| Abstrakt: |
Simple Summary: Vaccines prevent approximately 4 million deaths annually worldwide but around 3 times this number still die each year from infectious diseases. Most vaccines are injected, generating immune responses in the bloodstream but injected vaccines may be less effective against gut bugs that cause localised infections such as Clostridioides difficile. Oral vaccines have the advantage of promoting immune responses within the small intestine, protecting the gut. To develop an oral vaccine against C. difficile, the conventional animal model is the hamster as it develops similar clinical symptoms to humans. A challenge for oral vaccines is overcoming the harsh conditions of the stomach; however, capsules can be used that resist stomach acidity and dissolve once in the small intestine. We previously tested a protein vaccine candidate for responses in the small intestine following oral administration to hamsters using capsules. As the responses were variable, we questioned whether delivery could be improved after fasting hamsters. Using the same protein, we compared intestinal responses in fasted versus fed groups. The fasted group demonstrated significantly greater responses suggesting improved delivery of the capsules to the intestine. Our refined immunisation method can now be applied by the growing number of groups worldwide using the hamster model to test oral vaccines. Oral vaccines, unlike injected, induce intestinal secretory immunoglobulin A (sIgA) mimicking our natural defense against gut pathogens. We previously observed sIgA responses after administering the Clostridioides difficile colonisation factor CD0873 orally in enteric capsules to hamsters. Enteric-coated capsules are designed to resist dissolution in the stomach and disintegrate only at the higher pH of the small intestine. However, the variable responses between animals led us to speculate suboptimal transit of antigens to the small intestine. The rate of gastric emptying is a controlling factor in the passage of oral drugs for subsequent availability in the small intestine for absorption. Whilst in humans, food delays gastric emptying, in rats, capsules can empty quicker from fed stomachs than from fasted. To test in hamsters if fasting improves the delivery of antigens to the small intestine, as inferred from the immune responses generated, 24 animals were dosed intragastrically with enteric capsules containing recombinant CD0873. Twelve hamsters were fasted for 12 h prior to each dose and the other 12 fed. Significantly higher sIgA titres, with significantly greater bacterial-adherence-blocking activity, were detected in small intestinal lavages in the fasted group. We conclude that fasting in hamsters improves intestinal delivery leading to more robust responses. [ABSTRACT FROM AUTHOR] |
