Tuberculosis remains a major public health hazard worldwide, with neonates and young infants potentially more susceptible to
infection than adults. BCG, the only
vaccine currently available, provides some protection against
tuberculous meningitis in children but variable efficacy in adults, and is not safe to use in immune compromised individuals. A safe and effective
vaccine that could be given early in life, and that could also potentiate subsequent booster immunization, would represent a significant advance. To test this proposition, we have generated gene-based
vaccine vectors expressing Ag85B from Mycobacterium tuberculosis (Mtb) and designed experiments to test their immunogenicity and protective efficacy particularly when given in heterologous prime-boost combination, with the initial
DNA vaccine component given soon after birth. Intradermal delivery of
DNA vaccines elicited Th1-based immune responses against Ag85B in neonatal mice but did not protect them from subsequent
aerosol challenge with virulent Mtb H37Rv. Recombinant adenovirus vectors encoding Ag85B, given via the intranasal route at six weeks of age, generated moderate immune responses and were poorly protective. However, neonatal
DNA priming following by mucosal boosting with recombinant adenovirus generated strong immune responses, as evidenced by strong Ag85B-specific CD4+ and CD8+ T cell responses, both in the lung-associated lymph nodes and the spleen, by the quality of these responding cells (assessed by their capacity to secrete multiple antimicrobial factors), and by improved protection, as indicated by reduced bacterial burden in the lungs following pulmonary TB challenge. These results suggest that neonatal immunization with gene-based
vaccines may create a favorable immunological environment that potentiates the pulmonary mucosal boosting effects of a subsequent heterologous vector
vaccine encoding the same
antigen. Our data indicate that immunization early in life with mycobacterial
antigens in an appropriate
vaccine setting can prime for protective immunity against Mtb.