Antigenic Cartography Indicates That the Omicron BA.1 and BA.4/BA.5 Variants Remain Antigenically Distant to Ancestral SARS-CoV-2 after Sputnik V Vaccination Followed by Homologous (Sputnik V) or Heterologous (Comirnaty) Revaccination

Abstract

The rapid emergence of evasive SARS-CoV-2 variants is an ongoing challenge for COVID-19 vaccinology. Traditional virus neutralization tests provide detailed datasets of neutralization titers against the viral variants. Such datasets are difficult to interpret and do not immediately inform of the sufficiency of the breadth of the antibody response. Some of these issues could be tackled using the antigenic cartography approach. In this study, we created antigenic maps using neutralization titers of sera from donors who received the Sputnik V booster vaccine after primary Sputnik V vaccination and compared them with the antigenic maps based on serum neutralization titers of Comirnaty-boosted donors. A traditional analysis of neutralization titers against the WT (wild-type), Alpha, Beta, Delta, Omicron BA.1, and BA.4/BA.5 variants showed a significant booster humoral response after both homologous (Sputnik V) and heterologous (Comirnaty) revaccinations against all of the studied viral variants. However, despite this, a more in-depth analysis using antigenic cartography revealed that Omicron variants remain antigenically distant from the WT, which is indicative of the formation of insufficient levels of cross-neutralizing antibodies. The implications of these findings may be significant when developing a new vaccine regimen.

Keywords: COVID-19; SARS-CoV-2; antigenic cartography; revaccination; virus neutralization.

Figure 1

Study design.

Figure 2

Neutralization antibody titers (ID₅₀ values) against SARS-CoV-2 variant pseudoviruses for pre- and post-boost sera from individuals primarily vaccinated with Sputnik V. Sera from the uninfected donors revaccinated with (A–C) Sputnik V or (D–F) Comirnaty. Sera from (G–I) convalescent donors revaccinated with Sputnik V. Asterisks indicate a significant difference when comparing ID₅₀ values against the WT with variants. Connecting lines indicate serum from the same individual. (C,F,I) Summary of virus-neutralizing activities of serum samples against the WT and variants before (open bars) and after (solid bars) Sputnik/Comirnaty boost. Asterisks indicate a significant difference when comparing ID₅₀ values before and after a boost for each variant. Colors of points and bars correspond to the variants: black–WT, red–Alpha, orange–Beta, green–Delta, violet–Omicron BA.1, pink–Omicron BA.4/BA.5. Medians ± IQR of ID₅₀ values are shown. Statistical analysis was performed using the Friedman test and Dunn’s post hoc test, * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns = not significant.

Figure 3

Antigenic cartography of pre- and post-boost serum samples against the wild-type (WT), Alpha, Beta, Delta, and Omicron BA.1 and BA.4/BA.5 variants. The serum samples are shown in open ((A,D,G), before boost) or solid ((B,E,H), after boost) diamonds as follows: uninfected donors with Sputnik V boost (black), uninfected donors with Comirnaty boost (olive), and convalescent donors with Sputnik V boost (blue). Each grid square (one antigenic unit) corresponds to a twofold dilution in the neutralization assay. Antigens are shown as circles and labeled. Hat graphs represent changes in antigenic distances between the WT and spike variants during revaccination (C,F,I). The brim of the hat corresponds to the antigenic distance for pre-boost samples. The hat height indicates the change in the antigenic distance between the pre- and post-boost samples. The green/red hats indicate an increase/decrease in the antigenic distance. The numbers indicate the corresponding changes in the antigenic units. Breadth gain plots of serum samples from individuals primarily vaccinated with Sputnik V and who received homologous with Sputnik V or heterologous with Comirnaty revaccination (J). The x-axis represents the antigenic distances of Alpha, Beta, Delta, Omicron BA.1, and BA.4/BA.5 variants from the WT, which were taken from [7,10]. The y-axis represents the fold increase in neutralization titer after Sputnik V or Comirnaty revaccination.