Malaria vaccines cum antimalaria drugs, by bdollar

Current status and Trends of antimalarial drugs & Vaccine development

ByMPHIL/MSC BIOTECHNOLOGY

KWAME NKRUMAH UNIVERSITY OF SCIENCE & TECHNOLOGY 1

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.


Life Cycle


Source: WHO

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


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


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


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


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


Limitations/problems of the aforementioned drugs Parasite resistance

Current approach use of combinatorial therapies

E.g. ACT Vector resistance


Current status and trends


Organelle targeted based drugsTargeting the food vacuole

Protease inhibitors; three enzymes produced by the parasite viz aspartic (plasmepsin),

cysteine (falcipain) and metallo (falcilysin) proteasesPlasmepsin II inhibitors have been identified and

currently been pursuedTherapeutic 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


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


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


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


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


Malaria vaccine


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


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.


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


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…


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.


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


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


Future prospects in malaria vaccine development cont’d4. 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


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.


http://www.cdc.gov/malaria/about/history/Accessed

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Malaria vaccines cum antimalaria drugs, by bdollar