Immunology of COVID-19

Although extraordinary scientific progress has been made, emerging challenges mean that the struggle against SARS-CoV-2 continues

In this Perspective, Spaan and colleagues propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection.

In part of a series of commissioned pieces on coronavirus disease 2019 (COVID-19), Sekaly and colleagues discuss COVID-19 vaccine progress, the underlying biology and prospects for the future.

Kanneganti and Diamond review the key role played by innate immunity in the control and immunopathology of COVID-19.

Children are generally resistant to severe disease resulting from SARS-CoV-2 infection, but cases of pediatric COVID-19 and a new syndrome called MIS-C can occur. In this Review, the authors summarize what is known about the immunology of COVID-19 and MIS-C and how the pediatric response to SARS-CoV-2 is different from the immune response in adults.

Paul Moss reviews the current knowledge of T cell immunity in the control of SARS-CoV-2.

It is increasingly obvious that individuals are experiencing post-COVID-19 syndromes, or ‘long-haul COVID’. Here, Merad and Mehandru eview currently available knowledge of the underlying pathophysiological mechanisms of these sequelae, elaborating on persistent inflammation, induced autoimmunity and putative viral reservoirs.

Qi et al. provide an in-depth analysis of antibody responses generated in response to SARS-CoV-2.

Blish and Lee review the response of natural killer cells to SARS-CoV-2 infection.

Proal and colleagues review the evidence for long-term persistence of coronavirus SARS-CoV-2 in tissues of infected individuals and discuss how this viral reservoir may contribute to the pathogenesis of post-acute sequelae of COVID-19 (PASC).

In the midst of resurging COVID-19 cases, the second NIH/FDA virtual COVID-19 and Cytokines symposium was held on 1 December 2020, focusing on longitudinal studies of COVID-19 immunity, including long-term consequences, potential associations with autoimmunity and the multisystem inflammatory syndrome in children (MIS-C).

SARS-CoV-2-specific CD4⁺ and CD8⁺ T cell epitopes are found in both convalescent patients and virus-naive volunteers and are indicative of heterologous recognition shared with seasonal cold viruses.

Questions have arisen as to whether patients with severe COVID-19 disease can generate a T cell response against SARS-CoV-2. Tao Dong and colleagues report that convalescent patients with COVID-19 harbor functional memory CD4⁺ and CD8⁺ T cells that recognize multiple epitopes that span the viral proteome. CD4⁺ T cells predominated the memory response in patients with severe disease, whereas higher proportions of CD8⁺ T cells were found in patients with mild disease.

Severe COVID-19 is characterized—among other things—by a hyperinflammatory state. Wang and colleagues describe the single-cell transcriptional landscape of moderate, severe and convalescent cases of patients with COVID-19.

Sanz and colleagues examine B cell subsets in a cohort of patients with COVID-19. Severely ill patients have higher frequencies of activated extrafollicular T-bet⁺ B cells that form antibody-secreting cells, the majority of which express germline sequences and are reminiscent of antibody responses observed in patients with systemic lupus erythematosus during flares.

Farber and colleagues report distinct antibody responses to SARS-CoV-2 in pediatric cohorts, including those who developed multisystem inflammatory syndrome (MIS-C), and adult COVID-19 cohorts.

Diamond and colleagues generate a K18-hACE2 model of SARS-CoV-2 infection that shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.

COVID-19 is often characterized by a hyperinflammatory syndrome. Wang and colleagues show that low levels of IgG fucosylation enhance interactions with activating Fcγ receptors, boosting the inflammatory cytokines associated with severe COVID-19.

Andreakos and colleagues provide a longitudinal study comparing patients with COVID-19 to patients infected with influenza. They report a dysregulated interferon response whereby IFN-λ and type I IFN production were diminished and delayed in patients with COVID-19, exhibiting a response that is ‘untuned’ with other inflammatory cytokines.

Geisbert and colleagues report that African green monkeys infected with the SARS-CoV-2 virus develop disease symptoms that closely resemble those seen in infected humans, making this animal model a useful surrogate to investigate immune responses to coronavirus infection.

Mucosal surfaces of the respiratory tract are the first sites of entry and defense against SARS-CoV-2. Di Santo and colleagues perform paired analysis of the nasopharyngeal and systemic immune responses of SARS-CoV-2-infected patients and demonstrate distinct compartmentalization of immunity and shifts in the microbiome.

The innate sensors of SARS-CoV-2 are still being determined. Kanneganti and colleagues find that SARS-CoV-2 envelope protein is sensed by TLR2 and this drives pathogenic inflammatory cytokine production.

The antiviral factor ISG15 can be conjugated to other proteins through ISGylation. Sanyal and colleagues find that viruses can modulate ISGylation, which in turn alters macrophage responses and can result in exaggerated inflammation in COVID-19.

During homeostasis T_H1 cells activate a cell-intrinsic inflammatory shutdown program and shift to IL-10 production. Chauss et al. find that this T_H1 homeostatic program is dependent on vitamin D signaling and is disrupted in severe COVID-19.

SARS-CoV-2 infection is milder in children, but direct comparison with adults is rare. Here the authors show that immune responses are higher in children, retained for 12 months or longer and can neutralize Alpha, Beta and Delta variants.

Severe COVID-19 is characterized by hyperinflammation, and there is a need for accurate predictive biomarkers of progression. Lehuen et al. demonstrate that patients with severe COVID-19 show a dramatic loss of MAIT cells, and those that do remain are in a highly activated state.

The immunological processes occurring in the upper respiratory tract during COVID-19 are relatively poorly understood. Jochems and colleagues observe durable changes in the upper respiratory tract following SARS-CoV-2 infection, including evidence of virus-specific tissue memory T cells.

Peng et al. find that immunodominant cytotoxic T lymphocytes (CTLs) specific for NP_105–113-B*07:02 are associated with reduced COVID-19 severity. Mechanistically, NP_105–113-B*07:02-specific CTLs show potent antiviral functionality and may represent rational T cell vaccine targets.

The contribution of T cells to the SARS-CoV-2 response remains an important and unresolved question. Moss and colleagues examine T cell and antibody kinetics in a large cohort of patients with COVID-19 and find robust and durable T cell responses.

Accurate serology testing is urgently needed to help diagnose SARS-CoV-2 infection. Here Valkenburg and colleagues use a luciferase immunoprecipitation system to assess the antibody responses to 15 different SARS-CoV-2 antigens in patients with COVID-19 and find ORF8 and ORF3b antibodies, taken together as a cluster of points, identified 96.5% of COVID-19 samples at early and late time points of disease with 99.5% specificity

Phetsouphanh and colleagues show that individuals with long COVID have persistent activation of the innate and adaptive immune system at 8 months after infection and define a set of analytes associated with long COVID.

RNA vaccines have been associated with high reactogenicity. Mellman and colleagues demonstrate that lipid-formulated RNA vaccines trigger IL-1 production and inflammation in humans but this pathway is dampened in mice.

Stravalaci et al. examined recognition of SARS-CoV-2 by human soluble innate pattern recognition receptor. They report that pentraxin 3 and mannose-binding protein recognize viral nucleoprotein and spike, respectively. Mannose-binding lectin has antiviral activity, and human genetic polymorphisms of MBL2 are associated with more severe COVID-19.

Delaying a second COVID-19 vaccine dose is a common strategy to maximize vaccine coverage, but the immunological effects are unclear. Hall et al. demonstrate that a delayed second dose significantly enhances neutralizing humoral immunity.

Around the world, governments are urging populations to receive a third COVID-19 vaccine dose. Here, the authors compare immunogenicity, reactogenicity and effectiveness of a third dose versus the second dose of the BNT162b2 vaccine in a large group of healthcare workers in Israel.

Robbiani and colleagues show that antibodies against specific chemokines are detected in COVID-19 convalescents and may modulate the inflammatory response and disease outcome.