Journal articles on the topic 'Mucolas vaccination'
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1
Gary, Ebony N., and Michele A. Kutzler. "Defensive Driving: Directing HIV-1 Vaccine-Induced Humoral Immunity to the Mucosa with Chemokine Adjuvants." Journal of Immunology Research 2018 (December 13, 2018): 1–14. http://dx.doi.org/10.1155/2018/3734207.
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A myriad of pathogens gain access to the host via the mucosal route; thus, vaccinations that protect against mucosal pathogens are critical. Pathogens such as HIV, HSV, and influenza enter the host at mucosal sites such as the intestinal, urogenital, and respiratory tracts. All currently licensed vaccines mediate protection by inducing the production of antibodies which can limit pathogen replication at the site of infection. Unfortunately, parenteral vaccination rarely induces the production of an antigen-specific antibody at mucosal surfaces and thus relies on transudation of systemically generated antibody to mucosal surfaces to mediate protection. Mucosa-associated lymphoid tissues (MALTs) consist of a complex network of immune organs and tissues that orchestrate the interaction between the host, commensal microbes, and pathogens at these surfaces. This complexity necessitates strict control of the entry and exit of lymphocytes in the MALT. This control is mediated by chemoattractant chemokines or cytokines which recruit immune cells expressing the cognate receptors and adhesion molecules. Exploiting mucosal chemokine trafficking pathways to mobilize specific subsets of lymphocytes to mucosal tissues in the context of vaccination has improved immunogenicity and efficacy in preclinical models. This review describes the novel use of MALT chemokines as vaccine adjuvants. Specific attention will be placed upon the use of such adjuvants to enhance HIV-specific mucosal humoral immunity in the context of prophylactic vaccination.
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Eriksson, Kristina, Marianne Quiding-Järbrink, Jacek Osek, Åke Möller, Stellan Björk, Jan Holmgren, and Cecil Czerkinsky. "Specific-Antibody-Secreting Cells in the Rectums and Genital Tracts of Nonhuman Primates following Vaccination." Infection and Immunity 66, no. 12 (December 1, 1998): 5889–96. http://dx.doi.org/10.1128/iai.66.12.5889-5896.1998.
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ABSTRACT To determine optimal strategies to induce specific-antibody-secreting cells (specific ASC) in the rectal and vaginal mucosae, we immunized monkeys with a prototype mucosal immunogen, cholera toxin (CT), given locally or via gastric or parenteral administration. Repeated rectal or vaginal CT immunizations induced strong mucosal and systemic ASC responses. The mucosal responses were, however, confined to the immunization sites and comprised high levels of both specific antitoxin immunoglobulin A (IgA) and IgG. Large numbers of specific IgA and IgG ASC were detected in cell suspensions from dissociated genital and rectal tissues, demonstrating local accumulation of effector B cells at these sites. Intragastric immunization with CT did not per se give rise to cervicovaginal or rectal ASC responses but did prime for a rectal IgA ASC response to local booster immunization. Both rectal and vaginal immunizations also induced circulating blood IgG ASC and IgA ASC. In conclusion, these results show that local administration of antigen to the rectal or vaginal mucosa results in higher ASC responses than systemic or distant mucosal delivery. Furthermore, both the vaginal and the rectal mucosae can serve as inductive sites for systemic ASC responses. These observations should be relevant to the development of vaccines against sexually transmitted diseases such as that caused by human immunodeficiency virus.
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Tang, Jie, Larry Cai, Chuanfei Xu, Si Sun, Yuheng Liu, Joseph Rosenecker, and Shan Guan. "Nanotechnologies in Delivery of DNA and mRNA Vaccines to the Nasal and Pulmonary Mucosa." Nanomaterials 12, no. 2 (January 11, 2022): 226. http://dx.doi.org/10.3390/nano12020226.
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Recent advancements in the field of in vitro transcribed mRNA (IVT-mRNA) vaccination have attracted considerable attention to such vaccination as a cutting-edge technique against infectious diseases including COVID-19 caused by SARS-CoV-2. While numerous pathogens infect the host through the respiratory mucosa, conventional parenterally administered vaccines are unable to induce protective immunity at mucosal surfaces. Mucosal immunization enables the induction of both mucosal and systemic immunity, efficiently removing pathogens from the mucosa before an infection occurs. Although respiratory mucosal vaccination is highly appealing, successful nasal or pulmonary delivery of nucleic acid-based vaccines is challenging because of several physical and biological barriers at the airway mucosal site, such as a variety of protective enzymes and mucociliary clearance, which remove exogenously inhaled substances. Hence, advanced nanotechnologies enabling delivery of DNA and IVT-mRNA to the nasal and pulmonary mucosa are urgently needed. Ideal nanocarriers for nucleic acid vaccines should be able to efficiently load and protect genetic payloads, overcome physical and biological barriers at the airway mucosal site, facilitate transfection in targeted epithelial or antigen-presenting cells, and incorporate adjuvants. In this review, we discuss recent developments in nucleic acid delivery systems that target airway mucosa for vaccination purposes.
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Lindholm, Catharina, Andrew Naylor, Eva-Liz Johansson, and Marianne Quiding-Järbrink. "Mucosal Vaccination Increases Endothelial Expression of Mucosal Addressin Cell Adhesion Molecule 1 in the Human Gastrointestinal Tract." Infection and Immunity 72, no. 2 (February 2004): 1004–9. http://dx.doi.org/10.1128/iai.72.2.1004-1009.2004.
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ABSTRACT Homing of leukocytes to various tissues is dependent on the interaction between homing receptors on leukocytes and their ligands, addressins, on endothelial cells. Mucosal immunization results in homing of antigen-specific lymphocytes back to the mucosa where they first encountered the antigen. However, it is unknown whether this homing of antigen-specific cells is mediated by an altered endothelial addressin expression after vaccination. Using different immunization routes with an oral cholera vaccine, we show that the endothelial expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is increased in the gastric and upper small intestinal mucosae after immunization through various local routes in the upper gastrointestinal tract. In contrast, rectal immunization did not influence the levels of MAdCAM-1 in the gastric or duodenal mucosa. Furthermore, we show that MAdCAM-1 can be induced on human endothelial cells by tumor necrosis factor alpha (TNF-α) and gamma interferon. The vaccine component cholera toxin B subunit (CTB) increased MAdCAM-1 expression on endothelial cells in cultured human gastric explants, an effect that seemed to be mediated by TNF-α. In conclusion, MAdCAM-1 expression is increased in the upper gastrointestinal tract after local immunizations with a vaccine containing CTB. This strongly suggests the involvement of MAdCAM-1 in the preferential homing of mucosal lymphocytes to their original site of activation.
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González Aznar, Elizabeth, Belkis Romeu, Miriam Lastre, Caridad Zayas, Maribel Cuello, Osmir Cabrera, Yolanda Valdez, Mildrey Fariñas, and Oliver Pérez. "Mucosal and systemic immune responses induced by a single time vaccination strategy in mice." Canadian Journal of Microbiology 61, no. 8 (August 2015): 531–38. http://dx.doi.org/10.1139/cjm-2015-0063.
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Vaccination is considered by the World Health Organization as the most cost-effective strategy for controlling infectious diseases. In spite of great successes with vaccines, many infectious diseases are still leading killers, because of the inadequate coverage of many vaccines. Several factors have been responsible: number of doses, high vaccine reactogenicity, vaccine costs, vaccination policy, among others. Contradictorily, few vaccines are of single dose and even less of mucosal administration. However, more common infections occur via mucosa, where secretory immunoglobulin A plays an essential role. As an alternative, we proposed a novel protocol of vaccination called Single Time Vaccination Strategy (SinTimVaS) by immunizing 2 priming doses at the same time: one by mucosal route and the other by parenteral route. Here, the mucosal and systemic responses induced by Finlay adjuvants (AF Proteoliposome 1 and AF Cochleate 1) implementing SinTimVaS in BALB/c mice were evaluated. One intranasal dose of AF Cochleate 1 and an intramuscular dose of AF Proteoliposome 1 adsorbed onto aluminum hydroxide, with bovine serum albumin or tetanus toxoid as model antigens, administrated at the same time, induced potent specific mucosal and systemic immune responses. Also, we demonstrated that SinTimVaS using other mucosal routes like oral and sublingual, in combination with the subcutaneous route elicits immune responses. SinTimVaS, as a new immunization strategy, could increase vaccination coverage and reduce time–cost vaccines campaigns, adding the benefits of immune response in mucosa.
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Acosta-Ramirez, Elizabeth, Zhou Xing, Reto Schwendener, and Jun Wang. "Alveolar macrophages control the quality of CD4+ T lymphocytes in the respiratory tract upon recombinant adenoviral mucosal vaccination (39.34)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 39.34. http://dx.doi.org/10.4049/jimmunol.182.supp.39.34.
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Abstract Infectious diseases are acquired through mucosa surfaces making mucosal vaccination important for their control. Previously, using a recombinant adenoviral-based (Ad) vaccine we have demonstrated that a single mucosal but not parenteral immunization confers protection against intracellular bacterial challenge in the lung. Here, we examined the mechanisms regulating induction of OVA-specific CD4 T-cell responses at mucosal and systemic compartments in Balb/C mice after intranasal (i.n.) or intramuscular (i.m.) vaccination with an Ad expressing OVA. We found that i.n. vaccination induced local OVA-specific T cell activation whereas i.m. vaccination induced both local and systemic T-cell activation despite of the dosage used for vaccination. Remarkably, i.n. immunization induced a characteristic proliferative kinetic different from the one induced by i.m. vaccination. Furthermore, i.n. vaccination induced a highly polarized Th1 response while i.m. immunization induced a mixed Th1/Th2 response. Of importance, in vivo depletion of alveolar macrophages led to similar T-cell proliferation kinetics and comparable cytokine production in mice receiving i.n. and i.m. vaccination. Our data suggests that alveolar macrophages provide a special microenvironment at the mucosal site, which control the quantity and quality of CD4 T memory cells and protective immunity against mucosal infectious challenges.
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Hellfritzsch and Scherließ. "Mucosal Vaccination via the Respiratory Tract." Pharmaceutics 11, no. 8 (August 1, 2019): 375. http://dx.doi.org/10.3390/pharmaceutics11080375.
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Vaccine delivery via mucosal surfaces is an interesting alternative to parenteral vaccine administration, as it avoids the use of a needle and syringe. Mucosal vaccine administration also targets the mucosal immune system, which is the largest lymphoid tissue in the human body. The mucosal immune response involves systemic, antigen-specific humoral and cellular immune response in addition to a local response which is characterised by a predominantly cytotoxic T cell response in combination with secreted IgA. This antibody facilitates pathogen recognition and deletion prior to entrance into the body. Hence, administration via the respiratory mucosa can be favoured for all pathogens which use the respiratory tract as entry to the body, such as influenza and for all diseases directly affecting the respiratory tract such as pneumonia. Additionally, the different mucosal tissues of the human body are interconnected via the so-called “common mucosal immune system”, which allows induction of an antigen-specific immune response in distant mucosal sites. Finally, mucosal administration is also interesting in the area of therapeutic vaccination, in which a predominant cellular immune response is required, as this can efficiently be induced by this route of delivery. The review gives an introduction to respiratory vaccination, formulation approaches and application strategies.
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Lu, Bin, Wenbo Yu, Xiaoxing Huang, Haibo Wang, Li Liu, and Zhiwei Chen. "Mucosal Immunization Induces a Higher Level of Lasting Neutralizing Antibody Response in Mice by a Replication-Competent Smallpox Vaccine: Vaccinia Tiantan Strain." Journal of Biomedicine and Biotechnology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/970424.
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The possible bioterrorism threat using the variola virus, the causative agent of smallpox, has promoted us to further investigate the immunogenicity profiles of existing vaccines. Here, we study for the first time the immunogenicity profile of a replication-competent smallpox vaccine (vaccinia Tiantan, VTT strain) for inducing neutralizing antibodies (Nabs) through mucosal vaccination, which is noninvasive and has a critical implication for massive vaccination programs. Four different routes of vaccination were tested in parallel including intramuscular (i.m.), intranasal (i.n.), oral (i.o.), and subcutaneous (s.c.) inoculations in mice. We found that one time vaccination with an optimal dose of VTT was able to induce anti-VTT Nabs via each of the four routes. Higher levels of antiviral Nabs, however, were induced via the i.n. and i.o. inoculations when compared with the i.m. and s.c. routes. Moreover, the i.n. and i.o. vaccinations also induced higher sustained levels of Nabs overtime, which conferred better protections against homologous or alternating mucosal routes of viral challenges six months post vaccination. The VTT-induced immunity via all four routes, however, was partially effective against the intramuscular viral challenge. Our data have implications for understanding the potential application of mucosal smallpox vaccination and for developing VTT-based vaccines to overcome preexisting antivaccinia immunity.
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Reljic, Rajko, Laura Sibley, Jen-Min Huang, Ilaria Pepponi, Andreas Hoppe, Huynh A. Hong, and Simon M. Cutting. "Mucosal Vaccination against Tuberculosis Using Inert Bioparticles." Infection and Immunity 81, no. 11 (August 19, 2013): 4071–80. http://dx.doi.org/10.1128/iai.00786-13.
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ABSTRACTNeedle-free, mucosal immunization is a highly desirable strategy for vaccination against many pathogens, especially those entering through the respiratory mucosa, such asMycobacterium tuberculosis. Unfortunately, mucosal vaccination against tuberculosis (TB) is impeded by a lack of suitable adjuvants and/or delivery platforms that could induce a protective immune response in humans. Here, we report on a novel biotechnological approach for mucosal vaccination against TB that overcomes some of the current limitations. This is achieved by coating protective TB antigens onto the surface of inert bacterial spores, which are then delivered to the respiratory tract. Our data showed that mice immunized nasally with coated spores developed humoral and cellular immune responses and multifunctional T cells and, most importantly, presented significantly reduced bacterial loads in their lungs and spleens following pathogenic challenge. We conclude that this new vaccine delivery platform merits further development as a mucosal vaccine for TB and possibly also other respiratory pathogens.
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Feng, Fengling, Ziyu Wen, Jiaoshan Chen, Yue Yuan, Congcong Wang, and Caijun Sun. "Strategies to Develop a Mucosa-Targeting Vaccine against Emerging Infectious Diseases." Viruses 14, no. 3 (March 3, 2022): 520. http://dx.doi.org/10.3390/v14030520.
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Numerous pathogenic microbes, including viruses, bacteria, and fungi, usually infect the host through the mucosal surfaces of the respiratory tract, gastrointestinal tract, and reproductive tract. The mucosa is well known to provide the first line of host defense against pathogen entry by physical, chemical, biological, and immunological barriers, and therefore, mucosa-targeting vaccination is emerging as a promising strategy for conferring superior protection. However, there are still many challenges to be solved to develop an effective mucosal vaccine, such as poor adhesion to the mucosal surface, insufficient uptake to break through the mucus, and the difficulty in avoiding strong degradation through the gastrointestinal tract. Recently, increasing efforts to overcome these issues have been made, and we herein summarize the latest findings on these strategies to develop mucosa-targeting vaccines, including a novel needle-free mucosa-targeting route, the development of mucosa-targeting vectors, the administration of mucosal adjuvants, encapsulating vaccines into nanoparticle formulations, and antigen design to conjugate with mucosa-targeting ligands. Our work will highlight the importance of further developing mucosal vaccine technology to combat the frequent outbreaks of infectious diseases.
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Chen, Lihao, Jun Wang, Anna Zganiacz, and Zhou Xing. "Single Intranasal Mucosal Mycobacterium bovis BCG Vaccination Confers Improved Protection Compared to Subcutaneous Vaccination against Pulmonary Tuberculosis." Infection and Immunity 72, no. 1 (January 2004): 238–46. http://dx.doi.org/10.1128/iai.72.1.238-246.2004.
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ABSTRACT Whether the intranasal (i.n.) route of Mycobacterium bovis BCG vaccination provides better protection against pulmonary tuberculosis than subcutaneous (s.c.) vaccination remains an incompletely solved issue. In the present study, we compared both immune responses and protection elicited by single BCG vaccinations via the i.n. or s.c. route in BALB/c mice. While both i.n. and s.c. vaccination triggered comparable levels of primary immune activation in the spleen and draining lymph nodes, i.n. vaccination led to a greater antigen-specific gamma interferon recall response in splenocytes than s.c. vaccination upon secondary respiratory mycobacterial challenge, accompanied by an increased frequency of antigen-specific lymphocytes. There was also a quicker cellular response in the lungs of i.n. vaccinated mice upon mycobacterial challenge. Mice vaccinated i.n. were found to be much better protected, particularly in the lung, than s.c. vaccinated counterparts against pulmonary tuberculosis at both 3 and 6 months postvaccination. These results suggest that the i.n. route of vaccination improves the protective effect of the current BCG vaccine.
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Kanner, E. V., A. V. Gorelov, D. V. Pechkurov, E. A. Gorelova, M. L. Maksimov, and A. S. Ermolaeva. "Mucosal immune system of digestive and respiratory tracts: possibilities of prevention and treatment of infectious diseases." Medical Council, no. 11 (July 18, 2019): 100–107. http://dx.doi.org/10.21518/2079-701x-2019-11-100-107.
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The immune system of the body’s mucous membranes plays a huge role in the development, maintenance and regulation of immune homeostasis, being an important component of the multi-component immune system. The structural basis of local immunity is the lymphatic tissue associated with the mucous membranes (MALT). There is now scientific evidence that the mucous membrane sections of different body systems interact closely with each other, subject to the same regulatory influences. This relationship is particularly close between the digestive and respiratory tract, and studies have shown that vaccination of the mucosa of one part increases the protective function of the mucosa of another part, and that virus infection leads to virus-specific concentrations of immunoglobulins in the secretion of the mucosa of another part. The impact on the intestinal microbiota can be a convenient tool to prevent not only gastrointestinal, but also respiratory diseases. In a number of works the clinical effects confirming expediency of probiotics application both at healthy, and at sick children are confirmed. An extremely important component of the local immune system is the antimicrobial peptides, which play a key role in the formation of the first line of defense against infections. AMP have a number of proven biological effects: antibacterial, antiviral and antifungal effects, and some have antitumor properties. Thus, the prospects for prevention and treatment of many infectious diseases lie in the new possibilities for influencing mucosal immunity.
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Wassen, Lotta, and Marianne Jertborn. "Kinetics of Local and Systemic Immune Responses after Vaginal Immunization with Recombinant Cholera Toxin B Subunit in Humans." Clinical Diagnostic Laboratory Immunology 12, no. 3 (March 2005): 447–52. http://dx.doi.org/10.1128/cdli.12.3.447-452.2005.
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ABSTRACT Vaginal vaccination seems to be the best strategy for inducing specific immunoglobulin A (IgA) and IgG antibody responses in the female genital tract. The relative efficiencies of one, two, and three vaginal doses of recombinant cholera toxin B subunit (CTB) in generating mucosal and systemic immune responses in healthy women were evaluated, and the kinetics of the immune responses were monitored for responding volunteers for up to 12 months after the last vaccination. A single dose of CTB failed to generate CTB-specific IgA antibody responses in cervical secretions. Two vaccinations induced significant increases in IgA antitoxin titers in seven of nine volunteers, and four volunteers also developed IgG antitoxin responses. The magnitudes of the responses were 20-fold for IgA antitoxin and 7.1-fold for IgG antitoxin. A third vaccination did not significantly increase the antitoxin responses, although the frequency of IgG responses was slightly higher than that after the second vaccination. In serum, CTB-specific antibodies were observed already after a single vaccination. However, two vaccinations were required to induce marked IgA as well as IgG antitoxin titer increases in the majority of volunteers. The postvaccination levels of antitoxin antibodies in serum were comparable after two and three vaccinations. At 12 months after vaccination, significantly elevated IgA and IgG antitoxin levels in cervical secretions could still be detected in approximately half of the volunteers who had initially responded to the vaccine. Antitoxin titer increases in serum were found in most of the vaccinees at follow-up.
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Doherty, T. Mark, Anja Weinrich Olsen, Laurens van Pinxteren, and Peter Andersen. "Oral Vaccination with Subunit Vaccines Protects Animals against Aerosol Infection with Mycobacterium tuberculosis." Infection and Immunity 70, no. 6 (June 2002): 3111–21. http://dx.doi.org/10.1128/iai.70.6.3111-3121.2002.
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ABSTRACT Immunity against Mycobacterium tuberculosis depends largely on activation of cell-mediated responses, and gamma interferon has been shown to play a crucial role in this process in both humans and animal models. Since the lung is normally the organ in which infection is initiated and is the major site of pathology, immune responses in the lung play a significant role in restricting initial infection with M. tuberculosis. The aim of the present study was to stimulate efficient immunity in the lung by targeting the gut mucosa. Detoxified monophosphoryl lipid A (MPL) has been shown to be a relatively nontoxic adjuvant which efficiently promotes the induction of type 1 responses when it is given by the traditional subcutaneous route. We have therefore compared subcutaneous immunization of mice to oral immunization by using a model subunit vaccine carrying two immunodominant proteins from M. tuberculosis, in combination with MPL-based adjuvants. While less effective when used to prime a response, a heterologous priming and boosting vaccination strategy employing oral boosting induced significant systemic type 1 responses which equaled and surpassed those attained by subcutaneous immunization protocols. Moreover, the increased immune responses observed correlated with the induction of substantial protection against subsequent aerosol infection with virulent M. tuberculosis at levels comparable to, or better than, those obtained by multiple subcutaneous vaccinations. These results demonstrate that booster vaccinations via mucosal surfaces, by combining efficient subunit vaccines with the potent adjuvant MPL, may be an effective method of addressing some of the shortcomings of current vaccination strategies.
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Fujimoto, Kosuke, and Satoshi Uematsu. "Development of prime–boost-type next-generation mucosal vaccines." International Immunology 32, no. 9 (December 28, 2019): 597–603. http://dx.doi.org/10.1093/intimm/dxz085.
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Abstract Our bodies are constantly exposed to a wide variety of pathogenic micro-organisms through mucosal sites. Therefore, effective vaccines that can protect at the mucosa are vital; however, only a few clinically established mucosal vaccines are available. Although conventional injectable vaccines can induce antigen-specific serum immunoglobulin G (IgG) and prevent severe infection, it is difficult to efficiently inhibit the invasion of pathogens at mucosal surfaces because of the inadequate ability to induce antigen-specific IgA. Recently, we have developed a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides and reported its application. Unlike other conventional injectable vaccines, this immunization contributes to the induction of antigen-specific mucosal and systemic immune responses. Even if antigen-specific IgA at the mucosa disappears, this immunization can induce high-titer IgA after boosting with a small amount of antigen on the target mucosal surface. Indeed, vaccination with Streptococcus pneumoniae antigen effectively prevented lung infection induced by this bacterium. In addition, vaccination with Clostridium ramosum, which is a representative pathobiont associated with obesity and diabetes in humans, reduced obesity in mice colonized with this microorganism. This immunization approach might be an effective treatment for intestinal bacteria-mediated diseases that have been difficult to regulate so far, as well as common infectious diseases.
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Strbo, Natasa, Monica Vaccari, Savita Pahwa, Michael Kolber, Eva Fisher, Louis Gonzalez, Genoveffa Franchini, and Eckhard Podack. "Heat shock protein Gp96-Ig-peptide complexes based vaccine induce predominant immune responses at mucosal sites (46.13)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 46.13. http://dx.doi.org/10.4049/jimmunol.184.supp.46.13.
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Abstract We have developed a vaccine design that uses the unique ability of the endoplasmic reticulum (ER) chaperone, heat shock protein gp96, to bind antigenic peptides and deliver them to antigen-presenting cells. Secreted form of gp96, gp96-Ig, was generated by replacing the ER retention sequence KDEL with the IgG1-Fc domain. To generate a cellular SIV vaccine, HEK-293 cells were transfected with gp96-Ig and the cDNAs encoding the SIV antigens gag, env and retanef. Irradiated, transfected 293 cells that secrete 1, 5 or 50 micrograms gp96-Ig-SIV complexes in 24h, were injected intraperitoneally (IP) in Mamu-A*01+ Rhesus Macaques at 0, 4 and 25 weeks. To determine whether gp96-Ig vaccination induces mucosal immunity, we used the 3T3-OVA-gp96-Ig/OT-1 model. Our data indicate that the best route of vaccination for induction of mucosal CD8-CTL immunity is the IP route. Gp96-Ig immunization increases frequency of CD11chighMHC classIIhighCD103+ cells in peritoneal cavity and efficiently induces CCR9 on responding T cells. In nonhuman primate model, the frequency of SIV-specific cells in the rectal mucosa reached 30-50% after the third immunization. We conclude that gp96-Ig vaccination startegy induces antigen-specific effector memory CD8T cells migrating to the intestinal mucosa and thus could be extremely useful for improving protection against a range of mucosal pathogens.
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Park, Jang Hyun, and Heung Kyu Lee. "Delivery Routes for COVID-19 Vaccines." Vaccines 9, no. 5 (May 19, 2021): 524. http://dx.doi.org/10.3390/vaccines9050524.
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The novel coronavirus, SARS-CoV-2, which causes COVID-19, has resulted in a pandemic with millions of deaths. To eradicate SARS-CoV-2 and prevent further infections, many vaccine candidates have been developed. These vaccines include not only traditional subunit vaccines and attenuated or inactivated viral vaccines but also nucleic acid and viral vector vaccines. In contrast to the diversity in the platform technology, the delivery of vaccines is limited to intramuscular vaccination. Although intramuscular vaccination is safe and effective, mucosal vaccination could improve the local immune responses that block the spread of pathogens. However, a lack of understanding of mucosal immunity combined with the urgent need for a COVID-19 vaccine has resulted in only intramuscular vaccinations. In this review, we summarize the history of vaccines, current progress in COVID-19 vaccine technology, and the status of intranasal COVID-19 vaccines. Future research should determine the most effective route for vaccine delivery based on the platform and determine the mechanisms that underlie the efficacy of different delivery routes.
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Jiang, Yanping, Shuo Jia, Dianzhong Zheng, Fengsai Li, Shengwen Wang, Li Wang, Xinyuan Qiao, et al. "Protective Immunity against Canine Distemper Virus in Dogs Induced by Intranasal Immunization with a Recombinant Probiotic Expressing the Viral H Protein." Vaccines 7, no. 4 (December 10, 2019): 213. http://dx.doi.org/10.3390/vaccines7040213.
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Canine distemper virus (CDV) elicits a severe contagious disease in a broad range of hosts. CDV mortality rates are 50% in domestic dogs and 100% in ferrets. Its primary infection sites are respiratory and intestinal mucosa. This study aimed to develop an effective mucosal CDV vaccine using a non-antibiotic marked probiotic pPGΔCm-T7g10-EGFP-H/L. casei 393 strain expressing the CDV H protein. Its immunogenicity in BALB/c mice was evaluated using intranasal and oral vaccinations, whereas in dogs the intranasal route was used for vaccination. Our results indicate that this probiotic vaccine can stimulate a high level of secretory immunoglobulin A (sIgA)-based mucosal and IgG-based humoral immune responses in mice. SIgA levels in the nasal lavage and lungs were significantly higher in intranasally vaccinated mice than those in orally vaccinated mice. Both antigen-specific IgG and sIgA antibodies were effectively elicited in dogs through the intranasal route and demonstrated superior immunogenicity. The immune protection efficacy of the probiotic vaccine was evaluated by challenging the immunized dogs with virulent CDV 42 days after primary immunization. Dogs of the pPGΔCm-T7g10-EGFP-H/L. casei 393 group were completely protected against CDV. The proposed probiotic vaccine could be promising for protection against CDV infection in dogs.
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Kweon, Mi-Na. "Sublingual mucosa: A new vaccination route for systemic and mucosal immunity." Cytokine 54, no. 1 (April 2011): 1–5. http://dx.doi.org/10.1016/j.cyto.2010.12.014.
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Jakobsen, Håvard, Dominique Schulz, Mariagrazia Pizza, Rino Rappuoli, and Ingileif Jónsdóttir. "Intranasal Immunization with Pneumococcal Polysaccharide Conjugate Vaccines with Nontoxic Mutants of Escherichia coliHeat-Labile Enterotoxins as Adjuvants Protects Mice against Invasive Pneumococcal Infections." Infection and Immunity 67, no. 11 (November 1, 1999): 5892–97. http://dx.doi.org/10.1128/iai.67.11.5892-5897.1999.
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ABSTRACT Host defenses against Streptococcus pneumoniae depend largely on phagocytosis following opsonization by polysaccharide-specific immunoglobulin G (IgG) antibodies and complement. Since colonization of the respiratory mucosa is the first step in pneumococcal pathogenesis, mucosal immune responses may play a significant role. In addition to inducing systemic immune responses, mucosal vaccination with an effective adjuvant has the advantage of inducing mucosal IgA antibodies. The heat-labile enterotoxin (LT) ofEscherichia coli is a well-studied mucosal adjuvant, and adjuvant activity of nontoxic LT mutants has been demonstrated for several protein antigens. We investigated the immunogenicity of pneumococcal polysaccharide conjugate vaccines (PNC) of serotypes 1 and 3 in mice after intranasal (i.n.) immunization by using as an adjuvant the nontoxic LT mutant LT-K63 or LT-R72, which has minimal residual toxicity. Pneumococcal serotype-specific antibodies were measured in serum (IgM, IgG, and IgA) and saliva (IgA), and vaccine-induced protection was evaluated by i.n. challenge with virulent pneumococci of the homologous serotype. When administered with LT mutants, i.n. immunization with both conjugates induced systemic and mucosal immune responses, and serum IgG antibody levels were significantly higher than after subcutaneous immunization. All mice immunized i.n. with PNC-1 and LT mutants were protected against bacteremia and cleared the pneumococci from the lung 24 h after i.n. challenge; pneumococcal density correlated significantly with serum IgG antibody levels. Similarly, the survival of mice immunized i.n. with PNC-3 and LT mutants was significantly prolonged. These results demonstrate that i.n. vaccination with PNC and potent adjuvants can protect mice against invasive and lethal pneumococcal infections, indicating that mucosal vaccination with PNC may be an alternative vaccination strategy for humans.
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Kim, Sung-Kwon, Kimberly S. Schluns, and Leo Lefrançois. "Induction and Visualization of Mucosal Memory CD8 T Cells Following Systemic Virus Infection." Journal of Immunology 163, no. 8 (October 15, 1999): 4125–32. http://dx.doi.org/10.4049/jimmunol.163.8.4125.
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Abstract Whether CD8 T cell memory exists outside secondary lymphoid organs is unclear. Using an adoptive transfer system that enables tracking of OVA-specific CD8 T cells, we explored the antigenic requirements for inducing CD8 T cell memory and identified intestinal mucosa memory cells. Although systemic immunization with soluble OVA induced clonal expansion, memory CD8 cells were not produced. In contrast, infection with virus-encoding OVA induced memory CD8 cells in the periphery and the lamina propria and intraepithelial compartments of the intestinal mucosa. Mucosal memory cells expressed a distinct array of adhesion molecules as compared with secondary lymphoid memory cells, suggesting that there may be separate mucosal and systemic memory pools. Mucosal CD8 memory cells rapidly produced IFN-γ after Ag stimulation. Reactivation of memory cells by Ag feeding resulted in increased cell size and up-regulation of CD28 and CD11c. CD8 mucosal memory cells exhibited ex vivo lytic activity that was up-regulated dramatically following Ag reencounter in vivo. Interestingly, reactivation of memory cells did not require CD28-mediated costimulation. The ability of the intestinal mucosa to maintain CD8 memory cells provides a potential mechanism for effective mucosal vaccination.
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King, R. Glenn, Aaron Silva-Sanchez, Jessica N. Peel, Davide Botta, Alexandria M. Dickson, Amelia K. Pinto, Selene Meza-Perez, et al. "Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge." Vaccines 9, no. 8 (August 9, 2021): 881. http://dx.doi.org/10.3390/vaccines9080881.
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The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate.
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Glück, Ulrich, Jan-Olaf Gebbers, and Reinhard Glück. "Phase 1 Evaluation of Intranasal Virosomal Influenza Vaccine with and without Escherichia coli Heat-Labile Toxin in Adult Volunteers." Journal of Virology 73, no. 9 (September 1, 1999): 7780–86. http://dx.doi.org/10.1128/jvi.73.9.7780-7786.1999.
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ABSTRACT Virosomal vaccines were prepared by extracting hemagglutinin (HA) and neuraminidase from influenza virus and incorporating it in the membranes of liposomes composed of phosphatidylcholine. Two intranasal spray vaccine series were prepared: one series comprised 7.5 μg of HA of each of three strains recommended by the World Health Organization and 1 μg of Escherichia coli heat-labile toxin (HLT), and the other contained the HA without HLT. In addition, a third vaccine preparation contained 15 μg of HA and 2 μg of HLT. The parenteral virosomal vaccine contained 15 μg of HA without additional adjuvant. The immunogenicity of a single spray vaccination (15 μg of HA and 2 μg of HLT) was compared with that of two vaccinations (7.5 μg of HA with or without 1 μg of HLT) with an interval of 1 week in 60 healthy working adults. Twenty volunteers received one parenteral virosomal vaccine. Two nasal spray vaccinations with HLT-adjuvanted virosomal influenza vaccine induced a humoral immune response which was comparable to that with a single parenteral vaccination. A significantly higher induction of influenza virus-specific immunoglobulin A was noted in the saliva after two nasal applications. The immune response after a single spray vaccination was significantly lower. It could be shown that the use of HLT as a mucosal adjuvant is necessary to obtain a humoral immune response comparable to that with parenteral vaccination. All vaccines were well tolerated.
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Seong, Seung-Yong, Nam-Hyuk Cho, Ick Chan Kwon, and Seo Young Jeong. "Protective Immunity of Microsphere-Based Mucosal Vaccines against Lethal Intranasal Challenge withStreptococcus pneumoniae." Infection and Immunity 67, no. 7 (July 1, 1999): 3587–92. http://dx.doi.org/10.1128/iai.67.7.3587-3592.1999.
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ABSTRACT Mucosal vaccination of capsular polysaccharide (PS) ofStreptococcus pneumoniae and subsequent creation of the first line of immunological defense in mucosa were examined. Mucosal as well as systemic antibody responses to PS were evoked by peroral or intranasal immunization of BALB/c mice with PS-cholera toxin B subunit (CTB) conjugates entrapped in the alginate microspheres (AM). The bacterial colonization at the lung mucosa was most profoundly inhibited (<95%) by intranasal immunization with the naked conjugate (PS-CTB). The mice vaccinated orally with encapsulated conjugate [AM(PS-CTB)] showed significant reduction on the level of pneumococcal bacteremia (<99%). Eighty percent of the mice perorally immunized with AM (PS-CTB) were protected from lethal intranasal challenge with S. pneumoniae, whereas more than 60% of the mice in the other control groups died of infection. Our novel approach may prove to be important in the development of a mucosal vaccine that will provide protection of mucosal surfaces of host.
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Masek-Hammerman, Katherine, Hualin Li, Jinyan Liu, Peter Abbink, Annalena La Porte, Kara L. O'Brien, James B. Whitney, Angela Carville, Keith G. Mansfield, and Dan H. Barouch. "Mucosal Trafficking of Vector-Specific CD4+ T Lymphocytes following Vaccination of Rhesus Monkeys with Adenovirus Serotype 5." Journal of Virology 84, no. 19 (August 4, 2010): 9810–16. http://dx.doi.org/10.1128/jvi.01157-10.
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ABSTRACT Post hoc analysis of the phase 2b Step study evaluating a recombinant adenovirus serotype 5 (rAd5)-based HIV-1 vaccine candidate suggested a potential increased risk of HIV-1 acquisition in subjects who were baseline Ad5 seropositive and uncircumcised. These concerns had a profound impact on the HIV-1 vaccine development field, although the mechanism underlying this observation remains unknown. It has been hypothesized that rAd5 vaccination of baseline Ad5-seropositive individuals may have resulted in anamnestic, vector-specific CD4+ T lymphocytes that could have trafficked to mucosal sites and served as increased targets for HIV-1 infection. Here we show that Ad5-specific CD4+ T lymphocyte responses at mucosal sites following rAd5-Gag/Pol/Nef vaccination were comparable in rhesus monkeys with and without baseline Ad5 immunity. Moreover, the total cellular inflammatory infiltrates and the CD3+, CD4+, HLA-DR+, Ki67+, and langerin+ cellular subpopulations in colorectal and foreskin mucosa were similar in both groups. Thus, no greater trafficking of Ad5-specific CD4+ T lymphocytes to mucosal target sites was observed following rAd5 vaccination of rhesus monkeys with baseline Ad5 immunity. These findings from this nonhuman primate model provide evidence against the hypothesis that recruitment of vector-specific target cells to mucosal sites led to increased HIV-1 acquisition in Ad5-seropositive, uncircumcised vaccinees in the Step study.
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Vujanic, Ana, Kenneth J. Snibson, Janet L. K. Wee, Stirling J. Edwards, Martin J. Pearse, Jean-Pierre Y. Scheerlinck, and Philip Sutton. "Long-Term Antibody and Immune Memory Response Induced by Pulmonary Delivery of the Influenza Iscomatrix Vaccine." Clinical and Vaccine Immunology 19, no. 1 (November 9, 2011): 79–83. http://dx.doi.org/10.1128/cvi.05265-11.
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ABSTRACTPulmonary delivery of an influenza Iscomatrix adjuvant vaccine induces a strong systemic and mucosal antibody response. Since an influenza vaccine needs to induce immunological memory that lasts at least 1 year for utility in humans, we examined the longevity of the immune response induced by such a pulmonary vaccination, with and without antigen challenge. Sheep were vaccinated in the deep lung with an influenza Iscomatrix vaccine, and serum and lung antibody levels were quantified for up to 1 year. The immune memory response to these vaccinations was determined following antigen challenge via lung delivery of influenza antigen at 6 months and 1 year postvaccination. Pulmonary vaccination of sheep with the influenza Iscomatrix vaccine induced antigen-specific antibodies in both sera and lungs that were detectable until 6 months postimmunization. Importantly, a memory recall response following antigenic challenge was detected at 12 months post-lung vaccination, including the induction of functional antibodies with hemagglutination inhibition activity. Pulmonary delivery of an influenza Iscomatrix vaccine induces a long-lived influenza virus-specific antibody and memory response of suitable length for annual vaccination against influenza.
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Jensen, Owen, Shubhanshi Trivedi, Kelin Li, Jeffrey Aubé, J. Scott Hale, Edward T. Ryan, and Daniel T. Leung. "Use of a MAIT Activating Ligand, 5-OP-RU, as a Mucosal Adjuvant in a Murine Model of Vibrio cholerae O1 Vaccination." Pathogens and Immunity 7, no. 1 (August 24, 2022): 122–44. http://dx.doi.org/10.20411/pai.v7i1.525.
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Background: Mucosal-associated invariant T (MAIT) cells are innate-like T cells enriched in the mucosa with capacity for B-cell help. We hypothesize that targeting MAIT cells, using a MAIT-activating ligand as an adjuvant, could improve mucosal vaccine responses to bacterial pathogens such as Vibrio cholerae. Methods: We utilized murine models of V. cholerae vaccination to test the adjuvant potential of the MAIT-activating ligand, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU). We measured V. cholerae-specific antibody and antibody-secreting cell responses and used flow cytometry to examine MAIT-cell and B-cell phenotype, in blood, bronchoalveolar lavage fluid (BALF), and mucosal tissues, following intranasal vaccination with live V. cholerae O1 or a V. cholerae O1 polysaccharide conjugate vaccine. Results: We report significant expansion of MAIT cells in the lungs (P < 0.001) and BALF (P < 0.001) of 5-OP-RU treated mice, and higher mucosal (BALF, P = 0.045) but not systemic (serum, P = 0.21) V. cholerae O-specific-polysaccharide IgG responses in our conjugate vaccine model when adjuvanted with low-dose 5-OP-RU. In contrast, despite significant MAIT cell expansion, no significant differences in V. cholerae-specific humoral responses were found in our live V. cholerae vaccination model. Conclusions: Using a murine model, we demonstrate the potential, as well as the limitations, of targeting MAIT cells to improve antibody responses to mucosal cholera vaccines. Our study highlights the need for future research optimizing MAIT-cell targeting for improving mucosal vaccines.
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Zhang, Q., R. Lakshman, R. Burkinshaw, S. Choo, J. Everard, S. Akhtar, and A. Finn. "Primary and Booster Mucosal Immune Responses to Meningococcal Group A and C Conjugate and Polysaccharide Vaccines Administered to University Students in the United Kingdom." Infection and Immunity 69, no. 7 (July 1, 2001): 4337–41. http://dx.doi.org/10.1128/iai.69.7.4337-4341.2001.
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ABSTRACT Meningococcal group A+C capsular polysaccharide (PS) conjugate vaccines may prime for serum immunoglobulin G (IgG) memory responses to meningococcal capsular PS. It is not known whether these vaccines induce immunological memory at the mucosal level, which may be important in reducing nasopharyngeal carriage. Mucosal immune responses to meningococcal conjugate and PS vaccines in young adults were investigated. Healthy university students were randomized to receive either a groups A+C meningococcal conjugate vaccine (MACconj,n = 100) or a group A+C meningococcal PS vaccine (MACPS, n = 95). One year after the primary immunization, both groups were randomized again to receive a MACconj or a MACPS booster vaccination. Saliva samples were collected before and 1 month after the primary and booster vaccinations. Anti-meningococcal A (MenA) and C (MenC) PS IgA and IgG antibody levels were measured by a standard enzyme-linked immunosorbent assay. After the primary vaccination, salivary MenA and MenC IgG and MenA IgA concentrations were significantly increased after immunization with both MACconj and MACPS vaccines, but the salivary Men C IgA level was increased only after MACPS vaccine (P < 0.01). IgA responses to both serogroups were greater for MACPS than MACconj vaccine (P < 0.05), whereas no significant differences were seen for IgG responses. MenA IgG titers were higher after the MACPS booster in MACconj-primed subjects than after the MACPS primary vaccination, suggesting the presence of IgG memory. Antibody responses to a dose of either MACPS or MACconj were not significantly reduced in those previously given MACPS compared to the primary responses to those vaccines. Meningococcal A+C conjugate and PS vaccines induce significant mucosal responses in young adults. MACconj priming may induce IgG memory at the mucosal level, which is likely to be a reflection of an anamnestic serum IgG response. No evidence of mucosal hyporesponsiveness was observed after MACPS priming in this study.
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Clapp, Beata, Guan Yang, Bianca L. Artiaga, Carol Hoffman, Xinghong Yang, John P. Driver, and David W. Pascual. "Swine as a Surrogate Model for Human Brucellosis Following Oropharyngeal Vaccination with a Live Attenuated Brucella melitensis Mutant." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 199.7. http://dx.doi.org/10.4049/jimmunol.198.supp.199.7.
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Abstract Human brucellosis is a global health problem, and no human vaccines exist. Although Brucella infections primarily occur via the oropharynx and the upper respiratory tract mucosa, mucosal aspects of Brucella’s pathogenesis are often ignored. Mucosal vaccination with our live attenuated mutant was found to confer exceptional protection against Brucella challenge. While mice have been instrumental to study immunity to Brucella, they may be less suitable to evaluate mucosal infections. Domestic pigs’ close resemblance to human immune system and anatomical features of the oropharyngeal (OPG) mucosa enables studying mucosal brucellosis in a natural host. To assess our mutant’s immunogenicity, 8 wk-old pigs were vaccinated by directly applying 109 CFUs onto the tonsils and sublingual mucosa plus a buccal injection with 108 CFUs on days 0, 2, and 4, and study was terminated on day 60. Isolated peripheral blood mononuclear cells (PBMCs) on days 0, 15, 23, 35, and 60 as well as terminal head and neck lymphoid tissue lymphocytes were evaluated for IFN-g responses by flow cytometry. The greatest IFN-g came from CD8+ and CD4+ CD8+ T cells, as well as NK cells. Changes in peripheral blood T cells over the course of the response showed a significant reduction in the percentage of total CD4+ T cells, and a significant increase in the percentage of total CD8+ and CD4+ CD8+ T cells. Among the lymphoid tissues examined, with the exception of the tonsils where the IFN-g was mostly derived from CD8+ T cells, IFN-g came from CD4+CD8+ T cells, particularly in the mandibular lymph nodes. Thus, our Brucella mutant is immunogenic in swine and capable of eliciting elevated IFN-g responses following OPG vaccination. Work supported by R03 AI128123 & USDA-NIFA2013-01165.
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Bai, Sheng Jie, Lu Lu Han, Ruo Dan Liu, Shao Rong Long, Xi Zhang, Jing Cui, and Zhong Quan Wang. "Oral vaccination of mice with attenuated Salmonella encoding Trichinella spiralis calreticulin and serine protease 1.1 confers protective immunity in BALB/c mice." PLOS Neglected Tropical Diseases 16, no. 11 (November 29, 2022): e0010929. http://dx.doi.org/10.1371/journal.pntd.0010929.
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Background Trichinella spiralis is a foodborne parasitic nematode which is a serious risk to meat safety. Development of anti-Trichinella vaccine is needed to control Trichinella infection in food animals. In this study, two novel T. spiralis genes (calreticulin and serine protease 1.1) in combination were used to construct oral DNA vaccines, and their induced protective immunity was evaluated in a murine model. Methodology/Principal findings TsCRT+TsSP1.1, TsCRT and TsSP1.1 DNA were transformed into attenuated Salmonella typhimurium ΔcyaSL1344. Oral vaccination of mice with TsCRT+TsSP1.1, TsCRT and TsSP1.1 DNA vaccines elicited a gut local mucosal sIgA response and systemic Th1/Th2 mixed response. Oral vaccination with TsCRT+TsSP1.1 induced obviously higher level of serum specific antibodies, mucosal sIgA and cellular immune response than either of single TsCRT or TsSP1.1 DNA vaccination. Oral vaccination of mice with TsCRT+TsSP1.1 exhibited a 53.4% reduction of enteral adult worms and a 46.05% reduction of muscle larvae, conferred a higher immune protection than either of individual TsCRT (44.28 and 42.46%) or TsSP1.1 DNA vaccine (35.43 and 29.29%) alone. Oral vaccination with TsCRT+TsSP1.1, TsCRT and TsSP1.1 also obviously ameliorated inflammation of intestinal mucosa and skeletal muscles of vaccinated mice after challenge. Conclusions TsCRT and TsSP1.1 might be regarded the novel potential targets for anti-Trichinella vaccines. Attenuated Salmonella-delivered DNA vaccine provided a prospective approach to control T. spiralis infection in food animals.
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Holmgren, Jan. "Mucosal immunity and vaccination." FEMS Microbiology Letters 89, no. 1 (December 1991): 1–10. http://dx.doi.org/10.1111/j.1574-6968.1991.tb04964.x.
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van der Lubben, I. M., J. C. Verhoef, G. Borchard, and H. E. Junginger. "Chitosan for mucosal vaccination." Advanced Drug Delivery Reviews 52, no. 2 (November 2001): 139–44. http://dx.doi.org/10.1016/s0169-409x(01)00197-1.
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Meeusen, Els N. T., Jean-Pierre Y. Scheerlinck, Sean Wattegedera, and Gary Entrican. "Advances in mucosal vaccination." Animal Health Research Reviews 5, no. 2 (December 2004): 209–17. http://dx.doi.org/10.1079/ahr200470.
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AbstractPathogens that enter the body via mucosal surfaces face unique defense mechanisms that combine the innate barrier provided by the mucus layer with an adaptive response typified by the production and transepithelial secretion of pathogen-specific IgA. Both the measurement and induction of mucosal responses pose significant challenges for experimental and practical application and may need to be adapted to the species under study. In particular, for livestock, immunization procedures developed in small rodent models are not always effective in large animals or compatible with management practices. This paper reviews the latest advances in our understanding of the processes that lead to secretory IgA responses and how this relates to the development of mucosal immunization procedures and adjuvants for veterinary vaccines. In addition, it highlights the complex interactions that can take place between the pathogen and the host's immune response, with specific reference toChlamydia/Chlamydophilainfections in sheep.
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Giddings, O. K., C. S. Eickhoff, N. L. Sullivan, and D. F. Hoft. "Intranasal Vaccinations with the trans-Sialidase Antigen plus CpG Adjuvant Induce Mucosal Immunity Protective against Conjunctival Trypanosoma cruzi Challenges." Infection and Immunity 78, no. 3 (January 4, 2010): 1333–38. http://dx.doi.org/10.1128/iai.00278-09.
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ABSTRACT Trypanosoma cruzi is an intracellular protozoan parasite capable of infecting through mucosal surfaces. Our laboratory has previously elucidated the anatomical routes of infection after both conjunctival and gastric challenge in mice. We have shown that chronically infected mice develop strong immune responses capable of protecting against subsequent rechallenge with virulent parasites through gastric, conjunctival, and systemic routes of infection. We have also shown that intranasal immunizations with the unique T. cruzi trans-sialidase (TS) antigen protect against gastric and systemic T. cruzi challenge. In the current work we have investigated the ability of purified TS adjuvanted with CpG-containing oligonucleotides to induce immunity against conjunctival T. cruzi challenge. We confirm that intranasal vaccinations with TS plus CpG induce TS-specific T-cell and secretory IgA responses. TS-specific secretory IgA was detectable in the tears of vaccinated mice, the initial body fluid that contacts the parasite during infectious conjunctival exposures. We further show that intranasal vaccinations with TS plus CpG protect against conjunctival T. cruzi challenge, limiting local parasite replication at the site of mucosal invasion and systemic parasite dissemination. We also provide the first direct evidence that mucosal antibodies induced by intranasal TS vaccination can inhibit parasite invasion.
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Wyatt, Carol R. "Cryptosporidium parvumand mucosal immunity in neonatal cattle." Animal Health Research Reviews 1, no. 1 (June 2000): 25–34. http://dx.doi.org/10.1017/s1466252300000037.
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AbstractCryptosporidium parvumis an important zoonotic protozoan pathogen that causes acute infection and self-limiting gastrointestinal disease in neonatal calves. There are currently no consistently effective antimicrobials available to control cryptosporidiosis. Therefore, immunotherapeutic and vaccination protocols offer the greatest potential for long-term control of the disease. In order to devise effective control measures, it is important to better define mucosal immunity toC. parvumin young calves. This review summarizes the information that has accumulated over the last decade which helps to define the intestinal mucosal immune system in neonatal calves, and the events that occur in the intestinal mucosa after infection byC. parvum.
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Fernandez, Stefan, Emily D. Cisney, and Robert G. Ulrich. "Enhancement of Serum and Mucosal Immune Responses to a Haemophilus influenzae Type B Vaccine by Intranasal Delivery." Clinical and Vaccine Immunology 20, no. 11 (August 28, 2013): 1690–96. http://dx.doi.org/10.1128/cvi.00215-13.
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ABSTRACTIntranasal (i.n.) vaccination is potentially the most direct method for conveying upper respiratory and mucosal immunity to respiratory pathogens. However, for unclear reasons, vaccines introduced into the nasal sinuses often have lower efficacy than vaccines administered by the more frequently used parenteral routes. We examined i.n. vaccination in a mouse immune-response model with a commonly usedHaemophilus influenzaetype B vaccine (Hibv) composed of the polyribosylribitol phosphate (PRP) capsule antigen conjugated to tetanus toxoid. Intranasal vaccination with Hibv using a Toll-like receptor 4 (TLR4) agonist as an adjuvant significantly increased the levels of IgA specific for the PRP capsule antigen in blood serum, saliva, and mucosal secretion specimens. In contrast, control mice vaccinated transdermally (t.d.) with Hibv did not produce significant levels of PRP-specific IgA in the blood serum and saliva, and anti-PRP IgG was increased only in serum. The i.n. and t.d. vaccinations resulted in equivalent bactericidal antibody responses in blood serum, suggesting that vaccine-derived IgG is protective against infection. Elevated levels of IgG specific for the tetanus toxoid carrier protein were measured in nasal sinuses and vaginal secretions in mice vaccinated by either the t.d. or i.n. route. Tissue culture studies confirmed that the nasopharynx-associated lymphoid tissue (NALT) was at least one of the sources of PRP-specific IgA and carrier-specific IgG within the nasal sinuses. We conclude that i.n. vaccination aided by a TLR4 agonist results in robust immune responses to both the carrier protein and bacterial polysaccharide components of the Hibv.
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Blackwood, Catherine B., Emel Sen-Kilic, Dylan T. Boehm, Jesse M. Hall, Melinda E. Varney, Ting Y. Wong, Shelby D. Bradford, et al. "Innate and Adaptive Immune Responses against Bordetella pertussis and Pseudomonas aeruginosa in a Murine Model of Mucosal Vaccination against Respiratory Infection." Vaccines 8, no. 4 (November 3, 2020): 647. http://dx.doi.org/10.3390/vaccines8040647.
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Whole cell vaccines are frequently the first generation of vaccines tested for pathogens and can inform the design of subsequent acellular or subunit vaccines. For respiratory pathogens, administration of vaccines at the mucosal surface can facilitate the generation of a localized mucosal immune response. Here, we examined the innate and vaccine-induced immune responses to infection by two respiratory pathogens: Bordetella pertussis and Pseudomonas aeruginosa. In a model of intranasal administration of whole cell vaccines (WCVs) with the adjuvant curdlan, we examined local and systemic immune responses following infection. These studies showed that intranasal vaccination with a WCV led to a reduction of the bacterial burden in the airways of animals infected with the respective pathogen. However, there were unique changes in the cytokines produced, cells recruited, and inflammation at the site of infection. Both mucosal vaccinations induced antibodies that bind the target pathogen, but linear regression and principal component analysis revealed that protection from these pathogens is not solely related to antibody titer. Protection from P. aeruginosa correlated to a reduction in lung weight, blood lymphocytes and neutrophils, and the cytokines IL-6, TNF-α, KC/GRO, and IL-10, and promotion of serum IgG antibodies and the cytokine IFN-γ in the lung. Protection from B. pertussis infection correlated strongly with increased anti-B-pertussis serum IgG antibodies. These findings reveal valuable correlates of protection for mucosal vaccination that can be used for further development of both B. pertussis and P. aeruginosa vaccines.
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Johansson, Eva-Liz, Lotta Wassén, Jan Holmgren, Marianne Jertborn, and Anna Rudin. "Nasal and Vaginal Vaccinations Have Differential Effects on Antibody Responses in Vaginal and Cervical Secretions in Humans." Infection and Immunity 69, no. 12 (December 1, 2001): 7481–86. http://dx.doi.org/10.1128/iai.69.12.7481-7486.2001.
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ABSTRACT Sexually transmitted diseases are a major health problem worldwide, but there is still a lack of knowledge about how to induce an optimal immune response in the genital tract of humans. In this study we vaccinated 21 volunteers nasally or vaginally with the model mucosal antigen cholera toxin B subunit and determined the level of specific immunoglobulin A (IgA) and IgG antibodies in vaginal and cervical secretions as well as in serum. To assess the hormonal influence on the induction of antibody responses after vaginal vaccination, we administered the vaccine either independently of the stage in the menstrual cycle or on days 10 and 24 in the cycle in different groups of subjects. Vaginal and nasal vaccinations both resulted in significant IgA and IgG anti-cholera toxin B subunit responses in serum in the majority of the volunteers in the various vaccination groups. Only vaginal vaccination given on days 10 and 24 in the cycle induced strong specific antibody responses in the cervix with 58-fold IgA and 16-fold IgG increases. In contrast, modest responses were seen after nasal vaccination and in the other vaginally vaccinated group. Nasal vaccination was superior in inducing a specific IgA response in vaginal secretions, giving a 35-fold increase, while vaginal vaccination induced only a 5-fold IgA increase. We conclude that a combination of nasal and vaginal vaccination might be the best vaccination strategy for inducing protective antibody responses in both cervical and vaginal secretions, provided that the vaginal vaccination is given on optimal time points in the cycle.
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Nian, Xuanxuan, Jiayou Zhang, Shihe Huang, Kai Duan, Xinguo Li, and Xiaoming Yang. "Development of Nasal Vaccines and the Associated Challenges." Pharmaceutics 14, no. 10 (September 20, 2022): 1983. http://dx.doi.org/10.3390/pharmaceutics14101983.
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Viruses, bacteria, fungi, and several other pathogenic microorganisms usually infect the host via the surface cells of respiratory mucosa. Nasal vaccination could provide a strong mucosal and systemic immunity to combat these infections. The intranasal route of vaccination offers the advantage of easy accessibility over the injection administration. Therefore, nasal immunization is considered a promising strategy for disease prevention, particularly in the case of infectious diseases of the respiratory system. The development of a nasal vaccine, particularly the strategies of adjuvant and antigens design and optimization, enabling rapid induction of protective mucosal and systemic responses against the disease. In recent times, the development of efficacious nasal vaccines with an adequate safety profile has progressed rapidly, with effective handling and overcoming of the challenges encountered during the process. In this context, the present report summarizes the most recent findings regarding the strategies used for developing nasal vaccines as an efficient alternative to conventional vaccines.
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Matysiak, Colette, Samuel Kazer, Jose Ordovas-Montanes, and Ulrich H. von Andrian. "Intranasal, not parenteral, vaccination induces the formation of tissue-resident memory CD8 T cells in nasal mucosa that rapidly clear influenza virus infection." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 114.17. http://dx.doi.org/10.4049/jimmunol.208.supp.114.17.
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Abstract Respiratory tract infections are among the leading causes of death. While current vaccines reduce severe disease, they provide suboptimal mucosal protection (e.g. against influenza virus and SARS-CoV-2). Nasal vaccines offer an advantage by quickly limiting viral shedding, in part by generating tissue-resident memory (Trm) CD8 T cells in the nasal mucosa. But little is known about the molecular requirements for this Trm formation. The common paradigm is that lymphocytes home to tissues after having been imprinted within draining lymph nodes to express a tissue-specific combination of trafficking molecules, and Trm cells form rapidly from this pool. To probe the paradigm of tissue homing to the nasal mucosa, we compared CD8 T cell trafficking following intranasal and intramuscular vaccination. To investigate the trafficking molecules expressed by CD8 T cells and nasal cells we generated a single-cell RNA sequencing profile of the nasal mucosa over the course of an acute influenza infection. We found significantly more CD8 Trm cells in the nasal mucosa following intranasal vaccination that rapidly cleared influenza infection. Notably, CD8 T cells could be “pulled” into the nasal mucosa with an inflammatory stimulus following intramuscular vaccination, suggesting a new strategy for generating nasal CD8 Trm cells. Unlike canonical T cell homing to the gut and skin, nasal CD8 T cell trafficking depended on a4/VCAM1 (not a4b7/MADCAM1 or P and E-Selectin), and CD8 T cells expressed high levels of CXCR3 and CXCR6. This combination of trafficking molecules suggests a distinct multi-step adhesion cascade for CD8 T cell recruitment to the nasal mucosa and provides critical insights to rationally design vaccines for respiratory tract protection. Supported by grants from NIH (R01 AR068383-01, P01 AI 112521) and HMS-AbbVie Alliance
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Jarikre, Theophilus Aghogho, Jeremiah Olalekan Taiwo, Benjamin Obukowho Emikpe, and Stephen Owarioro Akpavie. "Protective effect of intranasal peste des petits ruminants virus and bacterin vaccinations: Clinical, hematological, serological, and serum oxidative stress changes in challenged goats." July-2019 12, no. 7 (July 2019): 945–50. http://dx.doi.org/10.14202/vetworld.2019.945-950.
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Background and Aim: The current vaccination for peste des petits ruminants virus (PPRV) is stalled by myriad challenges and continuous endemicity of pneumonia due to fulminant bacterial complication in goats. The present study evaluated the protective effect of intranasal PPRV linage 1 and bacterine vaccinations. Materials and Methods: Twelve West African Dwarf (WAD) goats aged 6 months were randomly grouped and vaccinated within 2 weeks using a combination of PPRV lineage 1 vaccine (Nig/75), and bacterin from Mannheimia haemolytica (Mh) or Pasteurella multocida intranasally. The goats were observed for 3 weeks post-vaccination before comingled with a known infected WAD goat with apparent clinical signs of peste des petits ruminants and further observed clinically for 5 weeks post-infection (PI). Blood samples were taken for hematology while sera were assayed for antioxidants (glutathione peroxidase, glutathione transferase, and superoxide dismutase) activities and pro-oxidants (malondialdehyde content, reduced glutathione, hydrogen peroxide generation, and myeloperoxidase) using spectrophotometric methods. Data were subjected to parametric statistics at α=0.05 using GraphPad Prism version 21. Results: Clinically, there were pyrexia, oculonasal discharge, diarrhea, anemia, leukopenia, and increased pro-oxidants in the unvaccinated goats, while moderate neutrophilia and leukocytosis were observed in PPRV and bacterin vaccinated goats. Two unvaccinated goats were weak and euthanized at 13 and 28 days PI. The goats vaccinated with PPRV and Mh showed better response clinically and biochemically. Conclusion: The mucosal vaccination of goats with PPRV vaccine and bacterine will protect against exposure and culminate in the development of protective mucosal, humoral, and cell-mediated immune responses. This vaccination strategy will provide framework needed in the prevention and control of endemic caprine pneumonia in Nigeria.
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Adekunle, Oluwaseyi, Alexandra Dretler, Robert C. Kauffman, Alice Cho, Nadine Rouphael, and Jens Wrammert. "Longitudinal analysis of human humoral responses after vaccination with a live attenuated V. cholerae vaccine." PLOS Neglected Tropical Diseases 15, no. 9 (September 3, 2021): e0009743. http://dx.doi.org/10.1371/journal.pntd.0009743.
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Vibrio cholerae is a bacterial pathogen which causes the severe acute diarrheal disease cholera. Given that a symptomatic incident of cholera can lead to long term protection, a thorough understanding of the immune response to this pathogen is needed to identify parameters critical to the generation and durability of immunity. To approach this, we utilized a live attenuated cholera vaccine to model the response to V. cholerae infection in 12 naïve subjects. We found that this live attenuated vaccine induced durable vibriocidal antibody titers that were maintained at least one year after vaccination. Similar to what we previously reported in infected patients from Bangladesh, we found that vaccination induced plasmablast responses were primarily specific to the two immunodominant antigens lipopolysaccharide (LPS) and cholera toxin (CT). Interestingly, the magnitude of the early plasmablast response at day 7 predicted the serological outcome of vaccination at day 30. However, this correlation was no longer present at later timepoints. The acute responses displayed preferential immunoglobulin isotype usage, with LPS specific cells being largely IgM or IgA producing, while cholera toxin responses were predominantly IgG. Finally, CCR9 was highly expressed on vaccine induced plasmablasts, especially on IgM and IgA producing cells, suggesting a role in migration to the gastrointestinal tract. Collectively, these findings demonstrate that the use of a live attenuated cholera vaccine is an effective tool to examine the primary and long-term immune response following V. cholerae exposure. Additionally, it provides insight into the phenotype and specificity of the cells which likely return to and mediate immunity at the intestinal mucosa. A thorough understanding of these properties both in peripheral blood and in the intestinal mucosae will inform future vaccine development against both cholera and other mucosal pathogens. Trial Registration: NCT03251495.
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Kraehenbuhl, Jean-Pierre. "Mucosa-targeted DNA vaccination." Trends in Immunology 22, no. 12 (December 2001): 646–48. http://dx.doi.org/10.1016/s1471-4906(01)02085-3.
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Shah, Saumi Saurin, Charmi Mahendrakumar Patel, Dhrumi Hiteshbhai Patel, Prapti Hiteshkumar Vadgama, Manan Patel, and Riddhi Trivedi. "A Review on Modern Use of Intranasal Vaccination in the Treatment of SARS-COV-2." Journal of Drug Delivery and Therapeutics 11, no. 4-S (August 15, 2021): 263–70. http://dx.doi.org/10.22270/jddt.v11i4-s.4942.
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The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for efficient SARS coronavirus 2 (SARS-CoV-2) preventative vaccines to limit the burden and spread of SARS-CoV-2 in humans. Intranasal immunization is a promising technique for preventing COVID-19 because the nasal mucosa acts as a first line of defense against SARS-CoV-2 entrance before the virus spreads to the lungs. Nasal vaccination has many advantages over traditional vaccine administration methods. These include the simplicity of administration without the use of needles, which decreases the risks of needle stick injuries and disposal. This channel also provides simple access to a crucial portion of the immune system that can stimulate other mucosal sites throughout the body. By targeting immunoglobulin A (IgA), antibodies found only in the mucosa, an intranasal vaccination would elicit immunological responses in the nose, throat, and lungs. Potential pathogens are trapped by the mucosa, which acts as a physical barrier to prevent them from entering the body. Given this, the intranasal vaccine would prevent virus transmission via exhaled droplets or aerosols because there would be no virus in the body to expel .There are several intranasal vaccines for protection against sars-cov2 are under preclinical and clinical trials .The key challenge is in Designing delivery strategies that take into account the wide range of diseases, populations, and healthcare delivery settings that stand to benefit from this unique mucosal route should be prioritized.
Keywords: COVID-19, Intranasal vaccine, Immunoglobulin A, Permeation
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Low, Jia Ming, Yue Gu, Melissa Shu Feng Ng, Liang Wei Wang, Zubair Amin, Youjia Zhong, and Paul A. MacAry. "Human Milk Antibodies after BNT162b2 Vaccination Exhibit Reduced Binding against SARS-CoV-2 Variants of Concern." Vaccines 10, no. 2 (January 31, 2022): 225. http://dx.doi.org/10.3390/vaccines10020225.
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SARS-CoV-2-specific antibody responses are engendered in human milk after BNT162b2 vaccination. However, the emergence of variants of concern (VOCs) raises concerns about the specificity of and potential cross-protection mediated by milk antibody responses, which are crucial for passive immunity transferred from breastfeeding mothers to their infants. In this study, we collected milk samples at three different time points pre- and post-vaccination, and measured milk IgA antibody binding to the receptor binding domain (RBD) of the original Wuhan-Hu-1 strain, and the four VOCs, namely Alpha, Beta, Gamma and Delta. We report a significant level of anti-RBD IgA in milk collected at 4–6 weeks after the second dose of vaccination compared to pre-vaccination. We observed around a 30% reduction in binding to most VOCs, including the major circulating Delta variant, compared to the original Wuhan-Hu-1 strain. As COVID-19 vaccines may take some time to be approved for infants, these individuals remain at risk for severe disease and rely mainly on transferred passive immunity. Our findings support the current recommendations for vaccinating lactating women with the aim of transferring mucosal immunity to breastfeeding infants.
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Shannon, John P., Glennys V. Reynoso, Olena Kamenyeva, Daniel T. McManus, and Heather D. Hickman. "Patrolling ILCs restrain mucosal viral replication through tissue-wide delivery of IFN-γ." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 75.18. http://dx.doi.org/10.4049/jimmunol.202.supp.75.18.
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Abstract Smallpox, caused by infection with variola virus, led to devastating human pandemics with high mortality until eradication through a global vaccination campaign. Despite eradication, the precise immune mechanisms underlying recovery from infection are incompletely understood. The most common model employed to study smallpox is murine infection with vaccinia virus (VACV), the virus used for human smallpox vaccination. VACV models of smallpox infection commonly employ intranasal or even intravenous routes of infection, with both resulting in widespread viral dissemination. However, variola virus infected humans through the oropharyngeal mucosa, after which oral lesions developed and ruptured, spilling copious infectious virus into the saliva (the route of human-to-human spread). To understand protection in this critical barrier site, we developed a mouse model of lip (labial mucosal) infection. After labial administration, VACV replicates to high titers and two waves of group I innate lymphoid cells (ILCs) are recruited in response to infection. Intravital imaging revealed highly mobile ILCs in the oral mucosa, most of which failed to contact virus-infected cells. Despite the lack of stable contacts, depletion of NK1.1+ cells enhanced viral replication and spread. Instead, ILCs delivered IFN-γ to the mucosal tissue, inducing an antiviral signature in the epithelium. Together, these data illustrate the complex nature of immune protection in a critical yet overlooked tissue during viral pathogenesis.
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Fernandez, Stefan, Emily D. Cisney, Shannan I. Hall, and Robert G. Ulrich. "Nasal Immunity to Staphylococcal Toxic Shock Is Controlled by the Nasopharynx-Associated Lymphoid Tissue." Clinical and Vaccine Immunology 18, no. 4 (February 16, 2011): 667–75. http://dx.doi.org/10.1128/cvi.00477-10.
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ABSTRACTThe nasopharynx-associated lymphoid tissue (NALT) of humans and other mammals is associated with immunity against airborne infections, though it is generally considered to be a secondary component of the mucosa-associated lymphoid system. We found that protective immunity to a virulence factor of nasal mucosa-colonizingStaphylococcus aureus, staphylococcal enterotoxin B (SEB), requires a functional NALT. We examined the role of NALT using intranasal (IN) vaccination with a recombinant SEB vaccine (rSEBv) combined with an adjuvant in a mouse model of SEB-induced toxic shock. The rSEBv was rapidly internalized by NALT cells at the mucosal barrier, and transport into NALT was accelerated by inclusion of a Toll-like receptor 4 (TLR4) agonist. Vaccine-induced germinal centers of B cells formed within NALT, accompanied by elevated levels of IgA+and IgG+cells, and these were further increased by TLR4 activation. The NALT was the site of specific anti-rSEBv IgA and IgG production but was also influenced by intraperitoneal (IP) inoculation and perhaps other isolated lymphoid follicles observed within the nasal cavity. Vaccination by the IN route generated robust levels of anti-rSEBv IgA in saliva, nasal secretions, and blood compared to much lower levels after IP vaccination. IN vaccination also induced secretion of anti-rSEBv IgG in the blood and nasal secretions. Significantly, the efficacy of IN vaccination was dependent on NALT, as surgical removal resulted in greater sensitivity to IN challenge with wild-type SEB. Thus, protective immunity to SEB within the nasal sinuses was elicited by responses originating in NALT.
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Gary, Ebony Nicole, Noshin Kathuria, Mariana Estrella Bernui, Laurent Humeau, David B. Weiner, and Michele A. Kutzler. "Co-delivery of mucosa-associated epithelial chemokine (MEC/CCL28) enhances anti-HIV-1 mucosal responses through CCR10 in the context of DNA vaccination." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 180.7. http://dx.doi.org/10.4049/jimmunol.200.supp.180.7.
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Abstract Mucosal antibody plays a vital role in protection against HIV transmission. Mucosa-associated epithelial chemokine (CCL28) is secreted by mucosal epithelial cells following commensal colonization, and binds CC-chemokine receptor 10 (CCR10), expressed on IgA+ plasma cells. Deletion of CCR10 impairs mucosal IgA production and memory responses. Thus, the CCL28/CCR10 axis is critical for regulating mucosal IgA production and memory immunity. Mice were vaccinated twice with consensus HIV-1 gp160 DNA alone (antigen-only), or antigen and plasmid-encoded CCL28 (pCCL28) via intramuscular injection and in vivo electroporation (EP). pCCL28 increased antigen-specific IgA in fecal extracts (average 36.7ng/ml IgA in the antigen only group compared with 90.9ng/ml in the pCCL28 group). The intestinal compartment from animals co-immunized with pCCL28 harbored a higher frequency of HIV-specific, IgA+ B cells compared to the antigen-alone group (13.1% compared to 5.7%, respectively), and these cells expressed significantly-higher levels of CCR10 than those from mice in the non-adjuvanted group (MFI 413 compared to 181, respectively). Colonization with commensals induces CCL28 secretion by intestinal epithelial cells. Indeed, In vitro experiments with human colonic epithelial cell lines indicate that these organisms increased expression of CCL28 at the transcript and protein level. These studies suggest that electroporated delivery of the mucosal chemokine CCL28, can enhance antigen-specific anti-HIV immunity in the mucosa. Ongoing studies will determine if supplementation of commensal flora during vaccination can enhance CCL28 secretion in vivo and promote retention of vaccine-induced IgA+ B cells at mucosal surfaces.
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White, A. D., L. Sibley, M. J. Dennis, K. Gooch, G. Betts, N. Edwards, A. Reyes-Sandoval, et al. "Evaluation of the Safety and Immunogenicity of a Candidate Tuberculosis Vaccine, MVA85A, Delivered by Aerosol to the Lungs of Macaques." Clinical and Vaccine Immunology 20, no. 5 (February 27, 2013): 663–72. http://dx.doi.org/10.1128/cvi.00690-12.
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ABSTRACTTuberculosis (TB) is a reemerging disease. The only available vaccine,Mycobacterium bovisBCG, is delivered intradermally and confers highly variable efficacy against pulmonary disease. There is an urgent need for improved vaccination strategies. Murine studies suggest that immunizations delivered directly to the respiratory mucosa might be a more effective route of vaccination. This study compared the immunogenicity of a leading candidate tuberculosis (TB) vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in rhesus macaques, delivered either as an aerosol or as an intradermal boost immunization 12 weeks after an intradermal BCG prime vaccine. Aerosol vaccination was well tolerated. MVA85A delivered by aerosol or by intradermal injection induced antigen-specific immune responses in the periphery and the lung, with a trend toward the highest response when the compartment and route of delivery were matched. The ability of poxvirus-vectored vaccines delivered by the systemic route to induce responses in the mucosal immune compartment in macaques is in contrast to the independent compartmentalization of mucosal and systemic immune systems described in mice. Unlike intradermal vaccination, aerosol vaccination did not induce a detectable serum anti-vector antibody response. The delivery of vaccines to the lungs might provide an immunization strategy that limits the induction of systemic anti-vector immunity, which would be extremely useful in the development of improved vaccine strategies. This is the first study to show a recombinant MVA-vectored vaccine to be highly immunogenic when delivered by the aerosol route to nonhuman primates. These results provide important safety and proof-of-concept data for further evaluation of this route of immunization for use in human clinical trials.
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Higaki, Megumu. "Clinical trials of mucosal vaccination." Drug Delivery System 15, no. 6 (2000): 521–24. http://dx.doi.org/10.2745/dds.15.521.
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