A role for immune modulation in achieving functional cure for chronic hepatitis B among current changes in the landscape of new treatments.

INTRODUCTION: Chronic hepatitis B (CHB) is rarely cured using available treatments. Barriers to cure are: 1) persistence of reservoirs of hepatitis B virus (HBV) replication and antigen production (HBV DNA); 2) high burden of viral antigens that promote T cell exhaustion with T cell dysfunction; 3) CHB-induced impairment of immune responses. AREAS COVERED: We discuss options for new therapies that could address one or more of the barriers to functional cure, with particular emphasis on the potential role of immunotherapy. EXPERT OPINION/COMMENTARY: Ideally, a sterilizing cure for CHB would translate into finite therapies that result in loss of HBV surface antigen and eradication of HBV DNA. Restoration of a functional adaptive immune response, a key facet of successful CHB treatment, remains elusive. Numerous strategies targeting the high viral DNA and antigen burden and aiming to restore the host immune responses will enter clinical development in coming years. Most patients are likely to require combinations of several drugs, personalized according to virologic and disease characteristics, patient preference, accessibility, and affordability. The management of CHB is a global health priority. Expedited drug development requires collaborations between regulatory agencies, scientists, clinicians, and within the industry to facilitate testing of the best drug combinations.

Chronic hepatitis B virus infection (CHB) is a major cause of liver cirrhosis and liver cancer worldwide. Persons with CHB have a dysfunctional immune response that is not capable of clearing the virus from the liver. Two types of treatment are currently available for individuals with CHB. These treatments can have some impact on reducing the risk of cirrhosis and cancer, but they rarely eliminate the virus, and relapse can occur. There are numerous new treatments, such as new antivirals and immunotherapies, being explored for their ability to restore an effective immune response, although to date, there has been little success in this area. Because of the many ways the hepatitis B virus uses to evade the immune system, it is unlikely that one drug or immunotherapy will be able to reliably silence the infection in significant proportions of patients with CHB. Combination regimens involving direct-acting drugs targeting different stages of the virus life cycle, along with stimulation of antiviral immune response are likely to be needed.

Maintaining a 'fit' immune system: the role of vaccines.

INTRODUCTION: Conventionally, vaccines are thought to induce a specific immune response directed against a target pathogen. Long recognized but poorly understood nonspecific benefits of vaccination, such as reduced susceptibility to unrelated diseases or cancer, are now being investigated and may be due in part to "trained immunity'. AREAS COVERED: We discuss 'trained immunity' and whether vaccine-induced 'trained immunity' could be leveraged to prevent morbidity due to a broader range of causes. EXPERT OPINION: The prevention of infection i.e. maintaining homeostasis by preventing the primary infection and resulting secondary illnesses, is the pivotal strategy used to direct vaccine design and may have long-term, positive impacts on health at all ages. In the future, we anticipate that vaccine design will change to not only prevent the target infection (or related infections) but to generate positive modifications to the immune response that could prevent a wider range of infections and potentially reduce the impact of immunological changes associated with aging. Despite changing demographics, adult vaccination has not always been prioritized. However, the SARS-CoV-2 pandemic has demonstrated that adult vaccination can flourish given the right circumstances, demonstrating that harnessing the potential benefits of life-course vaccination is achievable for all.

Vaccination as a preventative measure contributing to immune fitness.

The primary goal of vaccination is the prevention of pathogen-specific infection. The indirect consequences may include maintenance of homeostasis through prevention of infection-induced complications; trained immunity that re-programs innate cells to respond more efficiently to later, unrelated threats; slowing or reversing immune senescence by altering the epigenetic clock, and leveraging the pool of memory B and T cells to improve responses to new infections. Vaccines may exploit the plasticity of the immune system to drive longer-term immune responses that promote health at a broader level than just the prevention of single, specific infections. In this perspective, we discuss the concept of "immune fitness" and how to potentially build a resilient immune system that could contribute to better health. We argue that vaccines may contribute positively to immune fitness in ways that are only beginning to be understood, and that life-course vaccination is a fundamental tool for achieving healthy aging.

Novel Technologies to Improve Vaccines for Older Adults.

Vaccine development has traditionally been driven by the need to prevent high numbers of childhood deaths due to infectious disease. With few exceptions, vaccines for adults are the same as vaccines for infants, although it has long been apparent that they become less effective as age increases. It is only in the last few years that concerted efforts have commenced to develop life-long vaccination strategies through into older age. Impressive progress has been made in the field of vaccine technologies which, when they will be applied to vaccination of older adults, could change the landscape for disease prevention in this age group. The recently licensed adjuvanted herpes zoster vaccine shows that immunosenescence need not be a barrier to highly effective vaccination, and that highly effective vaccines for older adults can be achieved with good vaccine design. One of the greatest public health challenges of the 21st century is ensuring the health and well-being of the aged. New or improved vaccines targeting pathogens with a high disease burden in older adults have the potential to major contributions to the longevity and productivity of the older aged population.

The how's and what's of vaccine reactogenicity.

Reactogenicity represents the physical manifestation of the inflammatory response to vaccination, and can include injection-site pain, redness, swelling or induration at the injection site, as well as systemic symptoms, such as fever, myalgia, or headache. The experience of symptoms following vaccination can lead to needle fear, long-term negative attitudes and non-compliant behaviours, which undermine the public health impact of vaccination. This review presents current knowledge on the potential causes of reactogenicity, and how host characteristics, vaccine administration and composition factors can influence the development and perception of reactogenicity. The intent is to provide an overview of reactogenicity after vaccination to help the vaccine community, including healthcare professionals, in maintaining confidence in vaccines by promoting vaccination, setting expectations for vaccinees about what might occur after vaccination and reducing anxiety by managing the vaccination setting.

Adjuvant Systems for vaccines: 13 years of post-licensure experience in diverse populations have progressed the way adjuvanted vaccine safety is investigated and understood.

Adjuvant Systems (AS) are combinations of immune stimulants that enhance the immune response to vaccine antigens. The first vaccine containing an AS (AS04) was licensed in 2005. As of 2018, several vaccines containing AS04, AS03 or AS01 have been licensed or approved by regulatory authorities in some countries, and included in vaccination programs. These vaccines target diverse viral and parasitic diseases (hepatitis B, human papillomavirus, malaria, herpes zoster, and (pre)pandemic influenza), and were developed for widely different target populations (e.g. individuals with renal impairment, girls and young women, infants and children living in Africa, adults 50 years of age and older, and the general population). Clearly, the safety profile of one vaccine in one target population cannot be extrapolated to another vaccine or to another target population, even for vaccines containing the same adjuvant. Therefore, the assessment of adjuvant safety poses specific challenges. In this review we provide a historical perspective on how AS were developed from the angle of the challenges encountered on safety evaluation during clinical development and after licensure, and illustrate how these challenges have been met to date. Methods to evaluate safety of adjuvants have evolved based on the availability of new technologies allowing a better understanding of their mode of action, and new ways of collecting and assessing safety information. Since 2005, safety experience with AS has accumulated with their use in diverse vaccines and in markedly different populations, in national immunization programs, and in a pandemic setting. Thirteen years of experience using antigens combined with AS attest to their acceptable safety profile. Methods developed to assess the safety of vaccines containing AS have progressed the way we understand and investigate vaccine safety, and have helped set new standards that will guide and support new candidate vaccine development, particularly those using new adjuvants. FOCUS ON THE PATIENT: What is the context? Adjuvants are immunostimulants used to modulate and enhance the immune response induced by vaccination. Since the 1990s, adjuvantation has moved toward combining several immunostimulants in the form of Adjuvant System(s) (AS), rather than relying on a single immunostimulant. AS have enabled the development of new vaccines targeting diseases and/or populations with special challenges that were previously not feasible using classical vaccine technology. What is new? In the last 13 years, several AS-containing vaccines have been studied targeting different diseases and populations. Over this period, overall vaccine safety has been monitored and real-life safety profiles have been assessed following routine use in the general population in many countries. Moreover, new methods for safety assessment, such as a better determination of the mode of action, have been implemented in order to help understand the safety characteristics of AS-containing vaccines. What is the impact? New standards and safety experience accumulated over the last decade can guide and help support the safety assessment of new candidate vaccines during development.

Adjuvant system AS01: helping to overcome the challenges of modern vaccines.

INTRODUCTION: Adjuvants are used to improve vaccine immunogenicity and efficacy by enhancing antigen presentation to antigen-specific immune cells with the aim to confer long-term protection against targeted pathogens. Adjuvants have been used in vaccines for more than 90 years. Combinations of immunostimulatory molecules, such as in the Adjuvant System AS01, have opened the way to the development of new or improved vaccines. Areas covered: AS01 is a liposome-based vaccine adjuvant system containing two immunostimulants: 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and the saponin QS-21. Here we describe studies investigating the mode of action of AS01, and consider the role of AS01 in enhancing specific immune responses to the antigen for selected candidate vaccines targeting malaria and herpes zoster. The effects of AS01 are rapid and transient, being localized to the injected muscle and draining lymph node. AS01 is efficient at promoting CD4+ T cell-mediated immune responses and is an appropriate candidate adjuvant for inclusion in vaccines targeting viruses or intracellular pathogens. Expert commentary: AS01 activity to enhance adaptive responses depends on synergistic activities of QS-21 and MPL. AS01 adjuvantation shows good prospects for use in new vaccines targeted to populations with challenging immune statuses and against diseases caused by complex pathogens.

Vaccine development: From concept to early clinical testing.

In the 21st century, an array of microbiological and molecular allow antigens for new vaccines to be specifically identified, designed, produced and delivered with the aim of optimising the induction of a protective immune response against a well-defined immunogen. New knowledge about the functioning of the immune system and host pathogen interactions has stimulated the rational design of vaccines. The design toolbox includes vaccines made from whole pathogens, protein subunits, polysaccharides, pathogen-like particles, use of viral/bacterial vectors, plus adjuvants and conjugation technology to increase and broaden the immune response. Processes such as recombinant DNA technology can simplify the complexity of manufacturing and facilitate consistent production of large quantities of antigen. Any new vaccine development is greatly enhanced by, and requires integration of information concerning: 1. Pathogen life-cycle & epidemiology. Knowledge of pathogen structure, route of entry, interaction with cellular receptors, subsequent replication sites and disease-causing mechanisms are all important to identify antigens suitable for disease prevention. The demographics of infection, specific risk groups and age-specific infection rates determine which population to immunise, and at what age. 2. Immune control & escape. Interactions between the host and pathogen are explored, with determination of the relative importance of antibodies, T-cells of different types and innate immunity, immune escape strategies during infection, and possible immune correlates of protection. This information guides identification and selection of antigen and the specific immune response required for protection. 3. Antigen selection & vaccine formulation. The selected antigen is formulated to remain suitably immunogenic and stable over time, induce an immune response that is likely to be protective, plus be amenable to eventual scale-up to commercial production. 4. Vaccine preclinical & clinical testing. The candidate vaccine must be tested for immunogenicity, safety and efficacy in preclinical and appropriately designed clinical trials. This review considers these processes using examples of differing pathogenic challenges, including human papillomavirus, malaria, and ebola.

Superior antigen-specific CD4+ T-cell response with AS03-adjuvantation of a trivalent influenza vaccine in a randomised trial of adults aged 65 and older.

BACKGROUND: The effectiveness of trivalent influenza vaccines may be reduced in older versus younger adults because of age-related immunosenescence. The use of an adjuvant in such a vaccine is one strategy that may combat immunosenescence, potentially by bolstering T-cell mediated responses. METHODS: This observer-blind study, conducted in the United States (US) and Spain during the 2008-2009 influenza season, evaluated the effect of Adjuvant System AS03 on specific T-cell responses to a seasonal trivalent influenza vaccine (TIV) in ≥65 year-old adults.Medically-stable adults aged ≥65 years were randomly allocated to receive a single dose of AS03-adjuvanted TIV (TIV/AS03) or TIV. Healthy adults aged 18-40 years received only TIV. Blood samples were collected on Day 0, Day 21, Day 42 and Day 180. Influenza-specific CD4+ T cells, defined by the induction of the immune markers CD40L, IL-2, IFN-γ, or TNF-α, were measured in ex vivo cultures of antigen-stimulated peripheral blood mononuclear cells. RESULTS: A total of 192 adults were vaccinated: sixty nine and seventy three ≥65 year olds received TIV/AS03 and TIV, respectively; and fifty 18 - 40 year olds received TIV. In the ≥65 year-old group on Day 21, the frequency of CD4+ T cells specific to the three vaccine strains was superior in the TIV/AS03 recipients to the frequency in TIV (p < 0.001). On Days 42 and 180, the adjusted-geometric mean specific CD4+ T-cell frequencies were also higher in the TIV/AS03 recipients than in the TIV recipients (p < 0.001). Furthermore, the adjusted-geometric mean specific CD4+ T-cell frequencies were higher in the ≥65 year-old recipients of TIV/AS03 than in the18 - 40 year old recipients of TIV on Days 21 (p = 0.006) and 42 (p = 0.011). CONCLUSION: This positive effect of AS03 Adjuvant System on the CD4+ T-cell response to influenza vaccine strains in older adults could confer benefit in protection against clinical influenza disease in this population. TRIAL REGISTRATION: (Clinicaltrials.gov.). NCT00765076.

Immunotherapy via dendritic cells.

The immune system evolved to protect us from microbes. The antigen (Ag)-nonspecific innate immunity and Ag-specific adaptive immunity synergize to eradicate the invading pathogen through cells, such as dendritic cells (DCZ7) and lymphocytes, and through their effector proteins including antimicrobial peptides, complement, and antibodies. Its intrinsic complexity renders the immune system prone to dysfunction including cancer, autoimmunity, chronic inflammation and allergy. DCs are unique in their capacity to induce and regulate immune responses and are therefore attractive candidates for immunotherapy. However, DCs consist of distinct subsets with common as well as unique functions that lead to distinct types of immune responses. Therefore, understanding DC heterogeneity and their role in immunopathology is critical to design better strategies for immunotherapy. Indeed, what we learn from studying autoimmunity will help us induce strong vaccine specific immunity, either protective, as in the case of microbes, or therapeutic, as in the case of tumors.

Soluble HLA-G inhibits human dendritic cell-triggered allogeneic T-cell proliferation without altering dendritic differentiation and maturation processes.

The role of the nonclassical human leukocyte antigen (HLA) class Ib molecule HLA-G in immune tolerance was first reported at maternofetal interface. This immunomodulating role could be exerted more generally in tumoral or post-transplantation situations in inhibiting natural killer (NK) and T-lymphocyte mediated lysis. Among the different transcripts resulting from alternative splicing, the mainly secreted isoform, HLA-G5, corresponds to complete molecule and has been demonstrated to be elevated in melanomas and in serum from heart-transplanted patients. As dendritic cells expressed ILT4, an inhibitory receptor capable of interacting with HLA-G, we have studied the effect of soluble HLA-G (HLA-G5) on differentiation, maturation, apoptosis and function of monocyte or CD34+-derived dendritic cells (DC). Soluble HLA-G did not alter differentiation, maturation or apoptosis of DC whatever their origin. On the other hand, an inhibitory effect of HLA-G5 on T lymphocytes proliferation was found in 53% of mixed leukocyte reactions (MLR) and was variable in intensity. These data demonstrate an indirect way of HLA-G5 action on DC occurring via T lymphocytes that reinforces the immune inhibitory role of soluble HLA-G capable to be secreted during tumoral malignancies or following heart transplantation.

MHC class II-mediated apoptosis of mature dendritic cells proceeds by activation of the protein kinase C-delta isoenzyme.

The mature dendritic cell (DC) is considered to be the most potent antigen-presenting cell. Regulation of the DC, particularly its survival, is therefore critical. Mature DC are markedly more sensitive to HLA-DR-mediated apoptosis than immature DC. To further characterize this key survival difference, we compared the intracellular signals initiated via HLA-DR in mature versus immature DC. Apoptosis was unchanged by inhibition of tyrosine kinases or phosphatases. HLA-DR-mediated re-localization of protein kinase C (PKC)-delta to the nucleus was detected in mature DC by confocal microscopy and by immunoblotting. Activation of PKC-delta in mature DC was revealed by the detection of the PKC-delta catalytic fragment in the nuclear fraction isolated from mature DC which had been stimulated via HLA-DR. The broad-spectrum PKC inhibitor, Calphostin C, as well as the PKC-delta-selective inhibitor, Rottlerin, inhibited HLA-DR-mediated apoptosis of mature cells. Taken together, these data reveal a role for the PKC-delta isoenzyme in regulating HLA class II-mediated apoptosis of mature DC. Thus, the lifespan of the mature DC could be controlled by signals generated in the course of antigen presentation, and thereby prevent DC persistence and prolonged stimulation of T and B lymphocytes.

Polycyclic aromatic hydrocarbons affect functional differentiation and maturation of human monocyte-derived dendritic cells.

Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are environmental carcinogens exhibiting potent immunosuppressive properties. To determine the cellular bases of this immunotoxicity, we have studied the effects of PAHs on differentiation, maturation, and function of monocyte-derived dendritic cells (DC). Exposure to BP during monocyte differentiation into DC upon the action of GM-CSF and IL-4 markedly inhibited the up-regulation of markers found in DC such as CD1a, CD80, and CD40, without altering cell viability. Besides BP, PAHs such as dimethylbenz(a)anthracene and benzanthracene also strongly altered CD1a levels. Moreover, DC generated in the presence of BP displayed decreased endocytic activity. Features of LPS-mediated maturation of DC, such as CD83 up-regulation and IL-12 secretion, were also impaired in response to BP treatment. BP-exposed DC poorly stimulated T cell proliferation in mixed leukocyte reactions compared with their untreated counterparts. In contrast to BP, the halogenated arylhydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin, which shares some features with PAHs, including interaction with the arylhydrocarbon receptor, failed to phenotypically alter differentiation of monocytes into DC, suggesting that binding to the arylhydrocarbon receptor cannot mimic PAH effects on DC. Overall, these data demonstrate that exposure to PAHs inhibits in vitro functional differentiation and maturation of blood monocyte-derived DC. Such an effect may contribute to the immunotoxicity of these environmental contaminants due to the major role that DC play as potent APC in the development of the immune response.