NIGERIAN JOURNAL OF SCIENCE AND ENVIRONMENT
Journal of the Faculties of Science and Agriculture, Delta State University, Abraka, Nigeria
ISSN: 1119-9008
DOI: 10.5987/UJ-NJSE
Email: njse@universityjournals.org
THE QUEST FOR A MALARIA VACCINE: CLEARING THE AIR
DOI: 10.5987/UJ-NJSE.16.041.1 | Article Number: C5C5986 | Vol.11 (1) - September 2012
Authors: Emudainohwo J.O.T , Ejebe D.E , Pachankar S.S , Siddiqui I.A , Somarapu P and Zhang X
Keywords: Malaria parasites, Malaria vaccine, Mosquitoes, RTS, S/AS02A Vaccine.
Malaria has continued to be a life-threatening scourge predominantly in sub-Saharan Africa. Attempts to eradicate it in the past as failed and it is now re-emerging, at a very fast rate, in areas hitherto not known to inhabit the parasite. 40 % of the global population is at risk of malaria, with around 300 million persons, mainly children of 6 months to 5 years, suffering from malaria yearly. This situation is made possible by loop-holes in global malaria control programme; excruciating poverty; population movements; conflicts; environmental and climate changes. Malaria parasites are becoming resistant to drugs and mosquitoes are showing resistance to chemical means of control. Recognizing the failures of past initiatives, and in the light of emerging data on the potentials of vaccines in a sustained attack on malaria, malaria vaccine is increasingly being embraced as a solution to the menace of malaria. Presently, no malaria vaccine is licensed, but with funding from the Wellcome Trust in the U.K., and from the U.S., as well as grants from the Bill & Melinda Gates Foundation, research has reached a heightened peak and vaccine candidate, targeted at one or more stages of the Malaria parasite’s life-cycle and could interfere successfully with infection, and parasitemia in the host or vector, or even block the manifestations of clinical disease, are currently in different trial stages and leading to a successful development of a vaccine for malaria. In reviewing the different malaria vaccine candidates presently under development, we can conclude, based on data on percentage efficacy, that the RTS, S/AS02A - a pre-erythrocytic vaccine remains the leading candidate towards our search for a malaria vaccine.
Alonso, P.L., Sacarlal, J., Aponte, J.J.,
Leach, A., Macete, E., Aide, P., Sigaugue,
B., Milman, J., Mandomando, I.,
Basat, Q., Guinovart, C., Espasa, M.,
Corachan, S., Lievens, M., Navia, M.M.,
Dubios, m., Menendez, C., dubovsky, F.,
cohen, J., Thompson, R. And Ballou,
W.R. (2005). Duration of protection with
RTS,S/AS0: A malaria vaccine in prevention
of Plasmodium falciparum disease in
Mozambican children: single-blind extended
follow-up of a randomised controlled
trial. Lancet 366(9502): 2012-
2018.
Aponte, J.J., Aide, P., Renom, M., Mandomando,
I., Bassat, Q., Sacarial, J.,
manaca, M.N., Lafuente, S., Barbosa, A.,
Leach, A., Lievens, M., Vekemans, J.,
Sigaugue, B., Dubois, M.C., Demoitie,
M.A., Sillman, M., Savarese, B.,
McNeil, J.C., Macete, E., Ballou, W.R.,
Cohen, J. And Alonso, P.L. (2007).
Safety of the RTS,S/AS02D: Candidate
malaria vaccine in infants living in a
highly endemic area of Mozambique: a
double blind randomised controlled Phase
I/IIb trial. Lancet 370: 1543-1551
Aylward, B., Hennessey, K. A., Zagaria, N.,
Olive, J. and Cochi, S. (2000). When is
disease eradicable? 100 years of lessons
learned. American Journal of Public
Health 90:1515–1520.
Baniecki, M.L., Wirth, D.F. and Clardy, J.
(2007). High-throughput Plasmodium falciparum
growth assay for malaria drug
discovery. Antimicrob. Agents Chemotherapy
51: 716–723.
Baruch, D. I., Pasloske, B. L., Singh, H. B.,
Bi, X., Ma, X. C., Feldman, M., Taraschi,
T. F. and Howard, R. J. (1995).
Cloning the P. falciparum gene encoding
PfEMP1, a malarial variant antigen and
adherence receptor on the surface of parasitized
human erythrocytes. Cell 82:77–
87.
Bejon, P., Berkley, J.A., Mwangi, T.,
Ogada, E., Nwangi, I., Maitland, K.,
Williams, T., Anthony, J., Scott, G.,
English, M., Lowe, B.S., Peshu, N.,
Newton, R.J.C. and Marsh, K. (2007).
Defining childhood severe falciparum malaria
for intervention studies. PLoS Medicine
4(8): e251.
Bhattacharjee, S., Hiller, L.N., Konstatinos,
L., Win, J., Kanneganti, T., Young, C.,
Kamoun, S. And Haldar, K. (2006). The
malarial host-targeting signal is conserved
in the Irish potato famine pathogen. PLoS
Pathogens 2: e50
Bouharoun-Tayoun, H., Attanath, P., Sabchareon,
A., Chongsuphajaisiddhi, T.
and Druilhe, P. (1990). Antibodies that
protect humans against Plasmodium falciparum
blood stages do not on their own
inhibit parasite growth and invasion in vitro,
but act in cooperation with monocytes.
Journal of Experimental Medicine
172(6): 1633-1641
Breman, J.G. (2001). The ears of the hippopotamus:
manifestations, determinants and
estimates of the malaria burden. American
Journal of Tropical Medicine & Hygiene
64 (Suppl): 1-11.
CDC information website for malaria.
Available at http://www.cdc.gov/
malaria/.
Chen, Q., Pettersson, F., Vogt, A.M.,
Schmidt, B., Ahuja, S., Litjestrom, P.
And Wahigren, M. (2004). Immunization
with PfEMP1-DBL1a generates antibodies
that disrupt rosettes and protect against the
sequestration of Plasmodium falciparuminfected
erythrocytes. Vaccine 22: 2701-
2712.
Chen, Q., Fernandez, V., Sundstrom, Α.,
Schlichtherle, Μ., Datta, S., Hagblom,
P. and Wahlgren, M. (1998). Developmental
selection of var gene expression in
Plasmodium falciparum. Nature 394: 392
–395.
Daubersies, P., Thomas, A.W., Millet, P.,
Brahimi, K., Langermans, J.A., Ollomo,
B., BenMohamed, L., Slierendregt, B.,
Eling,W., VanBelkum, A., Dubreuil, G.,
Meis, J.F., Guerin-Marchand, C., Cayphas,
S., Cohen, J., Cras-Masse., A.and
Druiine, P. (2000). Protection against
Plasmodium falciparum malaria in chimpanzees
by immunization with the conserved
pre-erythrocytic liver-stage antigen
3. Nature Medicine 6(11): 1258-1263.
de Pontual, L., Poilane, I., Ledeur, F.,
Haouchine, D., Lachassine,
E.,Collignon, A., Le Bras, J. and
Gaudelus, J.(2006). Report of a case of
congenital malaria plasmodium malariae
in France. Journal of Tropical Pediatrics.
52(6): 448-450.
Doolan D.L., Hoffman S.L., Southwood
S.Wentworth, P.A., Sidney, J.,Chesnut,
R.W., Keogh, E., Appella, E., Nutman,
T.B., Lal, A.A., Gordon, D.M., Oloo, A.
and Sette, A.(1997). Degenerate cytotoxic
T-cell epitopes from P. falciparum restricted
by multiple HLA-A and HLA-B
supertype alleles. Immunity 7: 97-112
Ernea, V., Ellis, J., Zavala, F., Arnot,
D.E.,Asavanich, A., Masuda, A., Quakyi,
I. and Nussenzweig, R.S. (1984).
DNA cloning of Plasmodium falciparum
circumsporozoite gene: amino acid sequence
of repetitive epitope. Science 22:
628-630
Epstein, J.E., Giersing, B. and Mullen, G,
Moorthy V, Richie TL. (2007). Malaria
vaccines: are we getting closer? Current
Opinion in Molecular Therapeutics 9(1):
12-24
Fidock, D. A., Nomura, T., Talley, A.K.,
Cooper, R.A.,S. Dzekunov, S.M., Ferdig,
M.T., Ursos, L.M., Sidhu, A.B.,
Naude, B. Deitsch, K.W., Su, X.Z.,
Wootton, J.C., Roepe, P.D. And
Wellems, T. E. (2000). Mutations in the
P. falciparum digestive vacuole transmembrane
protein PfCRT and evidence
for their role in chloroquine resistance.
Molecular Cell 6: 861–871
Freitas-Junior, L.H., Bottius, E., Pirrit,
L.A., Dietsch,K.W., Scheidig, C.,
Guinet, F., Nehrbass, U., Wellems, T.E.
and Scherf, A. (2000). Frequent ectopic
recombination of virulence factor genes in
telomeric chromosome clusters of P. falciparum.
Nature 407: 1018-1022
Genton, B., Betuela, I. and Felger, I. (2002).
A recombinant blood-stage malaria vaccine
reduces Plasmodium falciparum density
and exerts selective pressure on parasite
populations in a Phase 1-2b trial in
Papua New Guinea. Journal of Infectious
Diseases 185: 820-827
Giersing, B.K., Dubovsky, F., Saul, A., Denamur,
F., Minor, P. and Meade, B.
(2006). Potency assay design for adjuvanted
recombinant proteins as malaria
vaccines. Vaccine 24(20): 4264-4270
Good, M.F., Xu, H., Wykes, M. and Engwerda,
C.R.. (2005). Development and
regulation of cell-mediated immune responses
to the blood stages of malaria. Implications
for vaccine research. Annual
Review of Immunology 23: 69-99
Graves, P.M., Doubrovsky, A., Carter, R.,
Eida, S. and Beckers, P. (1990). High
frequency of antibody response to Plasmodium
falciparum gametocyte antigens during
acute malaria infections in Papua New
Guinea highlanders. American Journal of
Tropical Medicine & Hygiene 42: 515-
520
Gupta, S., Snow, R.W., Donnelly,. C.A.,
Marsh, K., and Newbold, C.(1999). Immunity
to non-cerebral severe malaria is
acquired after one or two infections. Nature
Medicine 5(3):340-343
Haynes, J.D., Moch, J.K. and Smoot, D.S.
(2002). Erythrocytic malaria growth or
invasion inhibition assays with emphasis
on suspension culture GIA. Methods in-
Molecular Medicine 72, 535-554
Heppner, D.G., Jr, Kester, K.E., Ockenhouse,
C.F., Tornieporth, N. and Ofori,
O. (2005). Towards an RTS,S-based,
multi-stage, multi-antigen vaccine against
falciparum malaria: progress at the Walter
Reed Army Institute of Research. Vaccine
23(17-18): 2243-2250
Hill, A.V.S., Elvin, J., Willis A.C., Aidoo,
M., Allsopp, C.E., Gotch, F.M., Gao,
X.M., Takiguchi, M., Greenwood, B.M.,
Townsend, A.R., McMichael, A.J. And
Whittle, H.C. (1992). Molecular analysis
of the association of HLA-B53 and resistance
to severe malaria. Nature 360: 434
439
Hoffman, S.L., Goh, L.M., Luke, T.C.,
Schneider, J., Le, T.P., Doolan, D.L.,
Sacci, J., de la Vega, P., Dowler, M.,
Paul, C., Gordon, D.M., Stoute, J.A.,
Church, L.W., Sedegah, M., Heppner,
D.G., Ballou, W.R. and Richie, T.L.
(2002). Protection of humans against malaria
by immunization with radiationattenuated
Plasmodium falciparum sporozoites.
Journal of Infectious Diseases 185
(8): 1155-1164
John, C.C., O'Donnell, R.A., Sumba, P.O.,
Moormann, A.M., de Koning-Ward,
T.F., King, C.L., Kazura, J.W. And
Crab, B.S. (2004). Evidence that invasion
-inhibitory antibodies specific for the 19-
kDa fragment of merozoite surface protein
-1 (MSP-119) can play a protective role
against blood-stage Plasmodium falciparum
infection in individuals in a malaria
endemic area of Africa Journal of Immunology
173: 666-672
Kitchen, A.D and Chiodini, P.L. (2006).
Malaria and Blood Transfusion. Vox
Sang. 90(20): 77-84.
Konate, L., Zwetyenga, J., Rogier, C.,
Bischoff, E., Fontenille, D., Tall, A.,
Spiegel, A., Trape, J.F. and Merceraeu-
Puijalon, O (1999). The epidemiology of
multiple Plasmodium falciparum infections.
5. Variation of Plasmodium falciparum
msp-1 and msp-2 allele prevalence
and of infection complexity in two
neighboring Senegalese villages with different
transmission conditions. Transactions
of Royal Society of Tropical Medicine
& Hygiene 93(suppl):S1/21–S1/28.
Kumar, K.A., Oliveira, G.A., Edelman, R.,
Nardin, E.. and Nussenzweig, V.(2004).
Quantitative Plasmodium sporozoite neutralization
assay (TSNA). Journal of Immunological
Methods 292(1-2): 157-164
Kumar, K.A., Sano, G., Boscardin, S., Nussenzweig,
R.S., Nussenzweig, M.C., Zavala,
F. and Nussenzweig, V. (2006). The
circumsporozoite protein is an immunodominant
protective antigen in irradiated
sporozoites. Nature 444(7121): 937-
940
Kurtis, J.D., Hollingdale, M.R., Luty, A.J.,
Lanar, D.E., Krzych, U. and Duffy, P.E.
(2001). Pre-erythrocytic immunity to
Plasmodium falciparum: the case for an
LSA-1 vaccine. Trends in Parasitology 17
(5): 219-223
Kyes, S., Taylor, H., Craig, A., Marsh, K.
and Newbold, C. (1997). Genomic representation
of var gene sequences in Plasmodium
falciparum field isolates from different
geographic regions. Molecular and
Biochemical Parasitology 87: 235–238.
Lell, B. A. (2007). Randomized, observerblind
trial to compare safety and immunogenicity
of two adjuvanted RTS,S antimalaria
vaccine candidates in Gabonese
children. Presented at: 56th ASTMH Annual
Meeting. Philadelphia, PA, USA, 4-8.
Malaria vaccine technology roadmap
(2006). Retrieved on the 24-09=2010 from
www.malariavaccineroadmap.net/pdfs/
Malaria_Vaccine_TRM_Final.pdf
Malkin, E.M., Durbin, A.P., Diemert, D.J.
Sattabongkot, J., Wu, Y., Miura, K.,
Long, C.A.., Laubert, L., Miles, A.P.,
Wang, J., Stowers, A., Miller, L.H. And
Saul, A. (2005). Phase 1 vaccine trial of
Pvs25H: a transmission blocking vaccine
for Plasmodium vivax malaria. Vaccine 23
(24): 3131-3138
Marsh, K.(1999). Clinical features of malaria.
In: Malaria: Molecular and clinical
aspects (Wahlgren, M. And Perlmann, P.
eds.), Harwood Academic Publishers,
Amsterdam, pp. 87–117.
Marti, M., Good, R. T., Rug, M., Knuepfer,
E. and Cowman, A. F. (2004). Targeting
malaria virulence and remodelling proteins
to the host erythrocyte. Science 306:
1930–1933
Mehta, N.M. and Arnold, J.H. (2004) Mechanical
ventilation in children with acute
respiratory failure. Current Opinion in
Critical Care 10:7-12.
Moorthy, V., Reed, Z. and Smith, P.G.
(2007). WHO Study Group on Measures
of Malaria Vaccine Efficacy. Measurement
of malaria vaccine efficacy in Phase
III trials: report of a WHO consultation.
Vaccine 25(28): 5115-5123.
Mueller, I., Zimmerman, P.A. and Reeder,
J.C. (2007).. Plasmodium malariae and
Plasmodium ovale--the "bashful" malaria
parasites. Trends in Parasitology 23 (6):
278–83.
Mueller, M.S., Renard, A., Boato, F., Vogel,
D., Nargeli, M., Zubriggen, R., Robinson,
J.A. and Pluschke, G. (2003). Induction
of parasite growth-inhibitory antibodies
by a virosomal formulation of a peptidomimetic
of loop I from domain III of
Plasmodium falciparum apical membrane
antigen 1. Infection & Immunity 71(8):
4749-4758
Newbold, C. I. (1999). Antigenic variation in
Plasmodium falciparum: Mechanisms and
consequences. Current Opinion in Microbiology
2: 420– 425.
Nomura, T.J., Carlton, M.R., Baird, J.K.,
del Portillo, H.A., Fryauff, D.J., Rathore,
D., Fidock, D.A., Su, X., Collins,
W.E., McCutchan, T.F., Wooton, J.C.,
and Wellems, T.E. (2001). Evidence for
different mechanisms of chloroquine resistance
in two Plasmodium species that
cause human malaria. Journal of Infectious
Diseases 183: 1653–1661.
Ntoumi, F., Rogier, C., Dieye, A., Trape,
J.F., Millet, P. and Mercereau- Puijalon,
O. (1997). Imbalanced distribution of
Plasmodium falciparum MSP-1 genotypes
related to sickle cell anemia. Molecular
Medicine 3: 581–592.
Nussenzweig, R., Vanderberg, J. and Most,
H. (1969). Protective immunity produced
by the injection of x-irradiated sporozoites
of Plasmodium berghei. IV. Dose response,
specificity and humoral immunity.
Mil. Med. 134(10): 1176-1182
Pizarro, J.C., Vulliez-Le, N.B., Chesne-
Seck, M.L., Collins, C.R., Withers-
Martinez, C.,Hackett, F., Blackman,
M.J., Faber, B.W., Remargue, E.J.,
Kocken, C.H.,Thomas, A.W. and Bentley,
G.A.(2005). Crystal structure of the
malaria vaccine candidate apical membrane
antigen 1. Science 308(5720): 408-
411
Plebanski, M., Lee, E. A. M., Hannan, C.
M., Flanagan, K. L., Gilbert, S. C.,
Gravenor, M. B. and Hill, A. V. S.
(1999). Altered peptide ligands narrow the
repertoire of cellular immune responses by
interfering with T-cell priming. Nature
Medicine 5: 565–571.
Polhemus, M.E. (2006). A Phase IIb randomized,
double-blind, controlled study of the
safety, immunogenicity and proof-ofconcept
of RTS,S/AS02A, and RTS,S/
AS01B, two candidate malaria vaccines in
malaria-experienced adults living in Western
Kenya. Presented at: 55th ASTMH Annual
Meeting. Atlanta, GA, USA, 12-26
Pombo, D.J., Lawrence, G., Hirunpetcharat,
C., Rzepczyk, C., Bryden,
M., Cloonan, N., Anderson, K., Mahakunkijcharoen,
Y., Martin, L.D., Wilson,
D., Elliott, S., Elliott, S., Elsen,
D.P., Weinberg, J.B., Saul, A. and
Good, M.F. (2002). Immunity to malaria
after administration of ultra-low doses of
red cells infected with Plasmodium falciparum.
Lancet 360: 610-617
Raffenot, D., Rogeaux, De Goer, B. and
Zerr, B. (1999). Plasmodium falciparum
malaria acquired by accidental inoculation.
European Journal of Clinical Microbiology
& Infectious Diseases. 18(9): 680-
681
Rieckmann, K.H., Beaudoin, R.L., Cassells,
JS. and Sell, K.W. (1979). Use of attenuated
sporozoites in the immunization of
human volunteers against falciparum malaria.
Bulletin of World Health Organisation
57(Suppl. 1): 261-265
Rogerson, S.J., Hviid, L., Duffy, P.E., Leke,
R.F., Taylor, D.W. (2007). Malaria in
pregnancy: pathogenesis and immunity.
Lancet Infectious Diseases 2: 105-117
Ross and the Discovery that Mosquitoes
Transmit Malaria Parasites". CDC Malaria
website. http://www.cdc.gov/
malaria/history/ross.htm. Retrieved on
2009-03-15.
Rudenko, G. (1999). Genes involved in phenotypic
and antigenic variation in African
trypanosomes and malaria. Current Opinions
in Microbiology 2: 651–656.
Sachs, J. and Malaney, P. (2002). The economic
and social burden of malaria. Nature
415: 680–685
Saeij, J. P., Coller, S., Boyle, J.P., Jerome,
M.E., White, M.W. and Boothroyd, J.C.
(2007). Toxoplasma co-opts host gene expression
by injection of a polymorphic
kinase homologue. Nature 445: 324–327
Sauzet, J.P., Perlaza, B.L., Brahimi, K.,
Daubersies, P. and Druilhe, P.(2001).
DNA immunization by Plasmodium falciparum
liver-stage antigen 3 induces protection
against Plasmodium yoelii sporozoite
challenge. Infect. Immun. 69(2), 1202
-1206
Scherf, A., Hernandez-Viras, R., Buffet, P.,
Bottius, E., Benatar, C., Pouvelle, B.,
Gysin, J. and Lanzer. M. (1998). Antigenic
variation in malaria: in situ switching,
relaxed and mutually exclusive transcription
of var genes during intraerythrocytic
development in Plasmodium
falciparum. EMBO Journal 17: 5418–
5426.
Sharma, V. P. (1996). Re-emergence of malaria
in India. Indian Journal of Medicinal
Research 103: 26–45.
Silvie O, Franetich JF, Charrin S., Mueller,
M.S., Stau, A., Bodescot, M., Rubinstein,
E., Hannoun, L., Charoenvit, Y.,
Kocken, C.H., Thomas, A.W., van
Gemert, G.J., Sauerwein, R.W., Blackman,
M.J., Anders, R.F., Pluschke, G.
and Mazier, D. (2004). A role for apical
membrane antigen 1 during invasion of
hepatocytes by Plasmodium falciparum
sporozoites. Journal of Biological Chemistry
279(10): 9490-9496.
Singh, A.P., Buscaglia, C.A., Wang, Q., Levay,
A., Nussenzweig, D.R., Walker,
J.R., Winzeler, E.A., Fujii, H., Fontoura,
B.M. and Nussenzweig, V. (2007).
Plasmodium circumsporozoite protein promotes
the development of the liver stages
of the parasite. Cell 131(3): 492-504
Smith, J. D., Chitnis, C. E., Craig, A. G.,
Roberts, D. J., Hudson- Taylor, D. E.,
Peterson, D. S., Pinches, R., Newbold, C.
I. and Miller, L. H. (1995). Switches in
expression of Plasmodium falciparum var
genes correlate with changes in antigenic
and cytoadherent phenotypes of inherited
erythrocytes, Cell 82(1): 101-10.
Stewart, V.A., McGrath, S.M., Walsh, D.S.,
Davis, S., Hess, A.S., Ware, L.A., Kester,
K.E., Cummings, J.F., Burge, J.R.,
Voss, G., Delchambre, M., Garcon, N.,
Tang, D.B., Cohen, J.D. and Heppner,
D.G.Jr (2006). Pre-clinical evaluation of
new adjuvant formulations to improve the
immunogenicity of the malaria vaccine
RTS,S/AS02A. Vaccine 24(42-43): 6483-
6492
Stowers, A.W., Kennedy, M.C., Keegan,
B.P., Saul, A., Long, C.A. and Miller,
L.H. (2002). Vaccination of monkeys with
recombinant Plasmodium falciparum apical
membrane antigen 1 confers protection
against blood-stage malaria. Infection &
Immunity 70(12): 6961-6967.
Su, X., Heatwole, V. M., Wertheimer, F.,
Guinet, F., Herrfeldt, J. A., Peterson, D.
S., Ravetch, J.A. and Wellems, T. E.,
(1995). The large and diverse gene family
var encodes proteins involved in cytoadherence
and antigenic variation of Plasmodium
falciparum- infected erythrocytes.
Cell 82: 89–100.
Sun, P., Schwenk, R., White ,K., Stoute,
J.A., Cohen, J., Ballou, W.R., Voss, G.,
Kester, K.E., Heppner, D.C. and
Krzych, U. (2003). Protective immunity
induced with malaria vaccine, RTS,S, is
linked to Plasmodium falciparum circumsporozoite
protein-specific CD4+ and
CD8+ T cells producing IFN-γ. Journal of
Immunology 171(12): 6961-6967
Tarantola, D., Macklin, R., Reed, Z.H.,
Osmanov, S., Stobie, M., Hankins, C.
and Kieny, M.P. (2007). Ethical considerations
related to the provision of care
and treatment in vaccine trials. Vaccine 25
(26): 4863-4874
Taylor, S., Barragan, A., Su, C., Fux, B.,
Fentress, S.J., Tang, K., Beatty, W.L.,
Haii, H.E., Jerome, M., Behnke, M.S.,
White, M., Wootton, J.C. and Sibley,
L.D. (2006). A secreted serine-threonine
kinase determines virulence in the eukaryotic
pathogen Toxoplasma gondii.
Science 314: 1776–1780
Vreden, S.G., Verhave, J.P., Oettinger, T.,
Sauerwein, R.W. and Meuwissen, J.H.
(1991). Phase I clinical trial of a recombinant
malaria vaccine consisting of the circumsporozoite
repeat region of Plasmodium
falciparum coupled to hepatitis B
surface antigen. American Journal of
Tropical Medicine & Hygiene 45(5): 533-
538.
Webster, D.P., Dunachie, S., Vuola, J.M.,
Berthoud, T., Keating, S., Laidlaw, S.M.,
McConkey, S.J., Poulton, I., Andrews, L.,
Andersen, R.F., Bejon, P., Butcher, G.,
Sinden, R., Skinner, M.A., Gilbert, S.C.,
and Hill, A.V. (2005). Enhanced T cellmediated
protection against malaria in human
challenges by using the recombinant
poxviruses FP9 and modified vaccinia virus
Ankara. Proceeddings National Academy of
Science. USA 102(13): 4836-4841
Wellems, T. E., and Plowe, C.V. (2001).
Chloroquine-resistant malaria. Journal of
Infectious Diseases 184: 770–776.
Weller, P.F. (2003). Protozoan infections. In:
Infectious diseases (Dale, D.C. Ed.).
WebMD New York. 651-675.
Wernsdorfer, W. H. (1980). The importance of
malaria in the world. In: Epidemiology,
chemotherapy, morphology, and metabolism
(J. P. Kreier, J.P. ed.), Malaria: . Academic
Press, New York. pp. 1–79
Winzeler, E.A . (2008). Malaria research in the
post-genomic era. Nature 455, 751-756.
Withers, M.R., McKinney, D., Ogutu, B.R.,
Waitumbi, J.N., Milman, J.B., Apollo,
O.J., Allen, O.G., Tucker, K., Soisson,
L.A., Diggs, C., Leach, A., Wittes, J.,
Dubovsky, F., Stewart, V.A., Remich,
S.A., Cohen, J., Ballou, W.R., Holland,
A.C., Lyon, J.A., Angov, E., Stoute, J.A.,
Martin, S.K. And Heppner, D.G. (2007).
Safety and reactogenicity of an MSP-1 malaria
vaccine candidate: a randomized Phase
Ib dose-escalation trial in Kenyan children.
PLoS Clinical Trials 1(7): e32
Wootton, J. C., Feng, X., Ferdig, M. T., Cooper,
R. A., Mu, J., Baruch, D. I., Magill,
A. J. and Su. X. (2002). Genetic diversity
and chloroquine selective sweeps in Plasmodium
falciparum. Nature 418 (6895): 430
-323.
World Health Organization. WHO Fact Sheet
on Malaria. Fact Sheet No 94. World Health
Organization. Available at http://
www.who.int/mediacentre/factsheets/fs094/
en/print.html Retrieved , March 15, 2009.
World Health Organisation. (2010). Guidelines
for the treatment of malaria, (2nd Ed.).
pages: 194.