immunity. While vaccine development has been rightfully relatively prioritized to this point, the efforts of the medical and scientific community will only be complete with a renewed focus on therapeutics.This focus on therapeutics will be particularly important for certain populations. Patients on B cell-depleting therapies, used widely as a treatment in hematological malignancy, rheumatology, clinical immunology, and neurology, are particularly vulnerable. B cell-depleting therapy has been identified as a significant inhibitor of COVID-19 vaccine serological responses, but our understanding of cell-mediated immunity is more primitive (28). For these patients, and for those with inherited or acquired immunodeficiency, preexposure prophylaxis with long-acting neutralizing monoclonal antibodies clearly has a role, given that time is critically of essence for antibody generation if one wants to survive infection (29). Given that this approach does not rectify the underlying inadequate host immune response, efforts should also be focused on how we can prime these abnormal immune systems in focal ways to generate some immunity. This will be both a scientific and a logistical challenge, given the relative few who stand to benefit, but success in these efforts will likely have huge ramifications for those who are born with immune deficiencies or inherit them from treating cancer and autoimmune disease, and the broader measures required to protect them.The COVID-19 Therapeutic Landscape At different stages of COVID-19, pathology and relevant targets differ (Fig. 1). In the early stages, antivirals are key, compared to later in the disease where inflammation and its consequences are largely culpable. Regrettably, the important timing of therapy administration within relevant windows of opportunity remains inexact. In fact, while some overall success has been achieved in all therapeutic classes, the choice and best use of agents is evolving rapidly. Antivirals. Antivirals justifiably remain the focus for treatment in early COVID-19. Two main approaches exist: direct acting antivirals (DAAs) that target viral proteins, and less developed host-targeting agents (HTAs) that inhibit the human host cells that viruses need for replication and spread. The most developed DAA candidates for COVID-19 are repurposed drugs. Remdesivir, an intravenously administered polymerase inhibitor developed for hepatitis C is one of the only currently approved antiviral option for COVID-19, but with limited benefit: reducing median recovery time (10 vs. 15 d) but not mortality (hazard ratio for death 0.73; 95%CI, 0.52 to 1.03) in the ACTT-1 trial (5) (n = 1,062). Subgroup analysis suggested greater benefit with early administration. In contrast, the SOLIDARITY trial (2) (n = 11,330) found no survival benefit with remdesivir (rate ratio for death of 0.95, 95%CI 0.81 to 1.11), and consequently the WHO issued a conditional recommendation against its use in hospitalized patients. While inducible resistance to remdesivir has been reported (30), variants do not appear to lead to preexisting resistance to remdesivir (31, 32). Another repurposed polymerase inhibitor is molnupiravir, originally developed for Venezuelan equine encephalitis and influenza. It is a prodrug that undergoes rapid conversion to the active nucleoside triphosphate, which is a competitive substrate for virally encoded RNA-dependent RNA polymerase. On incorporation into the nascent chain RNA, it increases mutational frequency and hence viral “error catastrophe.” Promising data from an interim analysis of the phase 3 study showing an approximate 50% reduction in hospitalization or death has triggered emergency use authorization in the United States and approval in the United Kingdom (33). As the experience with influenza and oseltamivir has shown (34), there is potentially a narrow window where DAA can work, and this may be why remdesivir has not shown better efficacy in inpatient trials.Drugs that specifically target SARS-CoV-2 will likely have greater COVID-19 DAA potency than repurposed therapeutics; their development requires detailed structural knowledge of viral proteins. For SARS-CoV-2, the first relevant protein to be understood was the main protease, 3CLpro, as it is closely structurally related to the SARS-CoV-1 main protease; this understanding has accelerated development of protease inhibitors targeting it. PF-07321332/nirmatrelvir blocks the SARS-CoV-2/3CL protease and is delivered in combination with ritonavir. Ritonavir inhibits CYP3A4, prolonging exposure to PF-07321332/nirmatrelvir. A scheduled interim analysis showed an 89% reduction in risk of COVID-19–related hospitalization or death from any cause compared to placebo in patients treated within 3 d of symptom onset (NCT04960202). In both cases treatment needs to be started early in the illness (<5 d from symptoms). Their role in asymptomatic disease is unclear. The final analysis of the phase 3 studies and adverse effect profile is eagerly awaited and further assessment of effectiveness is likely to be required.Other DAA targeting other SARS-CoV-2 proteins are under development, including those targeting polymerase, papain-like protease, helicase, and viral replication transcription complexes (RTC) responsible for viral RNA synthesis, proofreading, and 5′-capping. RTC are critically