White spot syndrome virus (WSSV) is a highly virulent shrimp pathogen, causing huge economic loss to the aquaculture industry. We investigated the efficacy of recombinant VP39 protein against WSSV infection in Litopenaeus vannamei by intramuscular and oral administration, and also compared the efficacy with recombinant VP28 (rVP28). The VP39 is a 283 amino acid protein encoded by the structural gene vp39 which acts as an important mediator for virus entry to the host. Shrimp orally vaccinated with rVP39 and rVP28 showed a cumulative mortality of 50% and 60% respectively following challenge, and this indicates that rVP39 had a better protective effect against WSSV infection compared with rVP28. Vaccination by intramuscular injection with rVP39 and rVP28 resulted in survival rate of 60% and 50%, respectively. The transcriptional profiling of viral genes of vaccinated shrimp with recombinant viral proteins of VP28 showed higher transcriptional levels than VP39. The transcriptional level of rVP39 vaccinated animals was delayed by 6 days after WSSV infection, while the delay was only 4 days in the case of rVP28. These results indicate that vaccination delays the transcription of envelope genes of WSSV in shrimp. The present study could demonstrate the importance of VP39 as a prominent candidate for vaccination against WSSV