Ott Amy C, Loll Patrick J, Burns James M
Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 215 North 15th St., Philadelphia, PA 19102, USA.
Vaccines (Basel). 2025 Jun 28;13(7):702. doi: 10.3390/vaccines13070702.
To evaluate the mRNA vaccine platform for blood-stage parasites, we completed a proof-of-concept study using the mouse model of malaria and two mRNA-based vaccines. Both encoded MSP1 fused to MSP8 (MSP1/8). One was designed for secretion of the encoded protein (MSP1/8-sec); the other encoded membrane-bound antigen (MSP1/8-mem).
Secretion of MSP1/8-sec and membrane localization of MSP1/8-mem were verified in mRNA-transfected cells. As recombinant MSP1/8 (rMSP1/8) is known to protect mice against lethal 17XL infection, we first compared immunogenicity and efficacy of the MSP1/8-sec mRNA vaccine versus the recombinant formulation in outbred mice. Animals were immunized three times followed by challenge with a lethal dose of 17XL-parasitized RBCs (pRBCs). Similar immunization and challenge experiments were conducted to compare MSP1/8-sec versus MSP1/8-mem mRNA vaccines.
Immunogenicity of the MSP1/8-sec mRNA vaccine was superior to the recombinant formulation, inducing higher antibody titers against both vaccine components. Following challenge with 17XL pRBCs, all MSP1/8-sec-immunized animals survived, with 50% of these showing no detectible pRBCs in circulation (<0.01%). In addition, mean peak parasitemia in MSP1/8-sec mRNA-immunized mice was significantly lower than that in the rMSP1/8 vaccine group. Both MSP1/8-sec and MSP1/8-mem were protective against 17XL challenge, with MSP1/8-mem immunization providing a significantly higher level of protection than MSP1/8-sec immunization considering the number of animals with no detectable pRBCs in circulation and the mean peak parasitemia in animals with detectable parasitemia.
mRNA vaccines were highly immunogenic and potently protective against blood-stage malaria, outperforming a similar recombinant-based vaccine. The membrane-bound antigen was more effective at inducing protective antibody responses, highlighting the need to consider antigen localization for mRNA vaccine design.
为了评估针对血液期疟原虫的mRNA疫苗平台，我们利用疟疾小鼠模型和两种基于mRNA的疫苗完成了一项概念验证研究。两种疫苗均编码与MSP8融合的MSP1（MSP1/8）。一种设计用于分泌编码蛋白（MSP1/8-sec）；另一种编码膜结合抗原（MSP1/8-mem）。
在mRNA转染细胞中验证了MSP1/8-sec的分泌和MSP1/8-mem的膜定位。由于已知重组MSP1/8（rMSP1/8）可保护小鼠免受致死性17XL感染，我们首先在远交系小鼠中比较了MSP1/8-sec mRNA疫苗与重组制剂的免疫原性和效力。动物免疫三次，随后用致死剂量的17XL寄生红细胞（pRBC）进行攻击。进行了类似的免疫和攻击实验，以比较MSP1/8-sec与MSP1/8-mem mRNA疫苗。
MSP1/8-sec mRNA疫苗的免疫原性优于重组制剂，诱导产生针对两种疫苗成分的更高抗体滴度。用17XL pRBC攻击后，所有接受MSP1/8-sec免疫的动物均存活，其中50%的动物循环中未检测到pRBC（<0.01%）。此外，接受MSP1/8-sec mRNA免疫的小鼠的平均峰值寄生虫血症明显低于rMSP1/8疫苗组。MSP1/8-sec和MSP1/8-mem均对17XL攻击具有保护作用，考虑到循环中未检测到pRBC的动物数量和有可检测到寄生虫血症的动物的平均峰值寄生虫血症，MSP1/8-mem免疫提供的保护水平明显高于MSP1/8-sec免疫。
mRNA疫苗具有高度免疫原性，对血液期疟疾具有强大的保护作用，优于类似的基于重组的疫苗。膜结合抗原在诱导保护性抗体反应方面更有效，突出了在mRNA疫苗设计中考虑抗原定位的必要性。
