This presentation slides give an upto date information on antimalaria drugs and vaccines. It can be used for academic purpose or some other purpose. It highlights some of the successes and potentials of antimalaria drugs.

1. Current status and Trends of antimalarial drugs
& Vaccine development
By
MPHIL/MSC BIOTECHNOLOGY
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2. Introduction
 Malaria is an acute or chronic mosquito-borne disease caused by parasitic
protozoan of genus Plasmodium.
 characterised by chills, anemia, fever and damage to organs like brain and
liver.
 About 1 million deaths globally every year
 Currently, 40% of the world’s population, live in malaria endemic areas
 Species of the Plasmodia such as P. falciparum, P. ovale, and P. vivax cause
tertian malaria while P. malariae causes benign quartan malaria.
 The most common complications of malaria are seen during pregnancy and
some complications such as convulsion (in children)
 acute pulmonary edema are common.
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3. Life Cycle
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Source: WHO

4. Brief history of antimalarial drug and vaccines
 Malaria is one of the earliest known infectious diseases to man
 Believed to have played a role in the collapse of the roman empire.
 Created havoc in Europe and US until early 20th
century when it was
eradicated through national-led sanitation drives
 Despite over a decade of efforts toward developing malaria vaccines, there is
currently no effective malaria vaccine on the market
 Current major antimalarial drugs (quinine and artemisinim) were developed
to protect military deployed to tropics during WW1 and Vietnam conflicts
 The selective availability to allied troops tipped the balance at the warfront
against German army in WW1
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5. Anti-malarial drugs
 Antimalarial drugs are developed against specific stages of the malaria
parasite known as “targets” in antimalarial drug design.
 These targets are associated with pathways or components of pathway that
are either…
 Unique to the parasite or
 Sufficiently different from the host
 This case the drug will have no or little effect on the host
 Current drugs were designed based on conventional drug discovery
techniques
 Pathogen and host genomic and proteomic based drug design still in
exploratory phase.
 Major organelles identified for drug targeting include food vacuole, apicoplast
and mitochondrion
 These organelles were selected based on their role in the parasite growth
and survival
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6. Anti-malarial drugs cont’d
 Since the inception of malaria control interventions,
 quinine and artemisinim both naturally produced antimalarial agents were
used by traditional healers
 Quinine was obtained from the bitter bark of Cinchona tree grown in S.
America, neem
 Over the period of the 1930s to the 1980s the following drugs were developed
and prescribed for malaria treatment;
 Chloroquine, amodiaquine, piperaquine, pyronaridine, mefloquine,
halofantrine, lumefantrine, primaquine and tafenoquine
 These drugs targeted the food vacuole
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7. Other targeted organelles and pathways…..
 Inhibitors of apicoplast activity
 Antibiotics; tetracycline, doxycycline and clindamycin
 Usually administered alone or in combination with antimalarial agents to
treat uncomplicated P. falciparium malaria
 Limitation: have short half-life in circulation(6-8h); hence require 3 -4
times administration;
 This limits their usage in the field
 Others within the category include fosmidomycin
 Inhibitors of mitochondrial electron transport
 Drugs in this category include atovaquone, DB-289 and 4 (1H)-pyridones
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8. Other targeted organelles and pathways…..
Inhibitors of parasite metabolism
 Inhibitors of the folate pathway
 Pyrimethamine; inhibites dihydrofolate reductatse (DHFR); a critical
enzyme in the folate pathway of the parasite to reduce dihydrofolate to
tetrahydrofolate
 Limitation: mutation in the DHFR gene led to resistance for the drug in
P. falciparium
 Inhibitors of sarcoplasmic/endoplasmic reticulum Ca2+
-dependent ATPase
 Artemisinim and its derivatives- the elucidation of its structure led to
development of …
 Artemether and artesunate
 Lipophilic and hydrophilic derivatives; are metabolized in vivo to
dihydroartemisinm which are 5-10 fold effective than artemisinim.
 Limitation; have short half-life of 60mins hence needs to be taken on˂
daily basis to be effective
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9. Limitations/problems of the aforementioned drugs
 Parasite resistance
 Current approach
 use of combinatorial therapies
 E.g. ACT
 Vector resistance
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10. Current status and trends
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11. Organelle targeted based drugs
Targeting the food vacuole
Protease inhibitors;
 three enzymes produced by the parasite viz aspartic (plasmepsin), cysteine
(falcipain) and metallo (falcilysin) proteases
Plasmepsin II inhibitors have been identified and currently been
pursued
Therapeutic potential of fluoromethyl ketone in blocking falcipain
have been demonstrated to delay the progress of malaria in mouse
malaria model
In animal experiment, oral administration of synthetic vinyl
sulfones (50 or 100mg/kg) showed that about 40% of treated
animals were cured
Overall, protease-based antimalarial drug formulations for human
use remains to be developed
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12. Organelle targeted based drugs cont’d
 Inhibitors of apicoplast activity
 Inhibitors of fatty acid biosynthesis
 Fatty acid biosynthesis pathway in apicoplast utilises type II or
dissociative pathway
 This pathway encompasses a set of enzymes different from the type I
pathway in humans
 The differences allow selective targeting without affecting the host
 In vitro trials demonstrated the blockage of several enzymes in the
pathway using thiolactomycin
 In both in vitro and in vivo systems, triclosan have been shown to inhibit enoyl
carrier protein reductase in the type II fatty acid biosynthesis pathway
 Overall, using the core structure of triclosan have been used to synthesize
new compounds which are currently being evaluated
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13. Pathway targeted based drugs
 Inhibitors of parasite metabolism
 folate pathway
 Sulfadoxine-pyrimethamine (SP) is being tried in triple combinations
with other antimalarial drugs such as amodiaquine, quinine etc
 Phase III trial of Chloroproguanil-dapsone combination (LapDap) have been
completed
 Shown to have achieved high cure rates and will eventually replace the SP
regimen
 LapDap is also being evaluated in combination with artesunate and
currently is undergoing clinical trial
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14. Pathway targeted based drugs cont’d
 Glycolysis pathway inhibitor;
 a drug that catalyses the gycolytic enzyme in ATP generation pathway
is currently being pursued in in vitro studies
 NADH and NADPH transfer inhibitors;
 HE-2000 which acts a non-competitive inhibitor NADH oxidase have
been demonstrated during phase I/II trials to achieve complete
clearance of malaria parasite
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15. Pathway targeted based drugs cont’d
 Peptide deformylase (PDF) inhibitors;
 P. falciparum encodes PDF which is expressed during trophozoite,
schizont and segmented stages of erythrocytic development
 Inhibiting this first step prevents the maturation of the prokaryotic
protein
 in vitro trials with high concentrations suppressed the growth of P.
falciparum
 This suggest a promising leads in current efforts in drug design
 Manzamine alkaloids such as manzamine A and β-carboline alkaloid have
been shown to inhibit growth of P. berghei
 Exact mechanism of action not known
 The lack of in vivo toxicity makes manzamines promising candidates in
current drug design
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16. Malaria vaccine
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17. Current strategies in vaccine design
 Targeting of specific stages of the parasite development
 Pre-erythrocytic stage
 Blood (intra-erythrocytic) stage
 Sexual stage
 Use of irradiated sporozoite vaccine
 Malaria toxin neutralization
 by using anti-parasite vaccine toxin
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18. Pre-erythrocytic vaccines
 Target the infectious phase and aim either to
 prevent the sporozoites from getting into the liver cells or
 to destroy infected liver cells.
 The most significant challenge for a pre-erythrocytic vaccine is the time
frame:
 sporozoites reach the liver less than an hour after being injected by the
mosquito.
 As a result, the immune system has a limited amount of time to eliminate
the parasite.
 most of the potential pre-erythrocytic vaccines are still in Phase I or Phase
II trials e.g.CSP vaccines, DNA and live recombinant vaccines
 Only one vaccine is currently in Phase III trials and is showing promise:
the RTS,S vaccine.
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19. erythrocytic vaccines
 Aim to stop the rapid invasion and asexual reproduction of the parasite in the
red blood cells.
 An infected liver cell produces 40,000 merozoites
 vaccine can aim only to reduce the number of merozoites infecting red
blood cells rather than completely block their replication
 Currently there are no bloodstage vaccines that have had the success of
the RTS,S vaccine
 most are still undergoing Phase I or II trials.
 Examples include merozoite surface protein (MSP) vaccines
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20. Sexual stage vaccine
 This approach is known as a transmission blocking vaccine (TBV)
 because it aims to kill the vector, the Anopheles mosquito, to stop further
spread of the parasite.
 An indirect approach to a vaccine because it aims to stop the continued
spread; not direct protection to an individual
 One TBV candidate vaccine is the Pfs25EPA is being developed in the US
against Pfs25 antigen
 Examples include…
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21. Malaria Vaccine Technology Roadmap
Developed by the world’s leading global health organizations
The roadmap has two goals:
 Develop and license a first-generation vaccine by 2015 that reduces the risk of
severe malaria disease and death by 50% and that protects longer than one
year.
 Develop a malaria vaccine by 2025 that would have a protective efficacy of
more than 80 percent against clinical disease and that would provide
protection for longer than four years.
 The recent release of RTS,S attempts to meet the first goal.
 To meet the second will require a second-generation RTS,S vaccine or a
different vaccine.
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22. Barriers to Developing a Malaria Vaccine
 lack of a traditional market,
 few developers, and the technical complexity of developing any vaccine
against a parasite.
 Malaria parasites have a complex life cycle,
 Poor understanding of the complex immune response to malaria infection.
 Malaria parasites are also genetically complex, producing thousands of
potential antigens.
 Unlike the diseases for which we currently have effective vaccines, exposure to
malaria parasites does not confer lifelong protection.
 Acquired immunity only partially protects against future disease, and malaria
infection can persist for months without symptoms of disease
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23. Future prospects in malaria vaccine development
Five observations predict the eventual success of vaccine development for
malaria:
1. Human populations residing in malaria endemic areas naturally acquire
protective immunity against disease, although the patterns of immunity vary
with malaria transmission patterns.
2. Several studies showed that immunoglobulin purified from the blood of
immune adults from endemic regions can passively transfer protection against
P. falciparum.
3. Clinical studies carried out since the 1970's demonstrated that experimental
vaccination with attenuated sporozoites can effectively immunize patients
against a subsequent malaria infection though efficacy remains limited
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24. Future prospects in malaria vaccine development cont’d
4. Animal models of malaria clearly substantiate the potential for induction of
protective immunity with defined vaccines.
5. Two recent clinical trials of defined vaccines in endemic regions have
reported significant, though limited, efficacy eg the RTS’S
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25. Reference
 CDC. The history of malaria, and ancient disease
http://www.cdc.gov/malaria/about/history/Accessed 01/20/2016.
 Hoffman et al. Proctection of humans against maleria by immunization with
radiationatteuated Plasmodium falciparum sporozoites.J Inf Dis 185:1155–1164
http://www.ncbi.nlm.nih.gov/pubmed/11930326 Accessed 01/20/2016.
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