Mucosal Immunity

(2020). Development of SARS-CoV-2 vaccines: should we focus on mucosal immunity? Expert Opinion on Biological Therapy: Vol. 20, No. 8, pp. 831-836.

Toll-Like Receptor (TLR) 9 stimulation is required for induction of potent immune responses against pathogen invasion. The use of unmethylated CpG as adjuvants in vaccines provides an excellent means of stimulating adaptive immunity.

The development of an effective HIV vaccine to prevent and/or cure HIV remains a global health priority. Given their central role in the initiation of adaptive immune responses, dendritic cell (DC)-based vaccines are being increasingly explored as immunotherapeutic ...

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Vaxxel SAS, a French start-up, developing vaccines against respiratory viral infections, announces the acquisition of Transgene’s proprietary DuckCelt®-T17 cell line....| May 4, 2020...

The immune system mounts robust responses to infections, vaccines and cancer, but only now have scientists fully begun to unravel how non-circulating populations of T cells that reside in the body's "mucosal barrier tissues" ...

Edible Vaccine Edible vaccines are subunit preparations, do not involve attenuated pathogens, and improve the safety of individuals as compared to traditional vaccine since there is no possibility of proteins reforming into infectious organisms. From: Modern Applications of Plant Biotechnology in Pharmaceutical Sciences, 2015 Related terms: View all Topics Learn more about Edible Vaccine Edible Vaccines Saurabh Bhatia, Randhir Dahiya, in Modern Applications of Plant Biotechnology in Pharmaceutical Sciences, 2015 9.4.1 Advantages of Edible Vaccine • Edible vaccines are effective as a delivery vehicle for immunization because adjuvants that enhance the immune response are not required. • Edible vaccine can elicit mucosal immunity, which is not observed in traditional vaccines. • Edible vaccines are also cost effective in availability, storage, preparation, production, and transportation. Vaccines produced by biotechnological methods are stable at room temperature, unlike traditional vaccine, which needs cold chain storage, which multiplies the yearly cost to preserve vaccines. Moreover, the seeds of transgenic plants could be dried as there is less moisture content in seeds and the plants with oil or their aqueous extracts possess more storage opportunities. Manufacturing cost is low as there is no need for special premises to manufacture them. Edible vaccine can be easily produced at mass level in comparison to an animal system. • Edible vaccines are well tolerated, as they do not require administration by injection unlike traditional vaccines. Thus, there is also a reduced need for medical personnel and risk of contamination is low. The feasibility of oral administration compared to injection is also an advantage. • Plant-derived vaccines could be the source for new vaccines combining numerous antigens. These multicomponent vaccines are called second generation vaccines as they allow for several antigens to approach M-cells simultaneously. • Edible vaccines are subunit preparations, do not involve attenuated pathogens, and improve the safety of individuals as compared to traditional vaccine since there is no possibility of proteins reforming into infectious organisms. • The separation and purification of vaccines from plant materials is very easy and pathogenic contamination from animal cells can be effectively prevented. Read full chapter Purchase book Vaccines in Theory and Practice In Immunology for Pharmacy, 2012 Plant Vaccines Experimental edible vaccines, which offer protection against diarrheal disease, have been developed by using potatoes, rice, and bananas as vaccinating agents. To prepare a vaccine, microbial antigen genes are inserted into a Ti plasmid isolated from Agrobacterium tumefaciens. A modified Ti plasmid is capable of integrating into the plant cell genome and transforming the plant. The mature, transformed plant produces glycosylated microbial proteins in the edible parts of the plant. After the plant part is ingested, antigens stimulate local immunity, systemic immunity, or both. The benefits of edible vaccines are enormous. Inexpensive vaccines can be grown locally and administration of these vaccines does not require invasive medical procedures. Read full chapter Purchase book Vaccines and Clinical Immunization Tak W. Mak, Mary E. Saunders, in The Immune Response, 2006 One of the more intangible difficulties with edible vaccines is that these genetically engineered plants are negatively viewed by some as “frankenfoods,” or genetically modified organisms (GMOs) that may be harmful. Of course, these types of plants should be grown under strictly controlled conditions that limit their unintended spread. One technology that may alleviate concerns about the latter possibility is chloroplast transformation. Like mitochondria in mammals, chloroplasts in most plant species contain their own genome and are inherited maternally. Thus, exogenous genes introduced into the chloroplast genome stay with the transgenic plant and are not packaged and distributed in its pollen. The risk of transmission of the transgene beyond its prescribed borders is thus substantially reduced. Hopefully, sufficient clinical trial data can soon be accumulated that will demonstrate the efficacy and safety of edible vaccines, allowing us to finally achieve the worthy goal of vaccinating all the world's children against a wide spectrum of devastating diseases both cheaply and painlessly. Read full chapter Purchase book Plant-Based Biotechnological Products With Their Production Host, Modes of Delivery Systems, and Stability Testing Saurabh Bhatia, Randhir Dahiya, in Modern Applications of Plant Biotechnology in Pharmaceutical Sciences, 2015 8.2.1.1.6 Vaccines There has been considerable interest in developing low-cost, edible (i.e., oral) vaccines. Traditional edible vaccines, as for polio, use whole, attenuated organisms or semipurified materials to induce both systemic (Ig-G-mediated) and local membrane (Ig-A-mediated) immunity. Plant-based vaccines cover various proteins in form of antigens obtained from DNA encoded with antigenic sequences from pathogenic viruses, bacteria, and parasites. Key immunogenic proteins or antigenic sequences can be synthesized in plant tissues and subsequently ingested as edible subunit vaccines. The mucosal immune system can induce protective immune responses against pathogens or toxins, and may also be useful to induce tolerance to ingested or inhaled antigens. The production of secretory Ig-A (sIg-A) and provocation of specific immune lymphocytes can occur in mucosal regions, and these regions take on special importance in the development of edible vaccines. Aside from intrinsic low production cost, plant-based vaccines offer a number of unique advantages, including increased safety, stability, versatility, and efficacy. Plant produced vaccines can be grown locally where needed, avoiding storage and transportation costs. Relevant antigens are naturally stored in plant tissue, and oral vaccines can be effectively administered directly in the food product in which they are grown, eliminating purification costs. In many instances, it appears that refrigeration will not be needed to preserve vaccine efficacy, removing a major impediment to international vaccination efforts of the past. Plants engineered to express only select antigenic portions of the relevant pathogen may reduce immunotoxicity and other adverse effects, and plant-derived vaccines are free of contamination with mammalian viruses. Finally, the development of multicomponent vaccines is possible by insertion of multiple genetic elements or through cross-breeding of transgenic lines expressing antigens from various pathogenic organisms. There are, however, some limitations associated with the use of transgenic plants for vaccine production. A major limitation of the expression of recombinant antigens in transgenic plants is obtaining a protein concentration adequate to confer total immunity, given varying protein expression among and within the various plant species. Tight control of expression yields will likely be necessary to reduce variability and assure consistent, effective immunization. During the last decade, nearly a dozen vaccine antigens have been expressed in plants (Table 8.6). Transgenic potatoes can produce antigens of enterotoxigenic E. coli heat labile enterotoxin B subunit, and is effective in immunizing against viruses and bacteria that cause diarrhea. Still other “edible vaccines” are under development for rabies, foot and mouth disease (veterinary), cholera, and autoimmune diabetes. Transgenic lupin and lettuce plants can express hepatitis B surface antigen. Efforts are under way to develop an “edible vaccine” against the measles virus using the tobacco plant. A plant-based oral subunit vaccine for the respiratory syncytial virus (RSV) using either the apple or the tomato is under development. The plant species to be used for the production and delivery of an oral vaccine can be specifically selected to achieve desired goals. A large number of food plants (e.g., alfalfa, apple, asparagus, banana, barley, cabbage, canola, cantaloupe, carrots, cauliflower, cranberry, cucumber, eggplant, flax, grape, kiwi, lettuce, lupin, maize, melon, papaya, pea, peanut, pepper, plum, potato, raspberry, rice, service berry, soybean, squash, strawberry, sugar beet, sugarcane, sunflower, sweet potato, tomato, walnut, and wheat) have been transformed. Many of the high volume, high acreage plants such as corn, soybean, rice, and wheat may offer advantages. Corn, since it is a major component in the diet of the domestic animal, is a good candidate for vaccine production. In humans, particularly infants, the plant of choice to produce the vaccine might be the banana. Bananas are a common component of many infant diets and can be consumed uncooked, thus eliminating the possibility of protein denaturation due to high temperatures. Unfortunately, it is relatively difficult to create transgenic bananas and the production time is longer than for certain other food crops. Cereals and other edible plants are advantageous for vaccine production over plant species such as tobacco because of the lower levels of toxic metabolites. It is evident that there are numerous opportunities to identify and develop low-cost plant-derived vaccine materials, including edible plant-based vaccines [19]. Table 8.6. Recombinant Vaccines Expressed in Plants Year Vaccine antigen Species 1992 Hepatitis virus B surface antigen Tobacco 1995 Malaria parasite antigen Virus particle 1995 Rabies virus glycoprotein Tomato 1995 E. coli heat-labile Tobacco, enterotoxin, potato 1996 Human rhinovirus 14 (HRV-14) and human immunodeficiency virus type (HIV-1) epitopes Virus particle 1996 Norwalk virus capsid protein Tobacco, potato 1997 Diabetes-associated autoantigen Tobacco, potato 1997 Hepatitis B surface proteins Potato 1997 Mink enteritis virus epitope Virus particle 1997 Rabies and HIV epitopes Virus particle 1998 Foot and mouth disease virus VP1 structural protein Arabidopsis 1998 E. coli heat-labile enterotoxin Potato 1998 E. coli heat-labile enterotoxin Potato 1998 Rabies virus Virus particle 1998 Cholera toxin B subunit Potato 1998 Human insulin-cholera toxin B subunit fusion protein Potato 1999 Foot and mouth disease virus VP1 structural protein Alfalfa 1999 Hepatitis B virus surface antigen Yellow lupin, lettuce 1999 Human cytomegalovirus glycoprotein B Tobacco 1999 Dental caries (S. mutans) Tobacco 1999 Diabetes-associated autoantigen Tobacco, carrot 2002 Respiratory syncytial virus Tomato Read full chapter Purchase book Vaccines against Bacterial Enteric Infections Jan Holmgren, Myron M. Levine, in Mucosal Immunology (Fourth Edition), 2015 Plant-Based Vaccines An innovative live vector strategy in the 1990s was the concept of expressing protective vaccine antigens in transgenic plants for use as “edible vaccines” with the potential for generating affordable vaccines that would be easy to administer orally for impoverished populations in the developing world (see also Chapter 66). Various plants such as potatoes, tomatoes, lettuce, bananas, corn, and rice were used to express toxin antigens from V. cholerae and ETEC as well as antigens from Norwalk virus, hepatitis B virus, and rotavirus (Arntzen et al., 2005; Lugade et al., 2010). In early phase 1 clinical trials (Tacket, 2009), oral immunization with transgenic plant vaccines consisting of E. coli heat-labile enterotoxin B subunit expressed in potato (Tacket et al., 1998) or corn (Tacket et al., 2004a) induced toxin-neutralizing serum antibodies as well as intestine-derived IgA antibody-secreting cells and fecal IgA against the heat-labile toxin. Likewise, oral vaccination of human volunteers with potatoes expressing Norwalk virus capsid protein induced vaccine-specific IgA antibody-secreting cells as well as serum IgG antibodies. However, it is now generally accepted that the first-generation easy-to-make transgenic plant-based edible vaccines are unlikely to meet requirements for licensure; it remains to be seen if in future such plants, with increasing sophistication of expression of vaccine antigens, may still have usefulness for large-scale production of selected vaccine antigens. Read full chapter Purchase book History and Scope of Plant Biotechnology Saurabh Bhatia, in Modern Applications of Plant Biotechnology in Pharmaceutical Sciences, 2015 1.3.1 Biotechnology in Pharmaceutical Sciences Biotechnology in pharmaceutical sciences has brought about the production of monoclonal antibody, DNA, RNA probes for the diagnosis of various diseases; valuable drugs; edible vaccines like human hepatitis B; therapeutic drugs such as alkaloids, glycosides, steroids, flavonoids, tannins, proteins, enzymes, antibiotics, metabolites, etc. Interference with the plant genotype leads to the expression of various recombinant proteins, which forms antibodies, vaccines, and several other proteins having various pharmaceutical applications. Development of hairy root culture by means of Agrobacterium infection makes plants less dependent on growth hormones for their future growth. This genetic transformation of tumor in plants also gives a better yield of secondary metabolites. Even today, a variety of pharmaceutical drugs and chemicals are being produced by genetic engineering with better quality and increased quantity. Thus, plant biotechnology has provided us with a very efficient and economic technique for the production of a variety of biochemicals [133–136]. In industrial applications, plant biotechnology is used for the production of transgenic drugs. The major benefits are expected in medical, pharmaceutical, and health sciences. In medical sciences, it is used for the production of antibiotics, insulin, growth hormone, interferon, clotting factor VIII, vaccines, probes for infectious and gene therapy, etc. A major breakthrough in plant biotechnology was through rDNA technology, which led to the production of therapeutic recombinant proteins. The basis of the production of recombinant proteins is molecular pharming of therapeutic plants by rDNA technology, which is depicted in Fig 1.7. Genetic manipulation of DNA to form the final DNA construct is the initial step of rDNA technology. Further transfer of DNA construct in respective plants to conduct trangenesis is the second step of rDNA technology. This transfer is possible by using a suitable vector (medium) such as Agrobacterium sp. Successful transfer may lead to production of various transgenes. This transgenesis is followed by screening of plants. In this step, plants having the suitable gene expression for the desired recombinant protein are selected. Finally, recombinant proteins are purified to form various biopharmaceuticals and vaccines. Some of the popular plant-derived biopharmaceuticals are human growth hormone, enkephalin, IgG, human lactoferrin (antimicrobial), human serum albumin, human α- and β-interferon, human α1-antitrypsin, erythropoietin, hirudin, human α and β hemoglobin, etc. Some important vaccines such as envelope surface protein (hepatitis b virus (humans), glycoprotein (rabies virus), malarial B-cell epitope (malaria), and Escherichia coli Lt-B toxin (enterotoxigenic E. coli)) are also produced by rDNA technology [133–136]. Read full chapter Purchase book Mucosal Vaccines from Plant Biotechnology Hugh S. Mason, ... Tsafrir Mor, in Mucosal Immunology (Fourth Edition), 2015 Abstract The use of plants for production of recombinant proteins has evolved over the past 25 years. The first plant-based vaccines were expressed in stably transgenic plants, with the idea to conveniently deliver “edible vaccines” by ingestion of the antigen-containing plant material. These systems provided a proof of concept that oral delivery of vaccines in crude plant material could stimulate antigen-specific serum and mucosal antibodies. Transgenic grains like rice in particular provide a stable and robust vehicle for antigen delivery. However, some issues exist with stably transgenic plants, including relatively low expression levels and regulatory issues. Thus, many recent studies use transient expression with plant viral vectors to achieve rapid high expression in Nicotiana benthamiana, followed by purification of antigen and intranasal delivery for effective stimulation of mucosal immune responses. Read full chapter Purchase book Transgenic Plants for Mucosal Vaccines Hugh S. Mason, ... Charles J. Arntzen, in Mucosal Immunology (Third Edition), 2005 Viral diarrhea: Norwalk virus The Norwalk virus and related Norwalk-like viruses are responsible for 42% of outbreaks of acute epidemic gastroenteritis in the United States. The Norwalk virus capsid protein (NVCP) was the antigen chosen to develop an oral edible vaccine, since when expressed in insect cells it assembled into 38-nm Norwalk virus–like particles (VLPs) and reacted with serum of infected humans (Jiang et al., 1992). Tobacco and potato plants were transformed with constructs harboring the NVCP sequence; the plant recombinant protein assembled into VLPs identical to the insect cell–derived antigen (Mason et al., 1996). Mice that were gavaged with partially purified VLPs from tobacco leaf or fed with transgenic tubers developed serum IgG and fecal IgA antibodies specific for NVCP. A clinical trial was performed with the same potatoes used for the preclinical study (Tacket et al., 2000). Of 20 adult volunteers, 10 received two doses (days 0 and 7) and 10 received three doses (days 0, 7, and 21) of 150 g of raw transgenic potato tubers containing NVCP at 215 to 750 μg/dose. It is important to note that tuber expression was quite variable, and at most only half of NVCP in these potatoes was assembled as VLP; thus, the effective dose of potato vaccine was ∼325 μg/dose. Unassembled subunits are likely to be much less stable in the GI tract and thus less immunogenic. However, 19 of 20 subjects in the experimental group showed significant increases in the numbers of IgA antibody–forming cells (AFCs), ranging from 6 to 280 per 106 peripheral blood mononuclear cells (PBMCs), and 6 of 20 subjects in this group developed increases in IgG AFCs. Four volunteers showed increases in serum IgG anti-NVCP antibody titers, 4 had increased serum IgM, and 6 showed increased IgA in their stool samples (17-fold mean increase). Although the antibody responses were less impressive than those obtained with LT-B, the study showed that a plant-derived protein other than LT-B and CT-B can stimulate human immune responses after oral delivery. Insect cell–derived 250-µg doses of purified Norwalk VLP provided more effective seroconversion (Ball et al., 1999); thus it is likely that part of the potato-delivered NVCP was unavailable for uptake in the GI tract. More recent studies in transgenic tomato fruits with a plant-optimized NVCP gene resulted in higher expression and more potent immune responses in mice fed freeze-dried tomatoes (X. Zhang and H.S. Mason, unpublished results). A clinical trial is planned in which dried tomato powder formulated in gelatin capsules will be used to evaluate safety and immunogenicity (D. Kirk, H.S. Mason, and C.J. Arntzen, trial investigators). Read full chapter Purchase book Viruses as Tools for Vaccine Development Boriana Marintcheva, in Harnessing the Power of Viruses, 2018 8.6.2 Edible Vaccines A very attractive idea for alternative vaccine production and delivery is genetically engineering plants to produce vaccines that would be delivered to the human body as part of our diet, i.e., by eating traditional fruits and vegetables. Vaccine production in plants is already a fact due to advances of molecular farming (Chapter 4). However, the available vaccines are not edible, but rather traditional injectable component vaccines manufactured in plants. The bait rabies vaccine used to vaccinate wildlife is technically an edible vaccine; however, it contains attenuated vaccinia virus strain genetically modified to display rabies surface glycoprotein, i.e., newer generation subunit vaccine delivered in an edible packaging. The latter is effective because it uses the infectivity of the vaccinia virus to penetrate the animal body and is not limited by the so-called oral tolerance of our immune system. Oral tolerance essentially allows us to eat without detrimental immunological reaction to components of our food. Once a mechanism to overcome oral tolerance is found, it is envisioned that fruits and vegetables from our diet will be used to produce the vaccines. It is envisioned that plant material will be dried and packaged in capsules for oral delivery. It is hoped that the edible vaccines will not require refrigeration and will be significantly cheaper to produce. A huge hurdle in the process is the limited number of plants that can be easily manipulated by the tools of genetic engineering. The best candidates so far are tomatoes and potatoes, which are part of the human diet worldwide and happen to be relatives of tobacco, one of the most genetically amenable systems, but unfortunately, not edible due to toxicity. Progress has been made in genetically engineering bananas. Another problem to be solved is the delivery of consistent biologically active dose. Most likely, we are decades away from mass production of edible vaccines. Read full chapter Purchase book Plant-Based Vaccines Aboul-Ata E. Aboul-Ata, ... Pasquale Piazzolla, in Advances in Virus Research, 2014 3 Conclusion Constructed chimeric virus has to be inoculated, transfected, and/or infiltrated, using advanced methodologies, that is, nanoparticles and chitosan for transient expression through bioreactor plants (Dhama et al., 2013). Moreover, chimeric virus constructs are being commercially available (Yusibov & Rabindran, 2008), which makes edible vaccine development easy. Manns et al., (2001) have stated that sustained virological response (SVR) rate was 42% when peginterferon group was used after adjusting ribavirin. This type of therapeutics leads to using plant-based vaccines. Expression of potentially immunogenic peptides, either in transgenic plants or on the outer surface of genetically engineered chimeric viruses (Lico, Chen, & Santi, 2008; Tiwari, Verma, Singh, & Tuli, 2009), could offer remarkable advantages (Tacket & Mason, 1999). Specifically, the plant viruses are particularly attractive for producing oral vaccines because of their ability to infect edible crops. Plant components (fruits, leaves, and roots) can be eaten, providing an easy and inexpensive route of antigen (Ag) administration. In addition, edible plants are used as vehicles for delivering vaccines. This could protect these vaccines from degradation by gastric and intestinal fluids (Daniel, Streatfield, & Wyckoff, 2001; Webster, Thomas, Strugnell, Dry, & Wesselingh, 2002), because Ag delivery by plant cells protects the Ag during passage through the acid environment of the stomach. Finally, plant-derived vaccines eliminate the risk of contamination by zoonotic infections (Fischer, Stoger, Schillberg, Christou, & Twyman, 2004) such as virus or prion proteins, thereby diminishing the safety concerns associated with the use of many currently available types of vaccines. The use of plant viruses as nanoparticle platforms for producing a vaccine might have important clinical implications in oral vaccination, supporting the feasibility of producing a plant-derived Ag-presenting system. Read full chapter Purchase book

KEY POINTS VLP enhances antinorovirus IgA recall responses in humanized mice. Particulate structure is required for IgA enhancement. VLP-driven IgA responses are functionally superior to IgG responses. Abstract Virus-like particles (VLPs) provide a well-established vaccine platform; however, the immunogenic properties acquired by VLP structure remain poorly understood. In this study, we showed that systemic vaccination with norovirus VLP recalls human IgA responses at higher magnitudes than IgG responses under a humanized mouse model that was established by introducing human PBMCs in severely immunodeficient mice. The recall responses elicited by VLP vaccines depended on VLP structure and the disruption of VLP attenuated recall responses, with a more profound reduction being observed in IgA responses. The IgA-focusing property was also conserved in a murine norovirus-primed model under which murine IgA responses were recalled in a manner dependent on VLP structure. Importantly, the VLP-driven IgA response preferentially targeted virus-neutralizing epitopes located in the receptor-binding domain. Consequently, VLP-driven IgA responses were qualitatively superior to IgG responses in terms of the virus-neutralizing activity in vitro. Furthermore, the IgA in mucosa obtained remarkable protective function toward orally administrated virus in vivo. Thus, our results indicate the immune-focusing properties of the VLP vaccine that improve the quality/quantity of mucosal IgA responses, a finding with important implications for developing mucosal vaccines. Footnotes This work was partly supported by Grants-in-Aid for Scientific Research (C) 17K08895 and 25860377 from the Japan Society for the Promotion of Science and by the Research Program on Emerging and Re-emerging Infectious Disease from the Japan Agency for Medical Research and Development (Grant JP18fk0108051). The online version of this article contains supplemental material. Received April 29, 2019. Accepted October 8, 2019. Copyright © 2019 by The American Association of Immunologists, Inc. This article is distributed under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles.

Scientists have identified a pair of molecules critical for T cells, part of the immune system, to travel to and populate the lungs. A potential application could be strengthening vaccines against respiratory pathogens such ...

KEY POINTS Trout have limited IgM and IgT repertoire diversity in NALT. Intranasal vaccination in trout triggers systemic and mucosal Ig response. IgM and IgT respond to i.p. and intranasal bacterin vaccination. Abstract Bony fish represent the most basal vertebrate branch with a dedicated mucosal immune system, which comprises immunologically heterogeneous microenvironments armed with innate and adaptive components. In rainbow trout (Oncorhynchus mykiss), a nasopharynx-associated lymphoid tissue (NALT) was recently described as a diffuse network of myeloid and lymphoid cells located in the olfactory organ of fish. Several studies have demonstrated high levels of protection conferred by nasal vaccines against viral and bacterial pathogens; however, the mechanisms underlying the observed protection are not well understood. We applied 5′RACE and a deep sequencing–based approach to investigate the clonal structure of the systemic and mucosal rainbow trout B cell repertoire. The analysis of Ig repertoire in control trout suggests different structures of IgM and IgT spleen and NALT repertoires, with restricted repertoire diversity in NALT. Nasal and injection vaccination with a bacterial vaccine revealed unique dynamics of IgM and IgT repertoires at systemic and mucosal sites and the remarkable ability of nasal vaccines to induce spleen Ig responses. Our findings provide an important immunological basis for the effectiveness of nasal vaccination in fish and other vertebrate animals and will help the design of future nasal vaccination strategies. Footnotes This work was supported by USDA AFRI Grant 2DN70-2RDN7 (to I.S.). S.M. also received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA Grant Agreement 600391. The dataset presented in this article has been submitted to the National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/sra/) under accession number PRJNA551127. The online version of this article contains supplemental material. Abbreviations used in this article: D-NALT diffuse NALT ERM enteric red mouth HSD honestly significant difference HSR highly shared responding IMGT ImMunoGeneTics i.n. intranasally MID molecular identifier NALT nasopharynx-associated lymphoid tissue O-MALT MALT with well-organized SLOs O-NALT organized NALT PBT PBS pH 7.4 with 0.05% Tween 20 SLO secondary lymphoid organ UID unique molecular identifier. Received February 7, 2019. Accepted July 9, 2019. Copyright © 2019 by The American Association of Immunologists, Inc.

Streptococcus pneumoniae is a bacterial pathogen that causes various diseases of public health concern worldwide. Current pneumococcal vaccines target the capsular polysaccharide surrounding the cells.

Vaccines have saved millions of lives, but nobody likes getting a shot. That's why scientists are trying to develop oral vaccines for infectious diseases. But to be effective, the vaccine must survive digestion and reach ...

Mucosal surfaces provide a remarkably effective barrier against potentially dangerous pathogens. Therefore, enhancing mucosal immunity through vaccines—strengthening that first line of defense—hold...

As we continue to struggle to contain the pandemic of our age, scientists are exploring vaccines that do not prevent initial infection but may prevent or limit viral replication and delay disease p...

Bovine Coronavirus Related terms: View all Topics Coronaviridae In Fenner's Veterinary Virology (Fifth Edition), 2017 CORONAVIRUSES of Cattle and Horses BOVINE CORONAVIRUS Bovine coronavirus infections are associated with three distinct clinical syndromes in cattle: calf diarrhea, winter dysentery (hemorrhagic diarrhea) in adult cattle, and respiratory infections in cattle of various ages, including the bovine respiratory disease complex (shipping fever) in feedlot cattle. Coronaviruses were first reported as a cause of diarrhea in calves in the United States in 1973, and since then they have been recognized worldwide in association with the three clinical syndromes. The economic impact of respiratory disease and calf diarrhea is considerable. Although many coronaviruses have restricted host ranges, betacoronaviruses such as bovine and SARS coronaviruses (Table 24.1) can infect other animal species, including wildlife. Bovine coronavirus is closely related to the human coronavirus OC43 that causes the common cold; indeed, OC43 has been proposed to represent prior zoonotic transmission of bovine coronavirus. Bovine coronavirus has also been shown to infect dogs subclinically and to infect turkey poults, leading to fecal virus shedding, diarrhea, seroconversion, and transmission to contact controls. Genetically and/or antigenically related bovine coronavirus variants have been isolated from dogs with respiratory disease, humans with diarrhea, and captive or wild ruminants with intestinal disease similar to winter dysentery of cattle. The latter include Sambar deer (Cerous unicolor), waterbuck (Kobus ellipsiprymnus), giraffe (Giraffa camelopardalis), and white-tailed deer (Odocoileus virgineanus). Bovine coronavirus has also been linked to enteric disease in South American camelids. Interestingly, the human enteric coronavirus and wild ruminant coronaviruses both infected and caused diarrhea in experimentally exposed gnotobiotic calves, and the inoculated calves were subsequently immune to infection with bovine coronavirus. Despite the different disease syndromes and apparent interspecies transmission of bovine coronavirus and its variants, only a single serotype of bovine coronavirus is recognized, and there is little sequence diversity between the wild ruminant coronaviruses and coronaviruses associated with the different disease syndromes in cattle. Furthermore, there are few common sequence differences to explain differences in host or tissue tropism. The host cell receptor for bovine coronavirus is sialic acid, which reflects the wide tropism of this virus and explains the presence of a HE gene in the virus. Clinical Features and Epidemiology Coronavirus-induced diarrhea commonly occurs in calves under 3 weeks of age after the decline of passively acquired antibodies, but disease can occur in calves up to 3 months of age. The severity of diarrhea and dehydration depends on the infecting dose as well as the age and immune status of the calf. Coinfections with other enteric pathogens such as rotavirus, torovirus, cryptosporidia, and enterotoxigenic or enteropathogenic E. coli are common; their additive or synergistic effects increase the severity of diarrhea. Calf coronavirus diarrhea is often seasonal, being more common in winter in part because of the increased stability of the virus in the cold. Bovine coronavirus has also been implicated as a cause of winter dysentery, a sporadic, acute enteric disease of adult cattle worldwide that is especially prevalent during winter months, as the name implies. Winter dysentery is characterized by explosive, often bloody diarrhea, accompanied by decreased milk production, depression, anorexia, and frequent respiratory signs. Morbidity rates range from 20% to 100% in affected herds, but mortality rates are usually low (1–2%). A similar winter dysentery syndrome associated with bovine coronaviruses variants occurs in captive and wild ruminants. This finding suggests that certain wild ruminants (deer, elk, caribou, etc.) that share common grazing areas with cattle could be a reservoir for coronavirus strains transmissible to cattle, or vice versa. Bovine coronavirus also causes mild respiratory disease (coughing, rhinitis) or pneumonia in 2–6-month-old calves. An epidemiologic study of calves from birth to 20 weeks of age confirmed both fecal and nasal shedding of coronavirus, with diarrhea prominent upon initial infection. The calves subsequently shed virus intermittently via the respiratory route, with or without signs of disease, suggesting that long-term mucosal immunity in the upper respiratory tract is ineffective in mediating virus clearance. As a consequence, coronavirus may recycle among cattle of all ages and regardless of their immune status, with sporadic nasal or fecal shedding from individual animals. Alternatively, new virus strains may be introduced when cattle from different sources are comingled, or from cohabiting wild ruminants. Since 1993, bovine coronavirus has been incriminated as a precipitating cause of the bovine respiratory disease (shipping fever) complex. Both respiratory and enteric shedding of bovine coronavirus are common in affected feedlot cattle, peaking shortly after arrival at feedlots. Since its discovery, bovine coronavirus repeatedly has been identified in the lungs of feedlot cattle that died with bovine respiratory disease complex. Most feedlot cattle also seroconvert to bovine coronavirus within 3 weeks of arrival. Importantly, studies suggest that cattle arriving at feedlots with high serum titers of bovine coronavirus antibody were less likely to shed virus or to develop shipping fever. This observation suggests a role for serum antibodies in protection, or as an indicator of recent infection and active immunity. Pathogenesis and Pathology Concurrent fecal and nasal virus shedding persists for up to 10 days after coronavirus infection of calves. Coronavirus antigen is commonly detected in epithelial cells of both the upper respiratory and intestinal tracts, and occasionally in the lung. The pathogenesis of coronavirus enteritis in calves is similar to that caused by rotavirus, with the notable exception of extensive involvement of the large intestine by coronavirus. Disease occurs most commonly in calves at about 1–3 weeks of age, when virus exposure increases and antibody titers in the dam’s milk begin to wane. The pathogenesis and consequences of enteric coronavirus infection of calves are similar to those described for transmissible gastroenteritis in piglets. The destruction of the mature absorptive cells lining the intestinal villi and mucosal surface in the large intestine leads to maldigestion and malabsorption, with rapid loss of water and electrolytes. The resultant hypoglycemia, acidosis, and hypovolemia can progress to circulatory failure and death, especially in very young animals. The pathogenesis and lesions of winter dysentery of dairy and beef cattle resemble those of calf diarrhea, but often with marked intestinal hemorrhage and extensive necrosis of cells within the crypts of the large intestinal mucosa. Nasal and fecal shedding is more transient (up to 4–5 days). The anorexia and depression seen in dairy cattle with winter dysentery may explain the precipitous and sometimes prolonged decrease in milk production. The cause of the acute and often voluminous bloody diarrhea in some cattle is unexplained. Both nasal and fecal shedding of bovine coronavirus can occur soon after cattle are transported to feedlots. Coronavirus infection is probably important in predisposing cattle entering feedlots to secondary bacterial infection that results in the characteristic shipping fever pneumonia—a severe, often fatal fibrinous bronchopneumonia caused by Mannheimia haemolytica biotype A, serotype 1 infection. Bovine coronavirus antigen also has been detected in epithelial cells of the upper (trachea, bronchi) and lower (terminal bronchioles and alveoli) respiratory tract of some affected cattle, but the precise role of coronavirus in precipitating the bovine respiratory disease complex awaits definitive characterization. Diagnosis Initially, the diagnosis of enteric bovine coronavirus infections was based on the detection of virus by electron microscopy. Cell culture isolation became a viable option when it was discovered that the virus could be grown when trypsin was added to the medium—virus replication is recognized by hemadsorption or cytopathogenic effects, and the presence of coronavirus is confirmed by diagnostic tests. An array of assays is now available for detection of bovine (or variant) coronaviruses in cell culture or diagnostic specimens such as feces or nasal swabs, including ELISAs that incorporate monoclonal antibodies for antigen capture, immune electron microscopy using hyperimmune antiserum, and RT-PCR using bovine coronavirus or pan-coronavirus-specific primers to detect viral RNA. The use of RT-PCR for detection of bovine coronavirus has significantly increased the detection of this agent, particularly in respiratory samples, and has also substantially increased the recognized period of virus shedding by infected animals. Postmortem diagnosis is performed on acute fresh or fixed respiratory or intestinal tissues using hyperimmune antisera or monoclonal antibodies for immunofluorescence or immunohistochemical tissue staining. Immunity, Prevention, and Control Passive Immunity to Enteric Bovine Coronavirus Infections in Calves Because coronavirus diarrhea occurs in young calves during the nursing period, maternal vaccination is required to provide immediate passive (lactogenic) immunity. Passive immunity to enteric viral infections in calves correlates with high levels of IgG1 antibodies in colostrum and milk. In ruminants, IgG1 antibodies are dominant in colostrum and milk and are selectively transported from serum. Most adult cattle are seropositive for antibodies to bovine coronavirus. Therefore, parenteral vaccination of mothers with adjuvanted inactivated bovine coronavirus vaccines effectively boosts IgG1 antibody titers in serum and mammary secretions, to provide enhanced passive immunity to calves. Immunity to Respiratory Bovine Coronavirus Infections The correlates of immunity to respiratory coronavirus infections in cattle are not clearly defined. The serum antibody titer to bovine coronavirus may be a marker for respiratory protection, as coronavirus-specific antibody titers and isotype (IgG1, IgG2, IgA) were correlated with protection of calves and feedlot cattle against subsequent occurrence of respiratory disease, pneumonia, or coronavirus shedding. However, it can be difficult to distinguish whether serum antibodies are correlates of protection, or whether they merely reflect prior enteric or respiratory coronavirus infection. Intranasal vaccination using live-attenuated enteric coronavirus vaccine has been proposed to reduce the risk of bovine respiratory disease complex (so-called “shipping fever”) in cattle entering feedlots. Respiratory System Jeff L. Caswell, Kurt J. Williams, in Jubb, Kennedy & Palmer's Pathology of Domestic Animals: Volume 2 (Sixth Edition), 2016 Bovine coronavirus. Bovine coronavirus (BCoV) is an important cause of enteric disease in young calves, and the same strains occasionally induce respiratory disease in calves 2-16 weeks of age. BCoV is a less frequent but nonetheless important cause of respiratory disease in calves, and deserves more attention than it has received in the past. Isolates from occurrences of respiratory and diarrheic diseases have similar genotypes, and a single outbreak may include both forms of disease. Respiratory signs include fever, serous nasal discharge, sneezing, and coughing. The virus replicates primarily in the nasal and tracheal epithelium, and occasionally in the lung. Many calves shed BCoV in their nasal secretions and/or seroconvert to BCoV in the first month after arrival in feedlots, but the association between seroconversion or virus shedding and increased risk of respiratory disease has been variable in the studies reported. Bronchiolar necrosis is the typical lesion seen in BCoV-infected calves (eFig. 5-83). Bronchiolar syncytia have been described in feedlot calves with concurrent BCoV infection and bacterial pneumonia, but the contribution of other viruses, such as bovine respiratory syncytial virus, to these lesions is uncertain. BCoV may be demonstrated using immunohistochemistry or RT-PCR, or isolated using specific rectal tumor cell lines. Further reading Bidokhti MR, et al. Tracing the transmission of bovine coronavirus infections in cattle herds based on S gene diversity. Vet J 2012;193:386-390. Fulton RW, et al. Bovine coronavirus (BCV) infections in transported commingled beef cattle and sole-source ranch calves. Can J Vet Res 2011;75:191-199. Park SJ, et al. Dual enteric and respiratory tropisms of winter dysentery bovine coronavirus in calves. Arch Virol 2007;152:1885-1900. Storz J, et al. Isolation of respiratory bovine coronavirus, other cytocidal viruses, and Pasteurella spp from cattle involved in two natural outbreaks of shipping fever. J Am Vet Med Assoc 2000;216:1599-1604. Storz J, et al. Coronavirus and Pasteurella infections in bovine shipping fever pneumonia and Evans' criteria for causation. J Clin Microbiol 2000;38:3291-3298. Diseases of the Respiratory System In Veterinary Medicine (Eleventh Edition), 2017 Bovine Coronavirus Bovine coronavirus (BoCV) is one of the more newly identified viral respiratory pathogens of cattle, being first described in 1993. As a consequence, the clinical significance of BoCV in bovine respiratory disease, and enzootic pneumonia in particular, is still being determined. The current evidence indicates that BoCV plays a primary and important role in enzootic pneumonia. BoCV was the most commonly identified viral pathogen identified in nasal swabs from calves with respiratory disease in Ireland, being present in 23% of calves.3 BoCV was identified throughout the year, but at a much lower rate in summer.3 BoCV was the only virus detected in approximately 75% of respiratory disease outbreaks in two to 3-month calves in Italy.4 Biology and Diseases of Ruminants (Sheep, Goats, and Cattle) Wendy J. Underwood DVM, MS, DACVIM, ... Adam Schoell DVM, DACLAM, in Laboratory Animal Medicine (Third Edition), 2015 Coronavirus Bovine coronavirus, of the family Coronaviridae, produces a more severe, long-lasting disease compared to rotavirus. Clinical signs in lambs and calves are similar to above, although the incubation period tends to be shorter (20–36 h). In addition, mild respiratory disease may be noted (Janke, 1989). Coronavirus infections may be complicated by parasite infestation (e.g., Cryptosporidia, Eimeria) or bacterial infections (e.g., E. coli, Salmonella). Treatment is aimed at correcting dehydration, electrolyte imbalances, and acidosis. Strict hygiene and effective passive transfer by developing good colostrum-management protocols are critical. Bovine vaccines are available both for delivery to pre-partum dams and for the neonate. Rotaviruses, coronavirus, and adenoviruses affect neonatal goats; however, little has been documented on the pathology and significance of these agents in this age group. Unlike calves, it appears that bacteria play a more important role in neonatal kid diarrheal diseases than in neonatal calf diarrheas. Parvovirus and BVDV also may cause diarrhea in neonatal calves. Viral Diseases of the Bovine Respiratory Tract Robert W. Fulton, in Food Animal Practice (Fifth Edition), 2009 BOVINE CORONAVIRUS Bovine coronaviruses (BCVs) were initially associated with neonatal calf diarrhea.15 Then BCVs were identified with “winter dysentery” in adult dairy cattle.7,15 Later BCVs were detected in respiratory secretions of infected calves with subsequent isolation from cattle with BRD signs. This isolation of BCVs from calves with “shipping fever” pneumonias led to the assumption that BCVs were a major etiology for BRD. In some studies other agents such as BRSV, BVDV, and PI-3V along with bacteria were also found in these severely ill cattle. No doubt BCVs are found in conjunction with other respiratory tract infections, yet their sole or primary BRD role has not been clearly established. Including BCV along with other bovine respiratory tract viruses contributing to BRD is best. Clearly, experimental reproduction of detectable and severe respiratory tract disease such as pneumonia would better make the case for BCV as a significant primary pathogen in respiratory tract disease in cattle. Etiology/Epidemiology BCVs are RNA viruses of the viral family Coronaviridae.6,15 They are enveloped viruses, thus sensitive to disinfectants and the environment. It is not unexpected that cattle would have a coronavirus with tropism for the respiratory tract. Coronaviruses infect the respiratory tract of other species including humans, pigs, turkeys, and chickens. BCV infections in cattle are worldwide. Initially implicated in neonatal calf diarrhea, BCVs were also reported with etiology in “winter dysentery” of adult cattle. Subsequently BCVs have been isolated from the nasal samples of cattle undergoing respiratory tract disease.62-66 Thus this virus has a purported role in both respiratory tract disease and enteric diseases. Only one serotype is recognized, but likely there is some antigenic variability.15 The dilemma for working with BCV experimentally and diagnostic laboratories attempting to isolate the virus is that BCV replicates poorly or is quite difficult to isolate in standard cell cultures. A specialized cell line, a human rectal adenocarcinoma line, is permissive for BCV and has been used for virus isolation from feces and nasal swabs by selected laboratories. The BCV is considered relatively common in enteric infections in both beef and dairy operations. The virus has been isolated from cells with disease including calf pneumonias, as well as beef cattle entering feedlots in various U.S. regions. The BCV was isolated from both healthy and sick cattle in these BRD episodes. And BCV was detected by seroconversions during the first month in feedlots in transported cattle. Clinical Disease The association of BCV with BRD has been primarily by the isolation of virus from nasal swabs of cattle with BRD signs and seroconversions to BCV. The virus has been found in healthy calves as well. Likewise, antibody testing has detected seroconversions in cattle in BRD cases. The clinical signs in the BRD cases are not unlike other BRD cases with viral etiologies present such as BVDV; PI-3V; BRSV; and other viruses with fever, nasal and ocular discharges, anorexia, and coughing. Typically these BCV isolations and seroconversions occur soon after arrival to the feedlot. As expected there is often involvement of secondary bacteria such as M. haemolytica and/or P. multocida. Attempts have been made to demonstrate the pathogenicity of BCV for the bovine respiratory tract. After experimental challenge in young calves, the virus could be found in feces of diarrheic calves and nasal swabs for up to 5 days.15 Respiratory disease signs occurred in only a few calves. Lesions of emphysema and interstitial pneumonia were evident in only a few calves.67,68 For other studies, there are mixed reports of BCV detected in lung tissues of cattle with BRD, one report with no BCV detection in lungs of cattle with BRD,6 and another detecting BCV antigen by immunofluorescence in respiratory tissues.69 Diagnosis The virus can be isolated in cell culture provided that a unique cell culture is available to the diagnostic laboratory, the human rectal adenocarcinoma line (HRT-18).15 The nasal swabs collected appear to be the choice of collections from live cattle for testing. An antigen capture ELISA originally used for detecting BCV antigen in fecal samples is also used by some diagnostic laboratories for BCV detection in respiratory disease samples. Also, BCV immunofluorescence is available to detect BCV antigen. Selected diagnostic laboratories and research units have used PCR to detect BCV in diagnostic samples. Use of electron microscopy could detect BCV in respiratory samples similar to the use of EM for fecal samples. Selected research laboratories have used ELISA tests for BCV antibodies, and in some selected studies they found seroconversions when paired samples were available. Clinicians should consult with their respective diagnostic laboratory for their testing for BCV. Prevention and Control Although there are licensed BCV vaccines for enteric disease protection, there are no licensed BCV vaccines in the United States to control respiratory tract disease in cattle. Treatment focuses on the use of antimicrobials to control the bacterial secondary infections. As in prevention of the neonatal enteric disease, it is assumed that adequate colostrum is available to provide protection in the young calf. Diseases of the Alimentary Tract–Ruminant In Veterinary Medicine (Eleventh Edition), 2017 Synopsis Etiology Bovine coronavirus. Epidemiology Northern climates. Adult lactating dairy cows, usually during winter months when housed. Immunity develops and lasts variable periods. High morbidity with outbreaks; low mortality. Transmitted by fecal–oral route. Signs Sudden onset of diarrhea affecting almost entire herd within several days. Mild fever, decline in milk production, inappetence. Recover in few days. Some coughing. Clinical pathology None routinely. Lesions Crypt atrophy on intestinal mucosa; enterocolitis. Diagnostic confirmation Detection of virus in feces. Serology. Treatment None required. Control No specific control measures available. Hygiene. Minimize overcrowding in dairy housing. Alimentary System Francisco A. Uzal, ... Jesse M. Hostetter, in Jubb, Kennedy & Palmer's Pathology of Domestic Animals: Volume 2 (Sixth Edition), 2016 Bovine coronavirus. In neonatal calves, Bovine coronavirus (BCoV) infection is a common cause of diarrhea, either alone or in combination with other agents, particularly Rotavirus and Cryptosporidium. The disease may be severe in combination with BVDV infection. BCoV is capable of infecting absorptive epithelium in the full length of the small intestine, and in the large bowel. Viral antigen is also found in macrophages in the lamina propria of villi and in mesenteric lymph nodes. In field infections, microscopic lesions are found most consistently in the lower small intestine and colon. Calves with BCoV infection usually develop mild depression, but continue to drink milk despite developing profuse diarrhea. With progressive dehydration, acidosis, and hyperkalemia, the animals become weak and lethargic; death can ensue as a result of hypovolemia, hypoglycemia, and potassium cardiotoxicosis. Diarrhea in survivors resolves in 5-6 days. At autopsy, affected animals have the nonspecific lesions of undifferentiated neonatal calf diarrhea. Rarely, mild fibrinonecrotic typhlocolitis is recognized in calves with coronaviral infection. Mesenteric lymph nodes may be somewhat enlarged and wet. Virus replication is cytocidal and initially occurs throughout the length of the villi in all levels of the small intestine, eventually spreading throughout the large intestine up to the end of the large colon and rectum, causing a malabsorptive diarrhea. Large concentration of BCoV can be typically found in the spiral colon. Infected epithelial cells die, slough off, and are replaced by immature cells. The microscopic lesions of coronaviral infection in calves vary with the severity and duration of the infection; villus atrophy in combination with mild colitis is typical (Fig. 1-114). In the calf small intestine, villus atrophy is rarely as severe as that seen in neonatal swine with TGE. Rather, villi are moderately shortened, or have subtotal atrophy with stumpy, club-shaped, or pointed tips, and villus fusion may be common. In the early phase of the clinical disease, villi are often pointed and covered by cuboidal to squamous epithelium. Exfoliation of epithelium and microerosion may be evident. Later, the epithelium is cuboidal to low columnar, basophilic, with irregular nuclear polarity and an indistinct brush border. Cryptal epithelium is hyperplastic. The lamina propria may contain a moderate infiltrate of mainly mononuclear inflammatory cells, some of which may have pyknotic or karyorrhectic nuclei. In the early stages of infection, necrosis of cells in mesenteric lymph nodes is associated with viral replication. Peyer's patches in animals examined after 4-5 days of clinical illness often appear involuted, and are dominated by histiocytic cells. Whether this is the result of viral activity or the effect of endogenous glucocorticoids is unclear. In the colon during the early phase of infection, surface epithelium may be exfoliating, flattened, and squamous or eroded in patchy areas. Some colonic glands may be dilated, lined by flattened epithelium and contain exfoliated cells and necrotic debris. A moderate mixed inflammatory reaction is present in the lamina propria, and neutrophils may be in damaged glands or effusing into the lumen through superficial microerosions. Later in infection, some dilated debris-filled colonic glands will remain, but other glands will be lined by hyperplastic epithelium, and the surface epithelium will be restored to a cuboidal or low columnar cell type. Goblet cells are usually relatively uncommon. Colonic lesions may be recognizable in tissues from animals submitted dead, even though postmortem change has obscured changes in the small intestine. Live calves in the early stages of clinical disease are the best subjects for confirmation of an etiologic diagnosis. In calves becoming ill <7 days of age, enterotoxigenic Escherichia coli is the main alternative diagnosis. Rotavirus, Cryptosporidium, and combined infections must be considered in calves 5-15 days of age. Infectious bovine rhinotracheitis, salmonellosis, and bovine viral diarrhea must also be considered. Both salmonellosis and bovine viral diarrhea may be associated with depletion of Peyer's patches and colitis that can be confused with that of coronaviral infection; neither is common in the strictly neonatal age group (<7-14 days of age). Respiratory tract infection also occurs in calves and feeders infected with BCoV. The virus replicates in the epithelium of the nasal turbinates and tracheobronchial tree, and respiratory infection may precede, be concurrent with, or follow enteric infection. Calf pneumonia caused by BRCoV can be observed in calves 6-9 months of age. Affected animals may develop fever, serous to mucopurulent nasal discharge, coughing, tachypnea, and dyspnea. Respiratory infections may play a role in maintaining the virus within a herd, and significant, but poorly characterized, pneumonia has been reported in some experimentally infected calves. In addition, coronaviral infection may predispose to subsequent respiratory bacterial infections or contribute to more severe respiratory disease as part of the shipping fever syndrome. Virus may be identified in tissue or nasal secretions by immunofluorescence or immunohistochemistry. Winter dysentery is a syndrome in adult cattle that has been associated with BCoV in a number of areas around the world. Animals develop blood-tinged diarrhea, nasolacrimal discharge or cough, anorexia, and drop in milk production. Mortality is rare, but may occur. The disease is characterized by a high morbidity rate ranging from 50-100%, but usually low mortality rate, typically <2%. Winter dysentery outbreaks are predominantly seen in young postpartum dairy cows, which then experience a drop of 25-95% in milk production. Occasional cases are also observed in adult dairy and beef cattle. Despite its name, cases of winter dysentery can be observed, albeit infrequently, during the warmer season. The pathophysiologic characteristics of winter dysentery are mostly attributed to lesions of the colonic mucosa. Grossly, the colon of affected animals has linear congestion and hemorrhage along the crests of mucosal folds and there may be a large amount of blood mixed with colonic contents (Fig. 1-115). The histologic lesions are similar to those seen in calves with classical BCoV diarrhea, although they are mostly restricted to the colon with only occasional lesions seen in the terminal small intestine. Large amount of BCoV can be detected in colonic epithelium by immunohistochemistry. Coronaviruses are commonly demonstrated in the feces of cattle with winter dysentery; seroconversions occur, and seroprevalence increases in affected herds. Coronavirus antigen is found in the colonic glands of affected animals, in which there is necrosis and exfoliation of epithelial cells. Certain management practices, notably housing animals in stanchions and use of equipment that handles both manure and feed, have been associated with the development of winter dysentery. Further reading Blanchard PC. Diagnostics of dairy and beef cattle diarrhea. Vet Clin North Am Food Anim Pract 2012;28:443-464. Boileau MJ, et al. Bovine coronavirus associated syndromes. Vet Clin North Am Food Anim Pract 2010;26:123-146. Cho KO, et al. Detection and isolation of coronavirus from feces of three herds of feedlot cattle during outbreaks of winter dysentery-like disease. J Am Vet Med Assoc 2000;217:1191-1194. Heckert RA, et al. Epidemiologic factors and isotype-specific antibody responses in serum and mucosal secretions of dairy calves with bovine coronavirus respiratory tract and enteric tract infections. Am J Vet Res 1991;52:845-851. Kanno T. Bovine coronavirus infection: pathology and interspecies transmission. J Disast Res 2012;7:293-302. Kapil S, et al. Experimental infection with a virulent pneumoenteric isolate of bovine coronavirus. J Vet Diagn Invest 1991;3:88-89. Natsuaki S, et al. Fatal winter dysentery with severe anemia in an adult cow. J Vet Med Sci 2007;69:957-960. Park SJ, et al. Dual enteric and respiratory tropisms of winter dysentery bovine coronavirus in calves. Arch Virol 2007;152:1885-1900. Saif LJ, et al. Winter dysentery in dairy herds: electron microscopic and serological evidence for an association with coronavirus infection. Vet Rec 1991;128:447-449. Smith DR, et al. Epidemiologic herd-level assessment of causative agents and risk factors for winter dysentery in dairy cattle. Am J Vet Res 1998;59:994-1001. Traven M, et al. Experimental reproduction of winter dysentery in lactating cows using BCV—comparison with BCV infection in milk-fed calves. Vet Microbiol 2001;81:127-151. Zhang Z, et al. Application of immunohistochemistry and in situ hybridization for detection of bovine coronavirus in paraffin-embedded, formalin-fixed tissues. J Clin Microbiol 1997;35:2964-2965. Infectious Diseases of the Gastrointestinal Tract Simon F. Peek, ... Kevin J. Cummings, in Rebhun's Diseases of Dairy Cattle (Third Edition), 2018 Etiology Based on seroprevalence studies, the bovine coronavirus (BCoV) responsible for calf diarrhea is quite prevalent in U.S. cattle herds, as is rotavirus. There is much debate among researchers at this point as to whether BCoV isolates obtained from calf and adult diarrhea cases are the same virus or distinct from those that have been incriminated in respiratory disease outbreaks in feedlot and dairy calves. Whether or not there are antigenic or genomic differences in BCoV strains that mediate different organ tropism is similarly unclear. Winter dysentery in adult cattle has been associated with BCoV, and the same strain that causes diarrhea in calves has been used to experimentally create winter dysentery in adult cattle. Therefore, the upper age limit of susceptibility to infection by this agent is apparently longer than traditionally thought. Although not as common as rotavirus as a cause of viral enteritis in dairy calves, coronavirus has been identified in neonatal calf diarrhea outbreaks, especially in the winter months and with mixed infections. A number of studies indicate that clinical disease associated with BCoV in calves is more severe than rotavirus, with higher mortality rates. Affected calves tend to be slightly older than calves infected with pure ETEC or pure rotavirus. They average 7 to 10 days of age at onset, with some observed as late as 3 weeks of age. The virus causes a severe enterocolitis characterized by villous enterocyte destruction in the small intestine and destruction of both ridges and crypts in the large intestine. Maldigestion, malabsorption, and inflammation all contribute to the pathophysiology of coronavirus diarrhea in calves. The virus is cytolytic, and affected villous enterocytes in the small intestine are replaced by cuboidal cells from the crypts, but the colonic lesions leave denuded mucosa in affected areas of the colon. The severity of this damage helps explain why coronavirus enteritis, unlike rotavirus, may cause some flecks of blood to appear in the stool and can kill calves even in a germ-free isolation facility. Thus, in the natural setting, coronavirus enteritis creates a severe clinical diarrhea and can also be associated with > 50% mortality when combined with other viral, bacterial and C. parvum infections.

It's November, a time when breeders concentrate on getting their broodmares in top health for foaling and breeding season and horsemen ship yearlings to trainers for breaking and introduction to race training.

The generation of tissue-resident memory T cells (TRM) is an essential aspect of immunity at mucosal surfaces, and it has been suggested that preferential generation of TRM is one of the principal advantages of mucosally administered vaccines.

KEY POINTS Trout have limited IgM and IgT repertoire diversity in NALT. Intranasal vaccination in trout triggers systemic and mucosal Ig response. IgM and IgT respond to i.p. and intranasal bacterin vaccination. Abstract Bony fish represent the most basal vertebrate branch with a dedicated mucosal immune system, which comprises immunologically heterogeneous microenvironments armed with innate and adaptive components. In rainbow trout (Oncorhynchus mykiss), a nasopharynx-associated lymphoid tissue (NALT) was recently described as a diffuse network of myeloid and lymphoid cells located in the olfactory organ of fish. Several studies have demonstrated high levels of protection conferred by nasal vaccines against viral and bacterial pathogens; however, the mechanisms underlying the observed protection are not well understood. We applied 5′RACE and a deep sequencing–based approach to investigate the clonal structure of the systemic and mucosal rainbow trout B cell repertoire. The analysis of Ig repertoire in control trout suggests different structures of IgM and IgT spleen and NALT repertoires, with restricted repertoire diversity in NALT. Nasal and injection vaccination with a bacterial vaccine revealed unique dynamics of IgM and IgT repertoires at systemic and mucosal sites and the remarkable ability of nasal vaccines to induce spleen Ig responses. Our findings provide an important immunological basis for the effectiveness of nasal vaccination in fish and other vertebrate animals and will help the design of future nasal vaccination strategies. Footnotes This work was supported by USDA AFRI Grant 2DN70-2RDN7 (to I.S.). S.M. also received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA Grant Agreement 600391. The dataset presented in this article has been submitted to the National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/sra/) under accession number PRJNA551127. The online version of this article contains supplemental material. Received February 7, 2019. Accepted July 9, 2019. Copyright © 2019 by The American Association of Immunologists, Inc.

Vaxart, Inc.(Nasdaq: VXRT), a clinical-stage biotechnology company developing oral recombinant vaccines that are administered by tablet rather than by inj...

Recently, the risk of viral infection has dramatically increased owing to changes in human ecology such as global warming and an increased geographical movement of people and goods. Howev-er, the efficacy of vaccines and remedies for infectious diseases ...

The effect of the microbiome on the response to vaccines was the topic of the last talk of the "Microbiome Club", an initiative of the IMIM and Hospital de Mar.