Noninfectious Disease Vaccines

This

chapter provides an overview of the challenges and advances in vaccine development for chronic and noncommunicable diseases. Because of space limitations it is not possible to provide an exhaustive representation of the field; consequently, we address a few major themes with examples of challenges and vaccine-based solutions. There also is a vast literature on T-cell–based cancer vaccines, which are discussed comprehensively in Chapter 14 .

The incidence of many chronic conditions increases with age and with more individuals living longer, placing operational and financial pressures on healthcare systems. Some estimates suggest that a staggering one-third of all healthcare costs will be expended in the final year of life. More than 90% of all medications are administered in the last 10 years of life. Many long-term therapies that block self-molecules (e.g., hormones, cytokines) could be replaced with therapeutic vaccines with the advantage that they only need to be administered a few times. Here we describe two major types of therapeutic vaccines targeting self-molecules and drugs of abuse.

INTRODUCTION

Sizeable global demographic changes are leading to significant challenges for professionals charged with preserving the health and well-being of the population in the first century of the new millennium. There have been many successes in combating once prevalent global infectious diseases through vaccines and antimicrobials, leading to an estimated net increase in life expectancy of nearly 30 years in industrialized countries over the past decade. ^, Indeed, the “maturing” of global societies is a major achievement, with people today living longer and healthier lives than previous generations (with the World Health Organization quoting a global figure of an average life expectancy increase of 20 years compared to 50 years ago ). This demographic change offers enormous social and economic benefits in opportunities to harness the experience, expertise, and creativity of a large number of older people. However, it also brings difficulties caring for an aging population, given that healthcare costs associated with treating and caring for the elderly are considerable and are likely to increase. In addition, the prevalence of chronic diseases, long overlooked in the global context, has swiftly emerged as a major problem accounting for 48% of all global mortality. Although much of this can be addressed by existing knowledge and cost-effective solutions, there are many unmet medical challenges that require novel therapies.

One important objective must be to preserve health, prevent disease by encouraging “good” habits (e.g., exercise and nutrition), and intervene early in disease processes before they become debilitating. Of course, this presumes that we have the means to detect diseases early, effective tools for medical interventions, and accessibility to the population at risk (both in terms of compliance and costs). Vaccines are highly successful in preventing infectious and communicable diseases; thus there is precedent for the goal of repeating such feats in the combating of noncommunicable diseases.

Monoclonal antibodies targeting self-proteins have provided much needed relief and life-altering therapies for several chronic diseases. Current examples include anti–tumor necrosis factor (TNF) drugs such as adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), and infliximab (Remicade) for rheumatoid arthritis, ankylosing spondylitis, and Crohn disease, or anti IL-4 receptor antibody dupilumab (Dupixent) for asthma and inflammatory skin diseases, and for the latter also anti-IL-12 antibody ustekinumab (Stelara), and anti-IL-21 antibodies guselkumab (Tremfya), and risankizumab (Skyrizi). Most recently, Aducanumab (Aduhelm), a monoclonal antibody against Ab _1–42 for the treatment of Alzheimer’s disease has been added to the arsenal of new therapies. These products have been extensively evaluated in preclinical and clinical efficacy trials prior to their widespread use in clinical practice. Often, therapeutic effects are rapidly achieved, with a high degree of specificity inherent in antibody–target interactions, but are expensive, require fairly large doses, and must be given frequently. In addition, the potential for secondary treatment failures, when recipients mount an immune response against the therapeutic agent, ^{, ,} necessitates the development of alternative therapies.

The possibility to replace the passive immunization approaches with active immunization is an attractive proposition and presents opportunities for improved compliance (fewer injections), reduced risk of secondary failure (as the immune system is encouraged to produce an antibody response and almost never produces anti-idiotypic antibodies against polyclonal antibodies), and lower cost (smaller doses and cost-effective manufacture of vaccines). ^, However, this entails the not insignificant task of inducing a safe and efficient immune response against self-antigens.

OVERCOMING THE IMMUNE SYSTEM’S SAFETY MECHANISMS—UNRESPONSIVENESS AND TOLERANCE

In general, humans do not generate antibody responses against self-antigens even if they are administered with adjuvants, because the immune system has evolved a set of checkpoints to avoid autoreactive responses. Anti–self-immune responses are inhibited by several different mechanisms, including deletion of self-reactive lymphocytes (elimination of cells), anergy (functional silencing), and lack of stimulation (immune-competent lymphocytes are present in the periphery but are not stimulated, because they do not encounter the self-antigen in an immunogenic context). ^, This unresponsiveness toward self, also referred to as (self)-tolerance, occurs at the T- and/or B-cell level. Whereas autoreactive T cells are efficiently deleted or silenced in the thymus, B-cell tolerance is mainly induced in the bone marrow. Both B- and T-cell tolerance also occurs in the periphery. A key feature of deletion of B cells in the periphery is the crosslinking of the B-cell receptor (BCR). Hence, B cells specific for highly expressed membrane proteins are eliminated particularly efficiently, whereas B cells specific for soluble antigens typically escape negative selection and remain in circulation. In contrast, because of the expression of most antigens in the thymus and the transport of soluble antigens to the thymus, T-cell tolerance, in particular T-helper (T _H ) cell tolerance, is a much more efficient process. Thus, while most autoreactive T cells are eliminated, a largely normal B-cell repertoire exists for secreted and soluble self-antigens. Importantly, because naïve B cells critically depend on T-cell help to proliferate, undergo isotype switching, and differentiate into long-lived plasma cells, deletion or silencing of autoreactive T cells avoids self-specific B-cell responses and maintains B-cell unresponsiveness. Nevertheless, low-affinity autoreactive T cells can escape the thymic and peripheral tolerance processes and may be activated by administration of the antigen in the presence of strong adjuvants such as complete Freund adjuvant. However, bypassing rather than breaking T-cell tolerance appears to be the method of choice for the induction of antibodies against self-antigens. This is best achieved by fusing a strong foreign T-cell epitope to the self-antigen or by conjugating the self-antigen to a foreign carrier protein.

INDUCTION OF B-CELL RESPONSES

For a B-cell to generate a long-term response, two signals are needed: activation of the BCR and stimulation by antigen-specific T _H cells. Through covalent linkage of an antigen to a carrier molecule, B cells expressing a BCR specific for the antigen will acquire carrier-specific T-help ( Fig. 42.1 ). Carrier molecules successfully used for licensed glycoconjugate vaccines are pathogen-derived proteins like diphtheria toxoid, tetanus toxoid, meningococcus B outer membrane protein C, or Haemophilus influenzae protein D. Other clinically tested carriers include toxin B, Pseudomonas aeruginosa exoprotein A, and keyhole limpet hemocyanin (KLH). Well-established virus-like particle (VLP) systems (such as hepatitis B vaccine and human papillomavirus vaccine) induce excellent immune responses with increased attention to finding ways to generate responses to heterologous antigens. VLPs share many of the features of whole viruses but are not infectious. Their particulate nature, their highly ordered repetitive structure, and their Th cell epitopes are the source of their remarkable immunogenicity.

For this reason, VLPs have gained interest as platforms for vaccines against noninfectious diseases. Bacteriophage Qβ-derived VLPs, which are readily produced in large quantities under good manufacturing practice conditions in E. coli , have been extensively tested as immunological carriers in animals and humans. Using chemical heterobifunctional crosslinkers, ^, antigens can be directionally conjugated to their surface and presented in a highly ordered fashion to B cells. As a result, BCRs are efficiently crosslinked, resulting in potent immune responses. Moreover, during self-assembly in Escherichia coli , host RNA, a potent TLR7/8 agonist, is packaged into many RNA-virus derived VLPs acting as an adjuvant, thereby enhancing B-cell response, inducing class switching and promoting plasma cell formation. ^, In light of these virtues, bacteriophage VLPs have been successfully used as carriers, inducing potent immune responses against self-antigens and haptens in various preclinical and clinical studies. ^, These targets include examples such as tumor necrosis factor, interleukin-1β, angiotensin II, and amyloid beta (discussed later).

LONGEVITY OF THE RESPONSE AND GENERAL SAFETY CONSIDERATIONS

High antibody titers against a given target could be maintained by regular (e.g., yearly) restimulation. Regarding classical vaccines against infections, the memory responses are boosted by subsequent natural exposure to the pathogen. In contrast, in patients suffering from a chronic disease or drug addiction treated with vaccines, the relevant self-antigens are not naturally presented in an immunogenic form, because self-antigens are seen by B cells in the absence of specific T _H cells (which had been stimulated by the carrier during vaccination). ^, Hence, regular booster immunizations may be required to maintain antibody titers at therapeutic levels. The waning of the antibody response in the absence of continued boosting may be advantageous from a safety perspective, particularly if the vaccine targets self-antigens. In this case, lifelong immune responses may not be desired or required, and therapy could be stopped after improvement in health or if antibody-mediated adverse events occur.

For B-cell vaccines different adverse events may be envisaged and must be carefully assessed; toxic effects may arise and need to be addressed in detail in preclinical models and early phase clinical trials in a target-specific manner. Such adverse effects include generation of immune complexes with soluble target molecules or binding to self-antigens expressed on tissue with the subsequent induction of local inflammation by activation of antibody-dependent effector cells. Consequently, not all antigens make appropriate targets for vaccine approaches. In general, rare proteins may cause fewer problems than abundant proteins, as only low amounts of immune complexes can be formed because of a decreased chance of interactions occurring. Soluble proteins are generally preferred over membrane-bound targets because of the absence of antibody-dependent cellular cytotoxicity, which may only be observed with membrane proteins. Moreover, many membrane proteins are receptors, and antibodies can be either antagonistic (prevention of binding to the ligand) or agonistic (activating the receptor through crosslinking) to receptor engagement. This is problematic, as it is virtually impossible to exclude undesired agonistic antibody using a vaccination approach. Finally, safety issues associated with neutralization of the target molecule also have to be considered. These issues are best addressed in studies using target-specific monoclonal antibodies (mAbs), decoy receptors, or receptor antagonists. Valuable information can also be obtained from evaluating the clinical manifestations in rare human deficiencies of the target molecule, or in animal models rendered genetically or physiologically deficient for the target molecules. ^,

TARGETS FOR THERAPEUTIC B-CELL VACCINATION

In accordance with the better safety profile of immunodrugs against secreted antigens, many therapeutic vaccination approaches in humans have targeted such molecules. Meanwhile 18 self-antigens have been targeted in humans by many different vaccines in various indications (summarized in Table 42.1 ). Many of these molecules are also targets for small molecule pharmaceuticals or biopharmaceuticals and as such have been validated as appropriate therapeutic targets.