Pre-existing anti-SARS-CoV-2 immunity decreases viral spread but increase SARS-CoV-2 Omicron competitiveness in hamsters

By Pooja Toshniwal PahariaAug 2 2022Reviewed by Aimee Molineux

In a recent study posted to the bioRxiv* preprint server, researchers assessed the impact of pre-existing immunity against severe acute respiratory coronavirus 2 (SARS-CoV-2) acquired by previous infections (PI) or coronavirus disease 2019 (COVID-19) vaccination on the transmission of SARS-CoV-2 variants of concern (VOCs) such as Delta and Omicron.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

There has been a continual emergence of SARS-CoV-2 VOCs across the globe and the replacement of previous SARS-CoV-2 VOCs by novel variants has been mainly due to increases in variant transmissibility. However, the dissemination advantage of the Omicron VOC over the Delta VOC in humans is not completely understood.

About the study

In the present study, researchers assessed the impact of pre-existing anti-SARS-CoV-2 immunity on intra-host and inter-host Omicron competitiveness compared to Delta using Syrian hamsters.

Transmission chain experiments were performed using naïve, PI and intramuscularly (IM) or intranasally (IN) vaccinated hamsters. The RBD-ACE2 [SARS-CoV-2 spike (S) protein receptor-binding domain-angiotensin-converting enzyme 2] complex was modeled to investigate if S mutations affected the dynamics of SARS-CoV-2 VOCs.

SARS-CoV-2 S-facilitated cellular entry of Omicron and Delta was compared to the A lineage S by vesicular stomatitis virus (VSV)-pseudotype entry assays using hamster ACE2- or human ACE2-expressing baby hamster kidney (BHK) cells.

Subsequently, the team assessed respiratory shedding of SARS-CoV-2 in comparison to the Alpha, Beta, Gamma, Delta, or Lineage A VOCs. Airborne and contact transmission of Delta and Omicron were assessed using donor and sentinel hamsters of three generations. Donor hamsters received IN inoculations of Omicron and Delta in a 1:1 ratio, following which oral swabs, lung tissues, and nasal turbinate samples were examined.

Further, the subgenomic ribonucleic acid (sgRNA) levels were measured by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and next-generation sequencing (NGS) analysis was performed.

Pre-existing anti-SARS-CoV-2 immune responses were induced by IM or IN AZD1222 vaccinations or previous Delta infections. The hamsters (n=6 in each group) were intranasally inoculated with 10⁴ tissue culture infectious doses (TCID₅₀) Omicron and Delta. The extent of pulmonary damage was assessed based on the lung: bodyweight ratio of the hamsters.

Further, anti-S immunoglobulin G (IgG) titers were evaluated to quantify the immune pressure against Omicron, and live virus neutralization assays were performed. The cumulative [area under the curve (AUC)] shedding of sgRNA between the sentinels and the post-IN and post-intratracheal (IT) Omicron inoculation findings were compared.

Results

Moderate airborne transmission blockage (70%) by IM vaccinations, and >90% transmission blockage was observed by PI and IN vaccinations. Delta outcompeted Omicron in directly infected donors and sentinels across groups, although Omicron was more prevalent in hamsters with pre-existing immunity. Immune responses were stronger for Delta, especially in PI hamsters, and lower SARS-CoV-2 S-mediated cellular entry and delayed shedding of Omicron over Delta were observed. For human ACE2, S-mediated entry of Omicron and lineage A were similar and 1.4-fold lower than for the Delta VOC and for hamster ACE2, 1.6-fold differences were observed between Omicron and Delta.

Cumulative shedding by Alpha-inoculated hamsters was significantly more than that by Omicron- and Gamma-inoculated hamsters. All naïve hamsters were infected by contact transmission, whereas two sentinel 1 (generation 1 sentinels) animals, one sentinel 3 animal, and two sentinel 2 animals were infected by airborne SARS-CoV-2 transmission. No significant differences in sgRNA titers across samples were noted between donor and sentinel hamsters with both transmission routes combined.  

Delta infections showed increased with every subsequent transmission chain. Among naïve hamsters, SARS-CoV-2 replication was observed in the lungs, and nasal turbinates with median values of 8.3 and 6.9 sgRNA copies/gr log₁₀, respectively. In contrast, viral loads were significantly lower for PI-, IM-, and IN-hamsters. In donor hamsters, PI immunity significantly decreased the lung: bodyweight ratios (1.3, 0.7, 0.8 and 0.8 for naïve, IM, IN, and PI groups, respectively).

Naïve hamsters developed typical SARS-CoV-2 infection lesions. SARS-CoV-2 nucleoprotein Immunoreactivity was most prominent in pneumonia foci periphery in bronchi and alveoli and for the cluster of differentiation 3 (CD3) protein in peri-vascular and peri-bronchiolar regions.  IN vaccinations led to four-fold greater immune responses than IM vaccinations and PI hamsters had the highest titers. Neutralizing antibody titers were 10-fold higher for Delta than against Omicron among PI hamsters.

PI and IN vaccinations reduced SARS-CoV-2 replication compared to IM vaccinations and contact transmission was lower among PI and IN-vaccinated hamsters. The naïve hamsters, IM-vaccinated, IN-vaccinated and PI group hamsters showed 63%, 29% 7% and 7% airborne transmission efficiency, respectively. Omicron IT inoculation increased pulmonary SARS-CoV-2 replication and pathology but did not increase transmission and reduced spread in the lower respiratory tract due to reduced TMPRSS2 (transmembrane protease serin 2) affinity in Omicron due to S mutations.

Overall, the study findings demonstrated that pre-existing immunity and route of exposure directly influence COVID-19 manifestation and onwards transmission efficacy of SARS-CoV-2. The data underscore the need to assess transmission dynamics of SARS-CoV-2 VOCs in populations with pre-existing immunity and address the increase in evolutionary pressures exerted on SARS-CoV-2.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.