Measuring naturally acquired immune responses to candidate malaria vaccine antigens in Ghanaian adults

Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
Malaria Journal (Impact Factor: 3.11). 06/2011; 10(1):168. DOI: 10.1186/1475-2875-10-168
Source: PubMed

ABSTRACT To prepare field sites for malaria vaccine trials, it is important to determine baseline antibody and T cell responses to candidate malaria vaccine antigens. Assessing T cell responses is especially challenging, given genetic restriction, low responses observed in endemic areas, their variability over time, potential suppression by parasitaemia and the intrinsic variability of the assays.
In Part A of this study, antibody titres were measured in adults from urban and rural communities in Ghana to recombinant Plasmodium falciparum CSP, SSP2/TRAP, LSA1, EXP1, MSP1, MSP3 and EBA175 by ELISA, and to sporozoites and infected erythrocytes by IFA. Positive ELISA responses were determined using two methods. T cell responses to defined CD8 or CD4 T cell epitopes from CSP, SSP2/TRAP, LSA1 and EXP1 were measured by ex vivo IFN-γ ELISpot assays using HLA-matched Class I- and DR-restricted synthetic peptides. In Part B, the reproducibility of the ELISpot assay to CSP and AMA1 was measured by repeating assays of individual samples using peptide pools and low, medium or high stringency criteria for defining positive responses, and by comparing samples collected two weeks apart.
In Part A, positive antibody responses varied widely from 17%-100%, according to the antigen and statistical method, with blood stage antigens showing more frequent and higher magnitude responses. ELISA titres were higher in rural subjects, while IFA titres and the frequencies and magnitudes of ex vivo ELISpot activities were similar in both communities. DR-restricted peptides showed stronger responses than Class I-restricted peptides. In Part B, the most stringent statistical criteria gave the fewest, and the least stringent the most positive responses, with reproducibility slightly higher using the least stringent method when assays were repeated. Results varied significantly between the two-week time-points for many participants.
All participants were positive for at least one malaria protein by ELISA, with results dependent on the criteria for positivity. Likewise, ELISpot responses varied among participants, but were relatively reproducible by the three methods tested, especially the least stringent, when assays were repeated. However, results often differed between samples taken two weeks apart, indicating significant biological variability over short intervals.

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    • "The current data confirm the general observation that plasma levels of antibodies against sporozoite antigens (CelTOS and CSP) are comparatively lower than levels against blood stage antigens in populations with natural exposure to malaria [27]. For any of the three antigens, comparisons of OD data by sampling time point show that antibody levels were generally higher at month 0 compared independently to months 3 and 6 in the two younger age groups (one to five and six to 15 years) whilst antibody levels did not change significantly with time in the 16–30 years old group (Figure 1). "
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    ABSTRACT: Reported malaria cases continue to decline globally, and this has been attributed to strategic implementation of multiple malaria control tools. Gains made would however need to be sustained through continuous monitoring to ensure malaria elimination and eradication. Entomological inoculation rate (EIR) is currently the standard tool for transmission monitoring but this is not sensitive enough, especially in areas of very low transmission. Transmission estimation models based on seroconversion rates (lamda) of antibodies to Plasmodium falciparum blood stage antigens are gaining relevance. Estimates of lamda, which is the measure of transmission intensity, correlate with EIR but are limited by long-term persistence of antibodies to blood stage antigens. Seroprevalence of antibodies to sporozoite antigens may be better alternatives since these antigens usually have shorter immune exposure times. The aim of this study was to develop transmission estimation models based on the seroprevalence of antibodies to two P. falciparum sporozoite antigens (CSP, CelTOS) and compare with models based on the classical blood stage antigen AMA1. Antibody levels in archived plasma from three cross-sectional surveys conducted in 2009 in a low transmission area of Southern Ghana were assessed by indirect ELISA. Seroprevalence of antibodies against CSP, CelTOS and AMA1 were fitted to reversible catalytic models to estimate lamda and corresponding seroreversion rates (rho) for each antibody. Of the three models developed, the anti-CSP model predicted a 13-fold decrease in lamda four years prior to the time of sampling (2009). Anti-AMA1 antibodies formed at a four-fold greater rate compared to that of anti-CelTOS antibodies, and anti-CSP antibodies during the period of decreased lamda. In contrast, anti-AMA1 antibodies decayed at a five-fold slower rate relative to that of anti-CSP antibodies while anti-AMA1 and anti-CelTOS antibody decay rates were not significantly different. Anti-CSP antibodies were relatively short-lived as they formed at an 11.6-fold slower rate relative to their decay during the period of decreased lamda. These features of anti-CSP antibodies can be exploited for the development of models for predicting seasonal, short-term changes in transmission intensity in malaria-endemic areas, especially as the elimination phase of malaria control is approached.
    Malaria Journal 03/2014; 13(1):103. DOI:10.1186/1475-2875-13-103 · 3.11 Impact Factor
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    • "Nevertheless, our results indicated that transfer of antibodies from PvTRAP-immunized mice into naive recipients also contributed to protection. Reports have shown that in regions where malaria is endemic there are TRAP-specific antibodies in the blood of patients that correlate with protection (30) and that immunization of humans and mice with irradiated sporozoites can induce protective antibody responses against SSP2 (TRAP) and inhibit sporozoite invasion of human hepatoma cells (28, 31, 32). Crystal structures determined recently show PfTRAP and PvTRAP in two distinct conformational states, closed and open, respectively (26). "
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    Infection and immunity 03/2014; 82(3). DOI:10.1128/IAI.01187-13 · 3.73 Impact Factor
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    • "[14]–[20]. However, infection has only been associated with modest responses to well known pre-erythrocytic antigens (such as Thrombospondin Related Adhesion Protein (TRAP), Circumsporozoite Surface Protein (CSP), Cell-Traversal protein for Ookinetes and Sporozoites (CelTOS), Liver Stage Antigen 1 (LSA1), Exported Protein 1 (EXP1) and Merozoite Surface Protein (MSP) [21]–[27] which have never been correlated with protection. We sought to assess T-cell responses to other novel pre-erythrocytic antigens in the hope of identifying new antigenic targets for future vaccine development. "
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    ABSTRACT: Controlled human malaria infection (CHMI) studies have become a routine tool to evaluate efficacy of candidate anti-malarial drugs and vaccines. To date, CHMI trials have mostly been conducted using the bite of infected mosquitoes, restricting the number of trial sites that can perform CHMI studies. Aseptic, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) provide a potentially more accurate, reproducible and practical alternative, allowing a known number of sporozoites to be administered simply by injection. We sought to assess the infectivity of PfSPZ Challenge administered in different dosing regimens to malaria-naive healthy adults (n = 18). Six participants received 2,500 sporozoites intradermally (ID), six received 2,500 sporozoites intramuscularly (IM) and six received 25,000 sporozoites IM. Five out of six participants receiving 2,500 sporozoites ID, 3/6 participants receiving 2,500 sporozoites IM and 6/6 participants receiving 25,000 sporozoites IM were successfully infected. The median time to diagnosis was 13.2, 17.8 and 12.7 days for 2,500 sporozoites ID, 2,500 sporozoites IM and 25,000 sporozoites IM respectively (Kaplan Meier method; p = 0.024 log rank test). 2,500 sporozoites ID and 25,000 sporozoites IM have similar infectivities. Given the dose response in infectivity seen with IM administration, further work should evaluate increasing doses of PfSPZ Challenge IM to identify a dosing regimen that reliably infects 100% of participants. NCT01465048.
    PLoS ONE 06/2013; 8(6):e65960. DOI:10.1371/journal.pone.0065960 · 3.23 Impact Factor
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