1. Malaria vaccine
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malaria-infected mosquitoes in a screened cup which will infect a volunteer in a malaria
clinical trial
Malaria vaccines are an area of intensive research. However, there is no practical or
effective vaccine that has been introduced into clinical practice.
Contents
1 Context
2 Vaccination via irradiated mosquitoes
3 Agents under development
4 Considerations for vaccine development
4.1 The diversity of the parasite
4.2 Choosing to address the symptom or the source
4.3 Potential targets of a vaccine
4.3.1 Sporozoite
4.3.2 Infected hepatocyte
4.3.3 Asexual erythrocytic
4.3.4 Sexual erythrocytic
4.4 Mix of antigenic components
4.5 Vaccine delivery system
5 Vaccines Developed up until 2012
6 References
7 Bibliography
8 External links
Context
The global burden of P. falciparum malaria increased through the 1990s due to drugresistant parasites and insecticide-resistant mosquitoes; this is illustrated by reemergence of the disease in areas that had been previously malaria-free. The first
decade of the 21st century has seen reduction. 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
2. 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.
Vaccines are often the most cost-effective tools for public health. They have historically
contributed to a reduction in the spread and burden of infectious diseases and have
played the major part in previous elimination campaigns for smallpox and the ongoing
polio and measles initiatives. Yet no effective vaccine for malaria has so far been
developed. Despite this, researchers remain hopeful. Optimism is justified for several
reasons, the first of these being that individuals who are exposed to the parasite in
endemic countries develop acquired immunity against disease and death. Such
immunity does not however prevent malaria infection; immune individuals often harbour
asymptomatic parasites in their blood. Additionally, research shows that if
immunoglobulin is taken from immune adults, purified and then given to individuals that
have no protective immunity, some protection can be gained.[citation needed] In
addition to this, clinical and animal studies have shown that experimental vaccination
has some degree of success when using attenuated sporozites and using the
RTS,S/AS01 malaria vaccine candidate.[citation needed]
Vaccination via irradiated mosquitoes
In 1967, it was reported that a level of immunity to the Plasmodium berghei parasite
could be given to mice by exposing them to sporozoites that had been irradiated by xrays.[1] Subsequent human studies in the 1970s showed that humans could be
immunized against Plasmodium vivax and Plasmodium falciparum by exposing them to
the bites of significant numbers of irradiated mosquitos.[2]
From 1989 to 1999, eleven volunteers recruited from the United States Public Health
Service, United States Army, and United States Navy were immunized against
Plasmodium falciparum by the bites of 1001 to 2927 mosquitos that had been irradiated
with 15,000 rads of gamma rays from a Co-60 or Cs-137 source.[3] This level of
radiation being sufficient to attenuate the malaria parasites so that while they could still
enter hepatic cells, they could not develope into schizonts or infect red blood cells.[3]
Over a span of 42 weeks, 24 of 26 tests on the volunteers showed that they were
protected from malaria infection.[4]
3. Agents under development
A completely effective vaccine is not yet available for malaria, although several vaccines
are under development. SPf66 was tested extensively in endemic areas in the 1990s,
but clinical trials showed it to be insufficiently effective.[5] Other vaccine candidates,
targeting the blood-stage of the parasite's life cycle, have also been insufficient on their
own.[6] Several potential vaccines targeting the pre-erythrocytic stage are being
developed, with RTS,S showing the most promising results so far.[7]
RTS,S/AS01 (commercial name: Mosquirix),[8] was engineered using genes from the
outer protein of Plasmodium falciparum malaria parasite and a portion of a hepatitis B
virus plus a chemical adjuvant to boost the immune system response. It is being
developed by PATH and GlaxoSmithKline (GSK) with support from the Bill and Melinda
Gates Foundation. In November 2012 a Phase III trial of RTS,S found that it provided
modest protection against both clinical and severe malaria in young infants.[9]
Considerations for vaccine development
The task of developing a preventive vaccine for malaria is a complex process. There are
a number of considerations to be made concerning what strategy a potential vaccine
should adopt.
The diversity of the parasite
P. falciparum 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 cycle. This enables pharmaceutical treatments that are effective at
reducing the reproduction rate, but not halting it, to exert a high selection pressure, thus
favoring the development of resistance. The process of evolutionary change is one of
the key considerations necessary when considering potential vaccine candidates. The
development of resistance could cause a significant reduction in efficacy of any
potential vaccine thus rendering useless a carefully developed and effective treatment.
Choosing to address the symptom or the source
The parasite induces two main response types from the human immune system. These
are anti-parasitic immunity and anti-toxic immunity.
"Anti-parasitic immunity" addresses the source; it consists of an antibody response
(humoral immunity) and a cell-mediated immune response. Ideally a vaccine would
enable the development of anti-plasmodial antibodies in addition to generating an
elevated cell-mediated response. Potential antigens against which a vaccine could be
targeted will be discussed in greater depth later. Antibodies are part of the specific
immune response. They exert their effect by activating the complement cascade,
stimulating phagocytic cells into endocytosis through adhesion to an external surface of
the antigenic substances, thus ‘marking’ it as offensive. Humoral or cell-mediated
immunity consists of many interlinking mechanisms that essentially aim to prevent
infection entering the body (through external barriers or hostile internal environments)
4. and then kill any micro-organisms or foreign particles that succeed in penetration. The
cell-mediated component consists of many white blood cells (such as monocytes,
neutrophils, macrophages, lymphocytes, basophils, mast cells, natural killer cells, and
eosinophils) that target foreign bodies by a variety of different mechanisms. In the case
of malaria both systems would be targeted to attempt to increase the potential response
generated, thus ensuring the maximum chance of preventing disease.
"Anti-toxic immunity" addresses the symptoms; it refers to the suppression of the
immune response associated with the production of factors that either induce symptoms
or reduce the effect that any toxic by-products (of micro-organism presence) have on
the development of disease. For example, it has been shown that Tumor necrosis
factor-alpha has a central role in generating the symptoms experienced in severe P.
falciparum malaria. Thus a therapeutic vaccine could target the production of TNF-a,
preventing respiratory distress and cerebral symptoms. This approach has serious
limitations as it would not reduce the parasitic load; rather it only reduces the associated
pathology. As a result, there are substantial difficulties in evaluating efficacy in human
trials.
Taking this information into consideration an ideal vaccine candidate would attempt to
generate a more substantial cell-mediated and antibody response on parasite
presentation. This would have the benefit of increasing the rate of parasite clearance,
thus reducing the experienced symptoms and providing a level of consistent future
immunity against the parasite.
Potential targets of a vaccine
By their very nature, protozoa are more complex organisms than bacteria and viruses,
with more complicated structures and life cycles. This presents problems in vaccine
development but also increases the number of potential targets for a vaccine. These
have been summarised into the life cycle stage and the antibodies that could potentially
elicit an immune response.
The life cycle of the malaria parasite is particularly complex, presenting initial
developmental problems. Despite the huge number of vaccines available at the current
time, there are none that target parasitic infections. The distinct developmental stages
involved in the life cycle present numerous opportunities for targeting antigens, thus
potentially eliciting an immune response. Theoretically, each developmental stage could
have a vaccine developed specifically to target the parasite. Moreover, any vaccine
produced would ideally have the ability to be of therapeutic value as well as preventing
further transmission and is likely to consist of a combination of antigens from different
phases of the parasite’s development.
The initial stage in the life cycle, following inoculation, is a relatively short "preerythrocytic" or "hepatic" phase. A vaccine at this stage must have the ability to protect
against sporozoites invading and possibly inhibiting the development of parasites in the
hepatocytes (through inducing cytotoxic T-lymphocytes that can destroy the infected
5. liver cells). However, if any sporozoites evaded the immune system they would then
have the potential to be symptomatic and cause the clinical disease.
The second phase of the life cycle is the "erythrocytic" or blood phase. A vaccine
here could prevent merozoite multiplication or the invasion of red blood cells. This
approach is complicated by the lack of MHC molecule expression on the surface of
erythrocytes. Instead, malarial antigens are expressed, and it is this towards which the
antibodies could potentially be directed. Another approach would be to attempt to block
the process of erythrocyte adherence to blood vessel walls. It is thought that this
process is accountable for much of the clinical syndrome associated with malarial
infection; therefore a vaccine given during this stage would be therapeutic and hence
administered during clinical episodes to prevent further deterioration.
The last phase of the life cycle that has the potential to be targeted by a vaccine is
the "sexual stage". This would not give any protective benefits to the individual
inoculated but would prevent further transmission of the parasite by preventing the
gametocytes from producing multiple sporozoites in the gut wall of the mosquito. It
therefore would be used as part of a policy directed at eliminating the parasite from
areas of low prevalence or to prevent the development and spread of vaccine-resistant
parasites. This type of transmission-blocking vaccine is potentially very important. The
evolution of resistance in the malaria parasite occurs very quickly, potentially making
any vaccine redundant within a few generations. This approach to the prevention of
spread is therefore essential.
Another approach is to target the protein kinases, which are present during the entire
lifecyle of the malaria parasite. Research is underway on this, yet production of an
actual vaccine targeting these protein kinases may still take a long time.[10]
Report of a new candidate of vaccine capable to neutralize all tested strains of
Plasmodium falciparum, the most deadly form of the parasite causing malaria, was
published in Nature Communications by a team of scientists from the University of
Oxford.[11] The viral vectored vaccine, targeting a full-length P. falciparum reticulocytebinding protein homologue 5 (PfRH5) was found to induce an antibody response in
animal model. The results of this new vaccine confirmed the utility of a key discovery
reported from scientists at the Wellcome Trust Sanger Institute, published in Nature.[12]
The earlier publication reported P. falciparum relies on a red blood cell surface receptor,
known as ‘basigin’, to invade the cells by binding a protein PfRH5 to the receptor.[12]
Unlike other antigens of the malaria parasite which are often genetically diverse, the
PfRH5 antigen appears to have little genetic diversity even it was found to induce very
low antibody response in people naturally exposed to the parasite.[11] The high
susceptibility of PfRH5 to the cross-strain neutralizing vaccine-induced antibody
demonstrated a significant promise for preventing malaria in the long and often difficult
road of vaccine development. According to Professor Adrian Hill, a Wellcome Trust
Senior Investigator at the University of Oxford, the next step will be the safety tests of
this vaccine. If proved successful, the clinical trials in patients could begin in the next
two to three years.[13]
PfEMP1, one of the proteins known as variant surface antigens (VSAs) produced by
Plasmodium falciparum, was found to be a key target of the immune system’s response
against the parasite. Studies of blood samples from 296 mostly Kenyan children by
researchers of Burnet Institute and their cooperators showed that antibodies against
6. PfEMP1 provide protective immunity, while antibodies developed against other surface
antigens do not. Their results demonstrated that PfEMP1 could be a target to develop
an effective vaccine which will reduce risk of developing malaria.[14][15]
Sporozoite
Abs that block hepatocyte invasion
Abs that kill sporozoiteS via complement fixation (CF) or opsonization
Infected hepatocyte
CTL mediated lysis
CD4+ help for the activation and differentiation of CTL
Localized cytokine release by T cells or APCs
ADCC or C' mediated lysis,this CD4+ is useful in phagocytic cell to bind the MHC 11
Asexual erythrocytic
Localized cytokine release that directly kills infected erythrocyte or intracellular
parasite
Abs that agglutinate the merozoites before schizont rupture
Abs that block merozoite invasion of RBCs
Abs that kill iRBC via opsonization or phagocytotic mechanisms
Abs engulfed with the merozoite at time of invasion which kill intraerythrocytic
parasite
Abs which agglutinate iRBCs and prevent cytoadherence by blocking receptor-ligand
interactions (CD-36 is such a receptor)
Abs which neutralize harmful soluble parasite toxins
Sexual erythrocytic
Cytokines which kill gametocytes within the iRBC
Abs that kill gametocytes within iRBC via C'
Abs that interfere with fertilization
Abs that inhibit transformation of the zygote into the ookinete
Abs that block the egress of the ookinete from the mosquito midgut (Doolan and
Hoffman)
When selecting the most suitable vaccine target the following considerations are made:
a) How accessible is the antigen to the immune system?
b) How susceptible is the antigen to evolutionary change?
c) How critical is the antigen to parasitic biological functions?
7. d) How likely is a protective response in animal models?
e) Does the antigen contain epitopes that are recognisable by HLA allele superfamilies?
f) How compatible is the antigen with other potential antigens?
Mix of antigenic components
Increasing the potential immunity generated against Plasmodia can be achieved by
attempting to target multiple phases in the life cycle. This is additionally beneficial in
reducing the possibility of resistant parasites developing. The use of multiple-parasite
antigens can therefore have a synergistic or additive effect.
One of the most successful vaccine candidates currently in clinical trials consists of
recombinant antigenic proteins to the circumsporozoite protein.[16] (This is discussed in
more detail below.)
Vaccine delivery system
The selection of an appropriate system is fundamental in all vaccine development, but
especially so in the case of malaria. A vaccine targeting several antigens may require
delivery to different areas and by different means in order to elicit an effective response.
Some adjuvants can direct the vaccine to the specifically targeted cell type—e.g. the
use of Hepatitis B virus in the RTS,S vaccine to target infected hepatocytes—but in
other cases, particularly when using combined antigenic vaccines, this approach is very
complex. Some methods that have been attempted include the use of two vaccines, one
directed at generating a blood response and the other a liver-stage response. These
two vaccines could then be injected into two different sites, thus enabling the use of a
more specific and potentially efficacious delivery system.
To increase, accelerate or modify the development of an immune response to a vaccine
candidate it is often necessary to combine the antigenic substance to be delivered with
an adjuvant or specialised delivery system. These terms are often used interchangeably
in relation to vaccine development; however in most cases a distinction can be made.
An adjuvant is typically thought of as a substance used in combination with the antigen
to produce a more substantial and robust immune response than that elicited by the
antigen alone. This is achieved through three mechanisms: by affecting the antigen
delivery and presentation, by inducing the production of immunomodulatory cytokines,
and by affecting the antigen presenting cells (APC). Adjuvants can consist of many
different materials, from cell microparticles to other particulated delivery systems (e.g.
liposomes).
Adjuvants are crucial in affecting the specificity and isotype of the necessary antibodies.
They are thought to be able to potentiate the link between the innate and adaptive
immune responses. Due to the diverse nature of substances that can potentially have
this effect on the immune system, it is difficult to classify adjuvants into specific groups.
In most circumstances they consist of easily identifiable components of microorganisms that are recognised by the innate immune system cells. The role of delivery
8. systems is primarily to direct the chosen adjuvant and antigen into target cells to
attempt to increase the efficacy of the vaccine further, therefore acting synergistically
with the adjuvant. There is increasing concern that the use of very potent adjuvants
could precipitate autoimmune responses, making it imperative that the vaccine is
focused on the target cells only. Specific delivery systems can reduce this risk by
limiting the potential toxicity and systemic distribution of newly developed adjuvants.
Studies into the efficacy of malaria vaccines developed to date have illustrated that the
presence of an adjuvant is key in determining any protection gained against malaria. A
large number of natural and synthetic adjuvants have been identified throughout the
history of vaccine development. Options identified thus far for use combined with a
malaria vaccine include mycobacterial cell walls, liposomes, monophosphoryl lipid A
and squalene.
Vaccines Developed up until 2012
The epidemiology of malaria varies enormously across the globe, and has led to the
belief that it may be necessary to adopt very different vaccine development strategies to
target the different populations. A Type 1 vaccine is suggested for those exposed
mostly to P. falciparum malaria in sub-Saharan Africa, with the primary objective to
reduce the number of severe malaria cases and deaths in infants and children exposed
to high transmission rates. The Type 2 vaccine could be thought of as a ‘travellers’
vaccine’, aiming to prevent all cases of clinical symptoms in individuals with no previous
exposure. This is another major public health problem, with malaria presenting as one
of the most substantial threats to travellers’ health. Problems with the current available
pharmaceutical therapies include costs, availability, adverse effects and
contraindications, inconvenience and compliance many of which would be reduced or
eliminated entirely if an effective (greater than 85–90%) vaccine was developed.
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 CSP (Circum-Sporozoite Protein) was a vaccine developed that initially appeared
promising enough to undergo trials. It is also based on the circumsporozoite protein, but
additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR)
protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). 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
9. 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 circumsporozoite 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 protective immunity to 7 out of
8 volunteers when challenged with P. falciparum.[17]
References
Jump up ^ Nussenzweig, Ruth; J. VANDERBERG, H. MOST & C. ORTON (14
October 1967). "Protective Immunity produced by the Injection of X-irradiated
Sporozoites of Plasmodium berghei". Nature 216: 160–162. doi:10.1038/216160a0.
Retrieved 2013-08-09.
Jump up ^ Clyde, David; Vincent C. McCarthy, Roger M. Miller, & William E.
Woodward (May 1975). "IMMUNIZATION OF MAN AGAINST FALCIPARUM AND
VIVAX MALARIA BY USE OF ATTENUATED SPOROZOITES". American Society of
Tropical Medicine and Hygiene (University of Maryland School of Medicine) 24 (3): 397–
401. Retrieved 2013-08-09.
^ Jump up to: a b }Hoffman, Stephen L. (2002). "Protection of Humans against
Malaria by Immunization with Radiation-Attenuated Plasmodium falciparum
10. Sporozoites". The Journal of Infectious Diseases (Celera Genomics: Oxford University
Press) 185 (8): 1155–1164. doi:10.1086/339409. Retrieved 2013-08-09.
Jump up ^ "Protection of humans against malaria by immunization with radiationattenuated Plasmodium falciparum sporozoites.".National Naval Medical
Center.National Center for Biotechnology Information. 2002-04-15. Retrieved 2013-0809.
Jump up ^ Graves P, Gelband H (2006). "Vaccines for preventing malaria (SPf66)".
Cochrane Database Syst Rev (2): CD005966. doi:10.1002/14651858.CD005966. PMID
16625647.
Jump up ^ Graves P, Gelband H (2006). "Vaccines for preventing malaria (bloodstage)". Cochrane Database Syst Rev (4): CD006199.
doi:10.1002/14651858.CD006199. PMID 17054281.
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doi:10.1002/14651858.CD006198. PMID 17054280.
Jump up ^ Commercial name of RTS,S
Jump up ^ RTS,S Clinical Trials Partnership (December 2012). "A Phase 3 Trial of
RTS,S/AS01 Malaria Vaccine in African Infants". New England Journal of Medicine 367
(24): 2284–2295. doi:10.1056/NEJMoa1208394. PMID 23136909.edit
Jump up ^ Zhang VM, Chavchich M, Waters NC (March 2012). "Targeting protein
kinases in the malaria parasite: update of an antimalarial drug target". Curr Top Med
Chem 12 (5): 456–72. PMID 22242850.
^ Jump up to: a b Douglas, Alexander; et, al (2011). "The blood-stage malaria antigen
PfRH5 is susceptible to vaccine-inducible cross-strain neutralizing antibody". Nature
Communications 2 (12): 601. doi:10.1038/ncomms1615. Retrieved December 23, 2011.
^ Jump up to: a b Crosnier, Cecile; et, al (2011). "Basigin is a receptor essential for
erythrocyte invasion by Plasmodium falciparum". Nature 480 (7378): 534–537.
doi:10.1038/nature10606. PMC 3245779.PMID 22080952.
Jump up ^ Martino, Maureen (21 December 2011). "New candidate vaccine
neutralizes all tested strains of malaria parasite". fiercebiotech.com. FierceBiotech.
Retrieved December 23, 2011.
Jump up ^ Parish, Tracy (2 August 2012). "Lifting malaria’s deadly veil: Mystery
solved in quest for vaccine". Burnet Institute. Retrieved 14 August 2012.
Jump up ^ Chan, Jo-Anne; Howell, Katherine; Reiling, Linda; Ataide, Ricardo;
Mackintosh, Claire; Fowkes, Freya; Petter, Michaela; Chesson, Joanne; Langer,
Christine; Warimwe, George (2012). "Targets of antibodies against Plasmodium
falciparum-infected erythrocytes in malaria immunity".Journal of Clinical
Investigation.doi:10.1172/JCI62182.
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Jump up ^ "RTS,S malaria candidate vaccine reduces malaria by approximately onethird in African infants". malariavaccine.org. Malaria Vaccine Initiative Path. Retrieved
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11. Bibliography
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Vaccine".
Good, M.; Kemp, D. "Overview of Vaccine Strategies for Malaria".
Saul, A. "Malaria Transmission-Blocking Vaccines".
Heppner, et al. "Adjuvanted RTS,S and Other Protein- Based Pre-Erythrocytic
Stage Malaria Vaccines".
Good, et al. "Plasmodium falciparum Asexual Vaccine Candidates: Current
Status".
The Jordan Report
"Case studies: Potential malaria vaccine" (Press release).GlaxoSmithKline. August 21,
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"World’s largest malaria vaccine trial now underway in seven African countries" (Press
release).GlaxoSmithKline. November 3, 2009.
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Aponte JJ, Aide P, Renom M, et al. (November 2007). "Safety of the RTS,S/AS02D
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doi:10.1016/S0140-6736(07)61542-6. PMID 17949807.
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against Malaria in Children 5 to 17 Months of Age". The New England Journal of
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19064627.
Delves, Peter J.; Roitt, Ivan Maurice (2001). Roitt's essential immunology. Oxford:
Blackwell Science. ISBN 0-632-05902-8.
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External links
Malaria vaccine
National institute of health
Malaria vaccines UK
12. Gates Foundation Global Health: Malaria
Brown University
Gillis, Justin (25 April 2006). "Cure for Neglected Diseases: Funding". Washington
Post.
Isea, Raul (2010). "Identification of 11 potential malaria vaccine candidates using
Bioinformatics".arXiv:1009.5956.
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Artificial induction of immunity / Immunization: Vaccines, Vaccination, and Inoculation
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Malaria vaccine
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[hide]This article has multiple issues. Please help improve it or discuss these issues on
the talk page.
This article includes a list of references, related reading or external links, but its sources
remain unclear because it lacks inline citations. (July 2008)
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malaria-infected mosquitoes in a screened cup which will infect a volunteer in a malaria
clinical trial
Malaria vaccines are an area of intensive research. However, there is no practical or
effective vaccine that has been introduced into clinical practice.
Contents
1 Context
2 Vaccination via irradiated mosquitoes
3 Agents under development
4 Considerations for vaccine development
4.1 The diversity of the parasite
4.2 Choosing to address the symptom or the source
4.3 Potential targets of a vaccine
4.3.1 Sporozoite
4.3.2 Infected hepatocyte
4.3.3 Asexual erythrocytic
4.3.4 Sexual erythrocytic
4.4 Mix of antigenic components
14. 4.5 Vaccine delivery system
5 Vaccines Developed up until 2012
6 References
7 Bibliography
8 External links
Context
The global burden of P. falciparum malaria increased through the 1990s due to drugresistant parasites and insecticide-resistant mosquitoes; this is illustrated by reemergence of the disease in areas that had been previously malaria-free. The first
decade of the 21st century has seen reduction. 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.
Vaccines are often the most cost-effective tools for public health. They have historically
contributed to a reduction in the spread and burden of infectious diseases and have
played the major part in previous elimination campaigns for smallpox and the ongoing
polio and measles initiatives. Yet no effective vaccine for malaria has so far been
developed. Despite this, researchers remain hopeful. Optimism is justified for several
reasons, the first of these being that individuals who are exposed to the parasite in
endemic countries develop acquired immunity against disease and death. Such
immunity does not however prevent malaria infection; immune individuals often harbour
asymptomatic parasites in their blood. Additionally, research shows that if
immunoglobulin is taken from immune adults, purified and then given to individuals that
have no protective immunity, some protection can be gained.[citation needed] In
addition to this, clinical and animal studies have shown that experimental vaccination
has some degree of success when using attenuated sporozites and using the
RTS,S/AS01 malaria vaccine candidate.[citation needed]
Vaccination via irradiated mosquitoes
15. In 1967, it was reported that a level of immunity to the Plasmodium berghei parasite
could be given to mice by exposing them to sporozoites that had been irradiated by xrays.[1] Subsequent human studies in the 1970s showed that humans could be
immunized against Plasmodium vivax and Plasmodium falciparum by exposing them to
the bites of significant numbers of irradiated mosquitos.[2]
From 1989 to 1999, eleven volunteers recruited from the United States Public Health
Service, United States Army, and United States Navy were immunized against
Plasmodium falciparum by the bites of 1001 to 2927 mosquitos that had been irradiated
with 15,000 rads of gamma rays from a Co-60 or Cs-137 source.[3] This level of
radiation being sufficient to attenuate the malaria parasites so that while they could still
enter hepatic cells, they could not develope into schizonts or infect red blood cells.[3]
Over a span of 42 weeks, 24 of 26 tests on the volunteers showed that they were
protected from malaria infection.[4]
Agents under development
A completely effective vaccine is not yet available for malaria, although several vaccines
are under development. SPf66 was tested extensively in endemic areas in the 1990s,
but clinical trials showed it to be insufficiently effective.[5] Other vaccine candidates,
targeting the blood-stage of the parasite's life cycle, have also been insufficient on their
own.[6] Several potential vaccines targeting the pre-erythrocytic stage are being
developed, with RTS,S showing the most promising results so far.[7]
RTS,S/AS01 (commercial name: Mosquirix),[8] was engineered using genes from the
outer protein of Plasmodium falciparum malaria parasite and a portion of a hepatitis B
virus plus a chemical adjuvant to boost the immune system response. It is being
developed by PATH and GlaxoSmithKline (GSK) with support from the Bill and Melinda
Gates Foundation. In November 2012 a Phase III trial of RTS,S found that it provided
modest protection against both clinical and severe malaria in young infants.[9]
Considerations for vaccine development
The task of developing a preventive vaccine for malaria is a complex process. There are
a number of considerations to be made concerning what strategy a potential vaccine
should adopt.
The diversity of the parasite
P. falciparum 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 cycle. This enables pharmaceutical treatments that are effective at
reducing the reproduction rate, but not halting it, to exert a high selection pressure, thus
favoring the development of resistance. The process of evolutionary change is one of
the key considerations necessary when considering potential vaccine candidates. The
development of resistance could cause a significant reduction in efficacy of any
potential vaccine thus rendering useless a carefully developed and effective treatment.
16. Choosing to address the symptom or the source
The parasite induces two main response types from the human immune system. These
are anti-parasitic immunity and anti-toxic immunity.
"Anti-parasitic immunity" addresses the source; it consists of an antibody response
(humoral immunity) and a cell-mediated immune response. Ideally a vaccine would
enable the development of anti-plasmodial antibodies in addition to generating an
elevated cell-mediated response. Potential antigens against which a vaccine could be
targeted will be discussed in greater depth later. Antibodies are part of the specific
immune response. They exert their effect by activating the complement cascade,
stimulating phagocytic cells into endocytosis through adhesion to an external surface of
the antigenic substances, thus ‘marking’ it as offensive. Humoral or cell-mediated
immunity consists of many interlinking mechanisms that essentially aim to prevent
infection entering the body (through external barriers or hostile internal environments)
and then kill any micro-organisms or foreign particles that succeed in penetration. The
cell-mediated component consists of many white blood cells (such as monocytes,
neutrophils, macrophages, lymphocytes, basophils, mast cells, natural killer cells, and
eosinophils) that target foreign bodies by a variety of different mechanisms. In the case
of malaria both systems would be targeted to attempt to increase the potential response
generated, thus ensuring the maximum chance of preventing disease.
"Anti-toxic immunity" addresses the symptoms; it refers to the suppression of the
immune response associated with the production of factors that either induce symptoms
or reduce the effect that any toxic by-products (of micro-organism presence) have on
the development of disease. For example, it has been shown that Tumor necrosis
factor-alpha has a central role in generating the symptoms experienced in severe P.
falciparum malaria. Thus a therapeutic vaccine could target the production of TNF-a,
preventing respiratory distress and cerebral symptoms. This approach has serious
limitations as it would not reduce the parasitic load; rather it only reduces the associated
pathology. As a result, there are substantial difficulties in evaluating efficacy in human
trials.
Taking this information into consideration an ideal vaccine candidate would attempt to
generate a more substantial cell-mediated and antibody response on parasite
presentation. This would have the benefit of increasing the rate of parasite clearance,
thus reducing the experienced symptoms and providing a level of consistent future
immunity against the parasite.
Potential targets of a vaccine
By their very nature, protozoa are more complex organisms than bacteria and viruses,
with more complicated structures and life cycles. This presents problems in vaccine
development but also increases the number of potential targets for a vaccine. These
have been summarised into the life cycle stage and the antibodies that could potentially
elicit an immune response.
17. The life cycle of the malaria parasite is particularly complex, presenting initial
developmental problems. Despite the huge number of vaccines available at the current
time, there are none that target parasitic infections. The distinct developmental stages
involved in the life cycle present numerous opportunities for targeting antigens, thus
potentially eliciting an immune response. Theoretically, each developmental stage could
have a vaccine developed specifically to target the parasite. Moreover, any vaccine
produced would ideally have the ability to be of therapeutic value as well as preventing
further transmission and is likely to consist of a combination of antigens from different
phases of the parasite’s development.
The initial stage in the life cycle, following inoculation, is a relatively short "preerythrocytic" or "hepatic" phase. A vaccine at this stage must have the ability to protect
against sporozoites invading and possibly inhibiting the development of parasites in the
hepatocytes (through inducing cytotoxic T-lymphocytes that can destroy the infected
liver cells). However, if any sporozoites evaded the immune system they would then
have the potential to be symptomatic and cause the clinical disease.
The second phase of the life cycle is the "erythrocytic" or blood phase. A vaccine
here could prevent merozoite multiplication or the invasion of red blood cells. This
approach is complicated by the lack of MHC molecule expression on the surface of
erythrocytes. Instead, malarial antigens are expressed, and it is this towards which the
antibodies could potentially be directed. Another approach would be to attempt to block
the process of erythrocyte adherence to blood vessel walls. It is thought that this
process is accountable for much of the clinical syndrome associated with malarial
infection; therefore a vaccine given during this stage would be therapeutic and hence
administered during clinical episodes to prevent further deterioration.
The last phase of the life cycle that has the potential to be targeted by a vaccine is
the "sexual stage". This would not give any protective benefits to the individual
inoculated but would prevent further transmission of the parasite by preventing the
gametocytes from producing multiple sporozoites in the gut wall of the mosquito. It
therefore would be used as part of a policy directed at eliminating the parasite from
areas of low prevalence or to prevent the development and spread of vaccine-resistant
parasites. This type of transmission-blocking vaccine is potentially very important. The
evolution of resistance in the malaria parasite occurs very quickly, potentially making
any vaccine redundant within a few generations. This approach to the prevention of
spread is therefore essential.
Another approach is to target the protein kinases, which are present during the entire
lifecyle of the malaria parasite. Research is underway on this, yet production of an
actual vaccine targeting these protein kinases may still take a long time.[10]
Report of a new candidate of vaccine capable to neutralize all tested strains of
Plasmodium falciparum, the most deadly form of the parasite causing malaria, was
published in Nature Communications by a team of scientists from the University of
Oxford.[11] The viral vectored vaccine, targeting a full-length P. falciparum reticulocytebinding protein homologue 5 (PfRH5) was found to induce an antibody response in
animal model. The results of this new vaccine confirmed the utility of a key discovery
reported from scientists at the Wellcome Trust Sanger Institute, published in Nature.[12]
The earlier publication reported P. falciparum relies on a red blood cell surface receptor,
18. known as ‘basigin’, to invade the cells by binding a protein PfRH5 to the receptor.[12]
Unlike other antigens of the malaria parasite which are often genetically diverse, the
PfRH5 antigen appears to have little genetic diversity even it was found to induce very
low antibody response in people naturally exposed to the parasite.[11] The high
susceptibility of PfRH5 to the cross-strain neutralizing vaccine-induced antibody
demonstrated a significant promise for preventing malaria in the long and often difficult
road of vaccine development. According to Professor Adrian Hill, a Wellcome Trust
Senior Investigator at the University of Oxford, the next step will be the safety tests of
this vaccine. If proved successful, the clinical trials in patients could begin in the next
two to three years.[13]
PfEMP1, one of the proteins known as variant surface antigens (VSAs) produced by
Plasmodium falciparum, was found to be a key target of the immune system’s response
against the parasite. Studies of blood samples from 296 mostly Kenyan children by
researchers of Burnet Institute and their cooperators showed that antibodies against
PfEMP1 provide protective immunity, while antibodies developed against other surface
antigens do not. Their results demonstrated that PfEMP1 could be a target to develop
an effective vaccine which will reduce risk of developing malaria.[14][15]
Sporozoite
Abs that block hepatocyte invasion
Abs that kill sporozoiteS via complement fixation (CF) or opsonization
Infected hepatocyte
CTL mediated lysis
CD4+ help for the activation and differentiation of CTL
Localized cytokine release by T cells or APCs
ADCC or C' mediated lysis,this CD4+ is useful in phagocytic cell to bind the MHC 11
Asexual erythrocytic
Localized cytokine release that directly kills infected erythrocyte or intracellular
parasite
Abs that agglutinate the merozoites before schizont rupture
Abs that block merozoite invasion of RBCs
Abs that kill iRBC via opsonization or phagocytotic mechanisms
Abs engulfed with the merozoite at time of invasion which kill intraerythrocytic
parasite
Abs which agglutinate iRBCs and prevent cytoadherence by blocking receptor-ligand
interactions (CD-36 is such a receptor)
Abs which neutralize harmful soluble parasite toxins
Sexual erythrocytic
Cytokines which kill gametocytes within the iRBC
19. Abs that kill gametocytes within iRBC via C'
Abs that interfere with fertilization
Abs that inhibit transformation of the zygote into the ookinete
Abs that block the egress of the ookinete from the mosquito midgut (Doolan and
Hoffman)
When selecting the most suitable vaccine target the following considerations are made:
a) How accessible is the antigen to the immune system?
b) How susceptible is the antigen to evolutionary change?
c) How critical is the antigen to parasitic biological functions?
d) How likely is a protective response in animal models?
e) Does the antigen contain epitopes that are recognisable by HLA allele superfamilies?
f) How compatible is the antigen with other potential antigens?
Mix of antigenic components
Increasing the potential immunity generated against Plasmodia can be achieved by
attempting to target multiple phases in the life cycle. This is additionally beneficial in
reducing the possibility of resistant parasites developing. The use of multiple-parasite
antigens can therefore have a synergistic or additive effect.
One of the most successful vaccine candidates currently in clinical trials consists of
recombinant antigenic proteins to the circumsporozoite protein.[16] (This is discussed in
more detail below.)
Vaccine delivery system
The selection of an appropriate system is fundamental in all vaccine development, but
especially so in the case of malaria. A vaccine targeting several antigens may require
delivery to different areas and by different means in order to elicit an effective response.
Some adjuvants can direct the vaccine to the specifically targeted cell type—e.g. the
use of Hepatitis B virus in the RTS,S vaccine to target infected hepatocytes—but in
other cases, particularly when using combined antigenic vaccines, this approach is very
complex. Some methods that have been attempted include the use of two vaccines, one
directed at generating a blood response and the other a liver-stage response. These
two vaccines could then be injected into two different sites, thus enabling the use of a
more specific and potentially efficacious delivery system.
To increase, accelerate or modify the development of an immune response to a vaccine
candidate it is often necessary to combine the antigenic substance to be delivered with
an adjuvant or specialised delivery system. These terms are often used interchangeably
in relation to vaccine development; however in most cases a distinction can be made.
20. An adjuvant is typically thought of as a substance used in combination with the antigen
to produce a more substantial and robust immune response than that elicited by the
antigen alone. This is achieved through three mechanisms: by affecting the antigen
delivery and presentation, by inducing the production of immunomodulatory cytokines,
and by affecting the antigen presenting cells (APC). Adjuvants can consist of many
different materials, from cell microparticles to other particulated delivery systems (e.g.
liposomes).
Adjuvants are crucial in affecting the specificity and isotype of the necessary antibodies.
They are thought to be able to potentiate the link between the innate and adaptive
immune responses. Due to the diverse nature of substances that can potentially have
this effect on the immune system, it is difficult to classify adjuvants into specific groups.
In most circumstances they consist of easily identifiable components of microorganisms that are recognised by the innate immune system cells. The role of delivery
systems is primarily to direct the chosen adjuvant and antigen into target cells to
attempt to increase the efficacy of the vaccine further, therefore acting synergistically
with the adjuvant. There is increasing concern that the use of very potent adjuvants
could precipitate autoimmune responses, making it imperative that the vaccine is
focused on the target cells only. Specific delivery systems can reduce this risk by
limiting the potential toxicity and systemic distribution of newly developed adjuvants.
Studies into the efficacy of malaria vaccines developed to date have illustrated that the
presence of an adjuvant is key in determining any protection gained against malaria. A
large number of natural and synthetic adjuvants have been identified throughout the
history of vaccine development. Options identified thus far for use combined with a
malaria vaccine include mycobacterial cell walls, liposomes, monophosphoryl lipid A
and squalene.
Vaccines Developed up until 2012
The epidemiology of malaria varies enormously across the globe, and has led to the
belief that it may be necessary to adopt very different vaccine development strategies to
target the different populations. A Type 1 vaccine is suggested for those exposed
mostly to P. falciparum malaria in sub-Saharan Africa, with the primary objective to
reduce the number of severe malaria cases and deaths in infants and children exposed
to high transmission rates. The Type 2 vaccine could be thought of as a ‘travellers’
vaccine’, aiming to prevent all cases of clinical symptoms in individuals with no previous
exposure. This is another major public health problem, with malaria presenting as one
of the most substantial threats to travellers’ health. Problems with the current available
pharmaceutical therapies include costs, availability, adverse effects and
contraindications, inconvenience and compliance many of which would be reduced or
eliminated entirely if an effective (greater than 85–90%) vaccine was developed.
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
21. 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 CSP (Circum-Sporozoite Protein) was a vaccine developed that initially appeared
promising enough to undergo trials. It is also based on the circumsporozoite protein, but
additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR)
protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). 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 circumsporozoite 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
22. monophosphoryl A and QS21 (SBAS2), the vaccine gave protective immunity to 7 out of
8 volunteers when challenged with P. falciparum.[17]
References
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Retrieved 2013-08-09.
Jump up ^ Clyde, David; Vincent C. McCarthy, Roger M. Miller, & William E.
Woodward (May 1975). "IMMUNIZATION OF MAN AGAINST FALCIPARUM AND
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^ Jump up to: a b }Hoffman, Stephen L. (2002). "Protection of Humans against
Malaria by Immunization with Radiation-Attenuated Plasmodium falciparum
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Jump up ^ "Protection of humans against malaria by immunization with radiationattenuated Plasmodium falciparum sporozoites.".National Naval Medical
Center.National Center for Biotechnology Information. 2002-04-15. Retrieved 2013-0809.
Jump up ^ Graves P, Gelband H (2006). "Vaccines for preventing malaria (SPf66)".
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16625647.
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Jump up ^ Commercial name of RTS,S
Jump up ^ RTS,S Clinical Trials Partnership (December 2012). "A Phase 3 Trial of
RTS,S/AS01 Malaria Vaccine in African Infants". New England Journal of Medicine 367
(24): 2284–2295. doi:10.1056/NEJMoa1208394. PMID 23136909.edit
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^ Jump up to: a b Douglas, Alexander; et, al (2011). "The blood-stage malaria antigen
PfRH5 is susceptible to vaccine-inducible cross-strain neutralizing antibody". Nature
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^ Jump up to: a b Crosnier, Cecile; et, al (2011). "Basigin is a receptor essential for
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Jump up ^ Martino, Maureen (21 December 2011). "New candidate vaccine
neutralizes all tested strains of malaria parasite". fiercebiotech.com. FierceBiotech.
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23. Jump up ^ Parish, Tracy (2 August 2012). "Lifting malaria’s deadly veil: Mystery
solved in quest for vaccine". Burnet Institute. Retrieved 14 August 2012.
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External links
Malaria vaccine
National institute of health
Malaria vaccines UK
Gates Foundation Global Health: Malaria
Brown University
Gillis, Justin (25 April 2006). "Cure for Neglected Diseases: Funding". Washington
Post.
Isea, Raul (2010). "Identification of 11 potential malaria vaccine candidates using
Bioinformatics".arXiv:1009.5956.
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Artificial induction of immunity / Immunization: Vaccines, Vaccination, and Inoculation
(J07)
Categories:
Malaria
Vaccines
Hypothetical technology
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