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УДК 619: 615.371: 616.98
Maslianko R., Kravtsiv Y. ©
Lviv national university of veterinary medicine and biotechnology named after S. Gzhytskyj
PASSIVE IMMUNITY AGAINST ROTAVIRUS IN INFANTS
Passive immunity against a variety of gastrointestinal infections, using orally administered human antibodies, has been tried in a number of clinical trials. Recently, antibodies from other species such as cows and chickens, which have shown efficacy in experimental animal systems, have also been tried in humans. This review summarizes published data on the use of immunoglobulin-containing preparations for prophylaxis and therapy against rotavirus infections in infants and children, and directions for their future use are suggested.
Key words: antibodies, bovine, chicken, passive immunization, rotavirus.
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 immunodeficienciency involving IgA are known to be highly susceptible to respiratory and gastrointestinal tract infections (for a review on immunodeficiency see Ref. 1), supporting the notion of a crucial role for antibodies in the mucosal defence.
IgA antibodies are involved in protection against infectious organisms by a multitude of mechanisms such as binding and blocking of adherence to the mucosal surface and neutralization of toxins produced by pathogens. Indention, IgA is involved in intracel-lular cleaning in infected enterocytes [2] and may even help to transport invading infectious organisms through the enterocyte and deposit them on the exterior mucosal surface. Furthermore, IgA has been shown to express immunomodulatory properties and is able to down-regulate the interleukin cascade [3], a mechanism that might have evolved to dampen the inflammatory response in the gut. Supporting this notion is the recently noted beneficial effect of orally administered human IgA in children with inflammatory bowel disease [4].
Infants and children are highly susceptible to infections, as a result of both the relative immaturity of the immune system and the repertoire of antibodies, as they are not immune to pathogens against which they have not been vaccinated. Human breast milk, which contains secretory IgA, is known to protect against a variety of pathogens involved in the pathogenesis of diarrhoea in infants. Oral administration of purified human immunoglobulin has previously been shown to exhibit a prophylactic effect against the development of necrotizing enterocolitis in children born prematurely [5], and a therapeutic effect in diarrhoea induced by Campylobacter
© Maslianko R., Kravtsiv Y., 2008
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jejuni [6] and Clostridium difficile [7] and chronic diarrhoea of unknown aetiology in normal infants [8].
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 gastrointestinal infections during the neonatal period and are of major importance for their survival. Bovine immunoglobulin preparations from cows immunized against rotavirus and enteropathogenic and enterotoxigenic Escherichia coli have previously been shown to be effective as prophylaxis against infections and are already commercially available for use in farm animals. Antibodies from other i species such as chickens, where the antibodies are derived from the yolk of eggs laid by immunized chickens, are also available and are being used for similar indications.
During the past few years, immunoglobulin preparations from other species have also been shown to protect, against natural infection or challenge with a variety of different microorganisms in humans (for references see Ref. 9). This form of passive immunization requires continuous administration of antibodies and attempts have been made using bovine colostrum or purified antibodies for long-term prophylaxis in infants, which could be given separately or admixed with infant formula. The effect of therapeutically administered antibodies has not been as well documented, but , successful intervention has been demonstrated in a few instances using bovine antibodies against Helicobacter pylori and Cryptosporidia [9].
Table 1.
Protective role of orally administered antibodies against rotavirus
in animal models.
Donor species Recipient Treatment Preparation Reference
Chicken Cat Prophylaxis Egg yolk 32
Chicken Cow Prophylaxis IgY 33
Chicken Mouse Prophylaxis IgY 34
Chicken Mouse Prophylaxis Egg yolk 35
Chicken Mouse Prophylaxis IgY 36
Chicken Mouse Prophylaxis IgY 37
Chicken Cow Prophylaxis IgY 38
Cow Cow Prophylaxis Colostrum 39
Cow Cow Prophylaxis Colostrum 40
Cow Cow Prophylaxis Colostrum 41
Cow Cow Prophylaxis IgG 42
Cow Cow Therapy IgG 43
Cow Pig Prophylaxis Colostrum 44
Cow Pig Prophylaxis Colostrum 45
Cow Pig Prophylaxis IgG 46
Mouse Mouse Prophylaxis Milk 47
Clinical efficacy of human antibodies in rotavirus infection in children Rotavirus is a leading major childhood viral entero-pathogen in all areas of the world, causing close to one million deaths annually. In the USA alone, rotavirus is
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associated with 2% of all hospitalizations in children below 5 y of age [10], with an increasing trend during the latest available observation period (1993-1995). Although the nature of protection against infection has not been fully elucidated, it is likely that a major part of the effect is due to neutralization of the virus by specific antibodies. Considerable attention has therefore been directed towards the development of a vaccine and such efforts have resulted in a candidate product, which may protect children from rotavirus disease. However, even if a safe and effective vaccine were to become available, financial constraints in developing countries may prevent its use and it is likely to be less effective in children with malnutrition and concomitant immunodeficiency.
Marked progress has been achieved during the 1990s in reducing the mortality from dehydration in acute diarrhoea by using modern oral rehydration solutions. However, these preparations have little or no effect on the nutritional morbidity resulting from the 5-7 d of diarrhoea commonly associated with rotavirus infection and alternative forms of therapy are therefore needed.
IgA antibodies directed against rotavirus have been demonstrated in human milk [11-15], the main source of immunoglobulins in the intestine of newborns, including neutralizing antibodies [16], and breastfeeding has previously been suggested to play a protective role against rotavirus-induced diarrhoea in infants [1719]. However, the role of IgA antibodies in mitigating an ongoing rotavirus infection in children has been questioned [20].
Human IgG has also been given both as effective oral prophylaxis [21] and as therapy [22-24] against rotavirus infection in children, arguing in favour of the possibility of using antibodies for passive immunity against gastrointestinal infections [25].
Experimental use of antirota virus antibodies in animal models
The concept of passive immunity is used by a large number of animal species to protect their offspring and naturally occurring antibodies against rotavirus can often be found in milk and other secretions (for a few selected references see Refs) [26-31]. Although the titre may be moderately high in non-immunized animals, vaccination results in markedly improved titres, and this has formed the basis for subsequent studies to establish proof of principle. A large number of reports has been published [32-47], the results of which suggest that antibodies are indeed effective both as prophylaxis and possibly also as therapy in animal models of rotavirus infection (Table 1).
The finding that multiple sources of antibodies can be used across species barriers suggests that the main principle involved in protection is binding and blocking of adherence of the virus, and not interaction with cells in the immune system of the recipient. The active principle, i.e. the antibody class which is most effective, has been investigated in a few instances and seems to suggest that, in mice, the secreted form of IgA may be most efficacious [47]. However, in other species such as cows and chickens, IgG is the main class of antibody secreted into the colostrum and egg yolk respectively, which may suggest that they may be superior to
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IgA from the corresponding species, but formal proof of the latter is still not available.
Table 2.
Outcome of studies on the clinical effect of orally administered bovine
Reference Type No: of patientsa Clinical effect
48 Prophylaxis 6/7 Mitigated disease
49 Prophylaxis 55/65 Total protection
50 Prophylaxis 31/33 Mitigated disease
51 Prophylaxis 117/115 No effect
52 Prophylaxis 50/102 Total protection
48 Therapy 18/26 No effect
53 Therapy 73/65 Reduced viral shedding
54 Therapy 35/33 Mitigated disease
55 Therapy 40/40 Mitigated disease
a - Number of patients in the treatment/placebo groups, respectively.
Use of bovine antibodies in therapy against rotavirus in children Based on the successful application of bovine antibodies in animals, immunoglobulins from immunized cows have been employed prophylactically against rotavirus infection in children [48-52] (Table 2) and, although the results are variable, the overall picture suggests a beneficial clinical influence.
The clinical trials using therapeutically administered bovine antibodies have also yielded differing results (Table 2), possibly depending on the dose given (Table 3). However, a reduction in the period of shedding of rotavirus after administration of bovine immunoglobu-lins was published in 1987 [53] (Table 2), followed by a report on successful clinical intervention in rotavirus diarrhoea [54]. In the author's recent study [55], performed in Bangladesh, 80 infants with rotavirus diarrhoea were enrolled in a placebo-controlled trial and treated with hyperimmune bovine colostrum-derived antibodies. The results show a substantial reduction in the duration of diarrhoea, stool output and viral shedding in the group of children receiving the "active" preparation.
Recently, a non-structural glycoprotein, NSP4, has been recognized as a rotaviral enterotoxin, which causes diarrhoea in an experimental animal model. The symptoms could be eliminated by oral administration of a rabbit antiserum against the NSP4 114—135 peptide [56]. The toxin normally plays a role in viral assembly by acting as an intracellular receptor for single-shelled particles and assists in the translocation of these particles across the endoplasmic reticulum. Multiple genetic variants have been found [57-59], all of which act by altering cell-membrane permeability [60] and mobilization of intracellular calcium through receptor-mediated phospholipase C activation and inositol 1,4,5-triphosphate (IP3) production [61].
Thus, antitoxin antibodies in the bovine preparations may be crucial for the therapeutic effect of clinically applied bovine immunoglobulins. In fact, these antibodies have recently been demonstrated in preparations used in previous clinical trials
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[62], although they constituted only a minor proportion of the total reactivity against rotavirus antigens. Thus, a preparation enriched for antitoxin antibodies may be more efficacious, but these products are not yet available.
Discussion
The differing results obtained in the clinical studies published to date may cast some doubt on the concept of using oral immunoglobulins for human therapy. However, this is likely to be due to differences in study design or in the quality of the preparation it self, where the titre and subclass composition of the antibodies may differ.
The class and subclass composition of a given product may, at least theoretically, be of importance for the clinical outcome. In colostrum, IgG1 antibodies constitute the vast majority of all antibodies (owing to a selective transport mechanism at the time of parturition), whereas in milk-derived immunoglobulin products, the proportion of IgG1 is reduced. Antibodies against an antigen, which induces mainly or exclusively IgG2 or IgG3 would then be present in minute amounts in colostrum or a colostrum-derived product. Thus, as bovine antibodies against rotavirus are largely restricted to IgGi [31,63,64], a reduced proportion of IgGi in milk-derived products may result in a product, which is inferior from a therapeutic point of view. The poor response in the therapeutic trial against rotavirus using milk-derived antibodies [51, 53] may thus be a result of both the small amount of antibodies used and the proportionally reduced content of IgG1 antibodies.
Table.3
Reference Preparation Dose Estimated IgG content Daily dose (mg)
48 Colostrum 20ml *3d 30mgmr1 600
49 Colostrum 50ml * 1d 30mgml-' 1500
50 Infant formula' 12oz * 16-202d ? 9
51 Milk concentrate 100gformula * 180d ? 1000
52 Colostrum 5g * 4-10d 40% 2000
48 Colostrum 20-50ml * 3d 30mg ml-' 600-1500
53 Milk concentrate 2gkg-1 bodyweight * 5d 10% 2000b
54 Colostrum 300ml * 3d 30mg ml4 9000
55 Purified Ig 2.5g * 4 * 4d 36% 3600
a Fortified with bovine immunoglobulin 400 U ml-
a Assuming an average bodyweight of 10 kg.
Specific antibodies against a variety of pathogens are present in non-immunized cows but the amount of antibodies is clearly not sufficient for a
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therapeutic effect in humans. For example, while non-immunized 'cows possess low or moderate, levels of antibodies against rotavirus, acquired through natural exposure, these antibodies are directed against bovine serotypes (mainly serotypes 6 and 100) and therefore cannot effectively neutralize the most common serotypes [1-4] in humans. Through immunization, a 100-fold increase in the amount of relevant antirotavirus antibodies can be achieved but, when these antibodies are diluted with immunoglobulins from non-immunized animals (99% admixture), no prophylactic effect is either to be expected or observed in clinical trials as the titres in the final preparation, an infant formula, would be expected to be only slightly higher than a product derived from non-immune animals [51].
The dose of immunoglobulin needed for oral prophylaxis or therapy has not been clearly denned and may be dependent on the survival of the antibodies in the gastrointestinal tract. When using human IgG, approximately 10-25% of orally administered human IgG survives the passage through the gastrointestinal tract in children or adults with diarrhoea [65, 66] and IgA is detectable in the stools of premature children treated prophylactically with orally administered human IgA [5]. A number of clinical studies has also shown detectable amounts of bovine IgG in faeces after oral administration, where a gastrointestinal survival of 10-20% of bovine IgG in a macromolecular form has been shown in newbom infants. This would suggest that a daily dose of 0.5 g d-1 of immunoglobulins from an immunized cow could be sufficient as prophylaxis but that a higher, as yet undetermined dose would probably be needed for therapy. If the survival could be increased, by protecting the proteins from the acidic content of the stomach and/or proteolytic enzymes, the immunoglobulin dose required could be lowered and thereby also the cost.
Currently used adjuvants are not very effective in the cow and the litres that can be achieved against rotavirus are usually only 100-fold higher than in non-immunized animals, despite a heavy immunization schedule. The reason for this is presently unknown. It might therefore be worthwhile to explore the possibility of using additional animal species as providers of the desired antibodies. Chicken antibodies have been used extensively in various animal experiments and have been shown to be efficacious against a variety of pathogens, including rotavirus. Furthermore, chickens can be effectively hyperimmunized and results to date suggest that survival of chicken antibodies in the gastrointestinal tract is not inferior to that of bovine antibodies. A clinical trial using chicken antibodies against rotavirus would therefore be of potential interest and is currently underway.
In the developed world, a strategy of treating children with severe rotavirus infection early in the course of their disease could be cost effective given the high cost of hospitalization. In developing countries, the availability of a cheap source of antibodies, for both prophylaxis and therapy, could possibly help to reduce the mortality of the disease. Thus, in spite of recent developments in the vaccine field, there is still a role to be played for passive immunization against rotavirus.
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Резюме
Маслянко Р.П., Кравщв Ю.Р.
Львiвський нацюнальний утверситет ветеринарног медицины та бiотeхнологiй iмeнi С.З. Гжицького ПАСИВНИЙ 1МУН1ТЕТ ПРОТИ РОТА В1РУСНИХ 1НФЕКЦ1Й У НОВОНАРОДЖЕНИХ Д1ТЕЙ I ТВАРИН
На основi численних дослiдiв була доказана наявтсть пасивного iмунiтeту проти pi3rnx гастроентеритних тфекцш при оральному використант молозивних антиты. Нещодавно було випробувано на дтях коров 'я4i та курячi антитыа, ям давали позитивы результати в до^дах на тваринах. Ця розвiдка тдсумовуе опублтоваш дан про можливостi використання для немовлят i дтей прeпаратiв з коров 'ячого молозива, що вмщають iмуноглобулiни та зв'язан з ними спeцифiчнi антитыа для профыактики та лжування рота вiрусних тфекцш. Представлено також поради щодо подальшого використання подiбних прeпаратiв у пeдiатрiг та ветеринарнш медицит.
Стаття надшшла до редакци 5.04.2008
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