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a scourge of the tropics and subtropics
About 40 percent
of the world’s population live in areas with malaria, and an estimated 300-500
million are infected a year; of which 1.5-2.7 m die . In the year 2000,
malaria caused nearly 45 million Disability Adjusted Life Years (DALYs), accounting
for 13 percent of all DALYs associated with infectious diseases. Malaria is
caused by a protozoan (single celled animal) parasite transmitted by blood
sucking mosquitoes. There are four species of protozoa that cause malaria;
Plasmodium falciparum is responsible for the majority of infections
and is the most fatal.
The main strategies for combating malaria include controlling the mosquito
vectors with insecticides-treated bed nets, residual insecticides (insecticides
that remain active over extended periods) or treating
the parasite infection with combination therapy based on artimisinin (a natural
product of wormwood discovered in China), and other anti-malarial drugs such
as those based on quinine  (Two
Takes on Malaria, SiS 13/14). These measures have eradicated malaria, especially from Europe
and the United States. However, malaria remains a scourge
in the tropics and subtropics  (Fig. 1), and in recent years, much emphasis
has been placed on developing malaria vaccines  as an additional measure
in fighting malaria.
Figure 1. World map of malaria, black, areas where
malaria is transmitted, grey, areas with limited risk, white, areas with no
malaria (source WHO, 2003)
parasites that enter the bloodstream are called sporozoites. Sporozoites go
to the liver, where they multiply before changing into a different form called
merozoites. The merozoites enter into the red blood cells (erythrocytes) to
multiply; and this makes the person very sick with symptoms of malaria. A
person can look well but still have Plasmodium in the liver in a dormant
phase. Weeks or months later, the Plasmodium can leave the liver and
enter the bloodstream, and the person will get sick again. P. falciparum
causes the most dangerous type of malaria, making people sicker than other
Plasmodium species, because there are more of them in the blood. With
falciparum malaria, the red blood cells are sticky, so they block the
blood vessels .
have been attenuated (weakened) with irradiation, and injection of such sporozoites
provided complete protection. The production of attenuated sporozoites has
been improved and clinical trials will begin in the near future by injecting
the vaccine. Genetic attenuation of sporozoites is also
used to produce mutant strains unable to complete their life cycle . Attenuated
sporozoite vaccines are attractive for protection against malaria but difficult
and costly to produce on a global scale.
Synthetic and genetically
engineered sub-unit vaccines are usually based on either of two sporozoite surface proteins: circumsporozoite protein (CSP),
and thrombospondin related anonymous protein (TRAP) involved in sporozoite
motility and invasion of liver cells. The RTS,S vaccines, produced in yeast
cells, are made up of the tandem repeat tetrapeptide (R) and the C terminal
T-cell epitope (antigenic unit) containing (T) regions of CSP fused to hepatitis
B surface antigen (S), plus the unfused S antigen . The vaccine contains
an adjuvant.ASO2, oil in water emulsion of the immunostimulants monophosphoryl
lipid A and QS-21, a fraction of China bark extract
(Quillaia saponara). The RTS,S vaccine is the farthest advanced of
the malaria vaccines. There has been extensive clinical testing
of this vaccine, including several in infants (see later).
stage vaccines based on CSP, TRAP and other liver stage antigens are being
developed using viral vector delivery systems . A replication –defective
adenovirus strain 35 (Ad35) with chromosome deletions was grown in human embryo
cells (PER,C6/55k). A synthetic codon optimized part of the P. falciparum
CSP was inserted into the viral vector, and placed under the control of a
cytomegalovirus promoter and a simian virus 40 terminator signal. This vaccine
is intended to promote immune T cells to establish long lasting protection against malaria infection. The viral vaccine was tested
on rhesus macaques monkeys, boosted with the RTS,S/ASO1B vaccine. The test
animals’ immunity to malaria persisted at a high level for at least 6 months
after vaccination and the vaccine was predicted to have a more durable protection
against falciparum malaria in humans .
A replication-defective recombinant adenoma virus vector was used to produce
a vaccine specific for a surface antigen for the blood stages of falciparum
merozoite. The vaccine protected against the liver stages of the parasite as
well as the blood stages, and multistage protection and enhanced T cell production
was observed in experimental animals .
A phaseI/ IIa clinical trial was conducted in Oxford, UK, on healthy local
volunteers of two vaccines, FP9/MVA ME-TRAP and PEV3A, active against parasites
in the pre-erythrocyte, liver, and blood stages. PEV3A, developed by the Swiss
Pevion Biotech company, includes peptides from both the pre-eythrocyte CSP and
the blood stage antigen AMA-1, delivered with influenza virosomes, virus-like
particles that retain the cell binding and membrane fusion properties of the
native virus, but lack the viral genetic material. Antigens from the different
stages of the parasite were chemically linked to the surface of the virosome
to enhance their immune activity. FP9/MVA ME-TRAP is fowlpox strain FP9 and
modified vaccinia virus Ankar (MVA) vector expressing the pre-erthyrocyte antigen
TRAP fused to a multi-epitope (ME) string developed by Oxford University, previously
taken through phase I/II studies in adults and children in Gambia. Subjects
were vaccinated with PEV3A alone or in combination with FP9/MVA ME-TRAP. They
found evidence of specific immune responses induced by PEV3A vaccinated volunteers,
but no volunteers were completely protected from malaria. PEV3A induced high
antibody titres and these antibodies bound parasites in immunofluorescence assays;
and sporozoite challenge boosted the vaccine-induced immune response. Immune
responses induced by FP9/MVA ME-TRAP were unexpectedly low. A substantial number
of the volunteers experienced local pain, as well as general symptoms such as
joint pain, muscle pain, headache or malaise .
In general, protein vaccines that do not contain viral or other recombinant
nucleic acid sequences are preferable, because there is little risk from horizontal
gene transfer and recombination that can create more lethal parasites as well
as novel viral and bacterial pathogens  (see Horizontal Gene Transfer
from GMOs Does Happen, SiS 38).
Vaccines that block transmission
of the malaria parasite to human victims have been developed. Plasmodium
vivax is a major cause of malaria in Asia and South America,
and protein Pvs 25 from P. Vivax was used as vaccine. The immunized
subject produced antisera which was present in the blood meal of a mosquito. The mosquito that ingested such a blood meal prevented it
from transmitting the parasite to any further victim. A recombinant
vaccine was produced in yeast that went through
a phase I clinical trial and no vaccine-related
serious adverse events were observed .
A recombinant transmission-blocking vaccine directed at Plasmodium falciparum
was produced in the bacterium E. coli. The vaccine Pfs 48/45 contains
part of the protozoan proteins 48/45, which required four bacterial folding
proteins because the vaccine protein had to be folded properly to elicit antibodies.
The vaccine protein, folded correctly, was stable and highly active as well
as safe in mice, but it has not yet progressed to human subjects .
Trials of RST,T vaccine on infants raise questions over safety and efficacy
The RST,S vaccine
is the furthest along to clinical use. It gave satisfactory but short lived
protection of adults who had never been exposed to malaria . An efficacy
of more than 70 percent was reported in 250 male Gambian adults during the
first 2 months of follow-up, but falling to 0 percent in the last 6 weeks
. This vaccine has since been trialed on children and infants. Studies
with infants and children are considered important because they are the most
sensitive group for malaria infection.
A double-blind phase I/IIb randomised trial in Mozambique involved 124 infants
 assigned to receive three doses either of RTS,S/AS02D or hepatitis B vaccine
Engerix B at ages 10 weeks, 14 weeks and 18 weeks, as well as routine immunisations
(DTPs/HiB) given at 8, 12, and 16 weeks
In the three months after the third dose, there were 68 infections, 22 in RTS,S
group, 46 in controls. The adjusted vaccine efficacy was 65.9 percent. However,
at the end of the follow-up period, the prevalence of infection was 5 percent
in the RTS,S group compared with 8 percent in controls, and not significant.
This low prevalence of infection is in sharp contrast to the high incidence
of infection over this same period, and was due to the intensity of follow up
and treatment promptly applied.
In the 6 month period of the safety follow-up, there were17 children with adverse
events in each group (15.9 percent); 31 serious events in the RTS,S/AS02D group
and 30 serious adverse events in the Energerix-B group. But none was reported
as related to vaccination, and no further details were given. Four deaths occurred
during the same follow up period, 2 in each group. One in the RTS,S group was
due to septic shock, and the remaining due to gastroenteritis and severe dehydration.
The interpretation was that: “The RTS,S/AS02D malaria vaccine was safe, well
tolerated, and immunogenic in young infants. The findings set the stage for
expanded phase III efficacy studies to confirm vaccine efficacy against clinical
Seven authors were declared employees of GlaxoSmithKine Biologicals, the vaccine
manufacturer, four owning shares and 2 inventors of patented malarial vaccines
Another phase IIb single-center, double-blind controlled trial involved 340
infants in Eagamoya, Tanzania, randomised to receive three doses of either the
RTS, S/AS02D vaccine, or the hepatitis B vaccine at 8, 12, and 16 weeks of age.
All infants also received a vaccine containing diphtheria and teneus toxoids,
whole-cell pertussis vaccine, and conjugated Haemophilius influenzae
type b vaccine (DTPs/Hib) .
During the 6-months period after the
third dose of vaccine, the efficacy of the RTS,S/AS02D vaccine against first
infection with P. falciparum malaria was 65.2 percent.
At least one serious adverse event occurred in 31 of
170 infants (18 percent) who received the RTS,S/AS02D vaccineand in 42 out
of the 170 (24.7 percent) infants who received the hepatitis B vaccine.
The most frequent serious adverse event
was pneumonia, followed by anaemia, and gastroenteritis. There was one death
in the hepatitis B group following severe pneumonia and seizures. The adverse
events and death were deemed unrelated to vaccination.
The report concluded that the vaccine
had a “promising safety profile” and did not interfere with the immunologic
responses to co-administered EPI [WHO’s expanded program of immunization]
A previous study with AS02A adjuvant showed a 30 percent rate
of protection against malaria in children 1 to 4 years, so a more immunogenic
adjuvant was used with the vaccine for a study in Kilifi, Kenya, and Korogwe,
Tanzania, compared with rabies vaccine in a double-blind, randomized trial
. A total of 894 children were recruited; and 809 completed the study.
In the follow up period 32 of 402 receiving the malaria
vaccine developed clinical malaria compared with 66 of 407 assigned to the
rabies vaccine. So the efficacy was 53 percent.
total of 47 of 447 children receiving RTS,S/ AS01E had one or more serious
adverse events (11 percent), compared to 82 of the 227 receiving the rabies
vaccine (18 percent). The most frequent adverse events were: pneumonia, gastroenteritis,
and respiratory tract infection. There was one death each from malaria vaccine
and rabies vaccine. Again, the adverse events and deaths were considered unrelated
Potential conflict of interest
trials of malaria vaccines on infants in Africa raise serious concerns over
safety, not only of the malaria vaccine being tested, but of vaccines in general
administered in large numbers to the young and very young. The malaria vaccine
is being tested against a background of multiple vaccines, and furthermore,
against vaccines with highly controversial safety record such as the hepatitis
B vaccine [14, 15].
From 1990 to the end of 2002, the Vaccine Adverse Events Reporting System
(VAERS), set up by the Centers for Disease Control and Food and Drug Administration
in the United States, received reports of 9 520 serious adverse events in
children under one year of age after one dose of hepatitis B vaccine, either
alone or with other vaccines; among these were 627 deaths. In the same period,
there were 38 600 serious adverse events and 753 deaths over all ages for
the hepatitis B vaccine. Clearly deaths among infants less than 1 year after
hepatitis B vaccination were much higher than those in adults and older children.
In the malaria vaccine trials, serious adverse events of 10
to 20 percent or more and even deaths in both trial and control groups were
routinely dismissed as ‘unrelated to vaccination’, and hence did not even
enter into the VAERS statistics.
The level of protection offered by the malaria vaccine was at best 65.9 percent
in the follow up period of 3 months after the final dose, and there is no
evidence it lasted longer than that. This level of efficacy is insignificant
when treatment is promptly applied, and certainly not worth the risks of serious
adverse events including death.
Yet, all the trials concluded that the vaccine was safe, and “immunogenic
in young infants” and warrant a large scale phase III multi-centre trial.
trials were all sponsored by the vaccine manufacturer GlaxoSmithKline Biologicals,
with its employees making up a large proportion of the co-authors, some of
them holding shares in the company and patents for malaria vaccines [11-13].
The potential conflict of interest cannot be ignored. In addition, a large
charity, Program for Appropriate Technology in Health (PATH) was listed in
two of the three studies [12, 13]. PATH describes itself as a charity 
funded at US$168 million in 2007, by “foundations, the United States government, other governments, multilateral agencies, corporations,
and individuals.” Misguided governments and mega-foundations such as the Bill
and Melinda Gates Foundation are complicit in the promotion of these and other
even more aggressive vaccines in the pipelines that are of dubious benefit
to the countries whose infants are being recruited for clinical trials.
Alternatives to vaccination at a fraction of the cost
Ivan Tonna at Radcliffe Hospital,
Oxford, in the UK,
pointed out that vaccines are not cost-effective for developing countries
. The worst case scenario of using more and more aggressive vaccines is
that it may provoke the evolution of a parasite with a higher virulence. Plasmodium
falciparum is well-known for its genetic dexterity. It has multiple stages
in its life cycle, each stage expressing a different repertoire of antigens,
and many of these exhibit remarkable polymorphisms.
In the case of malaria, existing measures have succeeded
in eradicating the disease when they are adequately implemented especially
in European countries and the United States. The Roll Back Malaria campaign initiated by WHO  has had some
notable successes: Vietnam has seen its
malaria deaths reduced by 97 percent in five years, and in Kenya,
the promotion of bed nets has helped reduce malaria cases significantly.
There are safe and affordable alternatives to vaccines
Use the best available drug treatments, such as artemisinin-based
combinations therapy, and others recommended by WHO .
Encourage home-based management of malaria through availability
of unit-dose packaging of full-course therapy with pictorial labelling,
training parents and community health workers to recognize malarial symptoms
early and treat promptly, training retailers so they are able to offer appropriate
antimalarial drugs at the right dose, community-targeted information education,
and communication for behavioural change.
Invest in prophylaxis against the disease such as making
insecticide-impregnated mosquito nets widely available to the population,
which can have a major impact on the incidence of the disease.
Apply education and international political pressure to
control environmental changes that create new breeding sites for mosquitoes,
such as deforestation, mining, irrigation projects, and road building.
Use combination insecticides judiciously to control mosquito
Malaria perpetrates poverty through loss of work force, school drop-outs and
decreased financial investment. The World Health Organisation estimated that Africa’s
GDP would be up to USD 100 billion greater if malaria had been eradicated years
ago. Malaria could be prevented or treated for between 0.5 and $10.0. Many of
the developing countries could reduce malaria deaths by half if the already existing
tools are widely and wisely used, and at a small fraction of the cost of vaccines.