DNA vaccination represents a unique opportunity to overcome the limitations of conventional early life vaccine strategy which is restricted by the effects of maternally derived immunity. The pseudorabies virus (PRV) infection model in neonatal piglets was employed to demonstrate that a single DNA vaccination was able to prime memory humoral immune responses in the face of high concentrations of maternally derived antibodies. Immunity induced under these conditions protected against challenge with virulent PRV at the end of the fattening period, but long-term protective responses were not correlated with the kinetics of the initial serological responses. The bovine respiratory syncytial virus (BRSV) infection model in young calves was similarly studied, however the ability of DNA vaccination to prime memory humoral responses in the face of high concentrations of maternally derived antibodies was not confirmed, illustrating that the performance of DNA vaccination varies between species and/or infectious disease targets. However, in the BRSV model system it was evident that DNA vaccination could prime cell-mediated immunity in the face of high concentrations of maternally derived antibodies. Although not sufficient to ensure protection against clinical disease or viral excretion as a standalone vaccination strategy, priming by DNA vaccination was proven to establish cell-mediated immune responses for subsequent recall with an inactivated vaccine booster. Under these conditions, protection against challenge virus re-excretion was correlated with interferon (IFN) gamma-producing T-cell responses. The safety and the efficacy of DNA vaccine priming in very young animals in the face of high concentrations of maternally derived antibody provides a unique opportunity to design innovative and flexible vaccination programs to ensure uninterrupted protection under field conditions.