The efforts of the Biden administration to accelerate rollout of COVID-19 vaccines are enabling more adults in the US to be vaccinated each week. As of February 28, 2021, an estimated more than 48 million people have received at least 1 vaccine dose. Provided enough people are vaccinated, the US might be able to transition back toward prepandemic life at some point this year. However, one scenario that could adversely affect the vaccine program is the further evolution and spread of viral variants that are resistant to vaccine-induced neutralizing antibodies. It is prudent to discuss possible strategies to minimize the potential effects of this problem, and other scenarios for maximizing the benefit of available and future vaccine supplies.The viral variant problem became prominent at the end of 2020. Two categories of variants have different implications for vaccine efficacy. The first category involves variants that arise when RNA viruses like SARS-CoV-2 replicate in people. One selection pressure on the virus is simply to infect human cells more efficiently and maximize the replication of its genome. A more fit and transmissible virus will spread more rapidly in a population. This happened during spring 2020 when the D614G variant became the dominant strain worldwide. The same phenomenon is occurring now with the B.1.1.7 strain that was first detected in the UK. The B.1.1.7 strain is more infectious and is projected to soon dominate the US pandemic. But neither the D614G variant nor the B.1.1.7 strain is notably resistant to vaccine-induced neutralizing antibodies, and most researchers have substantial confidence that these variants will not affect the efficacy of the present generation of vaccines. 1,2 The second category involves variants that are more concerning, represented by the B.1.351 and P.1 lineages that emerged in South Africa and Brazil, respectively. These viruses have sequence changes in key positions suggesting that they arose under neutralizing antibody selection pressure within people infected with SARS-CoV-2. Unusual variants have been seen when the virus replicates at high levels for prolonged periods in immunocompromised individuals. 3 Even though what happens in such people is not identical to the environment in vaccine recipients who become infected, several similarities warrant consideration.Whether neutralizing antibodies are induced by infectionorvaccination,astrongneutralizingantibodyresponse suppressesvirusreplicationandaweakresponsedoeslittle to suppress replication, but neutralizing antibodies that have intermediate potency are thought to cause the virus to evolve and create ways to escape the constraint on its ability to replicate. 4,5 The combination of a high virus replicationratewithinanindividual(ahighviralload)andasuboptimallevelofneutralizingantibodiesistheexactenviron-VIEWPOINT