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Effect of the pre-erythrocytic candidate malaria vaccine RTS,S/AS01E on blood stage immunity in young children.

Bejon P, Cook J, Bergmann-Leitner E, Olotu A, Lusingu J, Mwacharo J, Vekemans J, Njuguna P, Leach A, Lievens M, Dutta S, von Seidlein L, Savarese B, Villafana T, Lemnge MM, Cohen J, Marsh K, Corran PH, Angov E, Riley EM, Drakeley CJ - J. Infect. Dis. (2011)

Bottom Line: Anti-MSP-3 antibody concentrations gradually increased, and GIA gradually decreased up to 32 months.Vaccination with RTS,S/AS01(E) resulted in modest reductions in AMA-1, EBA-175, MSP-1(42), and MSP-3 antibody concentrations and no significant change in GIA.Vaccination with RTS,S/AS01E reduces exposure to blood-stage parasites and, thus, reduces anti-merozoite antigen antibody concentrations.

View Article: PubMed Central - PubMed

Affiliation: Kenya Medical Research Institute, Centre for Geographic Medicine Research, Kilifi, Kenya. pbejon@kilifi.kemri-wellcome.org

ABSTRACT

Background: RTS,S/AS01(E) is the lead candidate malaria vaccine and confers pre-erythrocytic immunity. Vaccination may therefore impact acquired immunity to blood-stage malaria parasites after natural infection.

Methods: We measured, by enzyme-linked immunosorbent assay, antibodies to 4 Plasmodium falciparum merozoite antigens (AMA-1, MSP-1(42), EBA-175, and MSP-3) and by growth inhibitory activity (GIA) using 2 parasite clones (FV0 and 3D7) at 4 times on 860 children who were randomized to receive with RTS,S/AS01(E) or a control vaccine.

Results:  Antibody concentrations to AMA-1, EBA-175, and MSP-1(42) decreased with age during the first year of life, then increased to 32 months of age. Anti-MSP-3 antibody concentrations gradually increased, and GIA gradually decreased up to 32 months. Vaccination with RTS,S/AS01(E) resulted in modest reductions in AMA-1, EBA-175, MSP-1(42), and MSP-3 antibody concentrations and no significant change in GIA. Increasing anti-merozoite antibody concentrations and GIA were prospectively associated with increased risk of clinical malaria.

Conclusions: Vaccination with RTS,S/AS01E reduces exposure to blood-stage parasites and, thus, reduces anti-merozoite antigen antibody concentrations. However, in this study, these antibodies were not correlates of clinical immunity to malaria. Instead, heterogeneous exposure led to confounded, positive associations between increasing antibody concentration and increasing risk of clinical malaria.

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Kaplan Meier plots showing proportions of children without clinical malaria episodes according to quartile of antibody or GIA responses measured directly prior to periods of follow-up (ie, there are up to 3 observations for each individual: malaria incidence in the 2.5 months after antibody assessments at enrollment and at months 8 and 12 after the third vaccination).
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fig2: Kaplan Meier plots showing proportions of children without clinical malaria episodes according to quartile of antibody or GIA responses measured directly prior to periods of follow-up (ie, there are up to 3 observations for each individual: malaria incidence in the 2.5 months after antibody assessments at enrollment and at months 8 and 12 after the third vaccination).

Mentions: For Cox regression models, the unit of analysis was the period of observation after each antibody measurement. Therefore, each of the 866 participants could contribute up to 3 periods (after baseline and 1 and 6 months after the third vaccination). Among these time periods, there were 277 first or only episodes of clinical malaria (ie, axillary temperature ≥37.5oC and parasite load ≥2500 parasites/μL) during 9580 months of monitoring. After adjusting for vaccination group, there were positive associations between increasing antibody concentration and an increased subsequent risk of clinical malaria for anti–AMA-1, MSP142, and EBA-175 antibody concentrations and for GIA (Table 3). Survival plots by antibody quartile are shown in Figure 2.


Effect of the pre-erythrocytic candidate malaria vaccine RTS,S/AS01E on blood stage immunity in young children.

Bejon P, Cook J, Bergmann-Leitner E, Olotu A, Lusingu J, Mwacharo J, Vekemans J, Njuguna P, Leach A, Lievens M, Dutta S, von Seidlein L, Savarese B, Villafana T, Lemnge MM, Cohen J, Marsh K, Corran PH, Angov E, Riley EM, Drakeley CJ - J. Infect. Dis. (2011)

Kaplan Meier plots showing proportions of children without clinical malaria episodes according to quartile of antibody or GIA responses measured directly prior to periods of follow-up (ie, there are up to 3 observations for each individual: malaria incidence in the 2.5 months after antibody assessments at enrollment and at months 8 and 12 after the third vaccination).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105039&req=5

fig2: Kaplan Meier plots showing proportions of children without clinical malaria episodes according to quartile of antibody or GIA responses measured directly prior to periods of follow-up (ie, there are up to 3 observations for each individual: malaria incidence in the 2.5 months after antibody assessments at enrollment and at months 8 and 12 after the third vaccination).
Mentions: For Cox regression models, the unit of analysis was the period of observation after each antibody measurement. Therefore, each of the 866 participants could contribute up to 3 periods (after baseline and 1 and 6 months after the third vaccination). Among these time periods, there were 277 first or only episodes of clinical malaria (ie, axillary temperature ≥37.5oC and parasite load ≥2500 parasites/μL) during 9580 months of monitoring. After adjusting for vaccination group, there were positive associations between increasing antibody concentration and an increased subsequent risk of clinical malaria for anti–AMA-1, MSP142, and EBA-175 antibody concentrations and for GIA (Table 3). Survival plots by antibody quartile are shown in Figure 2.

Bottom Line: Anti-MSP-3 antibody concentrations gradually increased, and GIA gradually decreased up to 32 months.Vaccination with RTS,S/AS01(E) resulted in modest reductions in AMA-1, EBA-175, MSP-1(42), and MSP-3 antibody concentrations and no significant change in GIA.Vaccination with RTS,S/AS01E reduces exposure to blood-stage parasites and, thus, reduces anti-merozoite antigen antibody concentrations.

View Article: PubMed Central - PubMed

Affiliation: Kenya Medical Research Institute, Centre for Geographic Medicine Research, Kilifi, Kenya. pbejon@kilifi.kemri-wellcome.org

ABSTRACT

Background: RTS,S/AS01(E) is the lead candidate malaria vaccine and confers pre-erythrocytic immunity. Vaccination may therefore impact acquired immunity to blood-stage malaria parasites after natural infection.

Methods: We measured, by enzyme-linked immunosorbent assay, antibodies to 4 Plasmodium falciparum merozoite antigens (AMA-1, MSP-1(42), EBA-175, and MSP-3) and by growth inhibitory activity (GIA) using 2 parasite clones (FV0 and 3D7) at 4 times on 860 children who were randomized to receive with RTS,S/AS01(E) or a control vaccine.

Results:  Antibody concentrations to AMA-1, EBA-175, and MSP-1(42) decreased with age during the first year of life, then increased to 32 months of age. Anti-MSP-3 antibody concentrations gradually increased, and GIA gradually decreased up to 32 months. Vaccination with RTS,S/AS01(E) resulted in modest reductions in AMA-1, EBA-175, MSP-1(42), and MSP-3 antibody concentrations and no significant change in GIA. Increasing anti-merozoite antibody concentrations and GIA were prospectively associated with increased risk of clinical malaria.

Conclusions: Vaccination with RTS,S/AS01E reduces exposure to blood-stage parasites and, thus, reduces anti-merozoite antigen antibody concentrations. However, in this study, these antibodies were not correlates of clinical immunity to malaria. Instead, heterogeneous exposure led to confounded, positive associations between increasing antibody concentration and increasing risk of clinical malaria.

Show MeSH
Related in: MedlinePlus