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Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.Long COVID is an often debilitating illness of severe symptoms that can develop during or following COVID-19. In this Review, Davis, McCorkell, Vogel and Topol explore our knowledge of long COVID and highlight key findings, including potential mechanisms, the overlap with other conditions and potential treatments. They also discuss challenges and recommendations for long COVID research and care.

The Omicron variant of SARS-CoV-2 has been reported to cause milder disease in adults but lead to increased hospital admissions in children. How can we compare disease severity in Omicron and Delta infections, and how should differences be interpreted?

SARS-CoV-2 viral load and detection of infectious virus in the respiratory tract are the two key parameters for estimating infectiousness. As shedding of infectious virus is required for onward transmission, understanding shedding characteristics is relevant for public health interventions. Viral shedding is influenced by biological characteristics of the virus, host factors and pre-existing immunity (previous infection or vaccination) of the infected individual. Although the process of human-to-human transmission is multifactorial, viral load substantially contributed to human-to-human transmission, with higher viral load posing a greater risk for onward transmission. Emerging SARS-CoV-2 variants of concern have further complicated the picture of virus shedding. As underlying immunity in the population through previous infection, vaccination or a combination of both has rapidly increased on a global scale after almost 3 years of the pandemic, viral shedding patterns have become more distinct from those of ancestral SARS-CoV-2. Understanding the factors and mechanisms that influence infectious virus shedding and the period during which individuals infected with SARS-CoV-2 are contagious is crucial to guide public health measures and limit transmission. Furthermore, diagnostic tools to demonstrate the presence of infectious virus from routine diagnostic specimens are needed.A better understanding of the transmission of SARS-CoV-2 is essential to inform public health measures. In this Review, Puhach, Meyer and Eckerle explore insights into what influences SARS-CoV-2 shedding, how this drives transmission and the tools available to measure this and determine infectiousness.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths and substantial morbidity worldwide. Intense scientific effort to understand the biology of SARS-CoV-2 has resulted in daunting numbers of genomic sequences. We witnessed evolutionary events that could mostly be inferred indirectly before, such as the emergence of variants with distinct phenotypes, for example transmissibility, severity and immune evasion. This Review explores the mechanisms that generate genetic variation in SARS-CoV-2, underlying the within-host and population-level processes that underpin these events. We examine the selective forces that likely drove the evolution of higher transmissibility and, in some cases, higher severity during the first year of the pandemic and the role of antigenic evolution during the second and third years, together with the implications of immune escape and reinfections, and the increasing evidence for and potential relevance of recombination. In order to understand how major lineages, such as variants of concern (VOCs), are generated, we contrast the evidence for the chronic infection model underlying the emergence of VOCs with the possibility of an animal reservoir playing a role in SARS-CoV-2 evolution, and conclude that the former is more likely. We evaluate uncertainties and outline scenarios for the possible future evolutionary trajectories of SARS-CoV-2.In this Review, Markov, Katzourakis and colleagues explore the evolution of SARS-CoV-2 at different scales, the phases of the COVID-19 pandemic, factors that drive the evolution of the virus, theories for the emergence of epidemiologically important variants and potential future evolutionary scenarios and their likely health repercussions.

The lineages’ rise seems to stem from their ability to infect people who were immune to earlier forms of Omicron and other variants. The lineages’ rise seems to stem from their ability to infect people who were immune to earlier forms of Omicron and other variants. Credit: Morteza Nikoubazl/NurPhoto via Getty An elderly Iranian man who is infected by COVID-19 uses oxygen as he lies on a hospital bed in a COVID-19 ward in Iran.

Researchers are racing to determine whether a fast-spreading coronavirus variant poses a threat to COVID vaccines’ effectiveness. Researchers are racing to determine whether a fast-spreading coronavirus variant poses a threat to COVID vaccines’ effectiveness. People wearing personal protective equipment pick up a suspected COVID-19 patient

The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India 1 – 5 . Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries 6 . The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2—also termed the Delta variant—is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein. The SARS-CoV-2 Delta variant partially evades neutralization by several monoclonal antibodies and by sera from individuals who have had COVID-19, but two doses of anti-COVID-19 vaccines still generate a strong neutralizing response.

The role of T cells in the resolution or exacerbation of COVID-19, as well as their potential to provide long-term protection from reinfection with SARS-CoV-2, remains debated. Nevertheless, recent studies have highlighted various aspects of T cell responses to SARS-CoV-2 infection that are starting to enable some general concepts to emerge.In this Progress article, Zeyu Chen and E. John Wherry summarize early reports of the T cell responses observed in patients with COVID-19, emphasizing how different immune response characteristics in different patients may reflect a spectrum of disease phenotypes.

The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic strategies that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and/or human proteins to control viral infection, encompassing hundreds of potential drugs and thousands of patients in clinical trials. So far, a few small-molecule antiviral drugs (nirmatrelvir–ritonavir, remdesivir and molnupiravir) and 11 monoclonal antibodies have been marketed for the treatment of COVID-19, mostly requiring administration within 10 days of symptom onset. In addition, hospitalized patients with severe or critical COVID-19 may benefit from treatment with previously approved immunomodulatory drugs, including glucocorticoids such as dexamethasone, cytokine antagonists such as tocilizumab and Janus kinase inhibitors such as baricitinib. Here, we summarize progress with COVID-19 drug discovery, based on accumulated findings since the pandemic began and a comprehensive list of clinical and preclinical inhibitors with anti-coronavirus activities. We also discuss the lessons learned from COVID-19 and other infectious diseases with regard to drug repurposing strategies, pan-coronavirus drug targets, in vitro assays and animal models, and platform trial design for the development of therapeutics to tackle COVID-19, long COVID and pathogenic coronaviruses in future outbreaks.Since the COVID-19 pandemic began, many potential therapeutics that target SARS-CoV-2 and/or human proteins to control viral infection have been investigated, with a few receiving authorization by regulatory agencies. This Review article summarizes progress with COVID-19 drug discovery, and discusses the lessons learned about aspects such as drug repurposing, disease models and clinical development strategies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus. The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages. The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. Many are in preclinical and clinical development, and a few have been approved for emergency use. Here we summarize neutralizing antibodies that target four key regions within the SARS-CoV-2 spike (S) protein, namely the N-terminal domain and the receptor-binding domain in the S1 subunit, and the stem helix region and the fusion peptide region in the S2 subunit. Understanding the characteristics of these broadly neutralizing antibodies will accelerate the development of new antibody therapeutics and provide guidance for the rational design of next-generation vaccines.The ancestral strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a number of variants of concern. In this Review, Wang and colleagues discuss progress in the development and characterization of broadly neutralizing antibodies to SARS-CoV-2, which may lead to new antibody therapeutics and inform the design of next-generation vaccines.