SARS-CoV-2 Omicron Spike recognition by plasma from individuals receiving BNT162b2 mRNA vaccination with a 16-week interval between doses

Abstract

Continuous emergence of SARS-CoV-2 variants of concern (VOCs) is fueling the COVID-19 pandemic. Omicron (B.1.1.529) rapidly spread worldwide. The large number of mutations in its Spike raise concerns about a major antigenic drift that could significantly decrease vaccine efficacy and infection-induced immunity. A long interval between BNT162b2 mRNA doses elicits antibodies that efficiently recognize Spikes from different VOCs. Here, we evaluate the recognition of Omicron Spike by plasma from a cohort of SARS-CoV-2 naive and previously infected individuals who received their BNT162b2 mRNA vaccine 16 weeks apart. Omicron Spike is recognized less efficiently than D614G, Alpha, Beta, Gamma, and Delta Spikes. We compare with plasma activity from participants receiving a short (4 weeks) interval regimen. Plasma from individuals of the long-interval cohort recognize and neutralize better the Omicron Spike compared with those who received a short interval. Whether this difference confers any clinical benefit against Omicron remains unknown.

Keywords: COVID-19; Coronavirus; Omicron; SARS-CoV-2; delayed mRNA vaccine regimen; humoral responses; neutralization; spike glycoproteins; variants of concern.

Graphical abstract

Figure 1

Binding of vaccine-elicited antibodies to SARS-CoV-2 Spike variants (A) SARS-CoV-2 vaccine cohort design. (B–G) 293T cells were transfected with the indicated full-length Spike from different SARS-CoV-2 variants (D614G in B, Alpha in C, Beta in D, Gamma in E, Delta in F, and Omicron in G) and stained with the CV3-25 Ab or with plasma collected 3 weeks (V3) or 4 months (V4) after a second dose administered with a 16-week interval. Samples were analyzed by flow cytometry. The values represent the median fluorescence intensities (MFIs) normalized by CV3-25 Ab binding and presented as percentages of CV3-25 binding (B–G, left panels). Each curve represents the normalized MFIs obtained with the plasma of one donor at every time point. The mean of each group is represented by a bold line. In the right panels, plasma samples were grouped in different time points (V0, V3, and V4). (H–J) Comparison of Spike recognition by plasma from naive and previously infected donors, represented by red and black points, respectively. Each symbol/points identifies one donor. Error bars indicate means ± SEM. For naive donors, n = 20 at V3 and V4. For previously infected donors vaccinated with two doses, n = 15 at V0 (H), V3 (I), and V4 (J). Statistical significance was tested using (B–G, left panels, (H, I, J) a Wilcoxon test, or (B–G, right panels) a Mann-Whitney test (^∗p < 0.05; ^∗∗p < 0.01; ^∗∗∗p < 0.001; ^∗∗∗∗p < 0.0001; ns, non-significant).

Figure 2

Omicron Spike recognition and neutralization with plasma from naive individuals who received a short versus a long mRNA vaccine dose interval (A) SARS-CoV-2 vaccine cohort design. (B) 293T cells were transfected with the full-length Spike from different SARS-CoV-2 variants (D614G, Beta, Delta, and Omicron) and stained with the CV3-25 Ab or with plasma from naive donors who received a short (4 weeks, yellow) or long (16 weeks, red) interval between doses collected 3 weeks after the second dose (V3) and analyzed by flow cytometry. The values represent the MFI normalized by CV3-25 Ab binding and presented as percentages of CV3-25 binding. (C) Neutralizing activity was measured by incubating pseudoviruses bearing indicated SARS-CoV-2 Spikes (D614G, Beta, Delta, and Omicron), with serial dilutions of plasma for 1 h at 37°C before infecting 293T-ACE2 cells. Neutralization half-maximal inhibitory serum dilution (ID₅₀) values were determined using a normalized non-linear regression using GraphPad Prism software. Undetectable measures are represented as white symbols, and limits of detection are plotted. Error bars indicate means ± SEM. For naive donors vaccinated with the short interval, n = 19. For naive donors vaccinated with the long interval, n = 25. Each symbol/points identifies one donor. Statistical significance was tested using a Mann-Whitney test (^∗p < 0.05; ^∗∗p < 0.01; ^∗∗∗p < 0.001; ^∗∗∗∗p < 0.0001).