Delayed-type hypersensitivity (DTH) reaction to rotavirus EDIM and RRV. Conclusion
Much controversy still exists as to whether serum antibodies against rotavirus are directly involved in protection or merely reflect recent infection, leaving the protective role to mucosal or cell-mediated immunity. Reviewed data from a variety of studies in humans suggest that serum antibodies, if present at critical levels, are either protective themselves or are an important and powerful correlate of protection against rotavirus disease. Previous studies in infant mice, rabbits and humans have determined that rotavirus-specific IgM levels increase during the acute-phase of infection (before 7 days p.i.) and then decrease gradually. Therefore, rotavirus-specific IgM is seen as a marker of primary infection. Rotavirus-specific IgA and IgG levels were increased in the convalescent-phase of the infection. Administration of RRV at day 7 resulted in the development of an antibody titer after 21 days, predominantly of the IgG2a subclass. Similar subclass restriction after virus infections was seen previously. Administration of EDIM to previously RRV inoculated mice did not result in an increase of the antibody titer. Administration of EDIM at day 17 without a previous RRV inoculation resulted in normal levels of rotavirus-specific IgM and a small amount of rotavirus-specific IgG (subclass) antibodies, most likely due to the fact that 10 days p.i. is too early to measure the development of IgG antibodies. Intervention with Gastrogard-R® showed low antibody titers, but still significantly higher than the group who were inoculated with EDIM only, indicating that the rotavirus, although not able to induce diarrhea during the primary infection, could still provoke an antibody reaction.
Gastrogard-R® is prepared from colostrum of hyperimmunised cows and contains high antibody titers against four human rotavirus serotypes, as measured in a virus neutralisation test. The efficacy of passive immunization was established in calves which were immunized by subcutaneous injection of colostral whey with a high IgGl rotavirus antibody titer and challenged with virulent bovine rotavirus 48 h later. Calves were protected from rotavirus infection and diarrhea. Results further indicated that circulating IgG1 antibody appeared in the gastrointestinal tract of neonatal calves. Previous research already showed that rotavirus antibody activity survived passage through the human gastrointestinal tract [28]. Gastrogard-R® is used as prophylactic treatment of ‘at risk’ children aged one month to three years to prevent diarrhea due to rotavirus infection. The efficacy of treatment with Gastrogard-R® was established in a clinical trial in children aged 3 to 15 months. The in vitro inhibitory effect of Gastrogard-R® was established in our laboratory in a rotavirus (RRV) titration assay using MA-104 cells (data not shown). In this assay Gastrogard-R® was shown to have a strong inhibitory effect on the infectivity of rotavirus with an IC50 of 1 μg/ml. Bovine milk and bovine milk constituents like lactadherin have been studied on their inhibitory activity in vitro and in in vivo rotavirus models. Various compounds present in whey protein concentrate can ameliorate the severity and incidence of experimental rotaviral diarrhea and modulate the mucosal and systemic immune in suckling rats and suckling mice. However, none of these dairy compounds were able to completely inhibit clinical symptoms during a primary rotavirus infection, which is usually attended with the most severe clinical symptoms like diarrhea and vomiting.
Conclusions
In this study was found that oral administration of rotavirus antibodies can completely protect neonatal mice from clinical symptoms of illness during a primary rotavirus infection. Furthermore, an enhanced rotavirus-specific T cell proliferation and a small but detectable level of rotavirus-specific antibodies were found after re-infection suggesting improved T cell responses and a slight B cell response. Also shedding of rotavirus after EDIM inoculation seemed to disappear more rapidly in mice treated with rotavirus antibodies than in mice inoculated with EDIM alone. These results indicate that even though symptoms of a primary rotavirus infection were prevented, an activation of the immune system was still detectable. Preventing a primary infection by using Gastrogard-R®, activation of the immune system can still occur and could be helpful during re-infection knowing that both arms of the immune system play a pivotal role in immunity to rotavirus infection. These data show that this intervention model can be used for studying clinical symptoms as well as immune responses required for protection against viral re-infection.