Tissue T cells in prophylactic and therapeutic vaccination responses

In this conference report, I highlight the potential to target tissue-resident T cells to enhance prophylactic and therapeutic vaccine immunity. I describe our recent findings on exploiting frontline sentinal immunosurveillance by liver-resident immunity for functional cure of hepatitis B. We showed that therapeutic vaccine-induced HBV-specific T cells are constrained by liver-resident NK cells; cytokine-activation and PD-L1 blockade of NK cells converted them into helpers able to instead boost HBV-specific T cells. Turning to tissue-resident T cells in the lung, we found this pool can include T cells able to recognise SARS-CoV-2, including cross-reactive responses present prior to the pandemic. The importance of inducing T cells with future prophylactic vaccines was underscored by their selective expansion in a subset of donors aborting SARS-CoV-2 infection without detectable antibodies

Human antiviral B cell responses: Emerging lessons from hepatitis B and COVID-19

Humoral immunity is a critical component of the coordinated response required to resolve viral infections and mediate protection following pathogen clearance or vaccination. A better understanding of factors shaping the memory B cell response will allow tailored development of efficient preventative vaccines against emerging acute viral infections, therapeutic vaccines, and immunotherapies for chronic viral infections. Here, we use recent data obtained by profiling antigen-specific B cell responses in hepatitis B as a framework to explore lessons that can be learnt from different viral infections about the diverse influences on humoral immunity. Hepatitis B provides a paradigm where successful B cell responses in resolved or vaccinated individuals can be contrasted to the failed response in chronic infection, while also exemplifying the degree to which B cell responses within infected individuals can differ to two antigens from the same virus. Drawing on studies in other human and murine infections, including emerging data from COVID-19, we consider the influence of antigen quantity and structure on the quality of the B cell response, the role of differential CD4 help, the importance of germinal center vs extrafollicular responses and the emerging concept that responses residing in non-lymphoid organs can participate in B cell memory

Restoring, releasing or replacing adaptive immunity in chronic hepatitis B

Multiple new therapeutic approaches are currently being developed to achieve sustained, off-treatment suppression of HBV, a persistent hepatotropic infection that kills ~2,000 people a day. A fundamental therapeutic goal is the restoration of robust HBV-specific adaptive immune responses that are able to maintain prolonged immunosurveillance of residual infection. Here, we provide insight into key components of successful T cell and B cell responses to HBV, discussing the importance of different specificities and effector functions, local intrahepatic immunity and pathogenic potential. We focus on the parallels and interactions between T cell and B cell responses, highlighting emerging areas for future investigation. We review the potential for different immunotherapies in development to restore or release endogenous adaptive immunity by direct or indirect approaches, including limitations and risks. Finally, we consider an alternative HBV treatment strategy of replacing failed endogenous immunity with infusions of highly targeted T cells or antibodies

Shared immunotherapeutic approaches in HIV and hepatitis B virus: combine and conquer

Purpose of review: The aim of this study was to identify similarities, differences and lessons to be shared from recent progress in HIV and hepatitis B virus (HBV) immunotherapeutic approaches. Recent findings: Immune dysregulation is a hallmark of both HIV and HBV infection, which have shared routes of transmission, with approximately 10% of HIV-positive patients worldwide being coinfected with HBV. Immune modulation therapies to orchestrate effective innate and adaptive immune responses are currently being sought as potential strategies towards a functional cure in both HIV and HBV infection. These are based on activating immunological mechanisms that would allow durable control by triggering innate immunity, reviving exhausted endogenous responses and/or generating new immune responses. Recent technological advances and increased appreciation of humoral responses in the control of HIV have generated renewed enthusiasm in the cure field. Summary: For both HIV and HBV infection, a primary consideration with immunomodulatory therapies continues to be a balance between generating highly effective immune responses and mitigating any significant toxicity. A large arsenal of new approaches and ongoing research offer the opportunity to define the pathways that underpin chronic infection and move closer to a functional cure

Reconstitution of hepatitis B virus (HBV)-specific T cell responses with treatment of human immunodeficiency virus/HBV coinfection

Liver-related mortality is an increasing problem in human immunodeficiency virus (HIV)/hepatitis B virus (HBV)-coinfected patients receiving highly active antiretroviral therapy (HAART). In HIV-negative patients, HBV chronicity is associated with a reduction in specific T cell responses that can be partially restored by treatment with lamivudine. We studied 5 HIV/HBV-coinfected patients treated with HAART, either with or without addition of a drug with specific anti-HBV activity. Our data show that reconstitution of some HBV-specific T cell responses can also occur in HIV-positive patients after a reduction in HBV load. This potential to recover T cell responses, which has been thought to be critical for HBV control, provides support for the addition of anti-HBV therapy in the treatment of HIV/HBV-coinfected patients

T cell control of SARS-CoV-2: When, which, and where?

Efficient immune protection against viruses such as SARS-CoV-2 requires the coordinated activity of innate immunity, B and T cells. Accumulating data point to a critical role for T cells not only in the clearance of established infection, but also for aborting viral replication independently of humoral immunity. Here we review the evidence supporting the contribution of antiviral T cells and consider which of their qualitative features favour efficient control of infection. We highlight how studies of SARS-CoV-2 and other coronaviridae in animals and humans have provided important lessons on the optimal timing (When), functionality and specificity (Which), and location (Where) of antiviral T cells. We discuss the clinical implications, particularly for the development of next-generation vaccines, and emphasise areas requiring further study

Cholesterol-modifying drugs in COVID-19

Infection with severe acute respiratory syndrom coronavirus 2 (SARS-CoV-2) is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome. Here, we consider mechanisms by which dyslipidaemia and the use of cholesterol-modifying drugs could influence the virus–host relationship. Cholesterol is essential for the assembly, replication and infectivity of enveloped virus particles; we highlight several cholesterol-modifying drugs with the potential to alter the SARS-CoV-2 life cycle that could be tested in in vitro and in vivo models. Although cholesterol is an essential component of immune cell membranes, excess levels can dysregulate protective immunity and promote exaggerated pulmonary and systemic inflammatory responses. Statins block the production of multiple sterols, oxysterols and isoprenoids, resulting in a pleiotropic range of context-dependent effects on virus infectivity, immunity and inflammation. We highlight antiviral, immunomodulatory and anti-inflammatory effects of cholesterol-modifying drugs that merit further consideration in the management of SARS-CoV-2 infection

NK cells: a double-edged sword in chronic hepatitis B virus infection.

There is natural enrichment of NK cells in the human liver and this intrahepatic predominance underscores their potential importance in the control of infections with hepatotropic viruses such as hepatitis B virus (HBV). The contribution of innate components during chronic HBV infection has been a relatively under-investigated area. However, recent data have highlighted that NK cells are capable of exerting antiviral and immunoregulatory functions whilst also contributing to the pathogenesis of liver injury via death receptor pathways. We will present an overview of current knowledge regarding the complex biology of NK cells in the context of their antiviral versus pathogenic role in chronic hepatitis B as a clinically relevant avenue for further investigation

Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand

Hepatitis B virus (HBV) remains a major cause of morbidity and mortality worldwide. Treatments that can induce functional cure in patients chronically infected with this hepatotropic, non-cytopathic virus are desperately needed. Attempts to use therapeutic vaccines to expand the weak antiviral T-cell response and induce sustained immunity have been unsuccessful. However, exciting progress has been made in defining the molecular defects that must be overcome to harness T-cell immunity. A large arsenal of immunotherapeutic agents and direct-acting antivirals targeting multiple steps of the viral lifecycle is emerging. In this Review, we discuss how to translate the new insights into T-cell manipulation, combined with better understanding of patient heterogeneity, into optimisation of therapeutic vaccines against HBV. We review the opportunities and risks involved in boosting endogenous T-cell responses using combinations of next generation therapeutic vaccines and immunotherapy agents