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. 2025 Sep 4;13(9):949.
doi: 10.3390/vaccines13090949.

Cross-Neutralization of Distant Coronaviruses Strongly 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 J Tamura  3 , Gregory E Edelstein  3 , Yijia Li  3 , Rinki Deo  3 , Jeffrey A Sparks  3 , Julie Boucau  4 , Owen T Glover  4 , Amy K Barczak  4 , Jacob Lemieux  2 , Mark J Siedner  2 , Jonathan Z Li  3 , Ismael Ben Fofana  1
Affiliations

Cross-Neutralization of Distant Coronaviruses Strongly Correlates with Spike S2-Specific Antibodies from Immunocompetent and Immunocompromised Vaccinated SARS-CoV-2-Infected Patients

Sara V Patel et al. Vaccines (Basel). .

Abstract

Background/Objectives: Despite the lifting of the COVID-19 public health emergency, SARS-CoV-2 infections continue to be recorded worldwide. The continued prevalence of infection 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 has been associated with the S1 subunit of the spike protein. The other region of the spike, the S2 subunit, is the most conserved region amongst coronaviruses. We hypothesized that S2-specific antibody levels are modest in vaccinated and SARS-CoV-2-infected patients, resulting in suboptimal neutralization of distant coronaviruses. Methods: Here, we analyzed S1- and S2-specific antibody levels in SARS-CoV-2-infected individuals, including a mixed cohort of those with and without immunosuppression and prior vaccination. Results: We found that S2-specific antibody responses were generally lower than S1-specific antibody responses. Intriguingly, Omicron-S1-specific antibody levels were higher than Wuhan-S1-specific antibody levels despite all vaccinated participants having received Wuhan-spike-based immunogens. This emphasizes the importance of the infecting variant and vaccine immunogen in the production of spike-targeting antibodies and associated hybrid immunity. Although S1-specific antibody levels were generally higher than their S2-specific counterparts, the correlation between neutralization and binding antibody levels was mostly higher in S2- compared with S1-specific responses. Conclusions: We conclude that S2-based immunogens are suitable for the induction of antibody-based immunity against novel SARS-CoV-2 variants but also against more distant coronaviruses, which would support a better protection for the immunocompromised as well as other vulnerable populations.

Keywords: COVID-19; S2-specific antibodies; SARS-CoV-2; immunocompromised; neutralizing antibodies; spike-S1 dominance.

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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 or 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.

Figures

Figure 1
Figure 1
Maximum likelihood phylogenetic tree based on SARS-CoV-2 spike gene sequences, rooted to the SARS-CoV-2 (Wuhan-Hu-1 reference genome) with the addition of SARS-CoV reference genome and Bat SARS-CoV reference genome (WIV1-CoV).
Figure 2
Figure 2
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 HRP conjugated secondary anti-human IgG. Absorbance was determined at 450 nm. (a) S1- and S2-specific antibody levels from all participants are shown. Paired t-tests were used to compare antibody absorbance for S1 vs. S2 regions of Wuhan and Omicron antigens. (b) S1- and S2-specific antibody levels from all participants are shown 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 3
Figure 3
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 a skew in the data (log10 of NT50+1 transformation). (a) Neutralization titers for Wuhan, Omicron, and SARS-CoV and WIV1-CoV pseudoviruses are shown. 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 are shown. 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 4
Figure 4
Antibody titers were predominantly positively correlated to pseudovirus neutralization. Binding (measured by ELISA) and neutralizing (measured as 50% neutralization titer; log10 NT50+1 transformation) antibody levels were compared for the 87 study participants. S1-Wuhan-, S2-Wuhan-, S1-Omicron-, and S2-Omicron-specific antibody levels vs. (a) Wuhan pseudovirus neutralization, (b) Omicron pseudovirus neutralization, (c) SARS-CoV pseudovirus neutralization, and (d) WIV1-CoV pseudovirus neutralization. Curves show Loess smoothing as a way to visualize patterns, but the data were analyzed using the Spearman’s rank correlation test with a Benjamini–Hochberg correction for multiple comparisons. Significance was defined as ** Q < 0.01, and *** Q < 0.001.
Figure 5
Figure 5
Lower, but not significant, binding and neutralization antibody levels were observed with the immunocompromised individuals. Binding and neutralizing antibody levels were 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 WIV1-CoV pseudoviruses. For each measurement, immunocompetent and immunocompromised means were analyzed using a t-test.
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