key: cord-0935540-3lfomt6e
authors: Ryan, Kathryn A.; Watson, Robert J.; Bewley, Kevin R.; Burton, Christopher; Carnell, Oliver; Cavell, Breeze E.; Challis, Amy; Coombes, Naomi S.; Emery, Kirsty; Fell, Rachel; Fotheringham, Susan A.; Gooch, Karen E.; Gowan, Kathryn; Handley, Alastair; Harris, Debbie J.; Humphreys, Richard; Johnson, Rachel; Knott, Daniel; Lister, Sian; Morley, Daniel; Ngabo, Didier; Osman, Karen L.; Paterson, Jemma; Penn, Elizabeth J.; Pullan, Steven T.; Richards, Kevin S.; Shaik, Imam; Summers, Sian; Thomas, Stephen R.; Weldon, Thomas; Wiblin, Nathan R.; Vipond, Richard; Hallis, Bassam; Funnell, Simon G. P.; Hall, Yper
title: Convalescence from prototype SARS-CoV-2 protects Syrian hamsters from disease caused by the Omicron variant
date: 2021-12-26
journal: bioRxiv
DOI: 10.1101/2021.12.24.474081
sha: 855e3e061f570a3a525addab11beafb421b21278
doc_id: 935540
cord_uid: 3lfomt6e

The mutation profile of the SARS-CoV-2 Omicron variant poses a concern for naturally acquired and vaccine-induced immunity. We investigated the ability of prior infection with an early SARS-CoV-2, 99.99% identical to Wuhan-Hu-1, to protect against disease caused by the Omicron variant. We established that infection with Omicron in naïve Syrian hamsters resulted in a less severe disease than a comparable dose of prototype SARS-CoV-2 (Australia/VIC01/2020), with fewer clinical signs and less weight loss. We present data to show that these clinical observations were almost absent in convalescent hamsters challenged with the same dose of Omicron 50 days after an initial infection with Australia/VIC01/2020. The data provide evidence for immunity raised against prototype SARS-CoV-2 being protective against Omicron in the Syrian hamster model. Further investigation is required to conclusively determine whether Omicron is less pathogenic in Syrian hamsters and whether this is predictive of pathogenicity in humans.

A dose-down experiment was initiated to assess the impact of infection with a range 88 of lower doses of SARS-CoV-2 and to test for waning immunity over time, with a view 89 to performing homologous re-challenge at an optimised timepoint. During the early 90 stages of this experiment, the Omicron variant emerged and so the opportunity was 91 taken to test for cross-protection between a prototype SARS-CoV-2, 92 Australia/VIC01/2020, and this latest VOC. SARS-CoV-2 Australia/VIC01/2020 was 93 isolated in January 2020 and has greater than 99.99% sequence identity to the (Table 1) , providing a total of 12 VIC01 re-challenged hamsters and 12

Omicron re-challenged hamsters. Two naïve, age-matched control groups were 119 included in this study; six naïve hamsters were challenged with VIC01 (3.10E+03 FFU) 120 and eleven naïve hamsters were challenged with Omicron (8.18E+03 FFU), this 121 challenge was prepared in parallel with the re-challenge and used the same inocula.

All animals were culled 7 days later, except for a proportion of the Omicron control 123 group where 5 animals were allowed to continue to be monitored for full recovery.

Challenge inocula were back-titrated by foci forming assay on the day of challenge to 125 confirm doses. Back titration of the challenge stocks confirmed that comparable doses 126 of VIC01 and Omicron were administered to the re-challenged groups and to naïve 127 control groups challenged in parallel. (Fig. 1c) . There were no 149 significant differences between the amount of total viral RNA shed between groups. were analysed for SARS-CoV-2 spike-specific IgG binding antibodies (Fig. 1f) . Only 171 hamsters that received a target dose of 5E+04 showed a significant decrease 172 (P=0.0011) in SARS-CoV-2 spike-specific IgG binding antibodies from day 20 to 41. challenge, 24 previously infected (convalescent) hamsters were re-challenged.

Twelve hamsters were re-challenged intranasally with VIC01 (3.1E+10 3 FFU) and 12 214 with Omicron (8.18E+10 3 FFU). Following re-challenge, both groups of hamsters 215 continued to gain weight above baseline (Fig 3a) . The majority of hamsters remained 216 healthy ( Fig. 3b) following re-challenge with only four hamsters (two from each group) 217 experiencing clinical signs. Three of these hamsters were previously administered the 218 high target dose of 5E+04 and one administered the low target dose of 1E+02. 219 Hamsters in the VIC01 and Omicron groups were recorded as being ruffled with one 220 instance in the VIC01 group of laboured breathing 1 (see Table 2 ). These clinical the Omicron group and by day 6 in the VIC01 challenge group (Fig. 3d) . Omicron re-227 challenged hamsters were shown to be shedding significantly less (P <0.0001) viral 228 RNA from their URT by day 4 compared to VIC01 re-challenge hamsters. and counted using an ImmunoSpot S6 Ultra-V analyser and BioSpot software (CTL).

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