Accelerated prime-and-trap vaccine regimen in mice using repRNA-based CSP malaria vaccine.

Malaria, caused by Plasmodium parasites, remains one of the most devastating infectious diseases worldwide, despite control efforts that have lowered morbidity and mortality. The only P. falciparum vaccine candidates to show field efficacy are those targeting the asymptomatic pre-erythrocytic (PE) stages of infection. The subunit (SU) RTS,S/AS01 vaccine, the only licensed malaria vaccine to date, is only modestly effective against clinical malaria. Both RTS,S/AS01 and the SU R21 vaccine candidate target the PE sporozoite (spz) circumsporozoite (CS) protein. These candidates elicit high-titer antibodies that provide short-term protection from disease, but do not induce the liver-resident memory CD8 ⁺ T cells (Trm) that confer strong PE immunity and long-term protection. In contrast, whole-organism (WO) vaccines, employing for example radiation-attenuated spz (RAS), elicit both high antibody titers and Trm, and have achieved high levels of sterilizing protection. However, they require multiple intravenous (IV) doses, which must be administered at intervals of several weeks, complicating mass administration in the field. Moreover, the quantities of spz required present production difficulties. To reduce reliance on WO while maintaining protection via both antibodies and Trm responses, we have developed an accelerated vaccination regimen that combines two distinct agents in a prime-and-trap strategy. While the priming dose is a self-replicating RNA encoding P. yoelii CS protein, delivered via an advanced cationic nanocarrier (LION ^™ ), the trapping dose consists of WO RAS. This accelerated regime confers sterile protection in the P. yoelii mouse model of malaria. Our approach presents a clear path to late-stage preclinical and clinical testing of dose-sparing, same-day regimens that can confer sterilizing protection against malaria.
Competing Interests: COMPETING INTERESTS M.A., Z.M, K.H., J.D. are full-time employees of MalarVx, Inc. M.A. and Z.M. are co-inventors on international patent PCT/US2023/19674. J.D. has equity interests in MalarVx, Inc. A.S., J.H.E., A.P.K. and S.G.R. are full-time employees of HDT Bio. A.S., J.H.E., A.P.K and S.G.R. have equity interests in HDT Bio. J.H.E has consulting agreements with various life sciences companies. J.H.E. and A.P.K. are inventors on granted U.S. patents pertaining to HDT Bio’s proprietary cationic nanocarrier formulation. S. C. M. has a patent application on selected aspects of the prime-and-trap concept through the University of Washington and has equity in a startup company (Sound Vaccines, Inc.) that is negotiating with the University of Washington for rights to this intellectual property. All other authors declare that they have no competing interests.