Use of whole genome sequencing to estimate the contribution of immune evasion and waning immunity on decreasing COVID-19 vaccine effectiveness.

<bold>Background: </bold>The impact variant-specific immune evasion and waning protection have on declining COVID-19 vaccine effectiveness remains unclear. Using whole-genome-sequencing (WGS), we examined the contribution of these factors on the decline observed following the introduction of the Delta variant. Further, we evaluated the utility of calendar-period-based classification as an alternative to WGS.<bold>Methods: </bold>We conducted a test-negative-case-control study among people who received SARS-CoV-2 RT-PCR testing in the Yale New Haven Health System between April 1 and August 24, 2021. Variant classification was performed using WGS and calendar-period.<bold>Results: </bold>Overall, 2,029 cases (RT-PCR positive, sequenced samples [infections]) and 343,985 controls (negative RT-PCRs) were included. VE 14-89 days after 2nd dose was significantly higher against WGS-classified Alpha-infection (84.4%, CI: 75.6-90.0%) than Delta-infection (68.9%, CI: 58.0-77.1%, p-value = 0.013). The odds of WGS-classified Delta-infection were significantly higher 90-149 than 14-89 days after 2nd dose (p-value = 0.003). VE estimates against calendar-period-classified infections approximated estimates against WGS-classified infections, however, calendar-period-based classification was subject to outcome misclassification (35%: Alpha-period, 4%: Delta-period).<bold>Conclusions: </bold>Both waning protection and variant-specific immune evasion contributed to the lower effectiveness. While VE estimates against calendar-period-classified infections mirrored those against WGS-classified infections, our analysis highlights the need for WGS when variants are co-circulating and misclassification is likely. [ABSTRACT FROM AUTHOR]