Malaria Vaccines: TBV Antigens as Conjugates with Alternate Carriers

OMPC作为载体的评价：OMPC是Merck Research Laboratories的专有载体。 在与默克公司的合作中，我们先前已经证明，将Pfs 25与OMPC缀合显著增加了Pfs 25在多种动物模型（包括非人灵长类动物）中的免疫原性和应答寿命。 诱导的免疫血清有效地阻断疟疾传播，如在离体膜喂养测定中所评价的。在过去的一年中，我们已经建立了Pfs 25-OMPC缀合物的内部合成，并在小鼠中评估了免疫应答。基于这些显示增强的免疫应答的研究，我们已经开始在非人灵长类动物中进行研究以评估来自OMPC缀合物的抗体应答的寿命。此外，我们已经合成了Pfs 230-OMPC缀合物，并且这些缀合物也正在小鼠和非人灵长类动物中评估抗体应答和寿命。 TBV抗原的Vi多糖缀合物的评价：与首尔S.在韩国，我们正在开发Pfs 25和Pfs 230抗原与Vi多糖的缀合物，目的是生产针对疟疾和伤寒的二价疫苗。Vi多糖目前被批准作为伤寒疫苗。我们已经合成了许多Pfs 25和Pfs 230的Vi缀合物，并在小鼠中评价了它们的免疫应答。这些研究表明，针对TBV抗原的抗体反应与EPA缀合物获得的抗体反应相当。 缀合还导致针对Vi多糖的抗体应答增加，证明其作为针对疟疾和伤寒的二价疫苗的效用。目前，我们正在进行研究，以优化缀合物合成，并将其扩展到其他疟疾抗原，包括间日疟原虫抗原。这一领域的进展在下文的“科学进展”一节中作了概述。 TThc和EcoCRM作为载体的评估：与FinaBio合作，我们目前正在评估另外两种载体，TThc（破伤风毒素重链）和EcoCRM（在大肠杆菌中表达的CRM 197的一种版本）。大肠杆菌）作为潜在的携带者。目前的活动涉及合成TThc和EcoCRM与TBV抗原的缀合物，并在小鼠免疫原性研究中对其进行评估，以测试其作为TBV抗原载体的效用，并检查它们与其他载体如破伤风类毒素和CRM 197的比较。我们已经合成了TThc和EcoCRM的Pfs 25缀合物，并研究了它们在小鼠中的免疫原性，目前正在合成TThc和EcoCRM的Pfs 230缀合物。

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.