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[Preprint]. 2022 Feb 9:2022.02.07.479419.
doi: 10.1101/2022.02.07.479419.

Boosting with Omicron-matched or historical mRNA vaccines increases neutralizing antibody responses and protection against B.1.1.529 infection in mice

Baoling Ying  1 , Suzanne M Scheaffer  1 , Bradley Whitener  1 , Chieh-Yu Liang  1   2 , Oleksandr Dmytrenko  1 , Samantha Mackin  1   2 , Kai Wu  3 , Diana Lee  3 , Laura E Avena  3 , Zhenlu Chong  1 , James Brett Case  1 , LingZhi Ma  3 , Thu Kim  3 , Caralyn Sein  3 , Angela Woods  3 , Daniela Montes Berrueta  3 , Andrea Carfi  3 , Sayda M Elbashir  3 , Darin K Edwards  3 , Larissa B Thackray  1 , Michael S Diamond  1   2   4   5   6
Affiliations

Boosting with Omicron-matched or historical mRNA vaccines increases neutralizing antibody responses and protection against B.1.1.529 infection in mice

Baoling Ying et al. bioRxiv. .

Abstract

The B.1.1.529 Omicron variant jeopardizes vaccines designed with early pandemic spike antigens. Here, we evaluated in mice the protective activity of the Moderna mRNA-1273 vaccine against B.1.1.529 before or after boosting with preclinical mRNA-1273 or mRNA-1273.529, an Omicron-matched vaccine. Whereas two doses of mRNA-1273 vaccine induced high levels of serum neutralizing antibodies against historical WA1/2020 strains, levels were lower against B.1.1.529 and associated with infection and inflammation in the lung. A primary vaccination series with mRNA-1273.529 potently neutralized B.1.1.529 but showed limited inhibition of historical or other SARS-CoV-2 variants. However, boosting with mRNA-1273 or mRNA-1273.529 vaccines increased serum neutralizing titers and protection against B.1.1.529 infection. Nonetheless, the levels of inhibitory antibodies were higher, and viral burden and cytokines in the lung were slightly lower in mice given the Omicron-matched mRNA booster. Thus, in mice, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against B.1.1.529 infection with limited differences in efficacy measured.

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Figures

Figure 1.
Figure 1.. Antibody responses of mRNA vaccines in K18-hACE2 mice.
Seven-week-old female K18-hACE2 transgenic mice were immunized with 5 or 0.1 μg of mRNA vaccines. A. Scheme of immunizations, blood draw, and virus challenge. B. Binding of sarbecovirus cross-reactive monoclonal antibodies to Wuhan-1 and B.1.1.529 spike and RBD proteins. C-F. Serum IgG responses at three weeks after the second 5 μg (C-D) or 0.1 μg (E-F) dose of mRNA vaccines (control or mRNA-1273) against indicated spike (C, E) or RBD (D, F) proteins (n = 12, two experiments, boxes illustrate geometric mean values, dotted lines show the limit of detection (LOD)). G. Serum neutralizing antibody responses three weeks after second vaccine dose as judged by focus reduction neutralization test (FRNT) with WA1/2020 D614G (left panel) and B.1.1.529 (right panel) in mice immunized with 5 or 0.1 μg of control (n = 4) or mRNA-1273 (n = 12) vaccines (two experiments, boxes illustrate geometric mean titer (GMT) values, dotted lines show the LOD). H. Paired analysis of serum neutralizing titers against WA1/2020 D614G and B.1.1.529 from individual mice (data from G) from samples obtained three weeks after the second 5 μg (left panel) or 0.1 μg (right panel) dose of mRNA-1273 (n = 12, two experiments, dotted lines show the LOD). GMT values are indicated at the top of the graphs. Statistical analyses. C-F: Mann-Whitney test; G: One-way ANOVA with Dunn’s post-test; H: Wilcoxon signed-rank test (** P < 0.01; *** P < 0.001; **** P < 0.0001).
Figure 2.
Figure 2.. Protection against SARS-CoV-2 infection after mRNA vaccination in K18-hACE2 mice.
Seven-week-old female K18-hACE2 transgenic mice were immunized with 5 or 0.1 μg of mRNA vaccines as described in Fig 1A. Five weeks after completing a primary vaccination series, mice were challenged with 104 focus-forming units (FFU) of WA1/2020 D614G or B.1.1.529. A-B. Body weight change in animals immunized with 5 μg (A) or 0.1 μg (B) of control or mRNA-1273 vaccines between days 0 and 6 after challenge with WA1/2020 D614G or B.1.1.529. Data show mean values (n = 7–8, two experiments). C-H. Viral burden at 6 dpi in the nasal washes (C, F), nasal turbinates (D, G), and lungs (E, H) as assessed by qRT-PCR of the N gene after WA1/2020 D614G or B.1.1.529 challenge of mice immunized with 5 μg (C-E) or 0.1 μg (F-H) of control or mRNA-1273 vaccines (n = 7–8, two experiments, boxes illustrate median values, dotted lines show LOD). Statistical analyses: A-B, unpaired t test; C-H: Mann-Whitney test (ns, not significant; * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001). I. Correlation analyses comparing serum neutralizing antibody concentrations three weeks after the second vaccine dose and lung viral titers (6 dpi) in K18-hACE2 mice after challenge with WA1/2020 D614G (left panel) or B.1.1.529 (right panel); Pearson’s correlation R2 and P values are indicated as insets; closed symbols 5 μg vaccine dose; open symbols, 0.1 μg vaccine dose.
Figure 3.
Figure 3.. mRNA vaccine protection against disease in K18-hACE2 transgenic mice.
Seven-week-old female K18-hACE2 transgenic mice were immunized with two 5 or 0.1 μg doses of mRNA vaccines, and challenged with WA1/2020 D614G or B.1.1.529. as described in Fig 1 and 2. A-B. Heat-maps of cytokine and chemokine levels in lung homogenates at 6 dpi in animals immunized with 5 μg (A) or 1 μg (B) doses of indicated mRNA vaccines. Fold-change was calculated relative to naive uninfected mice, and log2 values are plotted (2 experiments, n = 7–8 per group except naive, n = 4). The full data set is shown in Table S1–S2. C-E. Hematoxylin and eosin staining of lung sections harvested from control or mRNA-1273 vaccinated animals (5 μg dose, C; 1 μg dose, D) at 6 dpi with WA1/2020 D614G or B.1.1.529. A section from an uninfected animal (E) is shown for comparison. Images show low- (left; scale bars, 1 mm), moderate- (middle, scale bars, 200 μm), and high-power (bottom; scale bars, 50 μm). Representative images of multiple lung sections from n = 3 per group.
Figure 4.
Figure 4.. A booster dose of mRNA-1273 enhances neutralizing antibody responses and confers protection in K18-hACE2 mice.
Seven-week-old female K18-hACE2 transgenic mice were immunized with 5 or 0.25 μg of mRNA vaccines and boosted 17 to 19 weeks later with 1 μg of mRNA-1273. A. Scheme of immunizations, blood draws, and virus challenge. B-C. Serum neutralizing antibody responses immediately before (B, pre-boost) and four weeks after (C, post-boost) a control or mRNA-1273 booster dose as judged by FRNT with WA1/2020 D614G (left panel) and B.1.1.529 (right panel) in mice immunized with 5 or 0.25 μg of control (n = 4) or mRNA-1273 (5 μg, n = 8; 0.25 μg, n =4) vaccines (one experiment, boxes illustrate geometric mean titer (GMT) values, dotted lines show the LOD). D-E. Paired analysis of pre-boost (D) and post-boost (E) serum neutralizing titers against WA1/2020 D614G and B.1.1.529 from individual mice (data from B-C) from samples obtained from animals that received a primary 5 μg (left panel) or 0.25 μg (right panel) dose series of mRNA-1273 vaccine (n = 4 to 8, one experiment, dotted lines show the LOD). GMT values are indicated at the top of the graphs. F-G. Four weeks after boosting with control or mRNA-1273, K18-hACE2 mice were challenged with 104 FFU of B.1.1.529. Viral burden at 6 dpi in the nasal washes, nasal turbinates, and lungs as assessed by N gene levels in animals that had received a primary series immunization with 5 μg (F) or 0.25 μg (G) doses of control or mRNA-1273 vaccines (n = 7–8, two experiments, boxes illustrate median values, dotted lines show LOD). Statistical analyses. D-E. Wilcoxon signed-rank test; F-G: Mann-Whitney test (ns, not significant; ** P < 0.01; *** P < 0.001).
Figure 5.
Figure 5.. Antibody responses in BALB/c mice after immunization with mRNA-1273 and mRNA-1273.529 vaccines.
Six-to-eight-week-old female BALB/c mice were immunized twice over a three-week interval with 1 μg of mRNA-1273 or mRNA-1273.529 vaccine or a PBS control (black circles). Immediately before (Day 21) or two weeks after (Day 36) the second vaccine dose, serum was collected. A. Scheme of immunization and blood draws. B. Serum antibody binding to Wuhan-1 or B.1.1.529 spike proteins by ELISA (n = 8, two experiments, boxes illustrate mean values, dotted lines show the LOD). C. Neutralizing activity of serum obtained two weeks after (Day 36) immunization with mRNA-1273 or mRNA-1273.529 vaccine against VSV pseudoviruses displaying the spike proteins of Wuhan-1 D614G, B.1.351 (Beta), B.1.617.2 (Delta), or B.1.1.529 (Omicron) (n = 8, two experiments, boxes illustrate geometric mean values, dotted lines show the LOD). GMT values are indicated above the columns.
Figure 6.
Figure 6.. Booster doses of mRNA-1273 or mRNA-1273.529 enhance neutralizing antibody responses in 129S2 mice.
Seven-week-old female 129S2 mice were immunized with 5 or 0.25 μg of mRNA vaccines and then boosted 10 to 11 weeks later with 1 μg of control mRNA, mRNA-1273, or mRNA-1273.529. A. Scheme of immunizations, blood draws, and virus challenge. B-C. Serum neutralizing antibody responses immediately before (B, pre-boost) and three to four weeks after (C, post-boost) a control, mRNA-1273, or mRNA-1273.529 booster dose as judged by FRNT with WA1/2020 N501Y/D614G (left panel(s)) and B.1.1.529 (right panel(s)) in 129S2 mice that received primary series immunizations with 5 or 0.25 μg of control (n = 6) or mRNA-1273 (n = 30) vaccines (two experiments, boxes illustrate geometric mean values, dotted lines show the LOD). D-E. Paired analysis of pre- and post-boost serum neutralizing titers against WA1/2020 D614G (D) and B.1.1.529 (E) viruses from samples obtained from animals (data from B-C) that received the following primary and booster immunizations: mRNA-1273 (5 or 0.25 μg) + control booster, mRNA-1273 (5 or 0.25 μg) + mRNA-1273 booster, mRNA-1273 (5 or 0.25 μg) + mRNA-1273.529 booster (n = 10, two experiments, dotted lines show the LOD). GMT values are indicated at the top of the graphs. Statistical analyses. B-C: One-way ANOVA with Dunn’s post-test; D-E. Wilcoxon signed-rank test (ns, not significant; * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001).
Figure 7.
Figure 7.. Booster doses of mRNA-1273 or mRNA-1273.529 enhance protection against B.1.1.529 infection in 129S2 mice.
Seven-week-old female 129S2 mice were immunized with 5 or 0.25 μg of mRNA vaccines, boosted with 1 μg of control mRNA, mRNA-1273, or mRNA-1273.529 and challenged with WA1/2020 N501Y/D614G or B.1.1.529, as described in Fig 6. A-B. Viral RNA levels at 3 dpi in the nasal washes, nasal turbinates, and lungs after WA1/2020 N501Y/D614G or B.1.1.529 challenge of mice immunized with 5 μg (A) or 0.25 μg (B) of control or mRNA-1273 vaccines and boosted with control, mRNA-1273, or mRNA-1273.529 vaccine (n = 8–10 per group, two experiments, boxes illustrate mean values, dotted lines show LOD; One-way ANOVA with Tukey’s post-test: ns, not significant; * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001). C-D. Heat-maps of cytokine and chemokine levels in lung homogenates at 3 dpi with WA1/2020 N501Y/D614G or B.1.1.529 in animals immunized with 5 μg (C) or 0.25 μg (D) doses of control or mRNA-1273 vaccines and then boosted with control, mRNA-1273, or mRNA-1273.529 vaccines. Fold-change was calculated relative to naive mice, and log2 values are plotted (2 experiments, n = 8 per group except naive, n = 4). The full data set is shown in Table S3–S4.
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