Immune Responses to Gametocyte Antigens in a Malaria Endemic Population-The African falciparum Context: A Systematic Review and Meta-Analysis

Abstract

Background: Malaria elimination remains a priority research agenda with the need for interventions that reduce and/or block malaria transmission from humans to mosquitoes. Transmission-blocking vaccines (TBVs) are in development, most of which target the transmission stage (i.e., gametocyte) antigens Pfs230 and Pfs48/45. For these interventions to be implemented, there is a need to understand the naturally acquired immunity to gametocytes. Several studies have measured the prevalence of immune responses to Pfs230 and Pfs48/45 in populations in malaria-endemic areas. Methods: We conducted a systematic review of studies carried out in African populations that measured the prevalence of immune responses to the gametocyte antigens Pfs230 and Pfs48/45. We assessed seroprevalence of antibody responses to the two antigens and investigated the effects of covariates such as age, transmission intensity/endemicity, season, and parasite prevalence on the prevalence of these antibody responses by meta-regression. Results: We identified 12 studies covering 23 sites for inclusion in the analysis. We found that the range of reported seroprevalence to Pfs230 and Pfs48/45 varied widely across studies, from 0 to 64% for Pfs48/45 and from 6 to 72% for Pfs230. We also found a modest association between increased age and increased seroprevalence to Pfs230: adults were associated with higher seroprevalence estimates in comparison to children (β coefficient 0.21, 95% CI: 0.05-0.38, p = 0.042). Methodological factors were the most significant contributors to heterogeneity between studies which prevented calculation of pooled prevalence estimates. Conclusions: Naturally acquired sexual stage immunity, as detected by antibodies to Pfs230 and Pfs48/45, was present in most studies analyzed. Significant between-study heterogeneity was seen, and methodological factors were a major contributor to this, and prevented further analysis of epidemiological and biological factors. This demonstrates a need for standardized protocols for conducting and reporting seroepidemiological analyses.

Keywords: Pfs230; Pfs48/45; Plasmodium falciparum; gametocytes; immunity.

Figure 1

Consort diagram showing the selection of studies to include in the systematic review and meta-analysis. Reasons for exclusion are included at each step. *Reasons for exclusion: six studies measured immune responses semi-quantitatively (four of these in the same population), 11 studies had a sample size of < 30, five studies were healthcare facility-based studies (i.e., primary care facilities or hospitals).

Figure 2

Forest plot of the prevalence of antibodies to Pfs230 in endemic sera from Africa. Seropositive individuals were defined as study participants with an antibody reactivity above a set cut-off defined from seronegative individuals as measured in an immunoassay.

Figure 3

Forest plot of the prevalence of antibodies to Pfs48/45 in endemic sera from Africa. Seropositive individuals were defined as study participants with an antibody reactivity above a set cut-off defined from seronegative individuals as measured in an immunoassay.

Figure 4

Forest plot of the prevalence of antibodies to Pfs48/45 in endemic sera from Africa grouped by gametocyte prevalence. Seropositive individuals were defined as study participants with an antibody reactivity above a set cut-off defined from seronegative individuals as measured in an immunoassay. ¹Participants samples during the dry season; ²Participants sampled during the rainy season.