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Delayed fractional dose regimen of the RTS,S/AS01 malaria vaccine candidate enhances an IgG4 response that inhibits serum opsonophagocytosis.

ABSTRACT: A recent study of the RTS,S malaria vaccine, which is based on the circumsporozoite protein (CSP), demonstrated an increase in efficacy from 50-60% to 80% when using a delayed fractional dose regimen, in which the standard 0-1-2 month immunization schedule was modified to a 0-1-7 month schedule and the third immunization was delivered at 20% of the full dose. Given the role that antibodies can play in RTS,S-induced protection, we sought to determine how the modified regimen alters IgG subclasses and serum opsonophagocytic activity (OPA). Previously, we showed that lower CSP-mediated OPA was associated with protection in an RTS,S study. Here we report that the delayed fractional dose regimen resulted in decreased CSP-mediated OPA and an enhanced CSP-specific IgG4 response. Linear regression modeling predicted that CSP-specific IgG1 promote OPA, and that CSP-specific IgG4 interferes with OPA, which we subsequently confirmed by IgG subclass depletion. Although the role of IgG4 antibodies and OPA in protection is still unclear, our findings, combined with previous results that the delayed fractional dose increases CSP-specific antibody avidity and somatic hypermutation frequency in CSP-specific B cells, demonstrate how changes in vaccine regimen alone can significantly alter the quality of antibody responses to improve vaccine efficacy.

SUBMITTER: Chaudhury S

PROVIDER: S-EPMC5554171 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Delayed fractional dose regimen of the RTS,S/AS01 malaria vaccine candidate enhances an IgG4 response that inhibits serum opsonophagocytosis.

Chaudhury Sidhartha S Regules Jason A JA Darko Christian A CA Dutta Sheetij S Wallqvist Anders A Waters Norman C NC Jongert Erik E Lemiale Franck F Bergmann-Leitner Elke S ES

Scientific reports 20170811 1

A recent study of the RTS,S malaria vaccine, which is based on the circumsporozoite protein (CSP), demonstrated an increase in efficacy from 50-60% to 80% when using a delayed fractional dose regimen, in which the standard 0-1-2 month immunization schedule was modified to a 0-1-7 month schedule and the third immunization was delivered at 20% of the full dose. Given the role that antibodies can play in RTS,S-induced protection, we sought to determine how the modified regimen alters IgG subclasses ...[more]

PMID: 28801554

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Project description:BackgroundRTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009-2014 phase III trial (MALARIA-055, NCT00866619), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted.MethodsWe implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6-12 weeks) and children (5-17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation.ResultsVaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner.ConclusionsVegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called "dambos" which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context.Trial registrationEfficacy of GSK Biologicals' Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009.

Project description:BackgroundThe candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules.MethodsWe conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child's home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group.ResultsOver 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], -17.0 to 21.9; P=0.66) in the intention-to-treat analysis and 7.0% (95% CI, -14.5 to 24.6; P=0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: -43.5%; 95% CI, -100.3 to -2.8 [P=0.03]; per-protocol analysis: -56.8%; 95% CI, -118.7 to -12.3 [P=0.008]).ConclusionsA three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.).

Dataset Information

Delayed fractional dose regimen of the RTS,S/AS01 malaria vaccine candidate enhances an IgG4 response that inhibits serum opsonophagocytosis.

Publications

Delayed fractional dose regimen of the RTS,S/AS01 malaria vaccine candidate enhances an IgG4 response that inhibits serum opsonophagocytosis.

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