Adaptive immunity to SARS-CoV-2 and COVID-19

Authors: Alessandro Sette1,2 and Shane Crotty1,2,* 1Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA
2Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA
92037, USA

SUMMARY
The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections and in vaccines, and thus it is critical to directly study adaptive immunity to SARS-CoV-2 to understand COVID-19. Knowledge is now available on relationships between antigen-specific immune responses and SARS-CoV-2 infection. Although more studies are needed, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both
non-hospitalized and hospitalized cases of COVID-19. The specific functions and kinetics of these adaptive immune responses are discussed, as well as their interplay with innate immunity and implications for COVID19 vaccines and immune memory against re-infection.


INTRODUCTION


Coronavirus disease 2019 (COVID-19), caused by the novel human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Hu et al., 2020), is a serious disease that has resulted in widespread global morbidity and mortality.


Our understanding of SARS-CoV-2 and COVID-19 has rapidly evolved during 2020. As of December 2020, the United States has experienced >300,000 deaths, winter cases are rising exceptionally fast, and the first interim phase 3 vaccine trial results have been reported. The scientific advances in understanding SARS-CoV-2 and COVID-19 have been extraordinarily rapid and broad, by any metric, which is an amazing testament to the commitment, creativity, collaboration, and expertise of the international scientific community, both in academia and industry, under extremely challenging conditions. This article will review our current understanding of the immunology of COVID-19, with a primary focus on adaptive immunity.


The immune system is broadly divided into the innate immune system and the adaptive immune system. Although the adaptive and innate immune systems are linked in important and powerful ways, they each consist of different cell types with different jobs.


The adaptive immune system consists of three major cell types: B cells, CD4+ T cells, and CD8+ T cells (Figure 1). B cells produce antibodies. CD4+ T cells possess a range of helper and effector functionalities. CD8+ T cells kill infected cells. Given that adaptive immune responses are important for the control and clearance of almost all viral infections that cause disease in humans, and adaptive immune responses and immune memory are central to the success of all vaccines, it is critical to understand adaptive responses to SARS-CoV-2.

ONE INTEGRATED MODEL OF IMMUNE RESPONSES TO SARS-CoV-2

This review first presents a working model of immune responses to SARS-CoV-2, to provide an overarching context, and then the review explores individual compartments and immunological facets of adaptive immunity to SARS-CoV-2 in greater detail. Importantly, this is an evolving model and should not be accepted as definitive; instead, it provides a reference point for interpreting much of the available data in the literature and to identify knowledge gaps that may provide directions for future studies.

For More Information: https://www.cell.com/cell/pdfExtended/S0092-8674(21)00007-6

Pre-existing immunity to SARS-CoV-2: the knowns and unknowns

Authors: Alessandro Sette 1 2Shane Crotty 3 4

Abstract

T cell reactivity against SARS-CoV-2 was observed in unexposed people; however, the source and clinical relevance of the reactivity remains unknown. It is speculated that this reflects T cell memory to circulating ‘common cold’ coronaviruses. It will be important to define specificities of these T cells and assess their association with COVID-19 disease severity and vaccine responses.

As data start to accumulate on the detection and characterization of SARS-CoV-2 T cell responses in humans, a surprising finding has been reported: lymphocytes from 20–50% of unexposed donors display significant reactivity to SARS-CoV-2 antigen peptide pools1,2,3,4.

In a study by Grifoni et al.1, reactivity was detected in 50% of donor blood samples obtained in the USA between 2015 and 2018, before SARS-CoV-2 appeared in the human population. T cell reactivity was highest against proteins other than the coronavirus spike protein, but T cell reactivity was also detected against spike. The SARS-CoV-2 T cell reactivity was mostly associated with CD4+ T cells, with a smaller contribution by CD8+ T cells1. Similarly, in a study of blood donors in the Netherlands, Weiskopf et al.2 detected CD4+ T cell reactivity against SARS-CoV-2 spike peptides in 1 of 10 unexposed subjects and against SARS-CoV-2 non-spike peptides in 2 of 10 unexposed subjects. CD8+ T cell reactivity was observed in 1 of 10 unexposed donors. In a third study, from Germany, Braun et al.3 reported positive T cell responses against spike peptides in 34% of SARS-CoV-2 seronegative healthy donors. Finally, a study of individuals in Singapore, by Le Bert et al.4, reported T cell responses to nucleocapsid protein nsp7 or nsp13 in 50% of subjects with no history of SARS, COVID-19, or contact with patients with SARS or COVID-19. A study by Meckiff using samples from the UK also detected reactivity in unexposed subjects5. Taken together, five studies report evidence of pre-existing T cells that recognize SARS-CoV-2 in a significant fraction of people from diverse geographical locations.

These early reports demonstrate that substantial T cell reactivity exists in many unexposed people; nevertheless, data have not yet demonstrated the source of the T cells or whether they are memory T cells. It has been speculated that the SARS-CoV-2-specific T cells in unexposed individuals might originate from memory T cells derived from exposure to ‘common cold’ coronaviruses (CCCs), such as HCoV-OC43, HCoV-HKU1, HCoV-NL63 and HCoV-229E, which widely circulate in the human population and are responsible for mild self-limiting respiratory symptoms. More than 90% of the human population is seropositive for at least three of the CCCs6. Thiel and colleagues3 reported that the T cell reactivity was highest against a pool of SARS-CoV-2 spike peptides that had homology to CCCs.

What are the implications of these observations? The potential for pre-existing crossreactivity against COVID-19 in a fraction of the human population has led to extensive speculation. Pre-existing T cell immunity to SARS-CoV-2 could be relevant because it could influence COVID-19 disease severity. It is plausible that people with a high level of pre-existing memory CD4+ T cells that recognize SARS-CoV-2 could mount a faster and stronger immune response upon exposure to SARS-CoV-2 and thereby limit disease severity. Memory T follicular helper (TFH) CD4+ T cells could potentially facilitate an increased and more rapid neutralizing antibody response against SARS-CoV-2. Memory CD4+ and CD8+ T cells might also facilitate direct antiviral immunity in the lungs and nasopharynx early after exposure, in keeping with our understanding of antiviral CD4+ T cells in lungs against the related SARS-CoV7 and our general understanding of the value of memory CD8+ T cells in protection from viral infections. Large studies in which pre-existing immunity is measured and correlated with prospective infection and disease severity could address the possible role of pre-existing T cell memory against SARS-CoV-2.

For More Information: https://www.nature.com/articles/s41577-020-0389-z

A long-term perspective on immunity to COVID

Determining the duration of protective immunity to infection by SARS-CoV-2 is crucial for understanding and predicting the course of the COVID-19 pandemic. Clinical studies now indicate that immunity will be long-lasting.

Authors: Andreas Radbruch & Hyun-Dong Chang

Generating immunity against the SARS-CoV-2 coronavirus is of the utmost importance for bringing the COVID-19 pandemic under control, protecting vulnerable individuals from severe disease and limiting viral spread. Our immune systems protect against SARS-CoV-2 either through a sophisticated reaction to infection or in response to vaccination. A key question is, how long does this immunity last? Writing in NatureTurner et al.1 and Wang et al.2 characterize human immune responses to SARS-CoV-2 infection over the course of a year.

There is ongoing discussion about which aspects of the immune response to SARS-CoV-2 provide hallmarks of immunity (in other words, correlates of immunological protection). However, there is probably a consensus that the two main pillars of an antiviral response are immune cells called cytotoxic T cells, which can selectively eliminate infected cells, and neutralizing antibodies, a type of antibody that prevents a virus from infecting cells, and that is secreted by immune cells called plasma cells. A third pillar of an effective immune response would be the generation of T helper cells, which are specific for the virus and coordinate the immune reaction. Crucially, these latter cells are required for generating immunological memory — in particular, for orchestrating the emergence of long-lived plasma cells3, which continue to secrete antiviral antibodies even when the virus has gone.

Immunological memory is not a long-lasting version of the immediate immune reaction to a particular virus; rather, it is a distinct aspect of the immune system. In the memory phase of an immune response, B and T cells that are specific for a virus are maintained in a state of dormancy, but are poised to spring into action if they encounter the virus again or a vaccine that represents it. These memory B and T cells arise from cells activated in the initial immune reaction. The cells undergo changes to their chromosomal DNA, termed epigenetic modifications, that enable them to react rapidly to subsequent signs of infection and drive responses geared to eliminating the disease-causing agent4. B cells have a dual role in immunity: they produce antibodies that can recognize viral proteins, and they can present parts of these proteins to specific T cells or develop into plasma cells that secrete antibodies in large quantities. About 25 years ago5, it became evident that plasma cells can become memory cells themselves, and can secrete antibodies for long-lasting protection. Memory plasma cells can be maintained for decades, if not a lifetime, in the bone marrow6.

The presence in the bone marrow of long-lived, antibody-secreting memory plasma cells is probably the best available predictor of long-lasting immunity. For SARS-CoV-2, most studies so far have analyzed the acute phase of the immune response, which spans a few months after infection, and have monitored T cells, B cells and secreted antibodies7. It has remained unclear whether the response generates long-lived memory plasma cells that secrete antibodies against SARS-CoV-2.

For More Information: https://www.nature.com/articles/d41586-021-01557-z

COVID-19 survivors may possess wide-ranging resistance to the disease

Authors: Rajee Suri rajee.suri@emory.edu

Recovered COVID-19 patients retain broad and effective longer-term immunity to the disease, suggests a recent Emory University study, which is the most comprehensive of its kind so far. The findings have implications for expanding understanding about human immune memory as well as future vaccine development for coronaviruses.

The longitudinal study, published recently on Cell Reports Medicine, looked at 254 patients with mostly mild to moderate symptoms of SARS-CoV-2 infection over a period for more than eight months (250 days) and found that their immune response to the virus remained durable and strong.

Emory Vaccine Center director Rafi Ahmed, PhD, and a lead author on the paper, says the findings are reassuring, especially given early reports during the pandemic that protective neutralizing antibodies did not last in COVID-19 patients.

“The study serves as a framework to define and predict long-lived immunity to SARS-CoV-2 after natural infection. We also saw indications in this phase that natural immunity could continue to persist,” Ahmed says. The research team will continue to evaluate this cohort over the next few years.

Researchers found that not only did the immune response increase with disease severity, but also with each decade of age regardless of disease severity, suggesting that there are additional unknown factors influencing age-related differences in COVID-19 responses. 

In following the patients for months, researchers got a more nuanced view of how the immune system responds to COVID-19 infection. The picture that emerges indicates that the body’s defense shield not only produces an array of neutralizing antibodies but activates certain T and B cells to establish immune memory, offering more sustained defenses against reinfection.

“We saw that antibody responses, especially IgG antibodies, were not only durable in the vast majority of patients but decayed at a slower rate than previously estimated, which suggests that patients are generating longer-lived plasma cells that can neutralize the SARS-CoV-2 spike protein.”

For More Information: https://news.emory.edu/stories/2021/07/covid_survivors_resistance/index.html

Adaptive immune responses to SARS-CoV-2 infection in severe versus mild individuals

Authors: Fan ZhangRui GanZiqi ZhenXiaoli HuXiang LiFengxia ZhouYing LiuChuangeng ChenShuangyu XieBailing ZhangXiaoke Wu & Zhiwei Huang Signal Transduction and Targeted Therapy volume 5, Article number: 156 (2020) 

Abstract

The global Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has affected more than eight million people. There is an urgent need to investigate how the adaptive immunity is established in COVID-19 patients. In this study, we profiled adaptive immune cells of PBMCs from recovered COVID-19 patients with varying disease severity using single-cell RNA and TCR/BCR V(D)J sequencing. The sequencing data revealed SARS-CoV-2-specific shuffling of adaptive immune repertories and COVID-19-induced remodeling of peripheral lymphocytes. Characterization of variations in the peripheral T and B cells from the COVID-19 patients revealed a positive correlation of humoral immune response and T-cell immune memory with disease severity. Sequencing and functional data revealed SARS-CoV-2-specific T-cell immune memory in the convalescent COVID-19 patients. Furthermore, we also identified novel antigens that are responsive in the convalescent patients. Altogether, our study reveals adaptive immune repertories underlying pathogenesis and recovery in severe versus mild COVID-19 patients, providing valuable information for potential vaccine and therapeutic development against SARS-CoV-2 infection.

Introduction

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised a global health emergency. Worldwide studies have contributed to the characterization, diagnosis, and treatment of the disease.1,2,3,4 However, the pathogenesis of SARS-CoV-2 infection in humans remains unclear. Previous studies on severe acute respiratory syndrome (SARS),5 Middle East respiratory syndrome,6 and influenza7 demonstrated that immune changes, especially those in peripheral blood lymphocyte subsets, play a critical role in defense against coronavirus infections. Consistently, several studies of COVID-19 patients showed that both humoral and cellular immunity are involved in the pathogenesis of COVID-19.8,9,10 Although most COVID-19 patients presented mild-to-moderate symptoms, some infected individuals did develop severe or critical outcomes. However, the immunological features associated with the disease severity remains largely unknown. In addition, earlier studies on the recovery of SARS patients have shown that complete restoration of peripheral lymphocyte may require a longer period.11 Thus, studies of the immune system of convalescent COVID-19 patients will facilitate understanding of their recovery state and establish the relationship between adaptive immune responses and disease severity if it exists.

For More Information: https://www.nature.com/articles/s41392-020-00263-y

Adaptive immunity to SARS-CoV-2 and COVID-19

Authors: Alessandro Sette1,2 and Shane Crotty1,2,∗

Abstract

The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections and in vaccines, and thus it is critical to directly study adaptive immunity to SARS-CoV-2 to understand COVID-19. Knowledge is now available on relationships between antigen-specific immune responses and SARS-CoV-2 infection. Although more studies are needed, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19. The specific functions and kinetics of these adaptive immune responses are discussed, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.

Introduction

Coronavirus disease 2019 (COVID-19), caused by the novel human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Hu et al., 2020), is a serious disease that has resulted in widespread global morbidity and mortality. Our understanding of SARS-CoV-2 and COVID-19 has rapidly evolved during 2020. As of December 2020, the United States has experienced >300,000 deaths, winter cases are rising exceptionally fast, and the first interim phase 3 vaccine trial results have been reported. The scientific advances in understanding SARS-CoV-2 and COVID-19 have been extraordinarily rapid and broad, by any metric, which is an amazing testament to the commitment, creativity, collaboration, and expertise of the international scientific community, both in academia and industry, under extremely challenging conditions. This article will review our current understanding of the immunology of COVID-19, with a primary focus on adaptive immunity.

The immune system is broadly divided into the innate immune system and the adaptive immune system. Although the adaptive and innate immune systems are linked in important and powerful ways, they each consist of different cell types with different jobs. The adaptive immune system consists of three major cell types: B cells, CD4+ T cells, and CD8+ T cells (Figure 1 ). B cells produce antibodies. CD4+ T cells possess a range of helper and effector functionalities. CD8+ T cells kill infected cells. Given that adaptive immune responses are important for the control and clearance of almost all viral infections that cause disease in humans, and adaptive immune responses and immune memory are central to the success of all vaccines, it is critical to understand adaptive responses to SARS-CoV-2.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803150/

Adaptive immunity to SARS-CoV-2 and COVID-19

Authors: Alessandro Sette 1Shane Crotty 2

Abstract

The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections and in vaccines, and thus it is critical to directly study adaptive immunity to SARS-CoV-2 to understand COVID-19. Knowledge is now available on relationships between antigen-specific immune responses and SARS-CoV-2 infection. Although more studies are needed, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19. The specific functions and kinetics of these adaptive immune responses are discussed, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.

For More Information: https://pubmed.ncbi.nlm.nih.gov/33497610/

Walking down the memory lane with SARS-CoV-2 B cells

Authors: Natalia T FreundMotti GerlicBen A Croker

The end of the coronavirus disease 2019 (COVID-19) pandemic is in sight. We have scientists to thank for that. However, while years of meticulous research by vaccinologists, molecular biologists and immunologists provided the framework for rapid deployment of vaccines, we are still learning what constitutes an effective lifelong immune response to pathogens. A more detailed understanding of human B-cell development and the nature of the antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or immunization may aid vaccine development for known pathogens and further reduce vaccine development times in the event of future pandemics.

Neutralizing antibodies are produced upon infection with SARS-CoV-2,12 but the transition to lifelong immunity awaits ongoing studies, and is of central importance to ending COVID-19. Immunological memory is the pillar by which vaccines offer education to our immune system to protect us from future exposure to pathogens, yet the nature and length of this memory vary. Some natural infections and vaccines provide a lifelong lesson to the immune system, thereby enabling it to “remember” pathogens and antigens for decades, while in other cases the immune system “forgets” the exposure, leading to a waning immune response over months to years. With the advent of vaccines against SARS-CoV-2, along with the emergence of variants of concern, understanding the nature and duration of protective immunity is key to SARS-CoV-2 eradication or, at least, minimalization of severe infections leading to hospitalization and death.

To study long-term immunity to SARS-CoV-2 infection and vaccination, Wang et al.3 have investigated memory B-cell responses to SARS-CoV-2 for a 12-month period in convalescent individuals, some of whom received a COVID-19 messenger RNA (mRNA) vaccine. SARS-CoV-2 convalescent individuals are advised to receive one dose, and in some countries two doses, of a COVID-19 vaccine to increase titers of SARS-CoV-2 antibodies to a level considered effective at virus neutralization. This recent study enables a longitudinal comparison of the natural B-cell response with infection, with and without a supplemental COVID-19 vaccine.

For More Information: https://onlinelibrary.wiley.com/doi/10.1111/imcb.12494

Not just antibodies: B cells and T cells mediate immunity to COVID-19

Authors: Rebecca J. Cox & Karl A. Brokstad Nature Reviews Immunology volume 20, pages581–582 (2020)

Recent reports that antibodies to SARS-CoV-2 are not maintained in the serum following recovery from the virus have caused alarm. However, the absence of specific antibodies in the serum does not necessarily mean an absence of immune memory. Here, we discuss our current understanding of the relative contribution of B cells and T cells to immunity to SARS-CoV-2 and the implications for the development of effective treatments and vaccines for COVID-19.

COVID-19 is caused by infection with SARS-CoV-2, which is a member of the coronavirus family. There are currently four human coronaviruses (HCoVs) that cause respiratory infections or the ‘common cold’ (namely, 229E, NL63, OC43 and HKU1), as well as three coronaviruses that have arisen through zoonosis and cause severe diseases in humans, namely, SARS-CoV, MERS-CoV and SARS-CoV-2, which emerged in 2003, 2012 and 2019, respectively. Immunity after infection with the coronaviruses may last from months to several years1. Interestingly, cross-reactive immune responses to HCoVs may be boosted after severe infection; 12 of 20 patients infected with SARS-CoV had at least fourfold increases in IgG that cross-reacted with OC43 and/or 229E HCoVs2. It is still unclear how long immunity to SARS-CoV-2 lasts after recovery from infection. A recent report suggesting that antibodies to the virus may only be maintained for 2 months has caused speculation that ‘immunity’ to the virus may not be long lived3. Similarly, a rapid decline in antibodies was reported in mild cases4, although with a half-life of approximately 21 days for IgG we would expect this decrease. It is important to remember that memory B cells and T cells may be maintained even if there are not measurable levels of serum antibodies. Below, we outline our current understanding of B cell and T cell immunity to SARS-CoV-2 and potential immune correlates of protection that could inform vaccine efficacy studies 

For More Information: https://www.nature.com/articles/s41577-020-00436-4

COVID-19 progression linked to B cell activation

Authors: By Dr. Liji Thomas, MD

The disease course of COVID-19 is diverse, ranging from asymptomatic to fatal respiratory failure. Emory University scientists have been working to uncover the immunological reasons behind this heterogeneity. A recent study on B cells, published on the preprint server medRxiv* in April 2020, shows that extrafollicular B cells could be a marker of severe infection in the early stages, predicting the need for earlier immunomodulatory therapy.

B cells (B lymphocytes) in the blood are involved in early effector responses via the production of protective antibodies, as well as in initiating the production of memory cells. Among the former class of responses, B cells take part in the extrafollicular (EF) pathway that is also active in systemic lupus erythematosus (SLE) flareups.

The EF pathway is associated with peripheral inflammation, and a high level of proinflammatory cytokines interleukin 6 (IL-6) and interferon gamma-induced protein 10 (IP-10), both of which are associated with poor outcomes.

This is triggered by newly activated naïve B cells, resulting in a large number of antibody-secreting cells (ASCs) that produce a large concentration of autoantibodies. These ASCs come from the expansion of a B cell precursor that has been epigenetically primed, and which lacks naïve IgD and memory CD27 markers, making them double negative (DN). They also fail to express CXCR5 and CD21 markers, so that they are termed DN2.

These very active cells express CD11c and T-bet molecular markers at high levels and respond to stimulation of Toll-like receptors (TLR7) by single-stranded RNA (ssRNA). TLR7 is essential in clearing viruses from infected cells.

As a result, researchers consider DN2 cells taking part in the EF pathway to be a significant part of the COVID-19 illness. Supporting evidence comes from the association of EF pathway B cell activity in SLE, in African-Americans, who also have a high reported incidence of severe COVID-19 cases.

This finding is in contradiction to earlier studies of vaccinated patients who show better protection with higher numbers of ASCs. Instead, in critically ill patients with COVID-19, higher ASC generation and maturation counts predict a poor outcome.

For More Information: https://www.news-medical.net/news/20200504/COVID-19-progression-linked-to-B-cell-activation.aspx