Advances in understanding the formation and fate of B-cell memory in response to immunisation or infection

Immunological memory has the potential to provide lifelong protection against recurrent infections. As such, it has been crucial to the success of vaccines. Yet, the recent pandemic has illuminated key gaps in our knowledge related to the factors influencing effective memory formation and the inability to predict the longevity of immune protection. In recent decades, researchers have acquired a number of novel and powerful tools with which to study the factors underpinning humoral memory. These tools have been used to study the B-cell fate decisions that occur within the germinal centre, a site where responding B-cells undergo affinity maturation and is one of the major routes for memory B-cell and high-affinity long-lived plasma cell formation. The advent of single-cell sequencing technology has provided an enhanced resolution for studying fate decisions within the germinal centre and cutting-edge techniques have enabled researchers to model this reaction with more accuracy both in vitro and in silico. Moreover, modern approaches to studying memory B-cells have allowed us to gain a better appreciation for the heterogeneity and adaptability of this vital class of B-cells. Together, these studies have facilitated important breakthroughs in our understanding of how these systems operate to ensure a successful immune response. In this review, we describe recent advances in the field of germinal centre and memory B-cell biology in order to provide insight into how humoral memory is formed, as well as the potential for generating lasting immunity to novel pathogens such as SARS-CoV-2.

Vaccine responses in ageing and chronic viral infection

Lay Summary Improved life expectancy in recent years has led to a growing population of adults over the age of 60. Age is commonly associated with increased inflammatory conditions and infections. Similar immunological changes have been observed during chronic infections, in particular HIV, where this is compounded by the success of antiretroviral therapy that has increased the number of people living with HIV into their sixties and beyond. The increased susceptibility of these groups to infection makes vaccination all the more important. However, the alterations to their immune systems call into question how effective those vaccinations may be. Here we discuss vaccine efficacy within elderly and chronically infected populations and investigate the immunological changes that may impact vaccine responsiveness. Over the last few decades, changing population demographics have shown that there is a growing number of individuals living past the age of 60. With this expanding older population comes an increase in individuals that are more susceptible to chronic illness and disease. An important part of maintaining health in this population is through prophylactic vaccination, however, there is growing evidence that vaccines may be less effective in the elderly. Furthermore, with the success of anti-viral therapies, chronic infections such as HIV are becoming increasingly prevalent in older populations and present a relatively unstudied population with respect to the efficacy of vaccination. Here we will examine the evidence for age-associated reduction in antibody and cellular responsiveness to a variety of common vaccines, and investigate the underlying causes attributed to this phenomenon, such as inflammation and senescence. We will also discuss the impact of chronic viral infections on immune responses in both young and elderly patients, particularly those living with HIV, and how this affects vaccinations in these populations.

T-follicular helper cells in malaria infection and roles in antibody induction

Immunity to malaria is mediated by antibodies that block parasite replication to limit parasite burden and prevent disease. Cytophilic antibodies have been consistently shown to be associated with protection, and recent work has improved our understanding of the direct and Fc-mediated mechanisms of protective antibodies. Antibodies also have important roles in vaccine-mediated immunity. Antibody induction is driven by the specialised CD4+ T cells, T-follicular helper cells, which function within the germinal centre to drive B cell activation and antibody induction. In humans, circulating T-follicular helper cells can be identified in peripheral blood, and are differentiated into subsets which appear to have pathogen/vaccination-specific roles in antibody induction. T-follicular helper cell responses are essential for protective immunity from Plasmodium infection in murine models of malaria. Our understanding of the activation of T-follicular helper cells during human malaria infection, and the importance of different T-follicular helper cell subsets in antibody development is still emerging. This review will discuss our current knowledge of T-follicular helper cell activation and development in malaria, and the potential avenues and pitfalls of targeting T-follicular helper cells to improve malaria vaccines.

The T cell response to SARS-CoV-2: kinetic and quantitative aspects and the case for their protective role

SARS-CoV-2, the etiological agent of COVID-19, triggers an adaptive immunity in the infected host that results in the production of virus-specific antibodies and T cells. While kinetic and quantitative aspects of antibodies have been analyzed in large patient cohorts, similar information about SARS-CoV-2-specific T cells are scarce. We summarize in this review the available knowledge of quantitative and temporal features of the SARS-CoV-2 T cell response. Currently, most of the data derived only from the analysis of the circulatory compartment. Despite this limitation, early appearance, multi-specificity and functionality of SARS-CoV-2-specific T cells are associated with accelerated viral clearance and with protection from severe COVID-19.

The role and uses of antibodies in COVID-19 infections: a living review

Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity.

Impact of obesity and SARS-CoV-2 infection: implications for host defence - a living review

The role of obesity in the pathophysiology of respiratory virus infections has become particularly apparent during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, where obese patients are twice as likely to suffer from severe coronavirus disease 2019 (COVID-19) than healthy weight individuals. Obesity results in disruption of systemic lipid metabolism promoting a state of chronic low-grade inflammation. However, it remains unclear how these underlying metabolic and cellular processes promote severe SARS-CoV-2 infection. Emerging data in SARS-CoV-2 and Influenza A virus (IAV) infections show that viruses can further subvert the host’s altered lipid metabolism and exploit obesity-induced alterations in immune cell metabolism and function to promote chronic inflammation and viral propagation. In this review, we outline the systemic metabolic and immune alterations underlying obesity and discuss how these baseline alterations impact the immune response and disease pathophysiology. A better understanding of the immunometabolic landscape of obese patients may aid better therapies and future vaccine design.

Mucosal immune responses in COVID19 - a living review

COVID-19 was initially characterized as a disease primarily of the lungs, but it is becoming increasingly clear that the SARS-CoV2 virus is able to infect many organs and cause a broad pathological response. The primary infection site is likely to be a mucosal surface, mainly the lungs or the intestine, where epithelial cells can be infected with virus. Although it is clear that virus within the lungs can cause severe pathology, driven by an exaggerated immune response, infection within the intestine generally seems to cause minor or no symptoms. In this review, we compare the disease processes between the lungs and gastrointestinal tract, and what might drive these different responses. As the microbiome is a key part of mucosal barrier sites, we also consider the effect that microbial species may play on infection and the subsequent immune responses. Because of difficulties obtaining tissue samples, there are currently few studies focused on the local mucosal response rather than the systemic response, but understanding the local immune response will become increasingly important for understanding the mechanisms of disease in order to develop better treatments.