A Heterologous Challenge Rescues the Attenuated Immunogenicity of SARS-CoV-2 Omicron BA.1 Variant in Syrian Hamster Model

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is becoming a dominant circulator and has several mutations in the spike glycoprotein, which may cause shifts of immunogenicity, so as to result in immune escape and breakthrough infection among the already infected or vaccinated populations. It is unclear whether infection with Omicron could generate adequate cross-variant protection. To investigate this possibility, we used Syrian hamsters as an animal model for infection of SARS-CoV-2. The serum from Omicron BA.1 variant-infected hamsters showed a significantly lower neutralization effect against infection of the same or different SARS-CoV-2 variants than the serum from Beta variant-infected hamsters. Furthermore, the serum from Omicron BA.1 variant-infected hamsters were insufficient to protect against rechallenge of SARS-CoV-2 Prototype, Beta and Delta variants and itself. Importantly, we found that rechallenge with different SARS-CoV-2 lineages elevated cross-variant serum neutralization titers. Overall, our findings indicate a weakened immunogenicity feature of Omicron BA.1 variant that can be overcome by rechallenge of a different SARS-CoV-2 lineages. Our results may lead to a new guideline in generation and use of the vaccinations to combat the pandemic of SARS-CoV-2 Omicron variant and possible new variants. IMPORTANCE The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant causes breakthrough infections among convalescent patients and vaccinated populations. However, Omicron does not generate robust cross-protective responses. Here, we investigate whether heterologous SARS-CoV-2 challenge is able to enhance antibody response in a sensitive animal model, namely, Syrian hamster. Of note, a heterologous challenge of Beta and Omicron BA.1 variant significantly broadens the breadth of SARS-CoV-2 neutralizing responses against the prototype, Beta, Delta, and Omicron BA.1 variants. Our findings confirm that vaccination strategy with heterologous antigens might be a good option to protect against the evolving SARS-CoV-2.

Keywords: Omicron; SARS-CoV-2; cross-variant neutralization; homologous and heterologous rechallenge; immunogenicity.

FIG 1

Inhibitory effects of the serum from Omicron BA.1 or Beta variant-infected hamsters on the infection-caused cytopathic effect (CPE) of different variants. (A) Scheme of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and serum sample collection in a hamster model. (B, C) The serum samples were collected from hamsters previously exposed to 1 × 10³ PFU of SARS-CoV-2 Omicron BA.1 (B) or Beta (C) variants at 0, 7, 14, and 21 days post infection (dpi), respectively (n = 6/group). The variant-specific serum neutralization titers against SARS-CoV-2 prototype, Beta, Delta, and Omicron BA.1 variants were measured by a titration method based on a titration method of 50% tissue culture infective dose (TCID₅₀) inhibition. ID₅₀, 50% infective dose; ns, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001.

FIG 2

Rechallenge of SARS-CoV-2 in hamsters previously exposed to Omicron BA.1 and Beta variants. (A) The experimental scheme of the infection and rechallenge of 1 × 10³ PFU of SARS-CoV-2 Omicron or Beta variants in hamsters. The infected animals were reinfected with 1 × 10³ PFU of SARS-CoV-2 prototype, Beta, Delta, and Omicron variants at 21 dpi, respectively (n = 6/group). All of the hamsters were euthanized at 25 dpi (4 days after rechallenge) for the desired analysis. (B) Body weight changes from 21 to 25 dpi were recorded. (C to E) Viral titers in the tissues collected from respiratory tract organs, including turbinate (C), trachea (D), and lung (E) were measured by a titration method of TCID₅₀. Because the detection limitation of titration method is at least 10 TCID₅₀/mL, the undetectable samples are shown as “0” in the figures.

FIG 3

Serological analysis for the hamsters with homologous and heterologous rechallenges. Serum samples were collected at 25 dpi (4 days after rechallenge). The variant-specific serum neutralization titers against SARS-CoV-2 prototype (A), Beta (B), Delta (C), and Omicron (D) BA.1 variants were measured by a by a titration method of TCID₅₀ inhibition (n = 6/group).

FIG 4

Variant-specific serum neutralization titer indicate the ability to defend homologous and heterologous rechallenge. Hamsters previously exposed to Omicron BA.1 and Beta variants were rechallenged with SARS-CoV-2 prototype (A), Beta (B), Delta (C), and Omicron (D) variants, respectively (n = 12/group; 6 hamsters were previously exposed to Omicron BA.1, and 6 hamsters were previously exposed to Beta). In all the groups of homologous and heterologous rechallenge, a high variant-specific serum neutralization antibody (NAb) titer before rechallenges (left y axis) suggested low viral titer in lung tissue (right y axis) after rechallenges.

FIG 5

Analysis for the reciprocal changes of variant-specific serum neutralization titers before and after rechallenge. Comparative analysis for the changes in variant-specific serum neutralization titers of the serum samples collected from hamsters with homologous and heterologous sequential infection patterns including Omicron BA.1-Omicron BA.1 (A), Omicron BA.1-Beta (B), Beta-Beta (C), and Beta-Omicron BA.1 (D) were performed (n = 6/group). The fold changes of variant-specific serum neutralization titers after rechallenge (25 dpi versus 21 dpi) were calculated.