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Cited by 401SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections Studiesvaccines and immunoinformatics approaches

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Neutralizing antibodies against the SARS-CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination

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Pérez-Then, Eddy, Lucas, Carolina, Monteiro, Valter Silva, Miric, Marija, Brache, Vivian, Cochon, Leila, Vogels, Chantal B. F., Malik, Amyn A., De la Cruz, Elena, Jorge, Aidelis, De los Santos, Margarita, Leon, Patricia, Breban, Mallery I., Billig, Kendall, Yildirim, Inci, Pearson, Claire, Downing, Randy, Gagnon, Emily, Muyombwe, Anthony, Razeq, Jafar, Campbell, Melissa, Ko, Albert I., Omer, Saad B., Grubaugh, Nathan D., Vermund, Sten H., Iwasaki, Akiko·2022·Nature Medicine
DOI 10.1038/s41591-022-01705-6PMC PMC8938264

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Abstract

Abstract The recent emergence of the SARS-CoV-2 Omicron variant is raising concerns because of its increased transmissibility and by its numerous spike mutations with potential to evade neutralizing antibodies elicited by COVID-19 vaccines. The Dominican Republic was among the first countries in recommending the administration of a third dose COVID-19 vaccine to address potential waning immunity and reduced effectiveness against variants. Here, we evaluated the effects of a heterologous BNT162b2 mRNA vaccine booster on the humoral immunity of participants that had received a two-dose regimen of CoronaVac, an inactivated vaccine used globally. We found that heterologous CoronaVac prime followed by BNT162b2 booster regimen induces elevated virus-specific antibody levels and potent neutralization activity against the ancestral virus and Delta variant, resembling the titers obtained after two doses of mRNA vaccines. While neutralization of Omicron was undetectable in participants that had received a two-dose regimen of CoronaVac vaccine, BNT162b2 booster resulted in a 1.4-fold increase in neutralization activity against Omicron, compared to two-dose mRNA vaccine. Despite this increase, neutralizing antibody titers were reduced by 6.3-fold and 2.7-fold for Omicron compared to ancestral and Delta variant, respectively. Surprisingly, previous SARS-CoV-2 infection did not affect the neutralizing titers for Omicron in participants that received the heterologous regimen. Our findings have immediate implications for multiples countries that previously used a two-dose regimen of CoronaVac and reinforce the notion that the Omicron variant is associated with immune escape from vaccines or infection-induced immunity, highlighting the global need for vaccine boosters to combat the impact of emerging variants.

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Fig. 1 Characterization of vaccine-induced immunity after heterologous CoronaVac–BNT162b2 vaccination. Dominican Republic (DR) participants received two doses of CoronaVac followed by a heterologous booster with BNT162b2 mRNA vaccine. Plasma samples were collected at baseline, before the booster (CoronaVac (2x) DR), and at 7 and 28 days after the booster (CoronaVac (2x) + Pfizer (1x)). The HCW participants from Yale-New Haven Hospital received two doses of the mRNA vaccine and the plasma samples were used for comparison (mRNAVac (2x) Yale). a,b, Plasma reactivity to the spike (S) protein (a) and RBD (b) measured with ELISA (DR n = 101 and Yale n = 32 at each respective time point). Horizontal lines indicate the mean values. c–f, Neutralization assay using wild-type SARS-CoV-2. c,d, Plasma neutralization capacity against the ancestral strain (WA1, USA) (c) and the Delta variant (d) by time (DR, n = 101 in each group; Yale, n = 32). The numbers in parentheses indicate the median fold change in neutralization resistance for the indicated variants compared with the ancestral strain. e, Plasma neutralization capacity against the ancestral strain and the Delta and Omicron variants at baseline (left) and at 28 days after the booster (right) (n = 64 for baseline Omicron variant, n = 101 in other group). f, Plasma neutralization capacity against Omicron by time. CoronaVac (2x) DR, n = 64; CoronaVac (2x) + Pfizer (1x) DR, n = 101; mRNAVac (2x) Yale, n = 32. Significance was assessed with one-way ANOVA corrected for multiple comparisons using Tukey’s method. Violin plots represent the mean ± s.d. Dotted lines indicate the mean and are colored accordingly. Each circle represents a single individual. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; NS, not significant.
Fig. 1 Characterization of vaccine-induced immunity after heterologous CoronaVac–BNT162b2 vaccination. Dominican Republic (DR) participants received two doses of CoronaVac followed by a heterologous booster with BNT162b2 mRNA vaccine. Plasma samples were collected at baseline, before the booster (CoronaVac (2x) DR), and at 7 and 28 days after the booster (CoronaVac (2x) + Pfizer (1x)). The HCW participants from Yale-New Haven Hospital received two doses of the mRNA vaccine and the plasma samples were used for comparison (mRNAVac (2x) Yale). a,b, Plasma reactivity to the spike (S) protein (a) and RBD (b) measured with ELISA (DR n = 101 and Yale n = 32 at each respective time point). Horizontal lines indicate the mean values. c–f, Neutralization assay using wild-type SARS-CoV-2. c,d, Plasma neutralization capacity against the ancestral strain (WA1, USA) (c) and the Delta variant (d) by time (DR, n = 101 in each group; Yale, n = 32). The numbers in parentheses indicate the median fold change in neutralization resistance for the indicated variants compared with the ancestral strain. e, Plasma neutralization capacity against the ancestral strain and the Delta and Omicron variants at baseline (left) and at 28 days after the booster (right) (n = 64 for baseline Omicron variant, n = 101 in other group). f, Plasma neutralization capacity against Omicron by time. CoronaVac (2x) DR, n = 64; CoronaVac (2x) + Pfizer (1x) DR, n = 101; mRNAVac (2x) Yale, n = 32. Significance was assessed with one-way ANOVA corrected for multiple comparisons using Tukey’s method. Violin plots represent the mean ± s.d. Dotted lines indicate the mean and are colored accordingly. Each circle represents a single individual. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; NS, not significant.CC BY · PubMed Central
Fig. 2 Comparison of neutralizing activity in CoronaVac–BNT162b2-vaccinated participants by SARS-CoV-2 infection status. a,b, Plasma neutralization titers against ancestral lineage A virus and variants of concern in HCW participants from Yale-New Haven Hospital who received two doses of the mRNA vaccine. a, Plasma neutralization titers measured at 28 days after the second dose in non-previously infected (left) and previously infected participants (right). Significance was measured using one-way ANOVA corrected using Dunnett’s test. Boxes represent the mean ± s.d. The numbers in parentheses indicate the median fold change in neutralization resistance for the indicated variants compared with the ancestral strain. b, Neutralization titers from the participants in a by SARS-CoV-2 infection status. Significance was measured using one-way ANOVA corrected using Tukey’s test. (–) Vaccinated–uninfected, n = 16; (+) vaccinated–previously infected, n = 14. c–g, Plasma neutralization titers from Dominican Republic participants who received two doses of CoronaVac followed by BNT162b2 booster. c, Neutralization titers against the ancestral virus and the Delta and Omicron variants at 28 days after the booster in non-previously infected (left; ancestral, n = 75; Delta, n = 75; Omicron, n = 75) and SARS-CoV-2-previously infected participants (right; ancestral, n = 26; Delta, n = 26; Omicron, n = 26). Significance was measured using one-way ANOVA corrected using Tukey’s test. Violin plots represent the mean ± s.d. Dotted lines indicate the mean and are colored accordingly. d, Neutralization titers from the participants in c by SARS-CoV-2 infection status. Significance was measured using one-way ANOVA corrected using Tukey’s test. (–) Vaccinated–uninfected, n = 57; (+) vaccinated–previously infected, n = 24. e, Plasma neutralization titers at 28 days after the booster dose by time from the second CoronaVac vaccination (n = 101 in each group). f,g, Plasma neutralization titers measured before (f) and 28 days after the booster dose (g) by time from SARS-CoV-2 infection. Ancestral, n = 26; Delta, n = 26; Omicron, n = 26. The lines indicate the cross-sectional average from each group and the shading represents the 95% CI. Each dot represents a single individual. A multivariable linear regression modeling was used to access significance. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
Fig. 2 Comparison of neutralizing activity in CoronaVac–BNT162b2-vaccinated participants by SARS-CoV-2 infection status. a,b, Plasma neutralization titers against ancestral lineage A virus and variants of concern in HCW participants from Yale-New Haven Hospital who received two doses of the mRNA vaccine. a, Plasma neutralization titers measured at 28 days after the second dose in non-previously infected (left) and previously infected participants (right). Significance was measured using one-way ANOVA corrected using Dunnett’s test. Boxes represent the mean ± s.d. The numbers in parentheses indicate the median fold change in neutralization resistance for the indicated variants compared with the ancestral strain. b, Neutralization titers from the participants in a by SARS-CoV-2 infection status. Significance was measured using one-way ANOVA corrected using Tukey’s test. (–) Vaccinated–uninfected, n = 16; (+) vaccinated–previously infected, n = 14. c–g, Plasma neutralization titers from Dominican Republic participants who received two doses of CoronaVac followed by BNT162b2 booster. c, Neutralization titers against the ancestral virus and the Delta and Omicron variants at 28 days after the booster in non-previously infected (left; ancestral, n = 75; Delta, n = 75; Omicron, n = 75) and SARS-CoV-2-previously infected participants (right; ancestral, n = 26; Delta, n = 26; Omicron, n = 26). Significance was measured using one-way ANOVA corrected using Tukey’s test. Violin plots represent the mean ± s.d. Dotted lines indicate the mean and are colored accordingly. d, Neutralization titers from the participants in c by SARS-CoV-2 infection status. Significance was measured using one-way ANOVA corrected using Tukey’s test. (–) Vaccinated–uninfected, n = 57; (+) vaccinated–previously infected, n = 24. e, Plasma neutralization titers at 28 days after the booster dose by time from the second CoronaVac vaccination (n = 101 in each group). f,g, Plasma neutralization titers measured before (f) and 28 days after the booster dose (g) by time from SARS-CoV-2 infection. Ancestral, n = 26; Delta, n = 26; Omicron, n = 26. The lines indicate the cross-sectional average from each group and the shading represents the 95% CI. Each dot represents a single individual. A multivariable linear regression modeling was used to access significance. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.CC BY · PubMed Central
Extended Data Fig. 1 Impact of SARS-CoV-2 Omicron on neutralization capacity of in mRNA-vaccinated participants. Plasma neutralization titers against ancestral lineage A virus, (WA1, USA) and VOCs: Alpha, Beta, Delta and Omicron. SARS-CoV-2 variants were isolated from nasopharyngeal swabs of infected individuals and ancestral (WA1, USA) isolate was obtained from BEI. Neutralization capacity was accessed using plasma samples from HCW participants that received 2 doses of the mRNA vaccine (mRNAVac (2x) Yale), 28 days post second vaccination dose at the experimental sixfold serial dilutions (from 1:3 to 1:2430). Significance was assessed by One-way ANOVA corrected for multiple comparisons using Dunnett’s method. Neutralization capacity to the variants was compared to neutralization capacity against the ancestral strain. Boxes represent mean values ± standard deviations. The numbers in parentheses indicate the median fold change in neutralization resistance for the indicated variants compared to ancestral strain. n = 32/group Each dot represents a single individual. ****p < 0.0001 **p < 0.005.
Extended Data Fig. 1 Impact of SARS-CoV-2 Omicron on neutralization capacity of in mRNA-vaccinated participants. Plasma neutralization titers against ancestral lineage A virus, (WA1, USA) and VOCs: Alpha, Beta, Delta and Omicron. SARS-CoV-2 variants were isolated from nasopharyngeal swabs of infected individuals and ancestral (WA1, USA) isolate was obtained from BEI. Neutralization capacity was accessed using plasma samples from HCW participants that received 2 doses of the mRNA vaccine (mRNAVac (2x) Yale), 28 days post second vaccination dose at the experimental sixfold serial dilutions (from 1:3 to 1:2430). Significance was assessed by One-way ANOVA corrected for multiple comparisons using Dunnett’s method. Neutralization capacity to the variants was compared to neutralization capacity against the ancestral strain. Boxes represent mean values ± standard deviations. The numbers in parentheses indicate the median fold change in neutralization resistance for the indicated variants compared to ancestral strain. n = 32/group Each dot represents a single individual. ****p < 0.0001 **p < 0.005.CC BY · PubMed Central
Extended Data Fig. 2 Plasma antibody kinetics post CoronaVac vaccination. a, Vaccinated participants plasma reactivity to RBD measured by ELISA. b, Plasma neutralization titers measured at baseline, previously to BNT162b2 booster shot against ancestral virus, Delta and Omicron variants. Regression lines are shown over time as days post 2 CoronaVac dose vaccination, as purple (ancestral), dark green (Delta) and light green (Omicron). Lines indicates cross-sectional averages from each group, with shading representing 95% CI and colored accordingly. Each dot represents a single individual. n = 101 (Ancestral); n = 101 (Delta); n = 80 (Omicron).
Extended Data Fig. 2 Plasma antibody kinetics post CoronaVac vaccination. a, Vaccinated participants plasma reactivity to RBD measured by ELISA. b, Plasma neutralization titers measured at baseline, previously to BNT162b2 booster shot against ancestral virus, Delta and Omicron variants. Regression lines are shown over time as days post 2 CoronaVac dose vaccination, as purple (ancestral), dark green (Delta) and light green (Omicron). Lines indicates cross-sectional averages from each group, with shading representing 95% CI and colored accordingly. Each dot represents a single individual. n = 101 (Ancestral); n = 101 (Delta); n = 80 (Omicron).CC BY · PubMed Central

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  1. Cele, S. et al. Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization. Nature https://doi.org/10.1038/s41586-021-04387-1 (2021). · DOI · Paper page

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Authors
Pérez-Then, E., Lucas, C., Monteiro, V. S., Miric, M., Brache, V., Cochon, L., Vogels, C. B. F., Malik, A. A., De la Cruz, E., Jorge, A., De los Santos, M., Leon, P., Breban, M. I., Billig, K., Yildirim, I., Pearson, C., Downing, R., Gagnon, E., Muyombwe, A., Razeq, J., Campbell, M., Ko, A. I., Omer, S. B., Grubaugh, N. D., Vermund, S. H., & Iwasaki, A.
Affiliations
  • Yale University (US)
  • Profamilia (DO)
  • Connecticut Department of Public Health (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Lucas, Carolina
  • Iwasaki, Akiko
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2022-01-20
Volume
28
Issue
3
Pages
481-485
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-022-01705-6
PMC
PMC8938264
OpenAlex
W4206675538
Cited by
401
References
20
Citations by year
2026: 10 · 2025: 22 · 2024: 47 · 2023: 114 · 2022: 207
FWCI
47.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute (N/A)
  • Pew Charitable Trusts (N/A)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
Omicron variant, Delta variant, neutralizing antibodies, CoronaVac, BNT162b2 mRNA vaccine, inactivated vaccine, spike protein mutations, immune evasion, humoral immunity, booster vaccination
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, BNT162 Vaccine, Antibodies, Viral, Humans, Vaccination, Vaccines, Synthetic, Antibodies, Neutralizing

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