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Current Status of Malaria Vaccinology

In order to assess the current status of malaria vaccinology one
must first take an overview of the whole of the whole disease.
One must understand the disease and its enormity on a global
basis. Malaria is a protozoan disease of which over 150 million
cases are reported per annum. In tropical Africa alone more than
1 million children under the age of fourteen die each year from
Malaria. From these figures it is easy to see that eradication of
this disease is of the utmost importance.

The disease is caused by one of four species of Plasmodium These
four are P. falciparium, P .malariae, P .vivax and P .ovale.
Malaria does not only effect humans, but can also infect a
variety of hosts ranging from reptiles to monkeys. It is
therefore necessary to look at all the aspects in order to assess
the possibility of a vaccine. The disease has a long and complex
life cycle which creates problems for immunologists. The vector
for Malaria is the Anophels Mosquito in which the life cycle of
Malaria both begins and ends. The parasitic protozoan enters the
bloodstream via the bite of an infected female mosquito. During
her feeding she transmits a small amount of anticoagulant and
haploid sporozoites along with saliva. The sporozoites head
directly for the hepatic cells of the liver where they multiply
by asexual fission to produce merozoites. These merozoites can
now travel one of two paths. They can go to infect more hepatic
liver cells or they can attach to and penetrate erytherocytes.

When inside the erythrocytes the plasmodium enlarges into
uninucleated cells called trophozites The nucleus of this
newly formed cell then divides asexually to produce a schizont,
which has 6-24 nuclei. Now the multinucleated schizont then
divides to produce mononucleated merozoites . Eventually the
erythrocytes reaches lysis and as result the merozoites enter the
bloodstream and infect more erythrocytes. This cycle repeats
itself every 48-72 hours (depending on the species of plasmodium
involved in the original infection) The sudden release of
merozoites toxins and erythrocytes debris is what causes the
fever and chills associated with Malaria.

Of course the disease must be able to transmit itself for
survival. This is done at the erythrocytic stage of the life
cycle. Occasionally merozoites differentiate into
macrogametocytes and microgametocytes. This process does not
cause lysis and there fore the erythrocyte remains stable and
when the infected host is bitten by a mosquito the gametocytes
can enter its digestive system where they mature in to
sporozoites, thus the life cycle of the plasmodium is begun again
waiting to infect its next host. At present people infected with
Malaria are treated with drugs such as Chloroquine, Amodiaquine
or Mefloquine. These drugs are effectiv e ateradicating the
exoethrocytic stages but resistance to them is becoming
increasing common. Therefore a vaccine looks like the only viable

The wiping out of the vector i.e. Anophels mosquito would also
prove as an effective way of stopping disease transmission but
the mosquito are also becoming resistant to insecticides and so
again we must look to a vaccine as a solution Having read certain
attempts at creating a malaria vaccine several points become
clear. The first is that is the theory of Malaria vaccinology a
viable concept? I found the answer to this in an article
published in Nature from July 1994 by Christopher Dye and
Geoffrey Targett. They used the MMR (Measles Mumps and Rubella)
vaccine as an example to which they could compare a possible
Malaria vaccine Their article said that “simple epidemiological
theory states that the critical fraction (p) of all people to be
immunised with a combined vaccine (MMR) to ensure eradication of
all three pathogens is determined by the infection that spreads
most quickly through the population; that is by the age of one
with the largest basic case reproduction number Ro.  If a vaccine
can be made against the strain with the highest Ro it could
provide immunity to all malaria plasmodium ”

Another problem faced by immunologists is the difficulty in
identifying the exact antigens which are targeted by a protective
immune response. Isolating the specific antigen is impeded by the
fact that several cellular and humoral mechanisms probably play a
role in natural immunity to malaria – but as is shown later there
may be an answer to the dilemma. While researching current
candidate vaccines I came across some which seemed more viable
than others and I will briefly look at a few of these in this
essay. The first is one which is a study carried out in the
Gambia from 1992 to 1995.(taken from the Lancet of April 1995).

The subjects were 63 healthy adults and 56 malaria identified
children from an out patient clinic Their test was based on the
fact that experimental models of malaria have shown that
Cytotoxic T Lymphocytes which kill parasite infected hepatocytes
can provide complete protective immunity from certain species of
plasmodium in mice. From the tests they carried out in the
Gambia they have provided, what they see to be indirect evidence
that cytotoxic T lymphocytes play a role against P falciparium in
humans Using a human leucocyte antigen based approach termed
reversed immunogenetics they previously identified peptide
epitopes for CTL in liver stage antigen-1 and the
circumsporozoite protein of P falciparium which is most lethal of
the falciparium to infect humans. Having these identified they
then went on to identify CTL epitopes for HLA class 1 antigens
that are found in most individuals from Caucasian and African
populations. Most of these epidopes are in conserved regions of
P. falciparium. They also found CTL peptide epitopes in a further
two antigens trombospodin related anonymous protein and
sporozoite threonine and asparagine rich protein. This indicated
that a subunit vaccine designed to induce a protective CTL
response may need to include parts of several parasite antigens.

In the tests they carried out they found, CTL levels in both
children with malaria and in semi-immune adults from an endemic
area were low suggesting that boosting these low levels by
immunisation may provide substantial or even complete protection
against infection and disease. Although these test were not a
huge success they do show that a CTL inducing vaccine may be the
road to take in looking for an effective malaria vaccine. There
is now accumulating evidence that CTL may be protective against
malaria and that levels of these cells are low in naturally
infected people. This evidence suggests that malaria may be an
attractive target for a new generation of CTL inducing vaccines.

The next candidate vaccine that caught my attention was one which
I read about in Vaccine vol 12 1994. This was a study of the
safety, immunogenicity and limited efficacy of a recombinant
Plasmodium falciparium circumsporozoite vaccine. The study was
carried out in the early nineties using healthy male Thai rangers
between the ages of 18 and 45. The vaccine named R32 Tox-A was
produced by the Walter Reed Army Institute of  Research,
Smithkline Pharmaceuticals and the Swiss Serum and Vaccine
Institute all working together. R32 Tox-A consisted of the
recombinantly produced protein R32LR, amino acid sequence
[(NANP)15 (NVDP)]2  LR, chemically conjugated to Toxin A
(detoxified) if Pseudomanas aeruginosa. Each 0.4 ml dose of R32
Tox-A contained 320mg of the R32 LR-Toxin-A conjugate (molar
ratio 6.6:1), absorbed to aluminium hydroxide (0.4 % w/v), with
merthiolate (0.01 %) as a preservative. The Thai test was based
on specific humoral immune responses to sporozoites are
stimulated by natural infection and are directly
predominantly against the central repeat region of the major
surface molecule, the circumsporozoite (CS) protein. Monoclonal
CS antibodies given prior to sporozoite challenge have achieved
passive protection in animals.

Immunization with irradiated sporozoites has produced protection
associated with the development of high levels of polyclonal
CS antibodies which have been shown to inhibit sporozoite
invasion of human hepatoma cells. Despite such encouraging animal
and in vitro data, evidence linking protective immunity in humans
to levels of CS antibody elicited by natural infection have been
inconclusive possibly this is because of the short serum half-
life of the antibodies. This study involved the volunteering of
199 Thai soldiers. X percentage of these were vaccinated using
R32 Tox -A prepared in the way previously mentioned and as
mentioned before this was done to evaluate its safety,
immunogenicity and efficacy. This was done in a double blind
manner all of the 199 volunteers either received R32Tox-A or a
control vaccine (tetanus/diptheria toxiods (10 and 1 Lf units
respectively) at 0, 8 and 16 weeks.

Immunisation was performed in
a malaria non-transmission area, after completion of which
volunteers were deployed to an endemic border area and monitored
closely to allow early detection and treatment of infection. The
vaccine was found to be safe and elicit an antibody response in
all vaccinees. Peak CS antibody (IgG) concentrated in malaria-
experienced vaccinees exceeded those in malaria-nave vaccinees
(mean 40.6  versus 16.1 mg ml-1; p = 0.005) as well as those
induced by previous CS protein derived vaccines and observed in
association with natural infections. A log rank comparison of
time to falciparium malaria revealed no differences between
vaccinated and non-vaccinated subjects. Secondary analyses
revealed that CS antibody levels were lower in vaccinee malaria
cases than in non-cases, 3 and 5 months after the third dose of
vaccine. Because antibody levels had fallen substantially before
peak malaria transmission occurred, the question of whether or
not high levels of CS antibody are protective still remains to be
seen. So at the end we are once again left without conclusive
evidence, but are now even closer to creating the sought after
malaria vaccine. Finally we reach the last and by far the most
promising, prevalent and controversial candidate vaccine. This I
found continually mentioned throughout several scientific

“Science” (Jan 95) and “Vaccine” (95) were two which
had no bias reviews and so the following information is taken
from these. The vaccine to which I am referring to is the SPf66
vaccine. This vaccine has caused much controversy and
raised certain dilemmas. It was invented by a Colombian physician
and chemist called Manual Elkin Patarroyo and it is the first of
its kind.

His vaccine could prove to be one the few effective
weapons against malaria, but has run into a lot of criticism and
has split the malaria research community. Some see it as an
effective vaccine that has proven itself  in various tests
whereas others view as of marginal significance and say more
study needs to be done before a decision can be reached on
its widespread use. Recent trials have shown some promise. One
trial carried by Patarroyo and his group in Columbia during 1990
and 1991 showed that  the vaccine cut malaria episodes by over 39
% and first episodes by 34%. Another trail which was completed in
1994 on Tanzanian children showed that it cut the incidence of
first episodes by 31%. It is these results that have caused the
rift within research areas. Over the past 20 years, vaccine
researchers have concentrated mainly on the early stages of the
parasite after it enters the body in an attempt to block
infection at the outset (as mentioned earlier).

Patarroyo however, took a more complex approach. He spent his
time designing a vaccine against the more complex blood stage of
the parasite – stopping the disease not the infection. His
decision to try and create synthetic peptides raised much
interest. At the time peptides were thought capable of
stimulating only one part of the immune system; the antibody
producing B cells whereas the prevailing wisdom required T cells
as well in order to achieve protective immunity. Sceptics also
pounced on the elaborate and painstaking process of  elimination
Patarroyo used to find the right peptides. He took 22
“immunologically interesting” proteins from the malaria
parrasite, which he identified using antibodies from people
immune to malaria, and injected these antigens into monkeys and
eventually  found four that provided some immunity to malaria. He
then sequenced these four antigens and reconstructed dozens of
short fragments of them. Again using monkeys (more than a
thousand) he tested these peptides individually and in
combination until he hit on what he considered to be the jackpot
vaccine. But the WHO a 31% rate to be in the grey area and so
there is still no decision on its use.

In conclusion it is obvious that malaria is proving a difficult
disease to establish an effective and cheap vaccine for in that
some tests and inconclusive and others while they seem to work do
not reach a high enough standard. But having said that I hope
that a viable vaccine will present itself in the near future
(with a little help from the scientific world of course).

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