Commercial modified live (MLV) and killed (KV) porcine reproductive and respiratory syndrome virus (PRRSV) vaccines induce slow development of effective immunity as measured by serum neutralizing (SN) antibody and cell-mediated immunity. The objective of the studies was to develop more effective vaccines or vaccination strategies based on commercial vaccines. The immune response and produced induced were characterized. Three separate studies were conducted to investigate the efficacy of vaccination protocols including vaccination with MLV and KV, either alone or in combination, KV with interleukin (IL)-12 added, and KV used as a booster vaccine in a PRRSV positive herd. The protection induced was also evaluated by challenging pigs with PRRSV.;It was found that the MLV followed by KV induced significantly higher SN antibody levels compared to either vaccine alone. This vaccination protocol significantly reduced serum viral RNA, severity of lung lesion, and clinical disease. In contrast, the addition of IL-12 did little to enhance the efficacy of the KV although clinical respiratory disease consistent with PRRSV following challenge was significantly reduced. However, no reduction of viral RNA in serum or reduced persistence of virus in tonsils or BAL was observed. The KV administration of gestational sows significantly increased SN antibodies in serum and colostrum at farrowing and at weaning compared to non-vaccinated sows. Furthermore, pigs farrowed from the vaccinated sows had significantly higher levels of maternally derived antibodies (MDA) as measured by both SN and ELISA assays than pigs farrowed from the non-vaccinated sows. Pigs farrowed from vaccinated sows and challenged at 10 days of age displayed the mildest clinical disease and had lower levels of serum viral RNA than pigs from non-vaccinated sows. Incomplete reduction of serum viral RNA and lung lesion suggests incomplete protection provided by MDA.;The present studies provide useful information to the swine industry as a combination vaccination protocol, MLV followed by KV, could be used to in the reduction of clinical disease and viremia. In addition, KV can be used as a booster vaccine to enhance the existing immunity of sows in a PRRSV positive herd resulting in enhanced MDA in piglets.