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Clinical Trial
. 2020 Mar 10:11:412.
doi: 10.3389/fimmu.2020.00412. eCollection 2020.

Epitope Mapping and Fine Specificity of Human T and B Cell Responses for Novel Candidate Blood-Stage Malaria Vaccine P27A

Kristina M Geiger  1   2 , Daniel Guignard  1 , Che Yang  3   4 , Jean-Pierre Bikorimana  5 , Bruno E Correia  3   4 , Sophie Houard  6 , Catherine Mkindi  7   8   9 , Claudia A Daubenberger  7   8 , François Spertini  5 , Giampietro Corradin  1 , Régine Audran  5
Affiliations
Clinical Trial

Epitope Mapping and Fine Specificity of Human T and B Cell Responses for Novel Candidate Blood-Stage Malaria Vaccine P27A

Kristina M Geiger et al. Front Immunol. .

Abstract

P27A is a novel synthetic malaria vaccine candidate derived from the blood stage Plasmodium falciparum protein Trophozoite Exported Protein 1 (TEX1/PFF0165c). In phase 1a/1b clinical trials in malaria unexposed adults in Switzerland and in malaria pre-exposed adults in Tanzania, P27A formulated with Alhydrogel and GLA-SE adjuvants induced antigen-specific antibodies and T-cell activity. The GLA-SE adjuvant induced significantly stronger humoral responses than the Alhydrogel adjuvant. Groups of pre-exposed and unexposed subjects received identical vaccine formulations, which supported the comparison of the cellular and humoral response to P27A in terms of fine specificity and affinity for populations and adjuvants. Globally, fine specificity of the T and B cell responses exhibited preferred recognized sequences and did not highlight major differences between adjuvants or populations. Affinity of anti-P27A antibodies was around 10-8 M in all groups. Pre-exposed volunteers presented anti-P27A with higher affinity than unexposed volunteers. Increasing the dose of GLA-SE from 2.5 to 5 μg in pre-exposed volunteers improved anti-P27A affinity and decreased the number of recognized epitopes. These results indicate a higher maturation of the humoral response in pre-exposed volunteers, particularly when immunized with P27A formulated with 5 μg GLA-SE.

Keywords: P27A; Plasmodium falciparum; adjuvant; clinical trial; immune response; malaria; populations; vaccine.

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Figures

Figure 1
Figure 1
Cellular responses to P27A and overlapping 20-mers at D84 in Phase 1a. PBMC from unexposed volunteers (CH-Alum/50 (n = 8) and CH-GLA2.5/50) (n = 8) at D84 were stimulated with P27A-LSP or the overlapping 20-mer peptides P1 to P10, individually or as a pool. The frequency of IFN-γ secreting cells was revealed by ELISPOT. Results are expressed as SFU/ million PBMC. Comparisons between groups were done using Mann-Whitney test; p-values are indicated. Responses at D0 and D84 to P27A-LSP and the pool of peptides are shown with Wilcoxon test p-values.
Figure 2
Figure 2
Repartition of the cellular recognition along the sequence of P27A at D84 in Phase 1a. PBMC from unexposed volunteers [CH-Alum/50 (n = 8) and CH-GLA2.5/50 (n = 8)] at D84 were individually stimulated with overlapping 20-mer peptides P1 to P10, and the frequency of IFN-γ secreting cells revealed by ELISPOT. (A) Heat map indicates the individual responses to each 20-mer peptide,Y-axis represents the volunteer ID and the X-axis represents the frequency of IFN-γ secreting cells as SFU/million PBMC, and individual pies illustrate the repartition of responses to the 20-mers as % of the total response. (B) Pie graphs show the median value per vaccination group of the percentage of IFN-γ secreting cells to each 20-mer peptide.
Figure 3
Figure 3
Repartition of the fine specificity of the humoral response along the sequence of P27A at D84 in Phase 1a and 1b. The fine specificity of the humoral response was determined by ELISA using sera from unexposed volunteers (CH-Alum/50 and CH-GLA2.5/50) and exposed volunteers (TZ-Alum/50, TZ-GLA2.5/50, and TZ-GLA5/50) against individual 20-mer peptides. (A) Heat map indicates the individual repartition of antibody responses to each 20-mer peptide, P1 to P10, over the sum of the responses, for each vaccination group. Right Y-axis represents the volunteer ID and the left Y-axis denotes the percentage value. (B) Pie graphs show the median proportion of humoral response to each 20-mer peptide for each vaccination group. (C) Pie graphs represent the median repartition of humoral responses of all volunteers grouped either by adjuvant type (Alum or GLA-SE) or by site (CH or TZ). Comparisons per peptide were done using Mann-Whitney test; *p < 0.05; **p < 0.01; ***p<0.001.
Figure 4
Figure 4
Relative affinity and avidity of specific IgG to P27A at Day 84 in Phase 1a and 1b. Strength of the binding of specific IgG to P27A was evaluated at day 84 for all volunteers (CH and TZ) by competition ELISA using soluble P27A as competitor (A–C) or guanidium chloride GuHCl (E). Results are expressed as EC50. (A) Comparison of relative antibody affinity for P27A in pre-exposed and unexposed subjects, from TZ (3 groups, n = 23) and CH (2 groups, n = 16), respectively. (B) Comparison of relative antibody affinity for P27A in each adjuvant group, Alum (n = 16) and GLA-SE (n = 23). (C) Comparison of relative antibody affinity for P27A in each TZ-GLA-SE dose group, 2.5 or 5 ug. (D) Correlation between anti-P27A IgG titer (log AU/mL) and affinity (log M) in pre-exposed TZ subjects, n = 23. Pearson r and p-values are indicated. (E) Comparison of antibody avidity for P27A in unexposed volunteers grouped by adjuvant type, Alum (n = 5) and GLA-SE (n = 5). (F) Antibody avidity for P27A in eight samples from TZ-GLA2.5/50 (n = 3, blue circles), CH-GLA2.5/50 (n = 3, blue triangles), and CH-Alum/50 (n = 2, yellow triangles). Antibody avidity was determined by SPR with kinetic constants Kon (association) and Koff (dissociation) and equilibrium KD = Koff/Kon. (A–C,E) Lines indicate medians and quartiles, p-values of Mann-Whitney tests are indicated. TZ subjects, circles; CH subjects, triangles; Alum, yellow symbols; GLA-SE, blue symbols.
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