Mucosal immunity and vaccination strategies: current insights and future perspectives

Immunization With a Bivalent Adenovirus-vectored Tuberculosis Vaccine Provides Markedly Improved Protection Over Its Monovalent Counterpart Against Pulmonary Tuberculosis

Intranasal DNA Vaccination Induces Potent Mucosal and Systemic Immune Responses and Cross-protective Immunity Against Influenza Viruses

It is well known that mucosal tissues contain the largest surface area of the human body and are the front line of natural host defense against various pathogens. In fact, more than 80% of infectious disease pathogens probably gain entry into the susceptible human hosts through open mucosal surfaces. Human immunodeficiency virus type one (HIV-1), a mainly sexually transmitted virus, also primarily targets the vaginal and gastrointestinal mucosa as entry sites for viral transmission, seeding, replication and amplification. Since HIV-1 establishes its early replication in vaginal or rectal mucosal tissues, the induction of sufficient mucosal immunity at the initial site of HIV-1 transmission becomes essential for a protective vaccine. However, despite the fact that current conventional vaccine strategies have remained unsuccessful in preventing HIV-1 infection, sufficient financial support and resources have yet to be given to develop a vaccine able to elicit protective mucosal immunity against sexual transmissions. Interestingly, Chinese ancestors invented variolation through intranasal administration about one thousand years ago, which led to the discovery of a successful smallpox vaccine and the final eradication of the disease. It is the hope for all mankind that the development of a mucosal AIDS vaccine will ultimately help control the AIDS pandemic. In order to discover an effective mucosal AIDS vaccine, it is necessary to have a deep understanding of mucosal immunology and to test various mucosal vaccination strategies.

Respiratory syncytial virus (RSV) is a major cause of serious acute lower respiratory tract infection in infants and the elderly. The lack of a licensed RSV vaccine calls for the development of vaccines with other targets and vaccination strategies. Here, we construct a recombinant protein, designated P-KFD1, comprising RSV phosphoprotein (P) and the E.-coli-K12-strain-derived flagellin variant KFD1. Intranasal immunization with P-KFD1 inhibits RSV replication in the upper and lower respiratory tract and protects mice against lung disease without vaccine-enhanced disease (VED). The P-specific CD4+ Tcells provoked by P-KFD1 intranasal (i.n.) immunization either reside in or migrate to the respiratory tract and mediate protection against RSV infection. Single-cell RNA sequencing (scRNA-seq) and carboxyfluorescein succinimidyl ester (CFSE)-labeled cell transfer further characterize the Th1 and Th17 responses induced by P-KFD1. Finally, we find that anti-viral protection depends on either interferon-γ (IFN-γ) or interleukin-17A (IL-17A). Collectively, P-KFD1 is a promising safe and effective mucosal vaccine candidate for the prevention of RSV infection.

BackgroundCurrent vaccination strategies against pertussis are sub-optimal. Optimal protection against Bordetella pertussis, the causative agent of pertussis, likely requires mucosal immunity. Current pertussis vaccines consist of inactivated whole B. pertussis cells or purified antigens thereof, combined with diphtheria and tetanus toxoids. Although they are highly protective against severe pertussis disease, they fail to elicit mucosal immunity. Compared to natural infection, immune responses following immunization are short-lived and fail to prevent bacterial colonization of the upper respiratory tract. To overcome these shortcomings, efforts have been made for decades, and continue to be made, toward the development of mucosal vaccines against pertussis.ObjectivesIn this review we systematically analyzed published literature on protection conferred by mucosal immunization against pertussis. Immune responses mounted by these vaccines are summarized.MethodThe PubMed Library database was searched for published studies on mucosal pertussis vaccines. Eligibility criteria included mucosal administration and the evaluation of at least one outcome related to efficacy, immunogenicity and safety.ResultsWhile over 349 publications were identified by the search, only 63 studies met the eligibility criteria. All eligible studies are included here. Initial attempts of mucosal whole-cell vaccine administration in humans provided promising results, but were not followed up. More recently, diverse vaccination strategies have been tested, including non-replicating and replicating vaccine candidates given by three different mucosal routes: orally, nasally or rectally. Several adjuvants and particulate formulations were tested to enhance the efficacy of non-replicating vaccines administered mucosally. Most novel vaccine candidates were only tested in animal models, mainly mice. Only one novel mucosal vaccine candidate was tested in baboons and in human trials.ConclusionThree vaccination strategies drew our attention, as they provided protective and durable immunity in the respiratory tract, including the upper respiratory tract: acellular vaccines adjuvanted with lipopeptide LP1569 and c-di-GMP, outer membrane vesicles and the live attenuated BPZE1 vaccine. Among all experimental vaccines, BPZE1 is the only one that has advanced into clinical development.

Progress towards an AIDS mucosal vaccine: An overview

The mucosae represent the first line of defense against the invasion of most pathogens, and the mucosal immune system plays a crucial role in the control of infection. Mucosal vaccination can trigger both humoral and cell-mediated immune responses mucosally as well as systemically. Hence, protective immune responses can be elicited effectively by mucosal vaccination. Microfold (M) cells being unique to the mucosal immune system can take up luminal antigens and initiating antigen-specific immune responses. The number of antigen uptake by M cells is directly related to the immune efficacy of mucosal vaccines. Utilizing M cell ligands, M cells-targeting antigen delivery can achieve highly effective mucosal immune responses. The strategy of targeted delivery of antigens to M cells and its applications can be used for the improvement of mucosal immune responses and the development of mucosal vaccines. Despite these efforts, successful development of safe and effective mucosal vaccines remains a big challenge and needs a long way to go, and provably still resort to further researches on cellular properties and functions as well as mucosal immune mechanisms.

Chapter 63 - Antigen Delivery Systems I: Nonliving Microparticles, Liposomes, and Immune-Stimulating Complexes (ISCOMs)

Mucosal immunity in sheep and implications for mucosal vaccine development

Infectious diarrhea in children can be life-threatening and imposes a large economic burden on healthcare systems, therefore more effective prophylactic and therapeutic drugs are needed urgently. Because most of the pathogens responsible for childhood diarrhea infect the gastrointestinal mucosa, providing protective immunity at the mucosal surface is an ideal way to control pathogen invasion and toxic activity. Mucosal (e.g. oral, nasal) vaccines are superior to systemic (subcutaneous or intramuscular) vaccination for conferring both mucosal and systemic pathogen-specific immune responses. Therefore, great efforts has been focused on the development of cost-effective mucosal vaccines for the past 50 years. Recent progress in plant genetic engineering has revolutionized the production of inexpensive and safe recombinant vaccine antigens. For example, rice plant biotechnology has facilitated the development of a cold-chain-free rice-based oral subunit vaccine against Vibrio cholerae. Furthermore, this technology has led to the creation of a rice-based oral antibody for prophylaxis and treatment of rotavirus gastroenteritis. This review summarizes current perspectives regarding the mucosal immune system and the development of mucosal vaccines and therapeutic antibodies, particularly rice-based products, and discusses future prospects regarding mucosal vaccines for children.

SARS-CoV-2 Vaccines: The Mucosal Immunity Imperative

Mucosal immune responses include a major B-cell component characterized by surface IgA-positive (SIgA+) B-cells that become plasma cells which produce polymeric IgA antibody (Ab). In addition, both T-helper (Th) cells and cytotoxic T-lymphocytes (CTLs) are induced in mucosa-associated lymphoreticular tissues (MALT) (1). These B- and T-cell responses can be induced by pathogens in organized mucosal inductive sites. In fact, the host has evolved a sophisticated network of cells and molecules that maintain the homeostasis of exposed mucosal surfaces (1,2). This system, termed MALT, is anatomically and functionally distinct from the systemic counterpart and is strategically located at the portal of entry of most microorganisms, including specific pathogens. Prior to the development of acquired immune responses, the mucosa are protected by innate defenses including the physical barrier provided by epithelial cells, secreted molecules with antibacterial activity, and the cytolytic activity of natural killer (NK) cells. However, effective protection against virulent mucosal pathogens requires prophylactic immune responses that can be achieved by mucosal vaccines, which, in contrast to systemic vaccines, can trigger both mucosal and systemic immunity. A major challenge for the development of mucosal vaccines will be to overcome the natural tendency of the host to suppress immune responses to orally administered antigens, a state commonly termed oral tolerance. In addition, effective protection against infectious agents will require the development of safe mucosal vaccines capable of promoting targeted immune responses.

The development of mucosal vaccines against pathogens is currently a highly explored area of research in both humans and animals. This is due to the fact that mucosal vaccines have the potential to best elicit protective responses at these mucosal surfaces, which represent the frontline of host defense, thus blocking the pathogen at its initial replication sites. However, in order to provide an efficient long-lasting protection, these mucosal vaccines have to be capable of eliciting an adequate systemic immune response in addition to local responses. In aquaculture, the need for mucosal vaccines has further practical implications, as these vaccines would avoid the individual manipulation of fish out of the water, being beneficial from both an economic and animal welfare point of view. However, how B and T cells are organized in teleost fish within these mucosal sites and how they respond to mucosally delivered antigens varies greatly when compared to mammals. For this reason, it is important to establish which mucosally delivered antigens have the capacity to induce strong and long-lasting B and T cell responses. Hence, in this review, we have summarized what is currently known regarding the adaptive immune mechanisms that are induced both locally and systemically in fish after mucosal immunization through different routes of administration including oral and nasal vaccination, anal intubation and immersion vaccination. Finally, based on the data presented, we discuss how mucosal vaccination strategies could be improved to reach significant protection levels in these species.

Exploring the potential benefits of mucosal COVID-19 vaccines: opportunities and challenges

Mucosal barrier tissues and their mucosal associated lymphoid tissues (MALT) are attractive targets for vaccines and immunotherapies due to their roles in both priming and regulating adaptive immune responses. The upper and lower respiratory mucosae, in particular, possess unique properties: a vast surface area responsible for frontline protection against inhaled pathogens but also simultaneous tight regulation of homeostasis against a continuous backdrop of non-pathogenic antigen exposure. Within the upper and lower respiratory tract, the nasal and bronchial associated lymphoid tissues (NALT and BALT, respectively) are key sites where antigen-specific immune responses are orchestrated against inhaled antigens, serving as critical training grounds for adaptive immunity. Many infectious diseases are transmitted via respiratory mucosal sites, highlighting the need for vaccines that can activate resident frontline immune protection in these tissues to block infection. While traditional parenteral vaccines that are injected tend to elicit weak immunity in mucosal tissues, mucosal vaccines (i.e., that are administered intranasally) are capable of eliciting both systemic and mucosal immunity in tandem by initiating immune responses in the MALT. In contrast, administering antigen to mucosal tissues in the absence of adjuvant or costimulatory signals can instead induce antigen-specific tolerance by exploiting regulatory mechanisms inherent to MALT, holding potential for mucosal immunotherapies to treat autoimmunity. Yet despite being well motivated by mucosal biology, development of both mucosal subunit vaccines and immunotherapies has historically been plagued by poor drug delivery across mucosal barriers, resulting in weak efficacy, short-lived responses, and to-date a lack of clinical translation. Development of engineering strategies that can overcome barriers to mucosal delivery are thus critical for translation of mucosal subunit vaccines and immunotherapies. This review covers engineering strategies to enhance mucosal uptake via active targeting and passive transport mechanisms, with a parallel focus on mechanisms of immune activation and regulation in the respiratory mucosa. By combining engineering strategies for enhanced mucosal delivery with a better understanding of immune mechanisms in the NALT and BALT, we hope to illustrate the potential of these mucosal sites as targets for immunomodulation.