Boosting with adjuvanted SCB-2019 elicits superior Fcγ-receptor engagement driven by IgG3 to SARS-CoV-2 spike

Abstract

With the continued emergence of variants of concern, the global threat of COVID-19 persists, particularly in low- and middle-income countries with limited vaccine access. Protein-based vaccines, such as SCB-2019, can be produced on a large scale at a low cost while antigen design and adjuvant use can modulate efficacy and safety. While effective humoral immunity against SARS-CoV-2 variants has been shown to depend on both neutralization and Fc-mediated immunity, data on the effectiveness of protein-based vaccines with enhanced Fc-mediated immunity is limited. Here, we assess the humoral profile, including antibody isotypes, subclasses, and Fc receptor binding generated by a boosting with a recombinant trimer-tag protein vaccine SCB-2019. Individuals who were primed with 2 doses of the ChAdOx1 vaccine were equally divided into 4 groups and boosted with following formulations: Group 1: 9 μg SCB-2019 and Alhydrogel; Group 2: 9 μg SCB-2019, CpG 1018, and Alhydrogel; Group 3: 30 μg SCB-2019, CpG 1018, and Alhydrogel; Group 4: ChAdOx1. Group 3 showed enhanced antibody FcγR binding against wild-type and variants compared to Groups 1 and 2, showing a dose-dependent enhancement of immunity conferred by the SCB-2019 vaccine. Moreover, from day 15 after vaccination, Group 3 exhibited higher IgG3 and FcγR binding across variants of concerns, including Omicron and its subvariants, compared to the ChAdOx1-boosted individuals. Overall, this highlights the potential of SCB-2019 as a cost-efficient boosting regimen effective across variants of concerns.

Fig. 1. Heatmap summary of antibody binding data by isotype, subclass, and Fcγ receptor-binding.

Shown are the binding profiles at baseline, day 15, and day 29 of the various treatment groups. Each row represents the Z-scored binding profile of an individual sample, and each column represents a single antigen (see the zoomed-in view at the bottom). Each isotype, subclass, and FcγR is shown in the same order. Z-scores are calculated across all samples for a single antibody feature. Groups 1, 2, 3, and 4 refer to treatment arms of 9 µg of SCB-2019 + Alum, 9 µg of SCB-2019 + Alum + CpG, 30 µg of SCB-2019 + Alum + CpG, and ChAdOx1, respectively (see “Methods”).

Fig. 2. Univariate differences in antibody binding titers among treatment groups.

a Baseline antibody features against the indicated antigen of Groups 1, 2, 3, and 4 (designated G1, G2, G3, and G4, respectively) are shown against VOC Spike and RBD, as well as WT Spike and RBD. Shown on the y axis is the binding median fluorescence intensity (MFI) in log base 10 of the indicated antibody isotype or subclass. b Same as (a), but for antibody binding profiles at day 15. c Same as (a), but for antibody binding profiles at day 29. *P < 0.05, **P < 0.01 ***P < 0.001 before multiple test correction (Wilcoxon rank-sum test). Groups 1, 2, 3, and 4 refer to treatment arms of 9 µg of SCB-2019 + Alum, 9 µg of SCB-2019 + Alum + CpG, 30 µg of SCB-2019 + Alum + CpG, and ChAdOx1, respectively. a.u. arbitraray unit.

Fig. 3. Univariate differences in FcγR-binding antibody titers among treatment groups.

a Baseline FcγR-binding profiles against the indicated antigens of Groups 1, 2, 3, and 4 (designated G1, G2, G3, and G4, respectively) are shown against VOC Spike and RBD, as well as WT Spike and RBD. Shown on the y axis is the binding median fluorescence intensity (MFI) in log base 10 of the indicated FcγR. b Same as (a), but for FcγR-binding profiles at day 15. c Same as (a), but for FcγR-binding profiles at day 29. *P < 0.05, **P < 0.01 ***P < 0.001 before multiple test correction (Wilcoxon rank-sum test). Groups 1, 2, 3, and 4 refer to treatment arms of 9 µg of SCB-2019 + Alum, 9 µg of SCB-2019 + Alum + CpG, 30 µg of SCB-2019 + Alum + CpG, and ChAdOx1, respectively. a.u. arbitraray unit.

Fig. 4. Multivariate clustering of immune profiles.

a PCA of all data at baseline and 15 and 29 days after vaccination. b A supervised PLS-DA model distinguishing G3 vs. G4 at day 15, c LV1 loadings for each corresponding PLS-DA. d Accuracy distributions over 100 fits of the PLS-DA model with the LASSO-selected features (model), 1000 fits of the PLS-DA model with randomly selected features (random features), and 1000 fits of the PLS-DA model with permuted labels.

Fig. 5. Correlation of selected features on day 15.

The chord diagram shows Spearman’s correlations of the features in Group 3 (a) and Group 4 (b) on day 15. Only spike protein-specific IgG1, IgG3, and FcγR binding were used. Red links indicates correlation between features with Spearman’s rho >0.7 and FDR < 0.05 after multiple test correction (Benjamini–Hochberg procedure) for all comparisons shown in each chord diagram.