Malaria Vaccines: TBV Antigens as Conjugates with Alternate Carriers

对OMPC作为载体的评估：OMPC是默克研究实验室的专有载体。在与默克公司的合作中，我们先前已经证明，将Pfs25与OMPC结合显著提高了Pfs25在包括非人灵长类动物在内的多种动物模型中的免疫原性和反应寿命。体外膜喂养试验表明，诱导的免疫血清有效阻断了疟疾的传播。在过去的一年里，我们建立了Pfs25-OMPC结合物的室内合成，并在小鼠身上评估了免疫反应。基于这些显示免疫反应增强的研究，我们已经开始在非人类灵长类动物中进行研究，以评估OMPC结合物的抗体反应的寿命。此外，我们已经合成了Pfs230-OMPC结合物，并正在对小鼠和非人类灵长类动物的抗体反应和寿命进行评估。 TBV抗原Vi多糖偶联物的评价：我们与韩国首尔国际疫苗研究所(IVI)合作，正在开发Pfs25和Pfs230抗原与Vi多糖偶联物，目标是生产抗疟疾和伤寒的双价疫苗。VI多糖目前被批准作为伤寒疫苗。我们合成了一系列Pfs25和Pfs230的Vi偶联物，并评价了它们在小鼠体内的免疫应答。这些研究表明，针对TBV抗原的抗体反应与EPA结合物获得的抗体反应相当。结合还导致了对Vi多糖的抗体应答增加，证明了它作为抗疟疾和伤寒的二价疫苗的用途。目前，我们正在进行优化偶联合成的研究，并将其扩展到其他疟疾抗原，包括间日疟原虫抗原。下面的科学进展一节概述了这一领域的进展。 TTHC和EcoCRM作为携带者的评估：与FinaBio合作，我们目前正在评估另外两个携带者，TTHC(破伤风毒素重链)和EcoCRM(CRM197在大肠杆菌中表达的版本)作为潜在的携带者。目前的活动包括合成TTHC和EcoCRM与TBV抗原的结合物，并在小鼠免疫原性研究中对它们进行评估，以测试它们作为TBV抗原载体的有效性，并检查它们与破伤风类毒素和CRM197等其他载体的比较。我们已经合成了TTHC和EcoCRM的Pfs25结合物，并研究了它们在小鼠身上的免疫原性，目前正在合成TTHC和EcoCRM的Pfs230结合物。

Evaluation of OMPC as a carrier: OMPC is a proprietary carrier from Merck Research Laboratories. In collaboration with Merck, we have previously demonstrated that conjugating Pfs25 with OMPC significantly increased immunogenicity and response longevity of Pfs25 in multiple animal models, including nonhuman primates. The induced immune sera effectively blocked malaria transmission as evaluated in an ex-vivo membrane feeding assay. During the past year, we have established synthesis of Pfs25-OMPC conjugates in house, and evaluated immune responses in mice. Based on these studies that showed enhanced immune response, we have started studies in nonhuman primates to evaluate the longevity of the antibody response from OMPC conjugates. In addition, we have synthesized Pfs230-OMPC conjugates and these are also being evaluated in mice and nonhuman primates for antibody responses and longevity. Evaluation of Vi Polysaccharide conjugates of TBV antigens: Working in collaboration with the International Vaccine Institute (IVI), Seoul S. Korea, we are developing conjugates of Pfs25 and Pfs230 antigens with Vi polysaccharide with the goal of producing a bivalent vaccine against malaria and typhoid fever. Vi polysaccharide is currently approved as a vaccine for Typhoid fever. We have synthesized a number of Vi conjugates of Pfs25 and Pfs230 and evaluated their immune response in mice. These studies showed antibody responses against the TBV antigens comparable to that obtained by EPA conjugates. Conjugation also resulted in increased antibody responses against the Vi polysaccharide, demonstrating its utility as a bivalent vaccine against malaria and typhoid. Currently, we are pursuing studies to optimize the conjugate synthesis and expand it to other malaria antigens including Plasmodium vivax antigens. Progress in this area is summarized in Scientific Advances section below. Evaluation of TThc and EcoCRM as carriers: In collaboration with FinaBio, we are currently evaluating two other carriers, TThc (Tetanus toxin heavy chain) and EcoCRM (a version of CRM197 expressed in E. Coli) as potential carriers. Current activities involve synthesizing conjugates of TThc and EcoCRM with TBV antigens and evaluating them in mouse immunogenicity studies to test their utility as carriers of TBV antigens and to examine how they compare with other carriers such as tetanus toxoid and CRM197. We have synthesized Pfs25 conjugates of TThc and EcoCRM and studied their immunogenicity in mice, and are currently working on synthesizing Pfs230 conjugates of TThc and EcoCRM.