Enhanced fitness of SARS-CoV-2 variant of concern Alpha but not Beta

Emerging variants of concern (VOC) drive the SARS-CoV-2 pandemic^1,2. Experimental assessment of replication and transmission of major VOC compared to progenitors are needed to understand successful emerging mechanisms of VOC³. Here, we show that Alpha and Beta spike (S) proteins have a greater affinity to human angiotensin converting enzyme 2 (hACE2) receptor over the progenitor variant (wt-S^614G) in vitro. Yet Alpha and wt-S^614G had similar replication kinetics in human nasal airway epithelial cultures, whereas Beta was outcompeted by both. In vivo, competition experiments showed a clear fitness advantage of Alpha over the progenitor variant (wt-S^614G) in ferrets and two mouse models, where the substitutions in S were major drivers for fitness advantage. In hamsters, supporting high replication levels, Alpha and wt-S^614G had comparable fitness. In contrast, Beta was outcompeted by Alpha and wt-S^614G in hamsters and hACE2-expressing mice. Our study highlights the importance of using multiple models for complete fitness characterization of VOC and demonstrates adaptation of Alpha towards increased upper respiratory tract replication and enhanced transmission in vivo in restrictive models, whereas Beta fails to overcome contemporary strains in naïve animals.