Booster of mRNA-1273 Strengthens SARS-CoV-2 Omicron Neutralization

Abstract

The Omicron variant of SARS-CoV-2 is raising concerns because of its increased transmissibility and potential for reduced susceptibility to antibody neutralization. To assess the potential risk of this variant to existing vaccines, serum samples from mRNA-1273 vaccine recipients were tested for neutralizing activity against Omicron and compared to neutralization titers against D614G and Beta in live virus and pseudovirus assays. Omicron was 41-84-fold less sensitive to neutralization than D614G and 5.3-7.4-fold less sensitive than Beta when assayed with serum samples obtained 4 weeks after 2 standard inoculations with 100 μg mRNA-1273. A 50 μg boost increased Omicron neutralization titers and may substantially reduce the risk of symptomatic vaccine breakthrough infections.

Figure 1.. Neutralization of D614G, Beta and Omicron Pseudoviruses by Serum Samples Obtained from Moderna mRNA-1273 Vaccine Recipients.

Serum samples obtained from 30 vaccine recipients 4 weeks after 2^nd inoculation with mRNA-1273 in the phase 3 COVE study (NCT04470427) were assayed against pseudoviruses bearing either the D614G, Beta or Omicron spike of SARS-CoV-2 in two independent laboratories (VRC: Vaccine Research Center, National Institutes of Health; Duke: Duke University Medical Center). Identical samples from the COVE study were assayed in both laboratories and were pre-selected for possessing either high (ID50 = 5,408 – 22,573, n=20) or medium (ID50 = 506 – 526, n=10) neutralization titers against prototypic D614G. The Duke laboratory assayed 20 high titer and 10 medium titer samples. The VRC laboratory assayed 11/20 high titer samples and all 10 medium titer samples. Both laboratories also assayed serum samples from participants who received the primary series of two mRNA-1273 inoculations (100 μg) and a late boost (50 μg mRNA-1273). The late boost samples in the VRC laboratory were obtained 2 weeks after boosting in 7 participants who received the primary series under EUA (VRC200 protocol); the same 7 participants are shown in Fig 2. The late boost samples in the Duke laboratory were obtained 2 weeks after boosting in a phase 1/2 “Mix and Match” study (DMID 21–0012, NCT04889209) and were preselected for possessing high neutralization titers against D614G (ID50 = 5,489 – 16,760); these participants were boosted at least 4 months after the second dose. Shown are ID50 titers (A) and fold reduction in ID50 geometric mean titers (GMT) compared to D614G (B). Values below the limit of detection (ID50 = 20) were assigned a value of ID50 = 10. Bars extend from the 25^th to 75^th percentile. Horizontal lines and values above each bar in the left panels are GMT. Values above each bar in the right panels are the geometric mean fold change relative to D614G. Solid circles, two participants infected 5–6 months after second dose. Open circles, uninfected participants.

Figure 2.. Neutralization of D614G, Beta and Omicron Live Viruses by Serum Samples Obtained from Moderna mRNA-1273 Vaccine Recipients.

Serum samples obtained from the same 30 vaccine recipients 4 weeks after 2nd inoculation with mRNA-1273 in the phase 3 COVE study in Figure 1 were assayed in the live virus focus-reduction neutralization (FRNT) assay in the Emory laboratory. Shown are individual FRNT₅₀ titers as solid dots, with GMT (values above each plot) and fold reduction in geometric mean titers (GMT) compared to D614G (values in parentheses). Values below the limit of detection (FRNT₅₀ = 20) were assigned a value of FRNT₅₀ = 10. Bars extend to the GMT.

Figure 3.. Longitudinal assessment of waning and recall neutralizing antibody responses in recipients of three doses of mRNA-1273.

A. Shown are ID50 neutralization titers of serum samples from 7 recipients of three doses of mRNA-1273 assayed against D614G, Beta and Omicron. Samples were obtained 2 weeks after second dose, day of boost and 2 weeks post boost from participants who received the vaccine under EUA. Thin lines are individual samples. Heavy lines are geometric mean titers (GMTs) of all 7 values per time point. B. Aggregate ID50 titers for the two peak immune time points. Values below the limit of detection (ID50 = 20) were assigned a value of ID50 = 10. Bars extend from the 25^th to 75^th percentile. Horizontal lines within the bars, and values above each bar, are GMT. Also shown are the geometric mean fold reduction in ID50 compared to D614G. Solid circles, two participants who were infected 5–6 months after second dose. Open circles, uninfected participants.