COVID-19 Watch

SARS-CoV-2 infection can lead to a diverse array of chronic symptoms, collectively termed ‘long COVID’. In this Review, Altmann and colleagues explore current thinking about the pathophysiology of long COVID and discuss potential immunological mechanisms.

In this Perspective, Francis Carbone considers the unique characteristics of the tissue-resident memory T (T_RM) cell populations that develop in the lungs. He discusses how the different properties of lung T_RM cells may affect immunity to lung infections, including SARS-CoV-2.

In addition to antibody-mediated neutralization, Fc-dependent effector functions of antibodies directed to SARS-CoV-2 are emerging as an important factor in determining the outcome of infection. This Review highlights the current state of the field and discusses remaining uncertainties regarding Fc-dependent, non-neutralizing functions of antibodies.

This Review discusses the evidence for pre-existing cross-reactive immune responses to SARS-CoV-2, which are mainly due to infections with common cold coronaviruses, and how such cross-reactivity affects adaptive immune responses. Furthermore, it explores cross-reactivity in the context of SARS-CoV-2 variants of concern and its implications for vaccine development.

Many viruses, including SARS-CoV-2, can induce cellular senescence and exacerbate the senescence-associated secretory phenotype, leading to detrimental hyperinflammatory responses. Here, Schmitt and colleagues discuss the role of cellular senescence in COVID-19 as well as progress in the development of therapeutic approaches to eliminate senescent cells.

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.

Here, the authors consider our emerging understanding of COVID-19-associated coagulopathy. They focus on the complex interactions between innate immune, coagulation and fibrinolytic pathways that can lead to potentially life-threatening thrombosis following SARS-CoV-2 infection.

In this Progress article, Male summarizes our current understanding of the risks associated with SARS-CoV-2 infection in pregnancy. Importantly, the article highlights the now substantial body of evidence supporting the safety and efficacy of COVID-19 vaccination in pregnancy.

Hyperactivation of the complement system has been implicated in the pathology of COVID-19. Here the authors bring together the latest information on the role of complement in COVID-19 and progress in targeting complement components for treatment of severe disease.

Here, Lipsitch and colleagues assess the impact of breakthrough SARS-CoV-2 infections that occur in individuals who have been vaccinated against COVID-19. The authors explain how the rate of breakthrough infections can be measured, what the causes of these infections are and discuss other key questions that need to be considered in light of these infections.

In this Review, Brian Laidlaw and Ali Ellebedy outline our current understanding of the germinal centre response in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its importance for establishing protective immunity against the virus. They also consider the germinal centre responses seen following vaccination and how germinal centre responses may be modulated to induce broad protection against new variants of SARS-CoV-2.

In this Perspective, Lok-Yin Roy Wong and Stanley Perlman consider how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses are able to drive immune dysregulation and immunopathology. They provide an overview of the coronavirus-derived molecules that interfere with key innate immune responses, including interferon pathways and complement, NF-κB signalling and inflammasome activation, as well as with the activation of host adaptive immunity.

Individuals with asymptomatic COVID-19 can transmit the virus and may be at risk of long-term disease. In this Progress article, Boyton and Altman present current insights into immune responses in asymptomatic SARS-CoV-2 infection and discuss the relevance of asymptomatic disease for public health strategies.

This Progress article provides an update on the COVID-19 vaccine effort in the light of ongoing vaccine efficacy studies and real-world data on vaccine effectiveness, including the impact of virus variants of concern and challenges for global deployment.

This Progress article brings us up to date on the role of inflammasomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19, describing how they may be activated during infection and contribute to the overexuberant inflammatory response in severe disease, and the efforts being taken to target them therapeutically.

This Progress article summarizes our current understanding of the immune mechanisms of protection induced by the available COVID-19 vaccines. The authors compare vaccine-induced antibody responses following one or two doses of different vaccines and consider the relative importance of neutralizing antibodies for vaccine-mediated protection against SARS-CoV-2.

Emerging diseases that affect humans often arise due to the crossover of infectious agents from animal reservoirs. In this Perspective, George Warimwe and colleagues discuss the concept of ‘One Health vaccinology’, an approach that aims to use key lessons from human and veterinary immunology to develop more effective vaccination strategies for emerging infectious diseases.

The duration of immunity to coronavirus disease 2019 (COVID-19) from prior infection and longer-term risk of reinfection are currently unclear. Cromer and colleagues discuss the immune control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the implications of this for the future control of the pandemic.

Peter Taylor and colleagues provide an overview of the neutralizing monoclonal antibody therapies that have been developed to target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and discuss the clinical utility of these antibodies.

Here, the authors propose that SARS-CoV-2 induces a prothrombotic state, with dysregulated immunothrombosis in lung microvessels and endothelial injury, which drive the clinical manifestations of severe COVID-19. They discuss potential antithrombotic and immunomodulating drugs that are being considered in the treatment of patients with COVID-19.

In this Perspective, Cobey, Larremore, Grad and Lipsitch argue that dose-sparing regimens of COVID-19 vaccines can reduce disease incidence, prevalence and burden and explain why they think that such strategies would also slow the rate of viral escape from vaccine or naturally induced immunity.

A timeline of the major scientific discoveries during the first year of the COVID-19 pandemic showcases the collaborative efforts that enabled the key aspects of the immune response to SARS-CoV-2 to be reported at unprecedented speed.

This Review, aimed at a broad scientific audience, provides an introductory guide to the history, development and immunological basis of vaccines, immunization and related issues to provide insight into the challenges facing immunologists who are designing the next generation of vaccines.

As the world races to develop vaccines against SARS-CoV-2, Dai and Gao highlight which viral targets are best to include in a vaccine and how this impacts the induced immune response and, ultimately, the safety and efficacy of a vaccine.

In this Perspective, Alon and colleagues discuss how insights into immune cell trafficking during pneumotropic influenza virus infections may inform our understanding of immune cell recruitment to the respiratory tract in patients with coronavirus disease 2019 (COVID-19). Moreover, they examine the emerging knowledge of vascular pathologies beyond the lung caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Are you new to virus research and trying to interpret the ever-expanding literature on immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)? Here, the authors compare the different assays and animal models used to measure immunity to SARS-CoV-2 infection and reconcile differences in apparent potency of antibodies assessed in different assays.

How does the discovery of SARS-CoV-2 cross-reactive T cells in unexposed individuals change our understanding of the COVID-19 pandemic? In this Perspective, the authors provide a thought experiment to explain why the discovery of cross-reactive T cells may affect disease severity in individuals, but is unlikely to change our estimate of the herd immunity threshold.

This Review outlines the guiding immunological principles for the design of coronavirus disease 2019 (COVID-19) vaccine strategies and analyses the current COVID-19 vaccine landscape and the challenges ahead.

Antibody-dependent enhancement (ADE) has been described as a mechanism that contributes to the pathogenesis of dengue virus infection. Limited evidence also suggests that it can also occur in other viral infections. Here, the authors explore the history of the ADE phenomenon, discuss the diversity of Fc effector functions and consider its potential relevance in the context of SARS-CoV-2 infection.

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.

Recombinant granulocyte–macrophage colony-stimulating factor (GM-CSF) as well as antibodies targeted at GM-CSF or its receptor are being tested in clinical trials for coronavirus disease 2019 (COVID-19). This Perspective introduces the pleiotropic functions of GM-CSF and explores the rationale behind these different approaches.

Why are males more susceptible to severe COVID-19 than females? In this Perspective, Sabra Klein and colleagues consider the sex differences in the immune system that may contribute to this sex bias.

This Progress article from Merad and Martin examines our current understanding of the excessive inflammatory responses seen in patients with severe COVID-19. The authors focus on the emerging pathological roles of monocytes and macrophages and discuss the inflammatory pathways that are currently being targeted in the clinic.

In the short time since SARS-CoV-2 infections emerged in humans, much has been learned about the immunological processes that underlie the clinical manifestation of COVID-19. Here, the authors provide an overview of the pathophysiology of SARS-CoV-2 infection and discuss potential therapeutic approaches.

Here a group of leaders in the field define our current understanding of ‘trained immunity’, which refers to the memory-type responses that occur in the innate immune system. The authors discuss our current understanding of the key epigenetic and metabolic processes involved in trained immunity and consider its relevance in immune-mediated diseases and cancer.

Hybrid immunity occurs in those who have been both infected with and vaccinated against SARS-CoV-2. But how well does such hybrid immunity protect against the virus and its emerging variants?

In the time of the COVID-19 pandemic, anti-vaccine activism in the USA accelerated, amplified and formed an alliance with political groups and even extremists. An organized, well-funded and empowered anti-science movement now threatens to spill over and threaten all childhood immunizations in the USA and globally.

Vitamin D has received much interest during the COVID-19 pandemic as a potential prophylactic or therapeutic agent — but do the available data support its use?

In early 2022, staff from the NIAID at the NIH organized a workshop focusing on the innate immune response to SARS-CoV-2. In this Viewpoint article, some of the organizers and invited speakers share their thoughts on key outcomes of this meeting.

Among the multi-organ complications of Long COVID, those associated with cardiometabolic syndrome were some of the most prevalent in recent studies of population-scale data. Given the potential health and economic burdens, there is an urgent need to better define the inflammatory processes involved.

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?

COVID-19 is associated with an unexpectedly high prevalence of arrhythmic events. In this Comment, Lazzerini et al. discuss how systemic inflammation is linked to cardiac arrhythmias.

In this Comment article, Gregory Poland and Richard Kennedy outline the importance of continued funding and infrastructure support for research into vaccine safety to inform public health decisions and increase public trust in new vaccine technologies.

In this Comment article, Nisreen Alwan discusses what her experience as both a public health academic and a person living with Long COVID has taught her about the importance of including those with lived experience of a condition in setting the research agenda.

Mathematical models have been used to guide strategies for COVID-19 vaccine distribution. But with the emergence of new SARS-CoV-2 variants and waning immunity, how should vaccine distribution be prioritized?

At the population level we are seeing milder disease during the Omicron wave of the SARS-CoV-2 pandemic. Is this due to the virus or pre-existing immunity, and what should we expect next?

Here, John Kelton and colleagues provide an overview of vaccine-induced immune thrombotic thrombocytopenia (VITT), a very rare complication that has been observed following vaccination with adenoviral vector-based COVID-19 vaccines.

Muhammad Suleman Rana and colleagues from the National Institute of Health in Pakistan discuss the urgent need to implement catch-up vaccination programmes for measles and polio to prevent resurgence of these deadly diseases.

This Comment article proposes that T cell-oriented vaccine strategies should be considered to control the COVID-19 pandemic in the longer term, given declining levels of neutralizing antibodies with time after vaccination or infection and the emergence of viral escape variants.

It took roughly 1 year for a COVID-19 vaccine to become available, yet, four decades after the first patient with HIV was described, we do not yet have a vaccine for HIV. Here, Barton Haynes examines the biological reasons why vaccine development for HIV is so exceptionally challenging.

In this Comment article, Sofonias Tessema and John Nkengasong provide an overview of the current state of the COVID-19 pandemic in Africa and the challenges posed by the triple burden of emerging, endemic and non-communicable diseases.

Immunology has illuminated the darkness of the COVID-19 pandemic — but what has been the impact of the pandemic on the immunology community?

This Comment discusses how the emerging SARS-CoV-2 variants of concern could impact on the hopes of long-term pandemic control through vaccination and the mutations that might be relevant to the design of modified vaccines.

The identification of elevated IL-6 levels in patients with severe COVID-19 led to the rapid development of clinical trials targeting this cytokine. Overall, these trials do not support the widespread use of IL-6 antagonists in hospitalized patients with mild-to-moderate disease, but IL-6 antagonists may be beneficial when rapidly deployed in patients with severe COVID-19, as we discuss here.

Preliminary data from Israel demonstrate real-life effectiveness of their COVID-19 vaccination campaign and provide insights that could inform rollout in other countries.

This Comment outlines how the recently licensed vaccines for COVID-19 activate innate immune mechanisms to promote immune memory to SARS-CoV-2. The authors also consider future challenges that could limit vaccine efficacy.

Reassuring data from accidental pregnancies that have occurred in the clinical trials of approved COVID-19 vaccines indicate that vaccination does not harm fertility or increase the rate of miscarriage.

Somewhat surprisingly, individuals with asthma do not seem to have a greater risk of developing severe COVID-19. Here, the authors offer mechanistic insights to explain the epidemiological data.

In this World View article, eminent immunologist Peter Doherty suggests that we should consider the COVID-19 crisis as a training run for future, potentially worse pandemics and organize accordingly.

Here, Veldhoen and Simas discuss why immunity to SARS-CoV-2 in populations may ultimately be driven by the endemic presence of the virus and not rely on continued mass vaccination programmes.

In this Comment article, Sandy Douglas and Adrian Hill discuss the immunological considerations associated with a risk–benefit analysis for controlled human infection models of SARS-CoV-2.

Neurological symptoms are increasingly being observed in patients with COVID-19; this Comment article considers whether cross-reactive antibodies might contribute to the pathology associated with SARS-CoV-2 infection.

This Web Watch introduces the VaC tracker, a web resource that features an overview of the COVID-19 ‘vaccine landscape’, a clinical trials database and a ‘living review’ that distils the results of vaccine trials as they become available.

For this Viewpoint, Nature Reviews Immunology asked the presidents of 16 immunology societies from around the world to discuss how their society and its members responded to the COVID-19 pandemic. Their answers highlight the incredible contributions that immunologists around the globe have made following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

During the current COVID-19 pandemic, the concept of herd immunity has become a topic of much debate. This Comment examines the factors that determine it, discusses how far we have come and considers what it will take to reach herd immunity safely.

Here, Cox and Brokstad briefly discuss T cell- and B cell-mediated immunity to SARS-CoV-2, stressing that a lack of serum antibodies does not necessarily equate with a lack of immunity to the virus.

In this Comment, Jeong Seok Lee and Eui-Cheol Shin discuss contradictory results regarding the downregulation or upregulation of type I interferon responses in patients with COVID-19 and the implications for therapies that target this pathway.

The corticosteroid dexamethasome has been shown to reduce mortality in patients hospitalized with COVID-19 who require mechanical ventilation. Here, the authors describe how this immunosuppressive drug might work.

In this Comment article, Becker and colleagues consider how the excessive release of reactive oxygen species by neutrophils may perpetuate red blood cell dysfunction, thrombosis and tissue damage in severe cases of COVID-19.

Recent studies have shown T cell reactivity to SARS-CoV-2 in 20–50% of unexposed individuals; it is speculated that this is due to T cell memory to common cold coronaviruses. Here, Crotty and Sette discuss the potential implications of these findings for disease severity, herd immunity and vaccine development.

In this Comment, Heidi Larson discusses the COVID-19 ‘infodemic’ and suggests the ways in which scientists can help to mitigate the spread of misinformation.

Why do some young and previously healthy individuals develop severe COVID-19? In this Comment, Casanova and colleagues suggest that monogenic inborn errors of immunity may be responsible based on lessons from other viral infections.

Rebecca Chandler from the Uppsala Monitoring Centre discusses how the COVID-19 pandemic could be the catalyst that propels vaccine safety surveillance into the twenty-first century.

In this Comment, Anne Rowley discusses what we know so far about the recently described multisystem inflammatory syndrome in older children associated with SARS-CoV-2 infection and how it differs from Kawasaki disease.

In this Comment, Jonathan Abraham highlights the potential of passive immunization strategies for COVID-19.

Beyond neutralization, antibodies have immune-modulating functions that can be protective but, in some cases, can enhance pathology. Understanding these functions is critical for the development of safe vaccines and antibody therapies for COVID-19.

Here, Peter Hotez and colleagues discuss the advantages of using an aluminium-based adjuvant in candidate COVID-19 vaccines.

In this Comment, Greg Lemke and Gregg Silverman propose that the excessive blood clotting and immune activation seen in severe COVID-19 may be mechanistically linked through protein S, a ligand for the immunosuppressive TAM receptor family.

In this Viewpoint article, members of the Optimmunize consortium discuss the evidence for non-specific and sex-differential effects of vaccines and how this information might inform vaccine design and policy, including in relation to the COVID-19 pandemic.

In this Comment, Michaela Gack and colleagues discuss how the dysregulation of type I interferon responses may contribute to COVID-19 pathology.

Here, Carmeliet and colleagues discuss the role of endothelial cells in inflammation and viral infection and propose novel therapeutic strategies for COVID-19.

Could the BCG vaccine be used to bridge the gap until a specific COVID-19 vaccine is developed? Luke O’Neill and Mihai Netea discuss the science behind this approach.

Levels of the cytokine IL-17 positively correlate with disease severity in COVID-19. Here, the authors argue that existing anti-IL-17 therapies should be considered for the treatment of severe COVID-19.

Helminth co-infections can skew systemic immunity towards type 2 responses. Here, Bradbury and colleagues consider how this may impact the severity of COVID-19 in helminth-endemic regions.

Here, Hotez and colleagues highlight the two ‘faces’ of immune enhancement that could impact COVID-19 vaccine design.

This Comment article from Lambris and colleagues considers the therapeutic potential of targeting the complement system in patients with COVID-19.

This Comment article from the Precision Immunology Institute at the Icahn School of Medicine (PrIISM), New York, describes their efforts to provide critical reviews of COVID-19 articles posted daily on the preprint servers bioRxiv and medRxiv.

Here, Iwasaki and Yang highlight the potential dangers of inducing suboptimal antibody responses to SARS-CoV-2. They stress the need for proper safety evaluation of candidate vaccines for COVID-19.

Immune-mediated inflammatory diseases are often treated with cytokine blocking therapy. This comment discusses whether such therapies may pose a risk — or even a benefit — in the context of the current COVID-19 pandemic.

In the short time since SARS-CoV2 emerged, much has been learned about the immunopathology of the infection. Here, Xuetao Cao discusses what these early insights imply for drug discovery and clinical management.

Three recent preprints investigate the entry route of SARS-CoV-2 Omicron variant into host cells and its cellular and host tropism.

A preprint by Tarke et al. suggests a neglible impact of SARS-CoV-2 variant mutations on T cell reactivity in convalescent individuals and mRNA vaccine recipients.

This preprint further characterizes a superantigen motif identified in SARS-CoV-2 spike protein and evaluates a monoclonal antibody targeting this region that can neutralize live virus.

Here, the authors consider our emerging understanding of COVID-19-associated coagulopathy. They focus on the complex interactions between innate immune, coagulation and fibrinolytic pathways that can lead to potentially life-threatening thrombosis following SARS-CoV-2 infection.

Less than a month after the sequence of the SARS-CoV-2 Omicron variant was first announced, a number of articles in Nature and Cell examine its immune evasion characteristics.

This study links the complement-mediated retraction of T helper 1 cell responses to vitamin D receptor signalling, an autoregulatory loop that might be impaired in patients with COVID-19.

Two studies provide detailed insight into SARS-CoV-2 pathology at the single-cell level.

The currently licensed mRNA vaccines for SARS-CoV-2 can elicit cross-neutralizing antibodies against B.1.351 variants of the virus, but are less potent against these variants.

Two studies from the Oxford COVID-19 vaccine team describe the immune responses that develop in healthy adults following a single dose or two doses of their adenovirus vector-based COVID-19 vaccine.