Impact of RTS,S/AS02(A) and RTS,S/AS01(B) on genotypes of P. falciparum in adults participating in a malaria vaccine clinical trial.
OBJECTIVE
RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals' proprietary Adjuvant Systems AS02(A) or AS01(B). A recent trial of the RTS,S/AS02(A) and RTS,S/AS01(B) vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02(A) and RTS,S/AS01(B) on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias.


METHODS
The distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in break-through infections from vaccinated individuals and from those receiving a non-malarial vaccine.


METHODS
The study was conducted in Kombewa District, western Kenya.


METHODS
Semi-immune adults from the three study arms provided isolates at baseline and during break-through infections.


RESULTS
Parasite isolates used for determining MOI and divergence of csp T cell-epitopes were 191 at baseline and 87 from break-through infections.


RESULTS
Grouping recipients of RTS,S/AS01(A) and RTS,S/AS02(B) together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/AS01(B) group, but not the RTS,S/AS02(A) group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339 were less common among pooled RTS,S/AS vaccine recipients than among recipients of rabies vaccine, whereas parasites with D371 were more common among the RTS,S/AS groups.


CONCLUSIONS
It is concluded that both RTS,S/AS vaccines reduce multiplicity of infection. Our results do not support the hypothesis that RTS,S/AS vaccines elicit preferential effects against pfcsp alleles with sequence similarity to the 3D7 pfcsp sequence employed in the vaccine construct.
Waitumbi
John N
JN
Walter Reed Project, Kenya Medical Research Institute, Kisumu, Kenya. jwaitumbi@wrp-ksm.org
Anyona
Samuel B
SB
Hunja
Carol W
CW
Kifude
Carolyne M
CM
Polhemus
Mark E
ME
Walsh
Douglas S
DS
Ockenhouse
Chris F
CF
Heppner
D Gray
DG
Leach
Amanda
A
Lievens
Marc
M
Ballou
W Ripley
WR
Cohen
Joe D
JD
Sutherland
Colin J
CJ
D000293:Adolescent; D000328:Adult; D000483:Alleles; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008288:Malaria / Q000469:parasitology* / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000627:therapeutic use*; D008297:Male; D010963:Plasmodium falciparum / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA
D018984:Epitopes, T-Lymphocyte; D017780:Malaria Vaccines; C526041:RTS,S-AS01B vaccine; C493155:RTS,S-AS02A vaccine