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. 2020 Aug:58:102890.
doi: 10.1016/j.ebiom.2020.102890. Epub 2020 Jul 21.

Lack of antibody-mediated cross-protection between SARS-CoV-2 and SARS-CoV infections

Ren Yang  1 , Jiaming Lan  2 , Baoying Huang  1 , Ruhan A  1 , Mingqing Lu  2 , Wen Wang  1 , Wenling Wang  1 , Wenhui Li  3 , Yao Deng  4 , Gary Wong  5 , Wenjie Tan  6
Affiliations

Lack of antibody-mediated cross-protection between SARS-CoV-2 and SARS-CoV infections

Ren Yang et al. EBioMedicine. 2020 Aug.

Abstract

Background: The novel coronavirus (SARS-CoV-2) shares approximately 80% whole genome sequence identity and 66% spike (S) protein identity with that of SARS-CoV. The cross-neutralization between these viruses is currently not well-defined.

Methods: Here, by using the live SARS-CoV-2 virus infection assay as well as HIV-1 based pseudotyped-virus carrying the spike (S) gene of the SARS-CoV-2 (ppSARS-2) and SARS-CoV (ppSARS), we examined whether infections with SARS-CoV and SARS-CoV-2 can induce cross-neutralizing antibodies.

Findings: We confirmed that SARS-CoV-2 infects cells via angiotensin converting enzyme 2 (ACE2), the functional receptor for SARS-CoV, and we also found that the recombinant receptor binding domain (RBD) of the S protein of SARS-CoV effectively inhibits ppSARS-2 entry in Huh7.5 cells. However, convalescent sera from SARS-CoV and SARS-CoV-2 patients showed high neutralizing activity only against the homologous virus, with no or limited cross-neutralization activity against the other pseudotyped virus. Similar results were also observed in vaccination studies in mice.

Interpretation: Our study demonstrates that although both SARS-CoV and SARS-CoV-2 use ACE2 as a cellular receptor, the neutralization epitopes are not shared by these two closely-related viruses, highlighting challenges towards developing a universal vaccine against SARS-CoV related viruses.

Funding: This work was supported by the National Key Research and Development Program of China, the National Major Project for Control and Prevention of Infectious Disease in China, and the One Belt and One Road Major Project for infectious diseases.

Keywords: ACE2; COVID-19; CoV; Cross-neutralization; SARS-CoV-2.

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Conflict of interest statement

Declaration of competing interest The authors declare no conflict of interests with respect to this study.

Figures

Fig 1
Fig. 1
Cell entry sensitivity test with pseudotyped SARS-CoV, SARS-CoV-2 and MERS-CoV viruses. (a) Huh7.5 cells are sensitive to infection with ppSARS, ppSARS-2 and ppMERS, with similar entry levels between ppSARS and ppSARS-2 (p > 0.1, two-way ANOVA). (b) HEK 293T cells were transiently transfected with the hACE2 expression plasmid. ppSARS and ppSARS-2 were both found to significantly enhance the infection ratio (p < 0.001, two-way ANOVA). Similar levels of entry were observed in hACE2 transfected 293T cells (p > 0.1, two-way ANOVA). (c) VeroE6 cells were infected with live SARS-CoV-2 in the presence of soluble ACE2 at different concentrations, in which 30 µg/mL of soluble ACE2 was found to inhibit virus replication. **P < 0.01, ****P < 0.0001.
Fig 2
Fig. 2
Alignment of RBD sequences for SARS-CoV and SARS-CoV-2, and competitive inhibition assays with RBD for pseudotyped SARS-CoV, SARS-CoV-2 and MERS-CoV viruses. (a) SARS-CoV-2 & SARS-CoV receptor binding domain alignment. Amino acid residues known to be important for binding were denoted by red triangles. (b) Competition assay for RBD-trimer or (c) RBD-monomer to the ACE2 receptor to block ppSARS, ppSARS-2 or ppMERS entry. Near-complete inhibition was observed at 100 μg/mL for RBD-trimer, with no significant differences observed between ppSARS and ppSARS-2 (p > 0.1, two-way ANOVA). Approximately 80% inhibition was observed at 100 μg/mL for RBD-monomer, with no significant differences observed between ppSARS and ppSARS-2 (p > 0.1). ** P < 0.01, **** P < 0.0001.
Fig 3
Fig. 3
Microneutralization of antisera from mice immunized with various SARS vaccine candidates with pseudotyped SARS-CoV, pseudotyped and live SARS-CoV-2 viruses. Immunized mice groups were denoted as G1-G5, whereas mock alum-immunized mice were denoted as C. (a) Neutralizing activity can be observed in all five immunized groups. (b) Cross-neutralizing activity to ppSARS-2 can be detected only in Group 1, with no cross-neutralization observed in the other four groups. (c) Reexamination of mice antisera with live SARS-CoV-2 showed that neutralizing activity was only observed in Group 1.
Fig 4
Fig. 4
Serum microneutralization of antisera from convalescent SARS-CoV-2 patients with pseudotyped SARS-CoV, pseudotyped and live SARS-CoV-2 viruses. Convalescent SARS-CoV-2 patients were denoted as P1-P5, and healthy controls were denoted as H1-H2. (a) None of the 5 tested patient samples can neutralize ppSARS. (b) All 5 serum samples can effectively neutralize ppSARS-2. (c) All 5 serum samples can effectively neutralize live SARS-CoV-2.
Fig 5
Fig. 5
Serum microneutralization of antisera from convalescent SARS-CoV patients with pseudotyped SARS-CoV, pseudotyped and live SARS-CoV-2 viruses.Convalescent SARS-CoV patients were denoted as P1-P5, and healthy controls were denoted as H1-H2. (a) Neutralization against ppSARS was observed in all five patients. (b) None of the 5 convalescent serum samples can effectively neutralize ppSARS-2. (c) None of the convalescent samples can effectively neutralize live SARS-CoV-2.
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