Nasal vaccination with attenuated Salmonella typhimurium strains expressing the Hepatitis B nucleocapsid: dose response analysis

Nasal vaccination of mice with recombinant attenuated strains of Salmonella typhimurium is more efficient at inducing antibody responses than oral vac cination. However, mortality was observed when high doses [10(9) colony for ming unit (CFU)], otherwise safe by the oral route, were administered. This observation was counterbalanced by the fact that nasal vaccination was sti ll highly efficient with lower doses (10(6) CFU), which are inefficient by the oral route and this, without any incidents of mortality. Here, we furth er analyse in mice the effect of nasal vaccination with differently attenua ted S. typhimurium strains expressing the Hepatitis B nucleocapsid (HBc). S urprisingly, as few as 100 CFU were sufficient to induce a maximal HBc spec ific antibody response, but only if the bacteria were inhaled. Furthermore, we observed no correlation between the inoculum dose and the number of sur viving bacteria in cervical lymph nodes and spleen. Examination of lung sec tions revealed strong inflammation and bronchopneumonia 24 h after nasal va ccination with 10(8) CFU, while only minor signs of inflammation were detec ted transiently when 10(3) CFU or phosphate buffered saline (PBS) were admi nistered. Our data suggest that the safety issue of nasal vaccination with low doses of the Salmonella vaccine strains should be addressed in humans, as it might be an efficient alternative to oral vaccination. (C) 2001 Elsev ier Science Ltd. All rights reserved.