Effect of transmission intensity and age on subclass antibody responses to Plasmodium falciparum pre-erythrocytic and blood-stage antigens

Abstract

Cytophilic immunoglobulin (IgG) subclass responses (IgG1 and IgG3) to Plasmodium falciparum antigens have been associated with protection from malaria, yet the relative importance of transmission intensity and age in generation of subclass responses to pre-erythrocytic and blood-stage antigens have not been clearly defined. We analyzed IgG subclass responses to the pre-erythrocytic antigens CSP, LSA-1, and TRAP and the blood-stage antigens AMA-1, EBA-175, and MSP-1 in asymptomatic residents age 2 years or older in stable (n=116) and unstable (n=96) transmission areas in Western Kenya. In the area of stable malaria transmission, a high prevalence of cytophilic (IgG1 and IgG3) antibodies to each antigen was seen in all age groups. Prevalence and levels of cytophilic antibodies to pre-erythrocytic and blood-stage P. falciparum antigens increased with age in the unstable transmission area, yet IgG1 and IgG3 responses to most antigens for all ages in the unstable transmission area were less prevalent and lower in magnitude than even the youngest age group from the stable transmission area. The dominance of cytophilic responses over non-cytophilic (IgG2 and IgG4) was more pronounced in the stable transmission area, and the ratio of IgG3 over IgG1 generally increased with age. In the unstable transmission area, the ratio of cytophilic to non-cytophilic antibodies did not increase with age, and tended to be IgG3-biased for pre-erythrocytic antigens yet IgG1-biased for blood-stage antigens. The differences between areas could not be attributed to active parasitemia status, as there were minimal differences in antibody responses between those positive and negative for Plasmodium infection by microscopy in the stable transmission area. Individuals in areas of unstable transmission have low cytophilic to non-cytophilic IgG subclass ratios and low IgG3:IgG1 ratios to P. falciparum antigens. These imbalances could contribute to the persistent risk of clinical malaria in these areas and serve as population-level, age-specific biomarkers of transmission.

Synthetic Antigens Derived from Plasmodium falciparum Sporozoite, Liver, and Blood Stages: Naturally Acquired Immune Response and Human Leukocyte Antigen Associations in Individuals Living in a Brazilian Endemic Area

“…Significant age-related increases in IgG3 antibodies to CSP have also been reported in areas of stable malaria transmission, but none were identified in unstable malaria transmission where IgG3 responses to CSP declined with age. 73 Here, the IgG1 and IgG4 isotypes were preferentially induced by the LSA-1 antigen. In a study performed in Kenya, John and others reported different data: most antibodies against LSA-1 belonged to the IgG1 and IgG3 subclasses, although IgG2 was observed at lower frequencies.…”

IgG subclass responses to excreted-secreted antigens of Plasmodium falciparum in a low-transmission malaria area of the Peruvian Amazon

“…However, the development of immunity to malaria depends on the balance between cytophilic (IgG1 and IgG3) and non-cytophilic IgG antibodies (IgG4), which interfere with the binding of Fcγ receptors with cytophilic antibodies, complicating the immune response [ 5 , 19 , 20 ]. Noticeably, in the presence of the H131 variant in the FcgRIIA receptor, IgG2 has a cytophilic role, whereas the R131 variant does not bind IgG2 [ 21 – 23 ].…”

Some evidence that seasonal malaria chemoprevention with SPAQ has an effect on blood stage antibody responses and pre-erythrocytic stage of Plasmodium falciparum infections in Niger.

“…SMC is an administration of full therapeutic doses of these drugs to children aged 3-59 months as monthly interval during period of greatest malaria risk in endemic areas [6]. In these areas, children develop slowly and naturally anti-Plasmodium antibodies and become semi-immune [7], [8].…”

“…Malaria immunity is partial, short-lived, and requires exposure to infected mosquitoes bites to be maintained [7]. Monthly given SMC reduce malaria morbidity in young children in West Africa [5,[9][10][11].…”