Summary/Abstract The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), causative agent of the coronavirus disease of 2019 (COVID-19) which was designated as a pandemic respiratory illness (WHO - 2020), has infected over 172 million people worldwide and resulted in over 3.7 million deaths, including > 596,000 in the United States (June 3, 2021, WHO; www.who.int). Multiple Phase 3 efficacy trials of SARS-CoV-2 vaccine constructs are underway or in long-term follow-up in the U.S, and these studies have supported 3 Emergency Use Authorizations (EUAs) for COVID vaccines. However, logistical and manufacturing obstacles are limiting the number of vaccines available at any one time. Further, the emergence of variant strains has raised concerns about the breadth of immunity and protection achieved by the current vaccines. WHO SAGE and CDC ACIP have identified the safety and immunogenicity of mixed schedules as a critical and immediate research priority to inform policy on the use of mixed schedules. Knowledge of the safety, tolerability, and immunogenicity of a delayed boost vaccine incorporating a heterologous platform or variant spike lineage administered following EUA prime dosing regimens may greatly stretch the ability to immunize against SARS-CoV-2 at a population level, induce immunity to variant circulating strains and improve upon the breadth and durability of protection. The heterologous boost strategy will also provide an opportunity to thoroughly evaluate innate, cellular, and humoral immune responses elicited from the multiple prime boost combinations using very similar immunogens, utilizing mRNA, adenovirus- vectored, and protein- based platforms. As new immunogens are manufactured to closely match emerging variants, these foundational data will be key to the evaluation of future variant and heterologous prime- boost strategies. This phase 1/2 clinical trial will evaluate the safety and immunogenicity of different heterologous delayed doses (boosts) in those who received an EUA vaccine (either prior to participation in this trial, or as part of this trial).