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Recently, there has been significant interest in developing combination adjuvants to achieve efficient vaccines. However, it remains uncertain which combinations of adjuvants could best enhance the immune response to the recombinant antigen. In the current study, to improve the immunogenicity of Plasmodium falciparum cell traversal protein for ookinetes and sporozoites (PfCelTOS), we tested three different adjuvants: MPL, Poly I:C, and QS-21 alone or in a triple mixture (MPL/Poly I:C/QS-21; MPQ) and a dual mixture (Poly I:C/QS-21; PQ). BALB/c mice were immunized with recombinant PfCelTOS, either alone or combined with MPL, Poly I:C, QS-21, or with dual and triple adjuvant mixtures. Humoral and cellular immune responses were assessed in the various mouse groups, along with the functional activity of anti-PfCelTOS antibodies in oocyst inhibition. The results showed that administering the PfCelTOS antigen with triple or dual adjuvant mixtures significantly increased specific antibody levels, as well as IFN-ɣ and TNF cytokine production (P < 0.05), compared to PfCelTOS alone or combined with single adjuvants. These vaccine adjuvant mixtures also enhanced transmission-reducing activity (TRA), resulting in 76%-84% reductions in oocyst intensity in functional assays. Interestingly, comparable antibody levels and functional inhibitory activity were observed in the groups that received antigen with both dual and triple adjuvants (P > 0.05). The findings indicate that the dual mixture of Poly I:C and QS-21 is the most effective formulation for a vaccine against PfCelTOS. This discovery has important cost and safety implications by minimizing the adjuvants required to achieve an optimal immune response., Competing Interests: Declaration of competing interest I hereby declare that this manuscript is original, is not published, in press, or submitted elsewhere in English or any other language, and is not currently being considered for publication elsewhere. All authors have seen and approved the content of this manuscript and have contributed significantly to the work., (Copyright © 2025 Elsevier Inc. All rights reserved.)