Passive immunity against human pathogens using bovine antibodies

The control and treatment of infectious diseases is increasingly complicated by the development of antibiotic-resistant organisms, the emergence and rapid dissemination of new pathogens, and the growing incidence of opportunistic infections. Identification and commercialization of new anti-microbial agents has always been a time-consuming and expensive process, and development of new strategies to control disease are therefore clearly warranted. The immune system has evolved to help combat various types of infections. As most pathogens enter through mucosal surfaces, the local immune defence may be of particular importance and evolutionary pressure has led to the development of a specialized immunoglobulin class in secretions—IgA. Patients with primary immunodeficiencies involving IgA are known to be highly susceptible to respiratory and gastrointestinal (GI) tract infections (for review see [1]), supporting the notion of a crucial role for antibodies in the mucosal defence. Infection-prone IgA-deficient patients are currently treated with human IgG given systemically [2]. However, a proportion of these patients still suffer from mucosal infections which necessitates development of additional forms of therapy, and human IgG in high doses has previously in fact been given orally, without adverse effects, to healthy volunteers [3] and to patients suffering from a variety of GI infections (for references see [4]). However, from a theoretical point of view human IgG is expected to be less effective than human IgA due to its comparatively low proteolytic stability, and it may also, due to its interaction with complement and phagocytosing cells, provoke an inflammatory reaction. Human breast milk, which contains secretory IgA, is known to protect against diarrhoea in infants. Oral administration of purified human immunoglobulin has previously also been suggested to exhibit a prophylactic effect against development of necrotizing enterocolitis in prematurely born children [5] and a therapeutic effect in Campylobacter jejuni [6] and Clostridium difficile [7] induced diarrhoea in immunodeficient patients as well as chronic diarrhoea of unknown aetiology in normal infants [8]. However, the titre against most human pathogens is rather low in the IgA-containing gammaglobulin preparations, and vaccination of volunteers for preparation of hyperimmune products is not feasible. Furthermore, there is always a risk of transmission of infectious agents when using human plasma as a starting material and since the cost for these preparations is high, alternative sources of antibodies must be sought. The common dairy cow may be one such alternative, as bovine antibodies are actively transported from plasma to milk in cows and are present in high concentrations in colostrum. The antibodies protect the calves from GI infections during the neonatal period and are of major importance for their survival. Bovine immunoglobulin preparations against rotavirus and Escherichia coli have previously been shown to be effective as prophylaxis against infections and have been commercially available for use in farm animals for decades. During the past few years, bovine immunoglobulin preparations have also been shown to protect against natural infection or challenge with a variety of different microorganisms in man. The effect of therapeutically administered bovine antibodies has not been as well documented, but successful intervention has been demonstrated in Helicobacter pylori, rotavirus and cryptosporidial infections (for references see [4,9]). Interaction between bovine antibodies and the human immune system is limited [10] and the preparation can be given without risk of serious adverse events. The titre of antibodies against many human pathogens is low in colostrum from non-immunized animals [4], and although a therapeutic effect has been suggested by oral administration of high doses of non-specific bovine immunoglobulins to patients with chronic diarrhoea [11–14], it is likely that a future product will have to be derived from immunized animals [10]. In this review, we will summarize published data on the use of bovine immunoglobulin-containing preparations for prophylaxis and therapy against selected mucosal infections in man and suggest directions for its future use. During the past century, a markedly raised incidence of dental caries has been noted. This has been brought about by the increased standard of living, which in turn has resulted in a diet rich in sucrose. The development of caries is thought to result from an interplay between the host, the diet and the endogenous microflora. The main bacteriological aetiological agent in dental caries is Streptococcus mutans, and several lines of evidence show that the presence of this organism is highly correlated to the incidence of caries. Although the incidence has been reduced due to prophylactic measures during the past decades, at least in the developed countries, there exist groups of patients where caries remains a major clinical problem. Thus, individuals with xerostomia due to side-effects of certain pharmaceutical products, systemic diseases with engagement of the salivary glands (such as Sjögren's syndrome), the elderly and patients have local due to in the and may suffer from caries as a of the of salivary of infections are to immune intervention and and have been with of during the past decades. The of the and the of in the dental is by the of from sucrose. antibodies may this by of the to of for or by of for vaccination against has been shown to result in a high of salivary which also correlated with prophylaxis against caries have been to the immune against the using different and various of However, has been by the of antibodies which are with in animals Thus, although still using selected purified in this have not been bovine antibodies against shown to of by the in at low and concentrations the of the in against has also been using oral administration of antibodies from animals with or purified such as the and Thus, bovine antibodies against derived from colostrum of immunized have been as prophylaxis against dental caries in an and in healthy volunteers In the of the effect of a in a with with The of the immune product reduced and less caries than animals given a product from non-immunized In the on human volunteers using a antibodies against resulted in an in the of and than from the control During the the of caries disease has and it is not a major in the However, there are still groups of individuals suffer from dental caries and future are the and a of administration for the be it a or in of the where dental are not administered bovine antibodies be to the normal transmission of from to During the the incidence of infections has the of and for of these infections are of endogenous and are most derived from of the GI The organism is to mucosal and the infections are most likely due to to the This is most a of in and GI of is likely to to the high incidence of infections in this and patients are with and highly susceptible to infections. is high in this and to of patients with In patients with a the may be with administered is given this of treatment has not been to be of in infections. a is highly against a variety of pathogens and is effective in and systemic have shown that prophylactic treatment with types of infections by The are therefore patients on This of prophylaxis has also, as been with an incidence of infections with such as in and patients (for review see therapeutic intervention against oral using bovine antibodies has also previously been suggested in man to in therefore a clinical in patients using antibodies from cows immunized with and purified patients in the of which with The of the to the of oral administration of of an IgG of given for various and on the of in and a between the antibodies given and the of organisms, and in the of patients with an high of the treatment resulted in low or of the organism in adverse in the and we are currently an of these in has been shown to an role in the of various infections and also an role in with have been groups involving (such as the and (such as the The product in contains antibodies against these as of to be demonstrated in a The future of the which to human the of a product of bovine where the animals be immunized with purified which the titre of antibodies and a of of of to in by of bovine immunoglobulins against from an and at The and to a of and with different concentrations of the bovine preparations for at in a by the mucosal of with which the and to the of antibodies and for of The of the to a and additional the with and control with an of where bovine immunoglobulin has been an of of of to human by with bovine antibodies against of of to human by with bovine antibodies against Helicobacter pylori, a in has as the agent in chronic and In countries, the of the is in in the of are to about of the by of However, infection is still in view of the of in the host, the can for the of the most show clinical the of additional in the of the disease such as and the of the The chronic infection has been correlated to the development of one of the most common forms of in and a class by the infection can be treated using a of and with of with such as or can be therapy to be and in of The development of and the common of point to a for therapeutic Helicobacter the human by to the and the the protect the from the of the and from the by such as and to in is the importance of for or that on the and in the have been for pylori, such as the which to the have shown that breast from of in infants that IgA antibodies in the milk may and oral administration of antibodies against Helicobacter may or the of in the of In antibodies from immunized cows are against Helicobacter that complement is present that may be of major importance for of the However, the infection is known to be a immune systemically IgA in the and in patients with IgA that of secretory IgA not to have major effect on the of the against a role for IgA in the against As a major in the may be to the low of antibodies in the there is oral administration of antibodies for therapeutic treatment has also been in patients are chronic of and although the using bovine antibodies in have shown In the in where treatment given with for using a preparation derived from of the patients the The preparation antibodies against a variety of as in the and the and As these preparations also of to and of a to the we that may also antibodies against against Helicobacter infection of patients with noted. against Helicobacter infection of patients with noted. and Helicobacter from and with human from an and with bovine IgG antibodies from cows immunized with and in a clinical and with from with a on the published The in and to the a of the with the and from the less with disease of of of Helicobacter to by with immunoglobulins from colostrum of animals immunized against the of of of Helicobacter to by with immunoglobulins from colostrum of animals immunized against the In to we the treatment period and the therapy with a However, this a for immunoglobulin preparations with an increased As a of the high in the of Helicobacter and the of the have been to the of as Thus, a product for particular such as against the may be and this to be in the is a major in of the to a In the rotavirus is with of in children Although the of against infection has not been it is likely that a major of the effect is due to of the by has therefore been the development of a and effective but to such have to a which children from rotavirus Furthermore, a in may its use and it is likely to be less effective in children with and has been during the past in the from in diarrhoea with the use of oral However, these preparations have or effect on the from the of diarrhoea with rotavirus milk, which contains secretory IgA, has previously been shown to protect against diarrhoea in infants. IgA antibodies against rotavirus have also been demonstrated in human milk, the main of immunoglobulins in the of although their role in or rotavirus infection in children has been Human IgG has also been given as effective prophylaxis and therapy against rotavirus infection in in of the of using against GI and prophylactic use of immunoglobulins from immunized cows has in fact shown an effect against rotavirus infection in man of on the clinical effect of administered bovine immunoglobulin on rotavirus infection of patients in the of on the clinical effect of administered bovine immunoglobulin on rotavirus infection of patients in the The effect of therapeutically administered bovine antibodies has shown on the given However, a in the period of of rotavirus administration of bovine immunoglobulins published as as by a on successful clinical intervention in rotavirus diarrhoea In in infants with rotavirus diarrhoea in a and treated with hyperimmune bovine The show a in the of and in the of children the of bovine immunoglobulins in clinical in children with bovine immunoglobulin an of of bovine immunoglobulins in clinical in children with bovine immunoglobulin an of a has been as a which diarrhoea in an and the be by oral administration of a against the Thus, the antibodies in the bovine preparations may be crucial for the therapeutic effect of bovine In these antibodies be demonstrated in preparations in clinical although a proportion of the against rotavirus Thus, a preparation for antibodies may be but these products are as not the of rotavirus by bovine antibodies from various preparations which have been in clinical of the bovine immunoglobulin with of or in a of of and to for and the by and immunoglobulin preparations and which have been with rotavirus or a the result using a against the The of antibodies on the of the and In the developed a of children with rotavirus infection in the of their disease be given the high cost of In countries, the of a of antibodies for prophylaxis and therapy help the of the Campylobacter jejuni is a which is with GI infection in is one of the most common of enterocolitis of animals have been shown to the infection to man. Although the disease is are and immunodeficient patients may chronic in of IgA antibodies protect against and we previously treated a with administered human IgA with clinical Oral administration of antibodies against different GI pathogens has also been shown to be effective and therapeutically in a variety of (for review see and oral administration of antibodies against Campylobacter jejuni shown to However, as these antibodies derived from the of immunized the of material is on of bovine immunoglobulins from milk from cows immunized with a of and clinical Campylobacter jejuni and Campylobacter coli against infection in administration of bovine antibodies resulted in a in the of an where administered to with or without of the bovine immunoglobulin preparation with the to administration to the additional antibodies given to the animals and the result by of for the of the of the treated animals still of the control animals bovine antibodies given to a in the of in the during the treatment with control In this the treated with an oral administration of bovine However, of the the of in In the therapeutic given oral doses of bovine antibodies or the the and a and in the of Campylobacter administration of antibodies and a in the of in a of of the treated In the control the of increased during the of the in a in the of in the treatment at The prophylactic of administered antibodies against Campylobacter jejuni has not been in man. be as prophylaxis against where suggest that to of may be with Campylobacter infection Furthermore, in the from prophylactic treatment in to or disease during the of may also be in immunodeficient patients are to infection with Campylobacter Clostridium the agent of diarrhoea and is a organism that is a common of infection in is for mucosal and is may from to and there is a incidence of disease successful therapy Although a of in the are the role of antibodies has not been in children has been with to Clostridium difficile and use of gammaglobulin therapy in of secretory IgA may of to its and disease In the of and has been Clostridium difficile as one of the most common of and the of of where chronic is common of patients at and of patients Clostridium difficile through oral of from the or by with by an most but one developed Clostridium difficile in to a variety of anti-microbial but many of the agents which have such are also as Clostridium difficile the most agents for the treatment of Clostridium difficile are and Although these in the treatment of in particular has major and incidence of disease The the of Clostridium difficile are to disease by the administration of oral challenge with Clostridium the and of the and with bovine immunoglobulins against Clostridium difficile for to and oral challenge with of treated and animals Clostridium difficile and when However, bovine immunoglobulins against Clostridium difficile in the Furthermore, of as by in in to in animals bovine antibodies against Clostridium control immunoglobulins effect clinical in Clostridium patients have as been using bovine preparation to that given to normal volunteers to IgG suggested that a proportion of the antibodies the through the GI tract and this may be increased by administration of or by additional during these the between the GI and bovine IgG that also the of the in volunteers with an but normal GI the of administered bovine IgG to the of the oral of bovine IgG and this IgG its Clostridium difficile and Thus, it is not that pathogens are to bovine therapy, and of IgG to the also against of infectious diarrhoea such as by Clostridium The is a that the GI tract the tract of with this organism can result in a diarrhoea with and the organism is in the the have been in the and of The organism to most groups and can be by and is also likely that transmission and is common is a common infection in with high of of the organism from patients with diarrhoea as well as evidence of of in the and in In countries, of children to with have and in the have from to In the chronic diarrhoea due to infection with from infection with the most in which is and patients or In countries, and forms of are the most common In the may and but is a The period is and of diarrhoea and for as as In the immunodeficient host, the diarrhoea can and due to and patients present with a and low are in of is and to of has been effective treatment for Although than and agents have been against this has therapy is involving a of and of in have shown that bovine immunoglobulins are effective for of chronic diarrhoea when is as the organism The of immune colostrum in cryptosporidial infection has been demonstrated in several and demonstrated that treatment with from an immunized cow reduced the of in oral with it that by since in by administration of with immune colostrum than in animals in control colostrum or and that to raised in immune bovine and immune bovine the of for in a of with and bovine but of of with bovine of The of to the may be in infection and in from in the In a immune also reduced in with immune bovine against with their of at the in in animals treated with purified or that with or IgA highly for treatment groups control This also that purified immunoglobulin from immune or not are present in bovine In a of at least of treated with non-specific or bovine immunoglobulin In of these immunoglobulin administered by an or and the of treatment from to In the using bovine colostrum and in one using non-specific bovine immunoglobulin most patients successful or of clinical In in which a non-specific colostrum product administered to clinical of on the clinical effect of administered bovine immunoglobulins on infection in patients of on the clinical effect of administered bovine immunoglobulins on infection in patients In a of a bovine immunoglobulin preparation for the treatment of diarrhoea with in there a in and a in in to The patients with infection patients with patients with non-specific diarrhoea with and one with an opportunistic The patients in the infection to the product in a or an patients the also increased by with in patients with the bovine may result from infection with one or of Escherichia The coli are the most common of diarrhoea in to the less developed use of prophylactic by has resulted in the development of coli are an of infectious diarrhoea in children the and a major to in The coli are as pathogens in the development of due to their of such as due to coli have been to in the coli must to the diarrhoea by that have a effect on the agents can be to this to diarrhoea in of anti-microbial their prophylactic use. therapeutic with side-effects be a The of bovine antibodies in against oral challenge has been demonstrated in In the a milk immunoglobulin effective in diarrhoea in volunteers with one of the for of developed diarrhoea In the bovine antibodies against purified The antibodies of from clinical of volunteers a preparation developed In the effect of breast in coli infection is well in human milk and bovine preparations in have been to disease in infants in one of the using antibodies infants to of with diarrhoea treated for with of a milk immunoglobulin patients with coli also present in the which to the cows for their of the one of infants with not in the of bovine immunoglobulins from has that these antibodies GI as and and from these infants in a coli challenge in infants an of a in the not successful in the incidence of diarrhoea or the of from in The of in than of a of coli due to the with a product derived from non-immunized may have for the in this particular of coli in the and have resulted in the of a of children due to a therapy is not in the infectious process, as of the in the may of As the of in is high, antibodies are thought to to the of calves against these and have demonstrated an in of bovine immunoglobulins from non-immunized cows in the of and on and of the on human in of may be administered in the of the Bovine colostrum has been therapeutically in man for decades. However, as the in the IgG it is by purified immunoglobulin This also to a from using a product to a pharmaceutical there is a for it is to be by the and as the the of bovine and previously we the bovine and The will to against and to which the different This is as a of an to immunoglobulins in different and to bovine antibodies of different and as The which have been in the clinical published to may on the of using bovine immunoglobulins for human This is likely to be due to in or in the of the preparation where the titre and of the antibodies may The class and of a given product at least be of importance for the clinical In antibodies the of antibodies to a at the of in immunoglobulin products, the proportion of is against an which or or be present in in colostrum or a Thus, as bovine antibodies against rotavirus are to a reduced proportion of in products may result in a product which is from a therapeutic point of The in the therapeutic against rotavirus using antibodies may be a result of the low of antibodies and the reduced of antibodies against a variety of pathogens are present in non-immunized but the of antibodies is clearly not for a therapeutic effect in man. non-immunized cows of antibodies against through natural these antibodies are against bovine and and can therefore not the most common in man. a in the of antibodies can be but when these antibodies are with immunoglobulins from non-immunized animals of the immunoglobulin prophylactic effect is to be expected or in clinical The titre of antibodies against different pathogens is by but for the preparations for therapy are not always Furthermore, these are not for the immunoglobulin of the products and between different clinical is therefore Although there a between the titre and the the is from and on the of the product be from also be that in the titre against the various may the of a clinical on the at the of the This is also for the vaccination where one have to to a high titre against and a high and of the antibodies may be crucial for The of immunoglobulins in the of normal healthy is in the of The proportion of antibodies be expected to a in individuals are immune to the in In the normal human of IgA are and at mucosal The in an be expected to be in the of that the has previously been or has from is to or immune against by the the oral administration of of human immunoglobulin from normal of immune against a variety of pathogens, has been to be as prophylaxis against necrotizing enterocolitis in infants The of immunoglobulin for oral prophylaxis or therapy has not been clearly as and may be on the of the antibodies in the GI using human of administered human IgG the through the GI tract in children or with diarrhoea and IgA is also in the of children treated with administered human IgA of clinical have also shown of bovine IgG in oral administration where a GI of of bovine IgG in a has been shown in patients with diarrhoea and in infants. the be by the from the of the proteolytic the immunoglobulin be and also the of with the in the The low the which the for the the in the are and of the are in the In the and and from the of the The of these to be by a of the and are through the in the where the of the are by and bovine antibodies are for or doses with human antibodies be expected to be effective that the cows are In challenge by and against coli challenge in volunteers using a oral administration of of bovine immunoglobulin from In a of human rotavirus also to that for a a of of immunoglobulins from an immunized cow be for This is clearly the given in the published but as the of the antibodies the preparation will also be of importance for the clinical the have not always been intervention in patients with an infection the use of of In on rotavirus infection of human an has been and in infections such as Clostridium difficile [6] and Clostridium jejuni doses have been intervention has also been when and cryptosporidial infections with administration of of immunoglobulin from immunized In the by of immunoglobulin given to Although these point to the of using high doses of immunoglobulins when to combat an the of antibodies still remains to be an to which necessitates development of alternative anti-microbial This is as of is on of and a product bovine antibodies be from an point of bovine antibodies a of and against to be the doses be in the However, in most against the effect of due to be expected to a period of and there is a in the for a has of of to the and is a which is by most that the has to that bovine antibodies also have a role to in human therapy and remains to be is the of the antibodies and the and of their This by the the and the and and the for in