Development of a successful HIV vaccine is dependent upon a determination of the optimum antigen and adjuvant as well as choosing an optimal site for vaccine delivery. The site of delivery is particularly relevant as HIV transmission generally requires that the virus crosses a mucosal membrane to infect a new host. Here we undertake a pilot study comparing three vaccine delivery routes, two to the oral cavity (intraepithelial (iEp) and needle-free (NF-Injex)) as well as intramuscular (IM) delivery. These vaccinations utilized a recombinant HIV-1 Env trimer 10042.05 from an elite neutralizer, subject VC10042, that has previously induced high titers of cross-clade reactive V1V2 antibodies. The 10042.05.SOSIP fused trimer was administered with adjuvants R848 (Resiquimod), MPLA and Alhydrogel to characterize the innate cellular and anti-HIV Envelope (Env) antibody responses following the administration of the vaccine to the oral mucosa. Oral delivery of the 10042.05.SOSIP induced high titers of anti-V1V2 antibodies, which together with previous studies, indicates an immunogenic bias toward the V1V2 regions in 10042-derived Envs. Both types of oral vaccine delivery resulted in immunologic and serologic responses that were comparable to the IM delivery route. Furthermore, induction of anti-V1-V2 specific antibodies was best following iEp delivery of the oral vaccine identifying this as the optimal method to orally deliver this vaccine formulation.