PfSPZ Vaccine for Prevention of Plasmodium falciparum malaria

摘要 该项目的目的是进行一个关键的临床试验Sanaria的恶性疟原虫（Pf）的整体 子孢子（SPZ）疫苗，Sanaria® PfSPZ疫苗，以支持旅行者的许可证。这是一个重要 为最需要的得不到充分服务的人群，特别是在非洲，提供许可证。的紧迫性 新型冠状病毒疫情凸显了疟疾疫苗的研发。2020年疟疾在非洲造成更多人死亡 与COVID-19和疟疾相比，估计残疾调整后的寿命是前者的5倍以上。 2020年全球损失的年数超过COVID-19。尽管每年在疟疾控制方面的投资超过30亿美元， 2019年是疟疾连续第五年没有出现有意义的下降;现有工具包括 不足以取得进一步的进展。此外，疟疾仍然是国际社会关注的一个主要问题。 特别是每年访问撒哈拉以南非洲的4400万游客。有一个紧急的未满足的医疗 需要一种预防疟疾的疫苗，可以在大规模疫苗接种计划中部署， 支持消灭疟疾。Sanaria的主要疫苗产品PfSPZ疫苗，由辐射减毒， 无菌、纯化、冷冻保存的PfSPZ在1726名婴儿、儿童和成人中安全且耐受良好， 在9个国家进行了20项临床试验，其中6项在非洲。它已诱导>90%的疫苗效力（VE）， 在美国、德国、马里和 坦桑尼亚;在2.5和8个月时，80%和54%的VE针对异源CHMI;以及VE针对强烈的天然CHMI。 在非洲进行的4次实地试验中，Pf疟疾传播的持续时间至少为18个月。Sanaria开发了一种 创新的方法，以更快地开发，许可和销售PfSPZ疫苗， PfSPZ疫苗的上市许可，用于非洲旅行者，基于关键的3期临床试验 160名受试者，而不是通常的约3,000名受试者。该计划已提交给欧洲药品 我们于二零二一年初与欧洲药品管理局（EMA）进行了磋商，EMA原则上同意我们的方法。有一条清晰的道路， 欧盟，我们正在迅速推进向EMA提出的临床计划， EMA推荐。该提案要求支持美国的一半临床试验， 美国和德国（在FDA和Paul-Ehrlich Institute（PEI）监督下进行）。的审判 设计160名受试者，以检验是否有可能拒绝零假设，即没有 疫苗接种者和对照者在研究受试者比例方面存在显著差异 在免疫后2、6和10周进行异源CHMI后发生寄生虫血症。基于 根据这项试验的结果，沿着我们在非洲的田间试验已经产生和正在产生的结果， 预期能够成功申请任何疟疾的第一个许可证（上市许可） 在欧洲或美国接种疫苗。成功将大大缩短产品许可和发布的时间， 这将导致销售大大提前比没有这个项目，并挽救许多生命。

ABSTRACT The aim of this project is to conduct a pivotal clinical trial of Sanaria’s Plasmodium falciparum (Pf) whole sporozoite (SPZ) vaccine, Sanaria® PfSPZ Vaccine, to support licensure for travelers. This is an important step toward licensure for the underserved populations who need it most, especially in Africa. The urgency of developing a malaria vaccine has been highlighted by COVID-19. Malaria killed more people in Africa in 2020 than did COVID-19 and malaria was responsible for an estimated >5 times as many disability adjusted life years lost worldwide in 2020 than COVID-19. Despite investments of >$3 billion annually in malaria control, 2019 was the 5th consecutive year in which there was no meaningful decrease in malaria; existing tools are inadequate to make further progress. In addition, malaria continues to be a major concern for international travelers, especially the 44 million who visit sub-Saharan Africa annually. There is an urgent unmet medical need for a vaccine that prevents malaria in individuals, and can be deployed in mass vaccination programs to support malaria elimination. Sanaria’s lead vaccine product PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved PfSPZ, has been safe and well tolerated in 1726 infants, children and adults in 20 clinical trials in 9 countries, 6 in Africa. It has induced >90% vaccine efficacy (VE) against homologous controlled human malaria infection (CHMI) at 3-11 weeks after immunization in the US, Germany, Mali and Tanzania; 80% and 54% VE against heterologous CHMI at 2.5 and 8 months; and VE against intense naturally transmitted Pf malaria in 4 field trials in Africa with durability of at least 18 months. Sanaria has developed an innovative approach to more rapidly developing, licensing, and marketing PfSPZ Vaccine by first receiving marketing authorization for PfSPZ Vaccine for use in travelers to Africa based on a pivotal Phase 3 clinical trial of 160 subjects instead of the usual ~3,000 subjects. This plan was presented to the European Medicines Agency (EMA) in early 2021 and the EMA agreed in principle to our approach. With a clear path to licensure in the EU, we are moving forward expeditiously with the clinical plan proposed to the EMA with modifications the EMA recommended. This proposal requests support for the US-half of a clinical trial that will be conducted in the US and Germany (to be conducted under both FDA and Paul-Ehrlich Institute (PEI) oversight). The trial in 160 subjects is designed to test whether it is possible to reject the null hypothesis that there will be no significant difference between vaccinees and controls with regard to the proportion of research subjects developing parasitemia following heterologous CHMI conducted 2, 6 and 10 weeks after immunization. Based on results from this trial, along with results we have generated and are generating from field trials in Africa, we anticipate being able to successfully apply for the first licensure (marketing authorization) of any malaria vaccine in Europe or the US. Success will significantly shorten the time until product licensure and launch, which will lead to sales significantly earlier than without this project, and save many lives.