigen (AMA)-
1, Erythrocyte Binding Antigen
(EBA)-175,
Serine Rich Antigen (SERA),
Ring-infected Erythrocyte Surface
Antigen (RESA),
All of which are involved in binding to or invading red blood
cells.
Erythrocyte Membrane Protein
(EMP), PfEMP-1
Found on the surface of late-infected red cells is involved in
sequestration . Undergoes antigenic variation. responsible
for the recrudescences that occur in falciparum malaria .
Antibodies against PfEMP-1 prevent sequestration and
facilitate parasite destruction in the spleen.

rts,s VacciNErts,s VacciNE: thE lEadiNg caNdidatE: thE lEadiNg caNdidatE
• Pre-erythrocytic vaccines: These target the infectious phase and
aim either to prevent the sporozoites from getting into the liver cells.
 The most significant challenge : the time frame. Sporozoites reach
the liver less than an hour after being injected by the mosquito.
 The sporozoite possesses an immunodominant 40–60 kDa protein
surface coat, the Circumsporozoite Protein (CSP), characterized by a
repeat region consisting of four amino acids repeated 37 times, and
three or four copies of a smaller repeat dispersed throughout the
molecule.
 As a result, the immune system has a limited amount of time to
eliminate the parasite.
 Although most of the potential pre-erythrocytic vaccines are still in
Phase I or Phase II trials, one vaccine is currently in Phase III trials
and is showing promise: the RTS,S vaccine.

 In order to develop the RTS,S vaccine, developers identified the
protein that was most responsible for protection in the irradiated
sporozoite trial from 2002 which was the circumsporozoite protein,
or CS protein(CSP) .
• Although this antigen is protective, it is not very immunogenic on its
own. Thus, The C-terminus (amino acids 207–395) of the CSP from
P.falciparum was fused to the hepatitis B surface antigen ,
formulated in a multi-component adjuvant named AS01 & expressed
in the form of virus-like particles (VLPs) in Saccharomyces cerevisiae.
 The goal is to induce high levels of antibodies to both block the
sporozoites from entering the liver cells and to tag specific infected
cells for destruction.

 R - central repeat (‘R’) of circumsporozoite protein
 T - T cell epitopes
 S - surface antigen of hepatitis B
• S - unfused S protein
• The RTS,S vaccine was tested in Phase III trials in 11 different African
countries.
• October 2011: in children aged 5-17 months, vaccination with RTS,S
reduced the risk of clinical malaria and severe malaria by 56% and
47%, respectively.
• November 2012: in infants aged 6-12 weeks, vaccination with RTS,S
led to one-third fewer episodes of both clinical and severe malaria.
• October 2015: Vaccine programme recommended by two WHO
advisory bodies.

RTS,S VaccineRTS,S Vaccine: The Leading candidaTe: The Leading candidaTe
• 17 NOVEMBER 2016 | GENEVA – WHO confirmed that the world’s
first malaria vaccine will be rolled out in pilot projects in sub-Saharan
Africa.
Vaccine financing and development
 RTS,S vaccine was conceived of and created in the late 1980s .
 It was developed through a partnership between GlaxoSmithKline
and the PATH Malaria Vaccine Initiative (MVI), with support from
the Bill & Melinda Gates Foundation and from a network of African
research centres.
 Global Fund to Fight AIDS, Tuberculosis and Malaria: approved US$
15 million for the malaria vaccine pilots.
 Gavi, the Vaccine Alliance and UNITAID announced commitments of
up to US$ 27.5 million and US$ 9.6 million, respectively.

MaLaRia VaccineSMaLaRia VaccineS
• Erythrocytic vaccines, or blood-stage vaccines, aim to stop the rapid
invasion and asexual reproduction of the parasite in the red blood
cells.
They are the easiest to study, they are responsible for much of the
disease and they are obvious targets for attack. A vast amount of
information about these stages has been accumulated and many of
the antigens involved have been characterized and cloned.
• Because of the huge number of merozoites (40,000)produced and
released from each infected liver cell during this stage,a blood-stage
vaccine can aim only to reduce the number of merozoites infecting
red blood cells rather than completely block their replication.
• Currently there are no blood-stage vaccines that have had the
success of the RTS,S vaccine and most are still undergoing Phase I or
II trials.

MaLaRia VaccineS:MaLaRia VaccineS: SPf66SPf66
 The only vaccine other than RTS,S that has been subject to extensive
field trials is SPf66, a synthetic vaccine consisting of a polymer of
three merozoite antigens: Pf83 (an 83 kDa peptide representing part
of MSP-1), Pf55, and Pf35.
• These antigens, none of which has been identified with any of the
known major malaria antigens, are linked trogether by the sporozoite
antigen NANP (asparagine-alanine-asparagine-proline) .
 In a number of extensive trials in Colombia, Ecuador, and Venezuela,
the results obtained indicated that the vaccine was safe and
immunogenic and, although it did not prevent malaria, it reduced the
number of malaria episodes. It has also undergone extensive trials in
natural populations of children in Africa and adults in Thailand but,
unfortunately, it did not prevent malaria in children in trials in
Tanzania or The Gambia & has now been discontinued in its original
form.

MSP-1, MSP-2 AND RESA combination
 This vaccine combined the merozoite surface proteins MSP-1 and
MSP-2 with P. falciparum ring-stage infected erythrocyte surface
antigen (RESA) in a Montanide adjuvant formulation.
 A Phase I/IIb trial in 5–9 years old children in Papua New Guinea
showed a 62% reduction in parasite density.
AMA-1/MSP-1 chimera
 Developed by the Second Military Medical University in Shanghai in
partnership with the WHO.
 A chimeric fusion of domain III of AMA-1 and the 19- kD portion of
MSP-1 called P. falciparum chimeric protein 2 (PfCP-2.9).
 Efficiently block parasitic growth

GLURP VACCINE
 GLUP present on parasitophorous membrane of mature schizont .
 Induce ADCC pathway.
Multiple –antigen DNA vaccine
 Encode five different liver-stage antigens: CSP, liver stage antigens 1
and 3 (LSA-1 and -3), exported protein 1 (EXP1), and the sporozoite
surface protein 2(TRAP).
 Induction of IFN- secreting CD4+ and CD8+T-cell responses .Ƴ

Sexual stage vaccine -Transmission blocking vaccine (TBV):
 Targets the stage of sexual reproduction that occurs in the mosquito
gut. It aims to kill the vector, the Anopheles mosquito, to stop further
spread of the parasite.
 One TBV candidate vaccine is the Pfs25-EPA being developed by US
National Institute of Allergy and Infectious Diseases Laboratory of
Malaria Immunology and Virology and Johns Hopkins University
Center for Vaccine Research.
 The idea behind this vaccine is that if the body can develop
antibodies against the Pfs25 antigen, a mosquito taking a blood meal
will take up some of these antibodies into its stomach. There the
antibodies will encounter the antigen, enabling them to interfere
with development and kill the parasite

Group (field collaboration) Vaccines (type) Target
Apovia, USA; New York University, USA ICC-1132 (protein) Pre-erythrocytic
GlaxoSmithKline Biologicals, Belgium; and WRAIR, USA (Medical Research
Council [MRC]
RTS,S (protein) Pre-erythrocytic
Laboratories, The Gambia; Centro de Investigacao em Saude de Manhica
[CISM], Mozambique),Malaria Vaccine Development Unit, National
Institutes Of Health, USA
Pvs25, AMA-1 (protein) Transmission
blocking,
blood stage
Naval Medical Research Center (NMRC),Vical, USA Pf-CS, Pf-SSP2/TRAP, Pf-
LSA-1, Pf-EXP-1, Pf-LSA-
3 (DNA vaccines)
Pre-erythrocytic
New York University, USA CS (synthetic polymers,
MAPs, polyoximes)
Pre-erythrocytic
Oxford University, UK (MRC Laboratories, The Gambia; Wellcome-Kenya
Medical Research Institute [KEMRI] collaboration, Kilifi, Kenya)
DNA ,MVA ME-TRAP,
FP9 ME-TRAP, MVA-CS
(DNA and recombinant
viral)
Pre-erythrocytic
Statens Serum Institut (SSI), Copenhagen; Institut Pasteur; Institute of
Lausanne, Switzerland
GLURP, MSP-3, CS
(synthetic Pre-
erythrocytic,
peptide)
Pre-erythrocytic,
Blood stage
Walter and Eliza Hall Institute of Medical Research, Melbourne;
Queensland Institute of Medical, Research (QIMR), Brisbane; Swiss
Tropical Institute; Biotech Australia Pty (Papua New Guinea Institute Of
Medical Research)
MSP-1, MSP-2, RESA
(protein)
Blood stage
Walter Reed Army Institute of Research (WRAIR), USA (KEMRI, Kisumu,
Kenya)
FMP-1 (protein) Blood stage

LeiShMania VaccineSLeiShMania VaccineS
Leishmanization
 It has been known since antiquity that individuals who had
healed cutaneous leishmaniasis skin lesions were protected
from further infections.
 Bedouin or some Kurdistani tribal societies traditionally expose
their babies' bottoms to sandfly bites in order to protect them
from facial lesions.
 Another ancient technique practised in the Middle East has been
the use of a thorn to transfer infectious material from lesions to
uninfected individuals.

• The leishmaniases are unique among parasitic diseases because a
single vaccine could successfully prevent and treat disease and has
the potential to protect against more than one Leishmania parasite
species.
I. Live Leishmania vaccine (Leishmanization, LZ)
II. First generation vaccines consisting of whole killed Leishmania or
fractions of the parasite
III.Second generation vaccines including all defined vaccines, i.e.,
recombinant proteins, DNA vaccines and combinations
IV. Live-attenuated Leishmania vaccines.

LEISHMANIZATION
 Not licensed, but used in Uzbekistan, former USSR, Iran, and Israel.
 Live virulent L. major promastigotes are harvested from cultures and used.
 At present, there is only one prophylactic live vaccine in use. This is a
mixture of live virulent L. major mixed with killed parasite registered in
Uzbekistan.
 Adverse side effects, include development of large persistent lesions,
psoriasis and immunosuppression.
First generation Vaccines: Whole killed/Fractions
 New World: Mayrink’s vaccine(L.amazonensis) ; Convit’s
Vaccine( L.mexicana+BCG).
 Incidence rate amongst the Montenegro Skin Test (MST) converted
individuals in the vaccine group was significantly lower than those in the
control (unvaccinated) group or vaccinated but MST nonconverted
individuals.

Old World: Autoclaved L.major+BCG (ALM+BCG)
• Two doses of the vaccine reduced the incidence by 43% in Leishmanin Skin
Test converted volunteers in Sudan against Visceral Leishmaniasis involving
2306 volunteers.
• To enhance the immunogenicity of the ALM+BCG vaccine, ALM was
adsorbed to alum and the resulting alum-ALM was mixed with BCG just
prior to injection.
• Appears to constitute a safe vaccine and an appropriate candidate for
further development.
• Fractionated Leishmania vaccine:
• Fucose Mannose ligand antigen; Soluble L. Donovani antigens ; soluble
exogenous antigens of L.major; L.donovani promastigote soluble antigen.
• Canine, hamster, and murine experimental stages.

Second Generation Vaccines: Recombinant protein vaccines.
 A variety of Leishmania vaccines consist of recombinant proteins;
poly-proteins produced by DNA cloning.
 More recent efforts aim at increasing the immunogenicity of DNA
cloned vaccines, including the use of genetic adjuvants and plasmid-
based expression of viral replicons.
 Some of the important recombinant protein candidate vaccines
include:
 Surface expressed glycoprotein leishmaniolysin (gp63),
 Leishmania activated C kinase(LACK),
 Parasite surface antigen (PSA),
 Leishmania derived recombinant polyprotein (Leish-111f) and serine
proteases.

• Leish-111f is a single polyprotein composed of three molecules fused
in tandem.
• The Leish-111f product is the first defined vaccine for leishmaniasis in
human clinical trials and has completed phase 1 and 2 safety and
immunogenicity testing in normal, healthy human subjects.
• Efficacious against cutaneous or mucosal leishmaniasis.
DNA Vaccine:
• DNA vaccines can be used therapeutically to treat CL caused by L.
major as well prophylactically.
Live-attenuated Leishmania vaccines:
• The live-attenuated anti-leishmanial vaccine is still at its early stages
of development.

OTheR PROTOzOan VaccineSOTheR PROTOzOan VaccineS
AMOEBIASIS: THE SERINE-RICH E. HISTOLYTICA PROTEIN:
• Mediates the binding of trophozoites of E. histolytica to the
mammalian cells.
• 85% of the vaccinated gerbils in a total of 3 trials were completely
protected from developing amebic liver abscess.
• The safety and immunogenicity has been well-documented in African
green monkeys.
THE N-ACETYLGALACTOSAMINE-INHIBITABLE E. HISTOLYTICA
LECTIN (GAL / GALNAC): Mediates adherence of trophozoites
• Although the vaccination has been protective in 66% of the animals,
in the remaining there has been evidence of a significant increase in
liver abscess size.
• OTHERS: 29-kDa cysteine-rich protein (peroxiredoxin) ,
lipophosphoglycan, oral/intranasal administration of lectins.

GIARDIASIS:
 Vaccines against giardiasis is potentially complicated by the fact that
the parasite can undergo antigenic variation.
 Cyst wall proteins are candidate antigens.
CRYPTOSPORIDIUM:
 Vaccination against C. parvum is focused on immuno-dominant
antigens expressed on the surface of sporozoites .
 Additional antigens, to which invasion-neutralizing antibody
responses are directed, included CpMuc4 and CpMuc5 which are
mucin-like glycoproteins.
 Recent approaches have used salmonella as a vaccine delivery
vehicle .

Chagas Disease:
• Bivalent therapeutic vaccine for the treatment of chronic Chagas
disease.
• The vaccine is comprised of two Trypanosoma cruzi recombinant
proteins formulated on alum. One of the antigens is a unique T. Cruzi
24 kDa antigen (Tc24) and the other is a unique T. cruzi surface
transialidase (TSA-1).
• Pre-clinical work.

HELMINTHS & THE IMMuNE SySTEMHELMINTHS & THE IMMuNE SySTEM
• Helminths (worm parasites) confront the immune system with
problems that are quite different from those posed by protozoa.
These problems are largely the consequences of greater size and
structural complexity, but are compounded by three additional
factors:
1. worms have the ability to move actively through the body of the host
2. as part of their life cycles, many undergo sequential developmental
changes in the host, during which their structure and antigenic make-
up may change dramatically
3. their bodies are covered by layers that are more complex and less
vulnerable to immune attack than conventional plasma membranes.

HELMINTHIC VACCINES: HOOKWORMHELMINTHIC VACCINES: HOOKWORM
Problems With Hookworm (+Other HELMINTHS) Vaccine
Development
1. The difficulty of maintaining human hookworms in animal models and the
cost of maintaining the hookworm in laboratory-canine model.
2. The absence of an laboratory animal that is permissive to human
hookworms and can accurately reproduce human disease (anemia).
3. Paucity of in vitro functional tests to determine the effectiveness of the
immune response induced by an experimental hookworm vaccine.
4. The lack of a protective immune response in humans and the consequent
absence of Correlates of Protection that can guide the discovery of vaccine
antigens and be used to assess their effectiveness in preclinical and clinical
trials.
5. No model of an effective immune response in humans to determine the
biological effect of the vaccine in humans

 Human Hookworm Vaccine Initiative (HHVI) is the only group currently working on
vaccines targeting this parasite.
 Ancylostoma Secreted Protein-2 of N. americanus (Na-ASP-2) is a 21 kDa protein
that is secreted by infective hookworm larvae upon entry into the host.
 Na-ASP-2 was chosen as a lead hookworm vaccine candidate in 2007-8.
 In a phase 1 study in hookworm-naïve adults living in the US, Na-ASP-2 adjuvanted
with Alhydrogel (wet gel suspension of alum) was well-tolerated and
immunogenic.
 However, a phase 1 safety and immunogenicity trial of this vaccine in healthy
adults from a hookworm endemic area in rural Brazil has to be halted when 3
participants developed immediate, generalized urticarial reaction.
 The urticarial reactions were associated with elevated levels of IgE antibodies
specific for Na-ASP-2, which were present before immunization most likely due to
previous hookworm infection.

PRESENT FOCuSPRESENT FOCuS
APR: Aspartic Protease (Haemoglobinase): Antibodies will block
haemoglobinase lining the digestive tract of parasites.
GST: Glutathione S Transferase: Antibodies will block
detoxification of host heme.

HELMINTHIC VACCINES: HOOKWORMHELMINTHIC VACCINES: HOOKWORM
• Sabin Vaccine Institute announced the start of Part II of its Phase I
clinical trial of the Na-GST-1 vaccine candidate in November, 2012.
• Part II of the trial commenced in American and Brazil, following
successful vaccinations in Part I of the study, which began in Belo
Horizonte, Brazil in late 2011.
• Ultimately, Na -GST-1 and Na -APR-1 would be used together a
bivalent vaccine.
• Aim of the vaccine will be to reduce moderate to heavy infections in
the host.

HELMINTHIC VACCINES: SCHISTOSOMAHELMINTHIC VACCINES: SCHISTOSOMA
• Only one schistosome antigen has entered into clinical trials.
• The Institute of Pasteur has taken a recombinant 28 kDa GST cloned
from S. haematobium through both phase 1 and 2 clinical testing in
Europe and West Africa (Senegal and Niger).
• Sh28-GST (Bilhvax) is a recombinant protein formulated with an
aluminum hydroxide adjuvant .
• Bilhvax appears to be immunogenic and well-tolerated in healthy
adults from non-endemic (France) and S. haematobium endemic
areas in Africa.

• The most important vaccine target of the schistosome is the
tegument.
• The tegument is thought to be involved in several key physiologic
processes: parasite nutrition, osmoregulation, and the evasion of
host immunity.
• Tetraspanins found in outer tegument play important role in
maintaining the integrity of the tegument.
• Sm-TSP-2 has been selected by the HHVI for development as a
human vaccine antigen.

• The Sm -TSP-2 recombinant schistosomiasis vaccine would be
intended primarily for school-aged children living in the S.
Mansoni endemic regions of sub-Saharan Africa and Brazil.
• The vaccine ideally would prevent the reacquisition of
schistosomes in the blood stream following initial treatment with
Praziquantel (vaccine-linked chemotherapy).

VETERINARy (TRANSMISSION-bLOCKINg) VACCINESVETERINARy (TRANSMISSION-bLOCKINg) VACCINES
• Field trials of the EG95 vaccine against echinococcosis in sheep are
currently underway in the Patagonian region of Argentina.
• Independent vaccine trials for Taenia solium carried out in pigs with
the TSOL18 antigen in Mexico, Peru, Honduras, and Cameroon have
all achieved 99–100% protection.
• Results were published of the first field trial of the TSOL18 vaccine,
which was carried out in north Cameroon. The vaccine completely
eliminated the transmission of T. solium by the pigs involved in the
trial.

CONCLuSION...CONCLuSION...
 In addition to the technological hurdles, the economic challenges
have until very recently discouraged the multinational
pharmaceutical companies from embarking on parasite vaccine R&D.
 Product development- Public Private Partnership (PDPPP) are non-
profit organizations that use industry practices or partner with
industry for purposes of developing, manufacturing, and clinically
testing vaccines . Because of their non-profit status, they attract
private and public donor support.
 International Vaccine Institute (S.Korea), Sabin Institute, MSD
Wellcome Trust Hilleman Lab (India) etc.

CONCLuSION...CONCLuSION...
 The availability of funds has speeded up the process of vaccine
development for many neglected diseases.
 To pursue vaccine manufacture through partnerships with innovative
developing countries (IDC). IDCs are middle-income countries, such
as Brazil, Cuba, China, and India, with modest economic productivity
but which have achieved a high level of innovation in
biotechnonology.

Snippets.. Latest News….Snippets.. Latest News….
• 24/10/2017: According to findings published in journal “ Proceedings
of the National Academy of Sciences”, researchers at the Wellcome
Trust Sanger Institute in the UK and colleagues studied the malaria
parasite at its most vulnerable stage - when invading human red
blood cells.
• By studying the parasite's genome and working backwards, in a
process known as Reverse Vaccinology, they have discovered five
vaccine targets which, if combined, show promise for further
development.

Snippets.. Latest News….Snippets.. Latest News….
• 16/10/2017 : Kenya, Ghana and Malawi were selected for the pilot phase of the
malaria vaccine implementation by WHO. The Kenyan ministry of health will
implement the malaria vaccine program in partnership with WHO and global
health agency, PATH. It will be administered to children in health facilities through
a four-dose schedule at ages 6, 7, 9 and 24 months.
• 31/10/2017 : GHIT is also investing US$4.09M to pursue a potentially
groundbreaking vaccine candidate that is being formulated to either prevent or
treat leishmaniasis. the team supported by GHIT has developed what is known as a
DNA vaccine that is "T cell-directed." This type of vaccine employs a different
approach to delivering disease antigens. Instead of using the disease antigens
themselves, this leishmaniasis vaccine candidate employs various sequences of
DNA that are intended to instruct human cells to produce five different
leishmaniasis antigens that in turn will serve as targets for the immune response.

REFERENCES…REFERENCES…
I. Topley and Wilson’s Mirobiology and Microbial Infections
II. Human Parasitic Vaccines - An Overview by Abhijit Chaudhury,
Department of Microbiology, Sri Venkateswara Institute of Medical
Sciences, Tirupathi, Andhra Pradesh, India. J Clin Biomed Sci 2014;
4(1):216-21
III. WHO Media Centre
IV. CDC : Centre for Disease Control, Atlanta
V. Textbook of Medical Parasitology by Dr S C Parija
VI. http://www.malariavaccine.org
VII. https://www.historyofvaccines.org Malaria and Malaria Vaccine
Candidates | History of Vaccines

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