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Randomized Controlled Trial
. 2017 Aug 11;7(1):7998.
doi: 10.1038/s41598-017-08526-5.

Delayed Fractional Dose Regimen of the RTS,S/AS01 Malaria Vaccine Candidate Enhances an IgG4 Response That Inhibits Serum Opsonophagocytosis

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Free PMC article
Randomized Controlled Trial

Delayed Fractional Dose Regimen of the RTS,S/AS01 Malaria Vaccine Candidate Enhances an IgG4 Response That Inhibits Serum Opsonophagocytosis

Sidhartha Chaudhury et al. Sci Rep. .
Free PMC article

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.

Conflict of interest statement

Dr. Erik Jongert is an employee of GSK Vaccine, Rixensart, Belgium.

Figures

Figure 1
Figure 1
Phagocytic activity by subjects in 012M and Fx017M cohorts. OPA, as measured by MFI (red) and Mfreq (blue) OPA titers for each subject in the 012M and Fx017M cohorts, denoted by their protection status as protected (‘P’, solid bars) or not protected (‘NP’, hatched bars). Subjects selected for low and high phagocytic activity pools are shown as ‘*’ and ‘**’, respectively, for both cohorts.
Figure 2
Figure 2
Opsonophagocytic activity in 012M and Fx017M cohorts. OPA titers for Mfreq (A) and MFI (B) for the 012M and Fx017M cohorts. OPA indices for Mfreq (C) and MFI (D), relative to CS antibody titer, for 012M and Fx017M cohorts. Protected and non-protected subjects are shown in blue and red, respectively.
Figure 3
Figure 3
IgG subclass titers for 012M and Fx017M cohorts. Antibody titers for IgG1, IgG2, IgG3, and IgG4 for the 012M and Fx017M cohorts against three CSP test antigens: full-length recombinant CSP (left column), NANP repeat region peptide (middle column), and C-terminal PF16 peptide (right column). Protected and non-protected subjects are colored in blue and red, respectively.
Figure 4
Figure 4
Serum opsonophagocytic activity following depletion of IgG isotype subclass antibodies. The change in peak OPA relative to the non-depleted sample, as measured by Mfreq, when the low-OPA and high-OPA pools from the 012M and Fx017M cohorts were depleted of IgG1, IgG3, IgG4, or IgG1 + IgG3.
Figure 5
Figure 5
Serum opsonophagocytic activity following depletion of IgG isotype subclasses at a range of serum concentrations. The change in Mfreq relative to the non-depleted sample is shown following depletion of IgG1, IgG3, and IgG4 for the low-OPA and high-OPA pools for the 012M and Fx017M cohorts.

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