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Sun News Publishing
Date:
Tue, 04/26/2011 - 16:40
Malaria vaccines are an area of intensive research, however,
no affective vaccines has yet been introduced into clinical
practice.
Malaria, a sickness caused by a parasite, plasmodium, that
has infected the saliva glands of a female is has been a major
health issue in many African and developing nations including
Nigeria.
The sickness is characterized by cyctes of chills, fever,
pain and sweating. Lately, the Artemisinin Combination Therapy
(ACT) anti-malarials were developed to give a double bared
attack on malaria, however, popular opinion maintain that
malaria vaccine will easily eradicate the disease.
The task of developing a vaccine that is of potentially preventive
benefit for malaria is a complex process. There are a number
of consideration to be made concerning what strategy a potential
vaccine should adopt. This is because the diversity of the
parasite continuous to be a stumbling black in the drive to
develop a vaccine.
Plasmodium falciparum, the parasite that causes malaria has
demonstrated the capability, through the development of multiple
drug-resistance parasites, of evolutionary change. “The
plasmodium species has a very high rate of replication, much
higher than that actually needed to ensure transmission in
the parasite’s life cycte,” experts say.
“This enables pharmaceutical treatments that are effective
in reducing the reproduction rate but not halting it to exert
a high selection pressure, thus favouring the development
of resistance.”
According to scientists, there are many antigens present throughout
the parasite life cycle that potentially could act as targets
for the vaccine. More than 30 of these are currently being
researched by teams all over the world in the hope of identifying
a combination that can elicit immunity in the inoculated individual.
Some of the approaches involve surface expression of the antigen,
inhibitory effects of specific antibodies on the life cycle
and the protective effects through immunization or passive
transfer of antibodies between an immune and a non-immune
host. The majority of research into malarial vaccines has
focused on the Plasmodium falciparum strain due to the high
mortality caused by the parasite and the ease of a carrying
out in vitro/in vivo studies. The earliest vaccines attempted
to use the parasitic circumsporozoite (CS) protein. This is
the most dominant surface antigen of the initial pre-erythrocytic
phase. However, problems were encountered due to low efficacy,
reactogenicity and low immunogenicity.
The first vaccine developed that has undergone field trials,
is the SPf66, developed by Manuel Elkin Patarroyo in 1987.
It presents a combination of antigens from the sporozoite
and merozoite parasites. During phase I trials a 75% efficacy
rate was demonstrated and the vaccine appeared to be well
tolerated by subjects and immunogenic. The phase IIb and III
trials were less promising, with the efficacy falling to between
38.8% and 60.2%. A trial was carried out in Tanzania in 1993
demonstrating the efficacy to be 31% after a year of follow
up, however the most recent (though controversial) study was
carried out in Gambia.
It did not show any effect despite the relatively long trial
periods and the number of studies carried out. It is still
not known how the SPf66 vaccine confers immunity; it therefore
remains an unlikely solution to malaria. The CSP was the next
vaccine developed that initially appeared promising enough
to undergo trials. It is also based on the circumsporoziote
protein, but additionally has the recombinant protein covalently
bound to a purified Pseudomonas aeruginosa toxin. However
at an early stage, a complete lack of protective immunity
was demonstrated in those inoculated. The study group used
in Kenya had an 82% incidence of parasitaemia whilst the control
group only had an 89% incidence.
The vaccine intended to cause an increased T-lymphocyte response
in those exposed, this was also not observed. The NYVAC-Pf7
multistage vaccine attempted to use different technology,
incorporating seven P.falciparum antigenic genes. These came
from a variety of stages during the life cycle. CSP and sporozoite
surface protein 2 (called PfSSP2) were derived from the sporozoite
phase. The liver stage antigen 1 (LSA1), three from the erythrocytic
stage (merozoite surface protein 1, serine repeat antigen
and AMA-1) and one sexual stage antigen (the 25-kDa Pfs25)
were included.
This was first investigated using Rhesus monkeys and produced
encouraging results: 4 out of the 7 antigens produced specific
antibody responses (CSP, PfSSP2, MSP1 and PFs25). Later trials
in humans, despite demonstrating cellular immune responses
in over 90% of the subjects had very poor antibody responses.
Despite this, following administration of the vaccine some
candidates had complete protection when challenged with P.falciparum.
This result has warranted ongoing trials.
In 1995 a field trial involving [NANP]19-5.1 proved to be
very successful. Out of 194 children vaccinated none developed
symptomatic malaria in the 12 week follow up period and only
8 failed to have higher levels of antibody present. The vaccine
consists of the schizont export protein (5.1) and 19 repeats
of the sporozoite surface protein [NANP]. Limitations of the
technology exist as it contains only 20% peptide and has low
levels of immunogenicity. It also does not contain any immunodominant
T-cell epitopes.
RTS,S is the most recently developed recombinant vaccine.
It consists of the P. falciparum cirumsporozoite protein from
the pre-erythrocytic stage. The CSP antigen causes the production
of antibodies capable of preventing the invasion of hepatocytes
and additionally elicits a cellular response enabling the
destruction of infected hepatocytes. The CSP vaccine presented
problems in trials due to its poor immunogenicity. The RTS,S
attempted to avoid these by fusing the protein with a surface
antigen from Hepatitis B, hence creating a more potent and
immunogenic vaccine. When tested in trials an emulsion of
oil in water and the added adjuvants of monophosphoryl A and
QS21 (SBAS2), the vaccine gave 7 out of 8 volunteers challenged
with P. falciparum protective immunity.
The global burden of P. falciparum malaria increased through
the 1990s due to drug-resistant parasites and insecticide-resistant
mosquitoes; this is illustrated by re-emergence of the disease
in areas that had been previously malaria-free. The first
decade of the 21st century has seen reductions in morbidity
and mortality in many settings. Though the reasons are not
entirely clear, improving socioeconomic indices, deployment
of artemisinin-combination drugs and insecticide-treated bednets
are all likely to have contributed. There has been a major
scaling-up in distribution of malaria control measures particularly
since the advent of The Global Fund to Fight AIDS, Tuberculosis
and Malaria.
It is unclear what the future will hold for disease burden
trends. If political will and funding is maintained, the disease
burden could drop further; if as in the past funding lapses
or clinically significant resistance develops to the main
antimalarial drugs and insecticides used, then the disease
burden may rise again. Early evidence of resistance to artemisinins,
the most important class of antimalarials, is now confirmed,
having manifested as delayed parasite clearance times in the
western region of Cambodia on the border with Thailand.
This is also the region where resistance to earlier antimalarial
drugs emerged and then subsequently spread throughout much
of the world in the case of chloroquine. The Bill and Melinda
Gates Foundation has launched a call for the aim of the malaria
community to shift from sustained control to eradication.
It is agreed that eradication is not possible with current
tools and that research and development of new drugs, diagnostics,
insecticides and a cost-effective deployable vaccine will
be needed to facilitate eradication. There has been a great
increase in funding for such research in the 21st century.
