hospitalization, might substantially reduce long-term morbidity and mortality and reduce the burden on healthcare resources (Fig. 1). For an early-intervention strategy to work, we need to accurately identify patients at greatest risk of clinical deterioration. Demographic factors help, as well as laboratory measures like elevation of CRP (7–9). Deep phenotyping studies, incorporating both clinical features and immunological biomarkers (10) and utilizing machine-learning techniques, are likely to deliver a more sophisticated understanding necessary to identify best targets for early therapy.Established therapies and future opportunities for intervention early in disease. Following infection with SARS-CoV-2, there are specific time points in the disease trajectory where different therapies could be optimally administered. At this time, the majority of treatments have been targeted during hospitalization and particularly at late stages of acute disease during ICU admission. Additionally, many of the therapies trialed are antibody therapies and are cost prohibitive, especially in low- to middle-income countries. There is currently a window of missed opportunity early in disease to reduce progression to hospitalization.Long-COVID.An important emerging issue is the symptom complex long-COVID. Prevalence appears high in both hospitalized patients and those with mild/moderate disease (11–13). Evidence suggests that long-COVID is more severe than other postviral syndromes. Patients admitted to hospital with COVID-19 had significantly higher rates of death, cardiovascular disease, neurological and mental health disorders, fatigue, and coagulation disorders than those admitted with influenza (14).The mechanism of long-COVID is not well understood. Theories include long-term cellular damage caused by the SARS-CoV2 virus during acute infection, SARS-CoV-2 persistence, postacute illness, and the development of autoimmunity (14, 15). Changes to social circumstances, including job loss and social isolation, may also negatively impact the clinical course. Without a clear understanding of the pathogenesis of long-COVID, the development of effective therapy is challenging.Encouragingly, studies are shedding light on the pathogenesis of the most common complaints in long-COVID, namely pulmonary and neurologic symptoms (14, 16). The highly sensitive hyperpolarized Xenon magnetic resonance imaging method of visualizing microstructure abnormalities in the lung shows persistent anomalies at the alveolar-endothelial-epithelial junction (17). Neuropathology studies, mainly from autopsies, show abnormalities similar to dementia, schizophrenia, and depression (18). Brain specimens show evidence of widespread inflammatory changes, including lymphoid infiltration and microglial activation (19). Coagulation abnormalities are also common (20, 21), with brain infarcts seen in about 20% of individuals and microthrombi and hemorrhages seen in 15% of individuals. These abnormalities might help to explain the symptoms of “brain fog” and fatigue in those with long-COVID.Therapeutics currently under investigation for long-COVID target different proposed mechanisms for pathogenesis. Strategies include antifibrotic medication due to the observation of fibrotic lung changes, anticoagulants, statins for their anti-inflammatory properties, and dedicated long-COVID rehabilitation centers (22–24). Observational data also suggests improvement in long-COVID symptoms postvaccination, the theory being that vaccination induces elimination of residual SARS-CoV-2 virus (25).Low- to middle-income countries will likely bear the greatest disease burden from COVID-19 due to delayed access to effective vaccination and the consequences of structural inequity, such as overcrowding. These countries need affordable, easily administered COVID-19 therapies, such as temperature-stable oral medicines or inhaled therapeutics. Robust and accountable collective purchasing and distribution systems will need to stand independently of national interest. Collective drug purchasing, driven by the WHO and nongovernment initiatives, like the Global Fund and the Gates Foundation, has proven effective in ongoing challenges, such as HIV/AIDS. A similar approach in COVID-19 is necessary (26), accompanied by preventative strategies and culturally appropriate community engagement, particularly as COVID-19 will likely persist as a global threat until all countries can sustainably access treatment.Even with widespread COVID-19 vaccination uptake, there will always be people with poor vaccination response. Immunomodulatory medications like glucocorticoids and rituximab lead to reduced response to SARS-CoV-2 vaccines (27), and it is possible that other immune-modifying therapies cause a similarly reduced response. Without herd immunity, these patients will remain vulnerable to severe infection. Huge resources have appropriately been allocated to the development and distribution of effective vaccines, and this remains one of the great successes of the pandemic. Despite this, effective and cheap therapeutics are critical given viral genome evolution, particularly for those who do not sufficiently respond to vaccines, for those who decline to receive vaccines, for those yet to be able to access vaccines on scale, and as a back-up should variants of concern evade vaccine-induced