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The SARS-CoV-2 B. 1.617. 2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B. 1.617. 1 (Kappa) and B. 1.1. 7 (Alpha). In vitro, B. 1.617. 2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against B. 1.617. 2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B. 1.617. 2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD), in particular to the clinically approved bamlavinimab and imdevimab monoclonal antibodies. B. 1.617. 2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems as compared to B. 1.1. 7, associated with B. 1.617. 2 spike being in a predominantly cleaved state compared to B. 1.1. 7. Additionally we observed that B. 1.617. 2 had higher replication and spike mediated entry as compared to B. 1.617. 1, potentially explaining B. 1.617. 2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed substantially reduced ChAdOx-1 vaccine efficacy against B. 1.617. 2 relative to non-B. 1.617. 2. Compromised vaccine efficacy against the highly fit and immune evasive B. 1.617. 2 Delta variant warrants continued infection control measures in the post-vaccination era.