Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[Preprint]. 2024 Dec 5:rs.3.rs-5487774.
doi: 10.21203/rs.3.rs-5487774/v1.

Cross-neutralization of distant coronaviruses correlates with Spike S2-specific antibodies from immunocompetent and immunocompromised vaccinated SARS-CoV-2-infected patients

Sara V Patel  1 , Brooke M Leeman  1 , Patricia J Botros  1 , Joanna Folta  1 , Dhiman Shahid  1 , Anya I Rocque  1 , Andrew S Joyal  1 , Joseph A Vecchio  1 , Eliza Passell  2 , Dessie Tien  2 , Zahra Reynolds  2 , Karry Su  2 , Tammy D Vyas  2 , Jatin M Vyas  2 , Emory Abar  2 , Mamadou Barry  2 , Andrew Alexandrescu  2 , Zachary Wallace  2 , Jeffrey M DaCosta  1 , Manish C Choudhary  3 , Trevor Tamura  3 , Gregory Edelstein  3 , Yijia Li  3 , Rinki Deo  3 , Jeffrey A Sparks  3 , Julie Boucau  4 , Owen Glover  4 , Amy Barczak  4 , Jacob Lemieux  2 , Mark J Siedner  2 , Jonathan Z Li  3 , Ismael Ben Fofana  1
Affiliations

Cross-neutralization of distant coronaviruses correlates with Spike S2-specific antibodies from immunocompetent and immunocompromised vaccinated SARS-CoV-2-infected patients

Sara V Patel et al. Res Sq. .

Update in

Abstract

As of May 2023, the public health emergency of COVID-19 was lifted across the globe. However, SARS-CoV-2 infections continue to be recorded worldwide. This situation has been attributed to the ability of the virus to evade host immune responses including neutralizing antibody-derived Immunity. The vast majority of antibody escape mutations have been associated with the S1 subunit of the spike protein, especially the Receptor Binding Domain (RBD) but also the N-terminal Domain (NTD). The other region of the spike, the S2 subunit, is the most conserved region amongst coronaviruses. We hypothesized that S2-specific antibody responses are suboptimal in vaccinated and SARS-CoV-2 infected patients resulting in an ineffective neutralization of distant coronaviruses. Here, we analyzed S2-specific antibody responses SARS-CoV-2-infected individuals, including a mixed cohort of those with and without immunosuppression and prior vaccination. We found that S2-specific antibody responses are generally lower than S1-specific antibody responses. Furthermore, we observed in immunocompetent individuals that S1 and S2-specific antibody responses are both positively correlated with Wuhan, Omicron, SARS-CoV and W1V1-CoV pseudovirus neutralization. Among the immunocompromised patients, S1-specific antibody responses were rarely correlated with pseudovirus neutralization in contrast to S2-specific antibody responses which frequently correlated with pseudovirus neutralization. These data highlight the potential of the S2-subunit as an ideal target for induction of cross-neutralizing antibody immunity against divergent coronaviruses.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests. J.Z.L has consulted for Abbvie and received a grant from Merck but none of these activities impacted nor influenced the design, performance and conclusions of this study. J.A.S. has received research support from Boehringer Ingelheim and Bristol Myers Squibb unrelated to this work. He has performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB unrelated to this work.Additional Declarations: No competing interests reported.

Figures

Figure 1:
Figure 1:. High S1-specific and low S2-specific antibody levels were observed with vaccinated and SARS-CoV-2-infected individuals.
Binding antibody levels were measured using serum obtained from 87 study participants. Serum binding antibody titers were measured by ELISA using S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron as antigens. Antibodies were detected using secondary anti-human IgG-HRP conjugated. Absorbance was determined at 450 nm. (a) S1- and S2-specific antibodies levels from all participants. Paired t-tests were used to compare antibody absorbance for S1 vs S2 regions of Wuhan and Omicron antigens. (b) S1- and S2-specific antibodies levels from all participants according to the number of vaccine doses. For each dose number, paired t-tests were used to compare antibody absorbance for S1 vs S2 regions of Wuhan and Omicron antigens. Means for each number of doses were compared using a linear mixed model with individual patient identification as a random effect. Statistical significance was defined as *P < 0.05, **P < 0.01, and *** P < 0.001.
Figure 2:
Figure 2:. Highest antibody neutralization concentrations were observed against Wuhan and Omicron pseudoviruses.
Neutralizing antibody levels were measured using serum obtained from 87 study participants. Neutralization concentrations were reported as a 50% neutralization titer (NT50). Values were transformed due to skew in the data (log10 of NT50+1 transformation). (a) Neutralization titers for Wuhan, Omicron, SARS-CoV, and W1V1-CoV pseudoviruses. Titer means of pseudoviruses were compared using a linear mixed model with individual patient identification as a random effect. (b) Neutralization titers analyzed according to the number of vaccine doses. Similar linear mixed models were used to compare values within and among the number of doses. Statistical significance was defined as *P < 0.05, **P < 0.01, and *** P < 0.001.
Figure 3:
Figure 3:. Antibody titers were predominantly positively correlated to pseudovirus neutralization.
Binding (measured by ELISA) and neutralizing (measured as 50% neutralization titer; NT50) antibody levels were compared for the 87 study participants. (a) S1-Wuhan, S2-Wuhan, S1-Omicron and S2-Omicron specific levels vs Wuhan pseudovirus NT50. (b) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs Omicron pseudovirus NT50. (c) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs SARS-CoV pseudovirus NT50. (d) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs W1V1-CoV pseudovirus NT50. Correlations were analyzed using Pearson’s correlation, with statistical significance defined as *P < 0.05, **P < 0.01, and ***P < 0.001.
Figure 4:
Figure 4:. Lower, but not significant, binding and neutralization antibody levels were observed with the immunocompromised individuals.
Binding and neutralizing antibody levels compared for 70 immunocompetent and 17 immunocompromised study participants. NT50 values were transformed due to skew in the data (log10 of NT50+1 transformation). (a) S1- and S2-specific antibody levels measured by ELISA using S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron as antigens. (b) Serum antibody neutralizing concentrations (50% neutralization titer; NT50) were determined against Wuhan, Omicron, SARS-CoV and W1V1-CoV pseudoviruses. For each measurement, immunocompetent and immunocompromised means were analyzed using a t-test. Statistical significance was defined as *P < 0.05, **P < 0.01, and *** P < 0.001.
Figure 5:
Figure 5:. Antibody titers were generally positively, but not significantly, correlated to pseudovirus neutralization in immunocompromised participants.
Binding (measured by ELISA) and neutralizing (measured as 50% neutralization titer; NT50) antibody levels were compared for the 17 immunocompromised participants. (a) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs Wuhan pseudovirus NT50. (b) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs Omicron pseudovirus NT50. (c) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs SARS-CoV pseudovirus NT50. (d) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs W1V1-CoV pseudovirus NT50. Correlations were analyzed using Pearson’s correlation, with statistical significance defined as *P < 0.05, **P < 0.01, and ***P < 0.001.
Figure 6:
Figure 6:. Antibody titers were predominantly positively and significantly correlated to pseudovirus neutralization in immunocompetent participants.
Binding (measured by ELISA) and neutralizing (measured as 50% neutralization titer; NT50) antibody levels were compared for the 70 immunocompetent participants. (a) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs Wuhan pseudovirus NT50. (b) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs Omicron pseudovirus NT50. (c) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs SARS-CoV pseudovirus NT50. (d) S1-Wuhan, S2-Wuhan, S1-Omicron, and S2-Omicron specific levels vs W1V1-CoV pseudovirus NT50. Correlations were analyzed using nonparametric Spearman correlation on GrapPad prism. Correlations were analyzed using Pearson’s correlation, with statistical significance defined as *P < 0.05, **P < 0.01, and ***P < 0.001.
See this image and copyright information in PMC

References

    1. Lu R., et al. , Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet, 2020. 395(10224): p. 565574. - PMC - PubMed
    1. Stawicki S.P., et al. , The 2019–2020 Novel Coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2) Pandemic: A Joint American College of Academic International Medicine-World Academic Council of Emergency Medicine Multidisciplinary COVID-19 Working Group Consensus Paper. J Glob Infect Dis, 2020. 12(2): p. 47–93. - PMC - PubMed
    1. Joshi G., et al. , Exploring the COVID-19 vaccine candidates against SARS-CoV-2 and its variants: where do we stand and where do we go? Hum Vaccin Immunother, 2021. 17(12): p. 4714–4740. - PMC - PubMed
    1. Watson O.J., et al. , Global impact of the first year of COVID-19 vaccination: a mathematical modelling study. Lancet Infect Dis, 2022. 22(9): p. 1293–1302. - PMC - PubMed
    1. Silk B.J., et al. , COVID-19 Surveillance After Expiration of the Public Health Emergency Declaration - United States, May 11, 2023. MMWR Morb Mortal Wkly Rep, 2023. 72(19): p. 523–528. - PMC - PubMed

Publication types

LinkOut - more resources