Mycobacterium-w (Mw), was shown to boost adaptive natural killer (ANK) cells and protect against COVID-19 during the first wave of the pandemic. As a follow-up of the trial, 50 healthcare workers (HCW) who had received Mw in September 2020 and subsequently received at least one dose of ChAdOx1 nCoV-19 vaccine (Mw+ChAdOx1 group) were monitored for symptomatic COVID-19, during a major outbreak with the delta variant of SARS-CoV-2 (April-June, 2021), along with 201 HCW receiving both doses of the vaccine without Mw (ChAdOx1 group). Despite 48% having received just a single dose of the vaccine in Mw+ChAdOx1 group, only 2 had mild COVID-19, compared to 36 infections in the ChAdOx1 group (HR-0.46, p=0.009). Transcriptomic studies revealed an enhanced adaptive NK cell-dependent ADCC in the Mw+ChAdOx1 group, along with downregulation of TLR2-MYD88 pathway and concomitant attenuation of downstream inflammatory pathways. This might have resulted in robust protection during the pandemic with the delta variant.