The dermal layer of human skin is rich in antigen-presenting cells, making it a promising site for intradermal (ID) vaccination. However, most vaccines are administered intramuscularly (IM). Vaccines often contain adjuvants, which are substances added to vaccines to help promote immunity against infections. FDA approved adjuvants are not suitable for dermal vaccination due to their local reactogenicity. Therefore, there is a need for novel adjuvants to access the likely benefits of ID vaccination. Here, we analyzed the immune response to ovalbumin (OVA) in BALB/c mice and pigs after ID vaccination with alpha-D-glucan nanoparticles (Nano-11), and cyclic-di-adenosine monophosphate (cdAMP), both which have adjuvant activities. The Nano-11 and cdAMP combination increased Th1, Th2, Th17, Tfh, and GC responses in mice and production of OVA-specific antibodies in both mice and pigs with no display of reactogenicity. This work suggests that the Nano-11 and cdAMP combination is a potent adjuvant for safe and effective intradermal vaccination.