INTRODUCTION: COVID-19-related social isolation and stress may have significant mental health effects, including post-traumatic stress, anxiety and depression. These factors are thought to disproportionately affect populations at risk of psychopathology, such as adolescents with a history of childhood adversity (CA). Therefore, examining which factors may buffer the impact of COVID-19-related stress and isolation in vulnerable adolescents is critical. The Resilience After the COVID-19 Threat (REACT) study assesses whether emotion regulation capacity, inflammation and neuroimmune responses to stress induced in the laboratory prior to the pandemic predict responses to COVID-19-related social isolation and stress in adolescents with CA. We aim to elucidate the mechanisms that enable vulnerable adolescents to maintain or regain good mental health when confronted with COVID-19. METHODS AND ANALYSIS: We recruited 79 adolescents aged 16-26 with CA experiences from the Resilience After Individual Stress Exposure study in which we assessed emotion regulation, neural and immune stress responses to an acute stress task. Our sample completed questionnaires at the start of the UK lockdown ('baseline'; April 2020) and three (July 2020) and 6 months later (October 2020) providing crucial longitudinal information across phases of the pandemic progression and government response. The questionnaires assess (1) mental health, (2) number and severity of life events, (3) physical health, (4) stress perception and (5) loneliness and friendship support. We will use multilevel modelling to examine whether individual differences at baseline are associated with responses to COVID-19-related social isolation and stress. ETHICS AND DISSEMINATION: This study has been approved by the Cambridge Psychology Research Ethics Committee (PRE.2020.037). Results of the REACT study will be disseminated in publications in scientific peer-reviewed journals, presentations at scientific conferences and meetings, publications and presentations for the general public, and through social media.