Rotavirus
Rotavirus
is the most common and most serious cause of gastroenteritis diarrhoea
and vomiting in young children. It has resulted in the deaths of
hundreds of thousands of children worldwide annually. The risk of
catching rotavirus increases in any situation where children are placed
together, including hospitals and daycare centers. Children under the
age of four are especially vulnerable.
If a child catches rotavirus, he or she usually falls sick with symptoms of vomiting, diarrhoea and dehydration that can last up to 10 days. It is highly contagious and can spread easily to friends and members of the family.
Description: Gastrogard-R® is a non-sterile, oral powder consisting of concentrated proteins including immunoglobulins harvested from the colostrum of hyperimmunised cows. The primary immunoglobulin is IgG1. Each sachet of Gastrogard-R® contains 5g of hyperimmune bovine colostrum.
Indication: Prophylactic treatment to prevent diarrhoea due to rotavirus in at-risk children aged one month to three years. Rotavirus is highly infectious in young children, and outbreaks occur frequently during the winter in hospitals, daycare centres, and in the family setting. Taking Gastrogard-R® during periods of risk helps prevent rotavirus cross-infection.
Gastrogard-R® History
The inception of Gastrogard-R® took place in 1985 with the initial clinical trial conducted in 1987 and published in the Lancet in 1989. By 1990 the State Government of South Australia proceeded to build a plant at Oakden, South Australia, and in 1991 the first production of Gastrogard-R® commenced. Additional clinical trials were performed in Hong Kong and India, and produced results documenting the prevention of rotavirus diarrhoea in children up to 3 years of age. By 1996 Numico Research Australia began to market Gastrogard-R®. In 2008 Immuron licensed the rights to rotavirus/Gastrogard-R® technology.
Mode of Action
It is likely that protection by Gastrogard-R® against diarrhoea caused by rotavirus infection is related to the presence of antibody within the lumen of the intestine, although the complete mechanisnm of action by which Gastrogard-R® prevents rotavirus diarrhoea has not been fully determined in our clinical studies. Studies in animals indicate that the presence of anti-rotavirus antibody in the intestinal lumen, rather than circulating antibody, is required to prevent rotavirus diarrhoea.
The IgG is known to be selectively transported by the udder from the circulation to the lacteal secretions, and is the principal immunoglobulin for passive immunisation of the calf. In contrast, IgG2 predominates in bovine serum. We believe that the single most important ingredient in Gastrogard-R® is IgG1.
In vitro studies have shown IgG1 to be responsible for more than 82% of the virus neutralising activity of Gastrogard-R®. It is proposed that the specific anti-rotavirus immunoglobulins, primarily IgG1, in Gastrogard-R® bind to antigens on the rotavirus particle, disrupting disease processes and preventing infection. The precise mechanism by which rotavirus causes diarrhoea has not been determined, but Gastrogard-R® could disrupt the disease process by binding to rotavirus outer capsid proteins, preventing attachment of rotavirus to the mature epithelial enterocytes neutralising viral products or toxins, and/or agglutinating the virus within the lumen of the intestine.
The anti-rotavirus activity of Gastrogard-R® survives passage through the gut.
Clinical Trials
Six hospital-based clinical studies were performed, four in Australia and two in other countries. Five of these studies were randomised, double blind, placebo controlled design and the other study was open. In all six studies patients ranged in age from 28 days to three (3) years. The control product was either low potency colostrum or milk. Combined analysis of these studies demonstrated a statistically significant reduction in the incidence of rotavirus infection in children given Gastrogard-R® compared with children who did not receive the drug (p<0.001).
Antibody Survival Trials: SURVIVAL OF ORALLY ADMINISTERED ANTIROTAVIRUS ANTIBODIES IN HUMAN GASTROINTESTINAL TRACT
Pacyna, J., Robertson, ES., Terry, S., Whyte, PBD., Davidson, GP., and Johnson, RB. Northfield Laboratories Pty Ltd, Adelaide, South Australia 5086.
INTRODUCTION: This study investigated the survival of rotavirus antibody activity in faeces of children receiving different doses of HBC-R.
METHODOLOGY: Hyperimmune colostrum containing different levels of rotavirus antibody was administered to 105 children attending nine Adelaide childcare centres. There were five experimental groups in the study. Subjects were asked to drink 100ml of whole milk supplemented with colostrum 3 times a day, for a period of 6 days. Three groups received specific amounts of HBC-R in liquid form, one group received a reconstituted powder form of Gastrogard-R®, and the control group received whole cow's milk. Stool samples were tested for the presence of rotavirus antigen or antibodies. Rotavirus activity was determined using a virus reduction and a virus neutralisation assay.
RESULTS: Rotavirus antibody activity was detected in 521 (86%) of 602 faecal specimens obtained during the study using the virus reduction ELISA. The antibody activity was detected as early as 8 hours after ingestion of hyperimmune colostrum and up to 72 hours after consumption had ceased.
There was a strong and positive relationship (r = 0.81) between the levels of antibody activity in faeces and the dose of HBC-R ingested. The relationship between the percent reduction of rotavirus by ELISA and the percent of rotavirus neutralisation using faecal extracts of subjects taking HBC-R was also investigated.
The results of the two assays correlated strongly (r = 0.96) and were of high functional dependence (R2 = 0.92) and significance (p = 0.004), providing evidence for the neutralizing capacity of rotavirus in faecal extracts. The results show that approximately 5% of relative rotavirus antibody activity had survived passage through the gut (mean activity, 4 groups, 602 samples). Therefore, passive immunotherapy may be used to prevent or treat infectious diseases that affect the entire length of the gastrointestinal tract. Furthermore, it is likely that antibody activity in the small intestine (where most viral and bacterial infections have their major impact) will be considerably higher than the activity in the faeces, thus providing even greater protection against and/or treatment of gastrointestinal diseases.
COMMUNITY BASED TRIAL:
A community based clinical study was carried out in childcare centres to evaluate the health and economic outcomes associated with daily use of an equivalent liquid product containing hyperimmune bovine colostrum - antirotavirus (HBC-A). The study was a double blinded, two-way parallel, cluster randomised design in over 700 children below the age of four (4) attending 22 childcare centres in South Australia, over a period of five months. Children received active product (HBC-A), control (milk), or no product, and were monitored. No statistical data are available to accurately report on the compliance rate with study treatment. The number of proven rotavirus infections in each group was divided by the person-time at risk of developing an infection for the respective group to yield incidence rates. The incidence of rotavirus diarrhoea in children given HBC-A was 0.04672/100 days of observation (n=245, observed over 21,403 days with one episode of diarrhoea). The incidence of rotavirus diarrhoea in children given cow’s milk or monitoring only was 0.25431/1000 days (n = 497, observed over 47,186 days, 12 episodes of rotavirus diarrhoea). The analyses are summarised as follows:
1. Adjusted for sex, race and stool consistence at baseline, the incidence density (IDR) ratio is 0.22, 95% confidence interval; 0.66 to 0.77, P = 0.018, showing a statistically significant protective effect of HBC-A.
2. The IDR of rotavirus diarrhoea for treated versus monitored in the active centres was 0.19, significantly different from 1; P = 0.03, the IDR for treated versus monitored in the control centres was 0.83, not significant: P = 0.69, the ratio of these two IDRs (0.19/0.083) is 0.229 and that this is significantly different from 1: P = 0.0436, that is, there is an interaction.
3. Children in active centres on the product are less likely to get rotavirus diarrhoea than those being monitored (P = 0.003), and this is a significantly different result than for children receiving the control (whole milk) in control centres (P = 0.436).
References
Saulsbury FT, Winkelstein JA, Yolken RH. “Chronic rotavirus infection in immunodeficiency.” J Pediatr 1980; 97: 61-65.
Losonsky G, Johnson JP, Winkelstein JA, Yolken RH. “Oral administration of human serum immunoglobulin in immunodeficient patients with viral gastroenteritis.” J Clin Invest 1985; 76: 2362-2367.
Stephen W, Dichtelmuller H, Lissner R. “Antibodies from colostrum in oral immunotherapy.” J Clin Chem Biochem 1990; 28: 19-23.
Davidson GP, Whyte PBD, Daniels E, et al. “Passive immunisation of children with bovine colostrum containing antibodies to human rotavirus.” Lancet 1989; 2: 709-712.
Davidson GP, Tam J, Kirubakaran C. “Passive protection against symptomatic hospital acquired rotavirus infection in India and Hong Kong.” J Pediatr Gastroenterol Nutr 1994; 19: 351.
Clinical Trial NLC: 01-95 (unpublished). “Passive prevention of rotavirus diarrhoea in infants and young children by oral administration of hyperimmune bovine colostrum containing antibodies which are cross-reactive against four human rotavirus serotypes.” Data on file at Numico Research Australia Pty Ltd. and with Immuron Ltd.
If a child catches rotavirus, he or she usually falls sick with symptoms of vomiting, diarrhoea and dehydration that can last up to 10 days. It is highly contagious and can spread easily to friends and members of the family.
Description: Gastrogard-R® is a non-sterile, oral powder consisting of concentrated proteins including immunoglobulins harvested from the colostrum of hyperimmunised cows. The primary immunoglobulin is IgG1. Each sachet of Gastrogard-R® contains 5g of hyperimmune bovine colostrum.
Indication: Prophylactic treatment to prevent diarrhoea due to rotavirus in at-risk children aged one month to three years. Rotavirus is highly infectious in young children, and outbreaks occur frequently during the winter in hospitals, daycare centres, and in the family setting. Taking Gastrogard-R® during periods of risk helps prevent rotavirus cross-infection.
Gastrogard-R® History
The inception of Gastrogard-R® took place in 1985 with the initial clinical trial conducted in 1987 and published in the Lancet in 1989. By 1990 the State Government of South Australia proceeded to build a plant at Oakden, South Australia, and in 1991 the first production of Gastrogard-R® commenced. Additional clinical trials were performed in Hong Kong and India, and produced results documenting the prevention of rotavirus diarrhoea in children up to 3 years of age. By 1996 Numico Research Australia began to market Gastrogard-R®. In 2008 Immuron licensed the rights to rotavirus/Gastrogard-R® technology.
Mode of Action
It is likely that protection by Gastrogard-R® against diarrhoea caused by rotavirus infection is related to the presence of antibody within the lumen of the intestine, although the complete mechanisnm of action by which Gastrogard-R® prevents rotavirus diarrhoea has not been fully determined in our clinical studies. Studies in animals indicate that the presence of anti-rotavirus antibody in the intestinal lumen, rather than circulating antibody, is required to prevent rotavirus diarrhoea.
The IgG is known to be selectively transported by the udder from the circulation to the lacteal secretions, and is the principal immunoglobulin for passive immunisation of the calf. In contrast, IgG2 predominates in bovine serum. We believe that the single most important ingredient in Gastrogard-R® is IgG1.
In vitro studies have shown IgG1 to be responsible for more than 82% of the virus neutralising activity of Gastrogard-R®. It is proposed that the specific anti-rotavirus immunoglobulins, primarily IgG1, in Gastrogard-R® bind to antigens on the rotavirus particle, disrupting disease processes and preventing infection. The precise mechanism by which rotavirus causes diarrhoea has not been determined, but Gastrogard-R® could disrupt the disease process by binding to rotavirus outer capsid proteins, preventing attachment of rotavirus to the mature epithelial enterocytes neutralising viral products or toxins, and/or agglutinating the virus within the lumen of the intestine.
The anti-rotavirus activity of Gastrogard-R® survives passage through the gut.
Clinical Trials
Six hospital-based clinical studies were performed, four in Australia and two in other countries. Five of these studies were randomised, double blind, placebo controlled design and the other study was open. In all six studies patients ranged in age from 28 days to three (3) years. The control product was either low potency colostrum or milk. Combined analysis of these studies demonstrated a statistically significant reduction in the incidence of rotavirus infection in children given Gastrogard-R® compared with children who did not receive the drug (p<0.001).
Antibody Survival Trials: SURVIVAL OF ORALLY ADMINISTERED ANTIROTAVIRUS ANTIBODIES IN HUMAN GASTROINTESTINAL TRACT
Pacyna, J., Robertson, ES., Terry, S., Whyte, PBD., Davidson, GP., and Johnson, RB. Northfield Laboratories Pty Ltd, Adelaide, South Australia 5086.
INTRODUCTION: This study investigated the survival of rotavirus antibody activity in faeces of children receiving different doses of HBC-R.
METHODOLOGY: Hyperimmune colostrum containing different levels of rotavirus antibody was administered to 105 children attending nine Adelaide childcare centres. There were five experimental groups in the study. Subjects were asked to drink 100ml of whole milk supplemented with colostrum 3 times a day, for a period of 6 days. Three groups received specific amounts of HBC-R in liquid form, one group received a reconstituted powder form of Gastrogard-R®, and the control group received whole cow's milk. Stool samples were tested for the presence of rotavirus antigen or antibodies. Rotavirus activity was determined using a virus reduction and a virus neutralisation assay.
RESULTS: Rotavirus antibody activity was detected in 521 (86%) of 602 faecal specimens obtained during the study using the virus reduction ELISA. The antibody activity was detected as early as 8 hours after ingestion of hyperimmune colostrum and up to 72 hours after consumption had ceased.
There was a strong and positive relationship (r = 0.81) between the levels of antibody activity in faeces and the dose of HBC-R ingested. The relationship between the percent reduction of rotavirus by ELISA and the percent of rotavirus neutralisation using faecal extracts of subjects taking HBC-R was also investigated.
The results of the two assays correlated strongly (r = 0.96) and were of high functional dependence (R2 = 0.92) and significance (p = 0.004), providing evidence for the neutralizing capacity of rotavirus in faecal extracts. The results show that approximately 5% of relative rotavirus antibody activity had survived passage through the gut (mean activity, 4 groups, 602 samples). Therefore, passive immunotherapy may be used to prevent or treat infectious diseases that affect the entire length of the gastrointestinal tract. Furthermore, it is likely that antibody activity in the small intestine (where most viral and bacterial infections have their major impact) will be considerably higher than the activity in the faeces, thus providing even greater protection against and/or treatment of gastrointestinal diseases.
COMMUNITY BASED TRIAL:
A community based clinical study was carried out in childcare centres to evaluate the health and economic outcomes associated with daily use of an equivalent liquid product containing hyperimmune bovine colostrum - antirotavirus (HBC-A). The study was a double blinded, two-way parallel, cluster randomised design in over 700 children below the age of four (4) attending 22 childcare centres in South Australia, over a period of five months. Children received active product (HBC-A), control (milk), or no product, and were monitored. No statistical data are available to accurately report on the compliance rate with study treatment. The number of proven rotavirus infections in each group was divided by the person-time at risk of developing an infection for the respective group to yield incidence rates. The incidence of rotavirus diarrhoea in children given HBC-A was 0.04672/100 days of observation (n=245, observed over 21,403 days with one episode of diarrhoea). The incidence of rotavirus diarrhoea in children given cow’s milk or monitoring only was 0.25431/1000 days (n = 497, observed over 47,186 days, 12 episodes of rotavirus diarrhoea). The analyses are summarised as follows:
1. Adjusted for sex, race and stool consistence at baseline, the incidence density (IDR) ratio is 0.22, 95% confidence interval; 0.66 to 0.77, P = 0.018, showing a statistically significant protective effect of HBC-A.
2. The IDR of rotavirus diarrhoea for treated versus monitored in the active centres was 0.19, significantly different from 1; P = 0.03, the IDR for treated versus monitored in the control centres was 0.83, not significant: P = 0.69, the ratio of these two IDRs (0.19/0.083) is 0.229 and that this is significantly different from 1: P = 0.0436, that is, there is an interaction.
3. Children in active centres on the product are less likely to get rotavirus diarrhoea than those being monitored (P = 0.003), and this is a significantly different result than for children receiving the control (whole milk) in control centres (P = 0.436).
References
Saulsbury FT, Winkelstein JA, Yolken RH. “Chronic rotavirus infection in immunodeficiency.” J Pediatr 1980; 97: 61-65.
Losonsky G, Johnson JP, Winkelstein JA, Yolken RH. “Oral administration of human serum immunoglobulin in immunodeficient patients with viral gastroenteritis.” J Clin Invest 1985; 76: 2362-2367.
Stephen W, Dichtelmuller H, Lissner R. “Antibodies from colostrum in oral immunotherapy.” J Clin Chem Biochem 1990; 28: 19-23.
Davidson GP, Whyte PBD, Daniels E, et al. “Passive immunisation of children with bovine colostrum containing antibodies to human rotavirus.” Lancet 1989; 2: 709-712.
Davidson GP, Tam J, Kirubakaran C. “Passive protection against symptomatic hospital acquired rotavirus infection in India and Hong Kong.” J Pediatr Gastroenterol Nutr 1994; 19: 351.
Clinical Trial NLC: 01-95 (unpublished). “Passive prevention of rotavirus diarrhoea in infants and young children by oral administration of hyperimmune bovine colostrum containing antibodies which are cross-reactive against four human rotavirus serotypes.” Data on file at Numico Research Australia Pty Ltd. and with Immuron Ltd.