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NASA implements required medical tests and clinical monitoring to ensure the health and safety of its astronauts. These measures include a pre-launch quarantine to mitigate the risk of infectious diseases. During space missions, most astronauts experience perturbations to their immune system that manifest as a detectable secondary immunodeficiency. On return to Earth, after the stress of re-entry and landing, astronauts would be most vulnerable to infectious disease. In April 2020, a crew returned from International Space Station to NASA Johnson Space Center in Houston, Texas, during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Post-flight quarantine protocols (both crew and contacts) were enhanced to protect this crew from SARS-CoV-2. In addition, specific additional clinical monitoring was performed to determine post-flight immunocompetence. Given that coronavirus disease 2019 (COVID-19) prognosis is more severe for the immunocompromised, a countermeasures protocol for spaceflight suggested by an international team of scientists could benefit terrestrial patients with secondary immunodeficiency.