Background: Multiple SARS-CoV-2 variants are still rampant across the United States (US). We aimed to evaluate the impact of vaccination scale-up and potential reduction in the vaccination effectiveness on the COVID-19 epidemic and social restoration in the US. Methods: We extended a published compartmental model and calibrated the model to the latest US COVID-19 data. We estimated the vaccine effectiveness against the variant and evaluated the impact of a potential reduction in vaccine effectiveness on the epidemics. We explored the epidemic trends under different levels of social restoration. Results: We estimated the overall existing vaccine effectiveness against the variant as 88.5% (95% CI: 87.4-89.5%) with the vaccination coverage of 70% by the end of August, 2021. With this vaccine effectiveness and coverage, there would be 498,972 (109,998-885,947) cumulative infections and 15,443 (3,828-27,057) deaths nationwide over the next 12 months, of which 95.0% infections and 93.3% deaths were caused by the variant. Complete social restoration at 60, 65, 70% vaccination coverage would increase cumulative infections to 1.6 (0.2-2.9) million 0.7 (0.1-1.2) million, and 511,159 (110,578-911,740), respectively. At same time it would increase cumulative deaths to 39,040 (5,509-72,570), 19,562 (3,873-35,250), 15,739 (3,841-27,638), respectively. However, if the vaccine effectiveness were reduced to 75%, 50% or 25% due to new SARS-CoV-2 variants, there would be 667,075 (130,682-1,203,468), 1.7 (0.2-3.2) million, 19.0 (5.3-32.7) million new infections and 19,249 (4,281-34,217), 42,265 (5,081-79,448), 426,860 (117,229-736,490) cumulative deaths to occur over the next 12 months. Further, social restoration at a lower vaccination coverage would lead to even greater secondary outbreaks. Conclusion: Current COVID-19 vaccines remain effective against the SARS-CoV-2 variant, and 70% vaccination coverage would be sufficient to restore social activities to a pre-pandemic level. Further reduction in vaccine effectiveness against SARS-CoV-2 variants would result in a potential surge of the epidemic. Multiple measures, including public health interventions, vaccination scale-up and development of a new vaccine booster, should be integrated to counter the new challenges of new SARS-CoV-2 variants.