Assessment of whole organism vaccinations in Malian Adults

马里成人全身疫苗接种评估

• 批准号: 9161708
• 负责人: Patrick Duffy
• 金额: $ 45.19万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9161708
• 关键词: Adjuvant; Adult; Adverse event; African; Animals; Antibody Response; Antigen Targeting; Antigens; Antimalarials; Attenuated; Bite; Blood; Chemoprophylaxis; Chloroquine; Clinical; Clinical Research; Clinical Trials; Collaborations; Control Groups; Culicidae; Data; Development; Dose; Double-Blind Method; Enrollment; Erythrocytes; Exposure to; Future; Grant; Hepatocyte; Human; Immune response; Immunity; Immunization; Incidence; Individual; Infection; Institutional Review Boards; Intervention; Learning; Licensing; Life Cycle Stages; Liver; Malaria; Malaria Vaccines; Mali; Mass Vaccinations; Measures; Methods; Modeling; Mus; National Institute of Allergy and Infectious Disease; Needles; Parasites; Participant; Pharmaceutical Preparations; Phase; Pilot Projects; Placebo Control; Placebos; Plasmodium falciparum; Play; Procedures; Production; Prophylactic treatment; Proteins; Protocols documentation; Pyrimethamine; Radiation; Randomized; Randomized Controlled Trials; Recombinants; Regimen; Reporting; Research Training; Role; Safety; Seasons; Series; Severities; Sporozoite vaccine; Sporozoites; Staging; Sterility; Syringes; Tanzania; Testing; Time; United States National Institutes of Health; Universities; Vaccination; Vaccines; Venous; Visit; Whole Organism; asexual; base; co-infection; design; expectation; experience; follow-up; human study; immunogenicity; immunoregulation; improved; intravenous administration; irradiation; man; manufacturing process; meetings; nonhuman primate; prevent; protective efficacy; response; safety testing; tool; transmission process; vaccine candidate; vaccine response; volunteer

Collaborations with Sanaria Inc and the Malaria Research and Training Center at the University of Bamako, Mali to conduct these PfSPZ related studies was initiated in 2012. PfSPZ Vaccine in Mali (NIAID Protocol 14-I-N010) Since January 2013, we have been preparing for a study to test the safety, immunogenicity and efficacy against naturally occurring malaria infection of PfSPZ Vaccine in Malian adults. The phase 1 double-blind, randomized, controlled trial to assess the safety, immunogenicity, and protective efficacy of repeated IV immunization with PfSPZ Vaccine in Mali started in January 2014 in Doneguebougou, Mali at the Malaria Research and Training Center with complete enrollment into the study by February 2014. Twelve subjects were initially enrolled in a staggered manner for safety in the pilot safety group and received their first vaccination (1.35x105 PfSPZ Vaccine) the week of 28 January 2014, and then received 2.7x105 PfSPZ Vaccine two weeks later. 97 subjects were initially enrolled of which 96 subjects were stratified by village and randomized for the main group. Of those 96 subjects, 93 subjects (46 PfSPZ Vaccine; 47 placebo) received their first vaccination starting the week of 24 February 2014. The final vaccinations were received by 88 subjects (44 PfSPZ Vaccine; 44 placebo) the week of 14 July 2014. The primary efficacy endpoint of the study started the week of 11 August 2014 (28 days following receipt of the fifth vaccination) and the final study visit was completed on 05 January 2014. Of the 88 subjects in the main group who received all five vaccinations, 86 subjects (42 PfSPZ Vaccine; 44 placebo) completed the study through the transmission season to the last study visit 88 healthy malaria exposed Malian adults (44 PfSPZ Vaccine; 44 Placebo) received five doses of vaccine and 86 (42 PfSPZ Vaccine; 44 Placebo) were followed actively every two weeks for up to 24 weeks post vaccination #5. PfSPZ Vaccine was easy to administer, and was safe and well tolerated. P. falciparum infections 28 days post vaccination 5 occurred significantly earlier in the control group than the PfSPZ Vaccine group. PfSPZ Vaccine is safe, well tolerated, and is the first vaccine to show evidence of sterile protection to African adults from natural P. falciparum infection over the course of an entire malaria season. PfSPZ Vaccine in Mali V2 (NIAID Protocol TBD) Our initial results from Protocol 14-I-N010 have been encouraging given the following: 1) the protective efficacy was significantly higher than has ever been demonstrated by immunization with a malaria vaccine in adult Africans, 2) the PfSPZ Vaccine was efficacious against heterogeneous African P. falciparum parasites and 3) there was no evidence of waning of immunity during the 6 month follow up period. In addition, all doses were safe and well tolerated with little reactogenicity or adverse events reported. On the other hand, protection in both Tanzania and efficacy in Mali were lower than what was recorded in the USA, and it does not meet our expectations for a licensed PfSPZ Vaccine. One possible explanation for the lower rates of efficacy was provided by our assessment of antibody responses seen in Mali and Tanzania as noted above. These results clearly demonstrate that healthy Tanzanian and Malian adults do not produce comparable antibody responses to PfCSP after immunization with PfSPZ Vaccine to the non-Pf malaria-exposed adults in the U.S. Because adults play a significant role in transmission of P falciparum, and if PfSPZ Vaccine is to be used as a tool for elimination, it must be protective in adults. We think that the most likely explanation for the poor immunogenicity and protection in the adult Africans is immunoregulation due to lifelong exposure to P falciparum infections. Thus, we hypothesize that we can improve efficacy by increasing the number of PfSPZ Vaccine per dose, increasing the interval between the first and second doses to 8 weeks (as was done in WRAIR 2080 in the group receiving 3 doses of 4.5x105 PfSPZ), and reducing the number of doses to three. Additionally, we hypothesize that we can learn how the standard CHMI model may be used in the field and start to explore the impact such factors as malaria co-infection and drug treatment have on vaccine responses. A protocol, with a defined dose escalation pilot study followed by a double blind, randomized placebo-controlled main study was drafted and has completed NIAID IRB submission and review. The protocol is planned to be implemented in Doneguebougou, Mali in November 2015 through January 2016. PfSPZ CVac-PYR (NIAID Protocol 15-I-0169) As previously noted, a human study suggested that anti-infection immunity might be achieved with a much smaller parasite inoculum. This method of immunization by experimental P. falciparum infection in conjunction with antimalarial prophylaxis is referred to as chemoprophylaxis with sporozoites (CPS), infection treatment vaccine (ITV), and chemoprophylaxis with sporozoites (CVac) by different authors. We use the term CVac in this Protocol to refer to this vaccine concept. Since chloroquine is a blood-stage schizonticide, the degree to which the protective immune response induced by the chloroquine CVac model targets liver or blood-stage antigens is unclear from the study of Roestenberg et al. Further, limited data in both animal and humans indicate that exposure to blood-stage parasites may abrogate liver-stage immune responses. It is important to further define whether sterile protective immunity to P. falciparum can be induced by wild-type (non-attenuated) sporozoite immunizations when exposure is limited to sporozoite and pre-erythrocytic stages of the parasite life cycle and by a low dose of sporozoite inoculum. This study will evaluate a CVac regimen using chloroquine weekly in addition to pyrimethamine. This combination will attempt to prevent the development asexual erythrocytic stages of the malaria parasite. By completely preventing the release of blood-stage parasites, this CVac regimen will extend the findings of Roestenberg et al. and explore whether highly protective anti-infection immunity and sterile protection from homologous P. falciparum challenge can be induced by exposure that is limited to the liver-stage of parasite development. Exploration of stage-specific immune responses involved in protective immunity to P. falciparum and discovery of new target antigens is critical for future development of malaria vaccine strategies. The intervention in this study is induction of stage specific immunity (pre-erythrocytic immunity) to malaria following direct venous inoculation (DVI) with aseptic, purified, vialed, cryopreserved, fully infectious NF54 PfSPZ (referred to as Sanaria PfSPZ Challenge) produced by Sanaria, Inc when exposure is limited to the SPZ and liver-stages of the parasite life cycle and at a low dose PfSPZ inoculum (51,200 Sanaria PfSPZ Challenge) via the following regimens: PfSPZ Challenge under chloroquine coverage or PfSPZ Challenge under chloroquine and pyrimethamine coverage for a total of 3 exposures while subjects are under one or two malaria prophylaxis regimens listed above. Protective efficacy will be assessed by homologous CHMI via PfSPZ Challenge via DVI. This study has been supported by the U01 grant mechanism (RPPR-5U01AI109700-02) and the study has been NIAID IRB approved to start in 2015. Current plans are for the clinical study to start in November 2015.

与Sanaria Inc和马里巴里大学巴马科大学的疟疾研究与培训中心合作进行了这些与PFSPZ相关的研究。 MALI中的PFSPZ疫苗（NIAID方案14-I-N010） 自2013年1月以来，我们一直在准备进行一项研究，以测试马里成人中PFSPZ疫苗自然发生的疟疾感染的安全性，免疫原性和功效。 1阶段双盲，随机，对照试验，以评估马里重复IV免疫的安全性，免疫原性和保护性的疗效2014年2月的研究。2014年1月28日，在试点安全组中最初以交错的方式招募了十二名受试者，以交错的方式进行安全安全，并接受了他们的第一次疫苗接种（1.35x105 PFSPZ疫苗），然后在两周后接受2.7x105 PFSPZ疫苗。 最初招募了97名受试者，其中96名受试者按村庄进行了分层，并将其随机分配给主要群体。 在这96名受试者中，有93名受试者（46名PFSPZ疫苗； 47个安慰剂）从2014年2月24日开始接受了第一次疫苗接种。2014年7月14日，由88名受试者（44个PFSPZ疫苗； 44个PFSPZ疫苗； 44个PFSPZ疫苗； 44个PFSPZ疫苗； 44个PFSPZ疫苗）收到最终疫苗接种。该研究的主要功效终点始于2014年8月11日（收到第五次接种疫苗后的28天），最终研究访问于2014年1月5日完成。 86名受试者（42个PFSPZ疫苗； 44个安慰剂）完成了整个传输季节的研究 88个健康的疟疾暴露于马里亚成年人（44名PFSPZ疫苗； 44个安慰剂）接受了5剂疫苗，每两周在疫苗后24周积极地接管了每两周24周，接受了五剂疫苗和86剂（42个PFSPZ疫苗； 44个安慰剂）。 PFSPZ疫苗易于施用，并且安全且耐受性良好。疫苗接种后28天后，恶性疟原虫感染在对照组中比PFSPZ疫苗组明显更早。 PFSPZ疫苗是安全的，耐受性的，并且是第一个在整个疟疾季节中向非洲成年人提供无菌保护的证据的疫苗。 Mali V2中的PFSPZ疫苗（NIAID方案TBD） 鉴于以下内容，我们从协议14-I-N010的最初结果令人鼓舞：1）保护性疗效明显高于成人非洲人的疟疾疫苗免疫证明，2）PFSPZ疫苗有效地针对异质非洲非洲人恶性疟原虫寄生虫和3）没有证据表明在6个月的随访期内免疫力减弱。此外，所有剂量都是安全且耐受性良好的，没有报道的反应生成或不良事件。另一方面，坦桑尼亚的保护和马里的疗效都低于美国记录的保护，并且不符合我们对持牌PFSPZ疫苗的期望。如上所述，我们对马里和坦桑尼亚中看到的抗体反应的评估提供了一种可能的解释。这些结果清楚地表明，健康的坦桑尼亚和马利亚成年人在用PFSPZ疫苗对非PF疟疾暴露的成年人进行免疫后，对PFCSP产生可比的抗体反应，因为成年人在P Falciparum的传播中起着重要作用，并且如果PFSPZ在PFSPZ的传播中起重要作用。疫苗应作为消除的工具，必须在成年人中具有保护作用。我们认为，由于终生暴露于p恶性疾病感染，对成年非洲人的免疫原性和保护性差的最可能解释是免疫调节。 因此，我们假设我们可以通过增加每剂量的PFSPZ疫苗的数量来提高功效，从而将第一剂和第二剂量之间的间隔增加到8周（就像2080年的Wrair 2080所做的，在接受3剂剂量的4.5x105 PFSPZ的组中），，并将剂量的数量减少到三个。此外，我们假设我们可以学习如何在现场使用标准的CHMI模型，并开始探索诸如疟疾共感染和药物治疗对疫苗反应的影响。 一项协议，进行了定义的剂量升级试点研究，然后起草了双盲，随机的安慰剂对照的主要研究，并完成了NIAID IRB提交和审查。 该协议计划于2015年11月至2016年1月在马里的Doneguebougou实施。 PFSPZ CVAC-PYR（NIAID协议15-I-0169） 如前所述，一项人类研究表明，使用较小的寄生虫接种物可以实现抗感染免疫。通过实验性恶性疟原虫感染与抗疟疾预防的实验性疫苗接种方法称为化学预防症，用孢子虫（CPS）（CPS），感染治疗疫苗（ITV）和化学预防疫苗，以及与孢子虫（CVAC）的化学预防疫苗（CVAC）。我们使用此协议中的CVAC一词来参考此疫苗概念。 由于氯喹是一种血液阶段的精神分裂症，因此Roestenberg等人的研究尚不清楚氯喹CVAC模型诱导的保护性免疫反应靶向肝脏或血液阶段抗原的程度。此外，动物和人类的数据有限表明，暴露于血液阶段的寄生虫可能会消除肝脏免疫反应。重要的是要进一步定义对恶性疟原虫的无菌保护性免疫是否可以通过野生型（未衰减）的孢子岩免疫诱导，当暴露仅限于孢子岩和寄生虫生命周期和低剂量的低剂量孢子岩接种物。这项研究还将使用氯喹周每周评估CVAC方案。 这种组合将试图防止疟原虫的发展无性红细胞阶段。 通过完全防止血阶段寄生虫的释放，该CVAC方案将扩展Roestenberg等人的发现。并探索是否可以通过仅限于寄生虫发育的肝脏阶段来引起高度保护性的抗感染免疫和免受同源恶性疟原虫挑战的无菌保护。探索涉及对恶性疟原虫的保护性免疫和发现新靶抗原的特定阶段特异性免疫反应对于未来疟疾疫苗策略的发展至关重要。 这项研究的干预措施是在直接静脉接种（DVI）（DVI）中诱导了阶段特异性免疫（前肉眼免疫），并具有无菌，纯化，纯净，瓶装，冷冻保存，完全感染的NF54 PFSPZ（由Sanaria PFSPZ挑战）引起，INC通过以下方案限制寄生生命周期的SPZ和肝脏阶段，以及低剂量的PFSPZ接种物（51,200 Sanaria PFSPZ挑战），通过以下方案：在氯喹覆盖或PFSPZ挑战下，在氯喹和Pyrimethamine coverage copperage下进行PFSPZ挑战在上面列出的一个或两个疟疾预防方案下，总共暴露了3次暴露。 保护功效将通过DVI通过PFSPZ挑战来评估同源CHMI。 这项研究得到了U01赠款机制（RPPR-5U01AI109700-02）的支持，该研究已获得NIAID IRB批准于2015年开始。当前的计划是临床研究于2015年11月开始。