COVID-19 and Mucosal Immunization: Assessing Current Efforts, Challenges, and Future Opportunities for Vaccine Development

SARS-CoV-2 Vaccines: The Mucosal Immunity Imperative

Mucosal immunity plays a crucial role in defending against coronaviruses, particularly at respiratory sites, serving as the first line of defense against viral invasion and replication. Coronaviruses have developed various immune evasion strategies at the mucosal immune system, hindering the recognition of infected cells and evading antibody responses. Understanding the immune mechanisms and responses is crucial for developing effective vaccines and therapeutics against coronaviruses. The role of mucosal immunity in COVID-19 is significant, influencing both local and systemic immune responses to the virus. Although most clinical studies focus on antibodies and cellular immunity in peripheral blood, mucosal immune responses in the respiratory tract play a key role in the early restriction of viral replication and the clearance of SARS-CoV-2. Identification of mucosal biomarkers associated with viral clearance will allow monitoring of infection-induced immunity. Mucosally delivered vaccines and those under clinical trials are being compared and contrasted to understand their effectiveness in inducing mucosal immunity against coronaviruses. A greater understanding of lung tissue-based immunity may lead to improved diagnostic and prognostic procedures and novel treatment strategies aimed at reducing the disease burden of community-acquired pneumonia, avoiding the systemic manifestations of infection and excess morbidity and mortality. This comprehensive review article outlines the current evidence about the role of mucosal immune responses in the clearance of SARS-CoV-2 infection, as well as potential mucosal mechanisms of protection against (re-)infection. It also proposes that there is a significant role for mucosal immunity and for secretory as well as circulating IgA antibodies in COVID-19, and that it is important to elucidate this in order to comprehend especially the asymptomatic and mild states of the infection, which appear to account for the majority of cases. Moreover, it is possible that mucosal immunity can be exploited for beneficial diagnostic, therapeutic, or prophylactic purposes. The findings from recent studies on mucosal immunity in COVID-19 can be used to develop effective vaccines and treatments that can effectively target both mucosal and systemic immune responses.

The majority of human immunodeficiency virus type 1 (HIV-1) infections occur via mucosal transmission through contact with genital secretions containing cell-associated and cell-free virus. However, few studies have assessed whether exposure to cells, HIV-1 infected or uninfected, plays a role in the sexual transmission of HIV-1. This study examined phenotypic changes in mucosal and systemic lymphoid tissue 24 hr after vaginal exposure to in vitro equilibrated infectious doses of cell-associated or cell-free feline immunodeficiency virus, uninfected heterologous cells, or medium alone. We found that even at this early time-point, mucosal exposure to virus induced substantial alterations in the phenotype and distribution of leucocytes, particularly in the tissues of the mucosal immune system. Second, we found that the type of virus inoculum directly influenced the phenotypic changes seen. Vaginal exposure to cell-free virus tended to induce more generalized phenotypic changes, typically in the peripheral immune system (blood and systemic lymph nodes). In contrast, exposure to cell-associated virus was primarily associated with phenotypic shifts in the mucosal immune system (gut and mucosal/draining lymph nodes). In addition, we found that exposure to uninfected heterologous cells also induced alterations in the mucosal immune system. These data suggest that significant immune changes occur within the first 24 hr of virus exposure, well before substantial replication would be anticipated. As the mucosal immune system, and particularly the gut, is an early and persistent target for lentiviral replication, these findings have substantial implications for HIV-1 pathogenesis and vaccine development.

The mucosal immune system is the largest component of the entire immune system, having evolved to provide protection at the main sites of infectious threat: the mucosae. As SARS-CoV-2 initially infects the upper respiratory tract, its first interactions with the immune system must occur predominantly at the respiratory mucosal surfaces, during both inductive and effector phases of the response. However, almost all studies of the immune response in COVID-19 have focused exclusively on serum antibodies and systemic cell-mediated immunity including innate responses. This article proposes that there is a significant role for mucosal immunity and for secretory as well as circulating IgA antibodies in COVID-19, and that it is important to elucidate this in order to comprehend especially the asymptomatic and mild states of the infection, which appear to account for the majority of cases. Moreover, it is possible that mucosal immunity can be exploited for beneficial diagnostic, therapeutic, or prophylactic purposes.

Mucosal immunization with a DNA vaccine induces immune responses against HIV-1 at a mucosal site

Galectin-9 Is Critical for Mucosal Adaptive Immunity through the T Helper 17–IgA Axis

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

Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA

Anatomical and cellular basis of immunity and tolerance in the intestine.

Induction of mucosal and systemic immunity against respiratory syncytial virus by inactivated virus supplemented with TLR9 and NOD2 ligands

Mucosal immunity is essential for preventing viral infections through the mucosal route. The emerging SARS-CoV-2 variants have posed additional hurdles to the efficiency of existing vaccines. The rapid development of novel vaccines that generate broad mucosal and systemic immunity could be the most effective strategy to address this issue. In this study, we developed a recombinant and replication-deficient type-5 adenoviral vaccine with a built-in double-strand RNA adjuvant and the vaccine expresses the SARS-CoV-2 Omicron BA.1 spike (S) antigen (hereinafter referred to as "the oral vaccine"). We found that two doses of the oral vaccine in BALB/c mice generated long-lasting S-specific mucosal and systemic immune responses, as well as broad neutralizing antibodies and SIgA antibodies. In addition, we found that compared to an mRNA vaccine booster, using the oral vaccine as a booster could induce both effective mucosal and systemic immunity, addressing the limitation of mRNA vaccines in eliciting mucosal immunity. Prospective oral vaccines require further investigation into development and potential applications, particularly viral challenge experiments, before clinical trials.

The mucosal immune system represents a critical defense mechanism, safeguarding the body from an array of external pathogens. As the body’s first line of immune protection, it plays an essential role in initiating both innate and adaptive immune responses. Through intricate networks of immune cells and complex molecular pathways, mucosal immunity orchestrates a robust defense not only at the local level but also activates systemic immune responses to ensure comprehensive protection. Consequently, the mucosal immune system has garnered immense interest in the field of vaccine development, given its potential to foster durable and effective immunization. Despite the profound promise of mucosal immunity, the development of mucosal vaccines faces significant challenges, particularly with existing technological platforms that primarily rely on live attenuated or inactivated vaccines. However, emerging innovative platforms, including subunit vaccines, viral vector vaccines, and the groundbreaking application of mRNA vaccines, are offering new perspectives, vastly improving the scope and efficacy of mucosal immunization. As mucosal immunity research continues to evolve, rapid advancements in biotechnology and immunology provide promising strategies to enhance immune responses and overcome inherent limitations. This review delves into the latest progress in oral, nasal, and other forms of mucosal vaccines, analyzing the intricate relationship between mucosal immune characteristics and vaccine design. Emphasis is placed on the pivotal role of advanced adjuvants and delivery systems in maximizing vaccine efficacy. This review addresses current challenges, highlights future research opportunities, and aims to provide a comprehensive framework for advancing the field of mucosal immunity and vaccine development.

Development of a vaccine that can simultaneously induce effective mucosal immunity and systemic immunity is an ideal goal to prevent mucosal pathogenic infections. The digestive tract has many sites for inducing mucosal immunity, including the mouth, stomach and small intestine. An ideal oral viral vaccine can not only induce better local and distal mucosal immunity, but also produce better systemic immunity. The oral viral vaccine has also attracted much attention because of its painless vaccination, self-administration and other advantages. Due to the complexity of human digestive tract environment and mucosal immunity, only three oral attenuated live vaccines have been successfully marketed for human use. This review summarizes the characteristics of gastrointestinal mucosal immunity, the current types and research status of oral viral vaccines, and the challenges faced by oral viral vaccines, with the hope to facilitate the research and development of oral viral vaccines for human use in China.

The oral cavity is the beginning of the aero-digestive tract, which is covered by mucosal epithelium continuously under the threat of invasion of pathogens, it is thus protected by the mucosal immune system. In the early phase of our scientific efforts for the demonstration of mucosal immune system, dental science was one of major driving forces due to their foreseeability to use oral immunity for the control of oral diseases. The mucosal immune system is divided functionally into, but interconnected inductive and effector sites. Intestinal Peyer’s patches (PPs) are an inductive site containing antigen-sampling M cells and immunocompetent cells required to initiate antigen-specific immune responses. At effector sites, PP-originated antigen-specific IgA B cells become plasma cells to produce polymeric IgA and form secretory IgA by binding to poly-Ig receptor expressed on epithelial cells for protective immunity. The development of new-generation mucosal vaccines, including the rice-based oral vaccine MucoRice, on the basis of the coordinated mucosal immune system is a promising strategy for the control of mucosal infectious diseases.

Induction of mucosal immunity by oral immunization with protein antigen alone is difficult: potent mucosal adjuvants, vectors, or other special delivery systems are required. Cholera toxin (CT) has been shown to be an effective adjuvant for the development of mucosal vaccines and, when given with vaccine, induces both mucosal and systemic immune responses via a Th2 cell-dependent pathway. However, and in addition to potential type-I hypersensitivity, a major concern for use of mucosal adjuvants such as CT is that this molecule is not suitable for use in humans because of its inherent toxicity. When we examined the potential toxicity of CT for the central nervous system, both CT and CT-B accumulated in the olfactory nerves/epithelium and olfactory bulbs of mice when given by the nasal route. The development of effective mucosal vaccines for the elderly is also an important issue; however, only limited information is available. When mucosal adjuvanticity of CT was evaluated in aged mice, an early immune dysregulation was evident in the mucosal immune system. The present review discusses these potential problems for effective mucosal vaccine development. Tolerance represents the most common and important response of the host to environmental antigens, including food and commensal bacterial components, for the maintenance of an appropriate immunological homeostasis. We have examined whether Peyer patches could play a more important role for the maintenance of oral tolerance. Using Peyer patch-null mice, we found that mice lacking this gut-associated lymphoid tissue retained their capability to produce secretory IgA antibodies but did not develop normal oral tolerance to protein antigens.