Vaccination is recognized to be the most cost-effective means of preventing, controlling, and even eradicating infectious diseases. Conventional poultry are vaccinated through various routes including eye/nose drops, drinking water, vent brush, or injection. Efficient vaccination is an essential part of any good poultry management.The bursa of Fabricius is intimately connected to the cloaca and the intestinal system. It is well-known as a primary lymphoid organ in the chicken and a major channel through which environmental antigens stimulate the immune system. In this study we tested whether direct instillation of various viral vaccines and antigens into the cloaca (per bursam), could stimulate higher antibody titers and generate improved protection. Despite the very rapid absorption of the vaccines or antigens from the cloaca to the lumen of the Bursa of Fabricius, per bursam inoculation failed to generate a satisfactory immune response. In contrast conventional administration of live or inactivated commercial vaccines led to an acceptable level of seroconversion and protection against challenge.An interesting finding in this study was the fact that administration of a single priming dose of antigenic material at age 1 or 5 days, did not improve the response to a second administration at 14 days of age as expected. Instead, in most cases there was a reduced serum antibody response suggesting the induction of tolerance. This was true for all routes of administration (intramuscular, per ocular and per bursam) and for all formulations of vaccine.The current study reveals: 1) no advantage for direct application of live or inactivated vaccines or antigens into the bursa of Fabricius compared to common routes of vaccination, 2) that apparent desensitization or tolerance effects have important implications for poultry management, since in many countries, vaccination of day old chicks is compulsory or a well-accepted part of flock vaccination.According to our results, early vaccination can in fact reduce or inhibit a secondary immune response to subsequent vaccination and increase susceptibility to disease agents.