Abstract
BackgroundA malaria vaccine based on Plasmodium falciparum apical membrane antigen 1 (AMA1) elicited strain specific efficacy in Malian children that waned in the second season after vaccination despite sustained AMA1 antibody titers. With the goal of identifying a humoral correlate of vaccine-induced protection, pre- and post-vaccination sera from children vaccinated with the AMA1 vaccine and from a control group that received a rabies vaccine were tested for AMA1-specific immunoglobulin G (IgG) subclasses (IgG1, IgG2, IgG3, and IgG4) and for antibody avidity.MethodsSamples from a previously completed Phase 2 AMA1 vaccine trial in children residing in Mali, West Africa were used to determine AMA1-specific IgG subclass antibody titers and avidity by ELISA. Cox proportional hazards models were used to assess correlation between IgG subclass antibody titers and risk of time to first or only clinical malaria episode and risk of multiple episodes. Asexual P. falciparum parasite density measured for each child as area under the curve were used to assess correlation between IgG subclass antibody titers and parasite burden.ResultsAMA1 vaccination did not elicit a change in antibody avidity; however, AMA1 vaccinees had a robust IgG subclass response that persisted over the malaria transmission season. AMA1-specific IgG subclass responses were not associated with decreased risk of subsequent clinical malaria. For the AMA1 vaccine group, IgG3 levels at study day 90 correlated with high parasite burden during days 90–240. In the control group, AMA1-specific IgG subclass rise and persistence over the malaria season was modest and correlated with age. In the control group, titers of several IgG subclasses at days 90 and 240 correlated with parasite burden over the first 90 study days, and IgG3 at day 240 correlated with parasite burden during days 90–240.ConclusionsNeither IgG subclass nor avidity was associated with the modest, strain-specific efficacy elicited by this blood stage malaria vaccine. Although a correlate of protection was not identified, correlations between subclass titers and age, and correlations between IgG subclass titers and parasite burden, defined by area under the curve parasitaemia levels, were observed, which expand knowledge about IgG subclass responses. IgG3, known to have the shortest half-life of the IgG subclasses, might be the most temporally relevant indicator of ongoing malaria exposure when examining antibody responses to AMA1.
Highlights
A malaria vaccine based on Plasmodium falciparum apical membrane antigen 1 (AMA1) elicited strain specific efficacy in Malian children that waned in the second season after vaccination despite sustained AMA1 antibody titers
Children were randomized in a 1:1 ratio to receive FMP2.1/AS02A, which comprises recombinant AMA1 based on the 3D7 P. falciparum strain formulated with GSKBio’s adjuvant system AS02A, or unadjuvanted rabies vaccine as a control, as three vaccinations given intramuscularly 1 month apart
As previously observed for whole immunoglobulin G (IgG) titers, in both the pilot study and the main study, baseline anti-AMA1 antibody titers for all four IgG subclasses in the FMP2.1/ AS02A group increased after vaccination and remained elevated 180 days after the last vaccination (Fig. 1, Additional file 1)
Summary
A malaria vaccine based on Plasmodium falciparum apical membrane antigen 1 (AMA1) elicited strain specific efficacy in Malian children that waned in the second season after vaccination despite sustained AMA1 antibody titers. Differences in structural composition determine functionality: IgG1 and IgG3 are associated with T-cell dependent, cytophilic activity and typically recognize proteins [6]. They are the predominant subclasses observed in antibody dependent cellular cytotoxic responses to blood-stage merozoite antigens [7,8,9,10,11,12,13,14]. IgG4 binds allergens and chronically persistent antigens [15] and is, thought to exert anti-inflammatory effects
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