Automating mosquito microdissection for a malaria PfSPZ vaccine

产品说明：疟疾每年造成> 2.5亿临床病例和约100万人死亡，造成非洲GDP损失>1%，是旅行者和军事人员的严重关切。迫切需要高度有效的疫苗，并且通过蚊子叮咬施用的放射减毒的恶性疟原虫（Pf）子孢子（SPZ）和具有氯喹化学预防的非减毒PfSPZ（具有子孢子的化学预防，CPS）在人类中诱导针对疟疾的最有效（>90%）和持久（10-28个月）的保护。在其最近的临床试验中，Sanaria的PfSPZ疫苗由辐射减毒、无菌、纯化、冷冻保存的PfSPZ组成，保护了6/6（100%）的志愿者，6/9的受试者接受了最高和第二高剂量的PfSPZ静脉注射（IV），这在疟疾疫苗开发史上是无与伦比的。PfSPZ疫苗将在明年接受针对美国个人的临床试验的严格测试，德国、坦桑尼亚、马里和赤道几内亚将在4年内获得在非洲开展大规模行政消灭运动和预防旅行者疟疾的许可。此外，根据Sanaria的非减毒感染性PfSPZ（PfSPZ攻毒）可以感染欧洲和美国100%的志愿者的证明，PfSPZ攻毒与化学预防结合是Sanaria的第二种疫苗产品，PfSPZ-化学预防（C）疫苗（Vac）（PfSPZ-CVac）。加快获得许可证的道路需要扩大规模，以满足预计的市场需求。尽管每年所需PfSPZ的绝对数量将取决于PfSPZ/剂量的数量以及每只蚊子可以获得的PfSPZ数量，但我们预计很快需要处理10^7只蚊子，然后是10^8只蚊子，最后是>2x10^8只蚊子/年。在我们目前的生产设施内，手动解剖10^7只蚊子/年是可以实现的，但在相同的物理空间内，自动化可以促进吞吐量进一步增加5至10倍（5x10^7 - 10^8只蚊子/年）。相比之下，每年手工解剖10^8只蚊子将需要相当大的扩展，以便容纳一个巨大扩展的解剖器工作组。预计成本曲线的建模也表明，疫苗的价格将下降 只有在自动化到位的情况下，才能逐步制造每一个增量，而不是手动解剖。事实上，在处理前10^7只蚊子后，疫苗的成本/瓶下降> 50%。基于自动化原型的初步开发，我们建议构建第一个集成的自动化蚊子显微切割系统（AMMS），并微调性能参数和材料符合性，以实现工业规模的高通量cGMP处理。这些目标的成功完成将使Sanaria的生产进展与其临床开发和商业化计划走上正轨，允许在不需要显著扩张的情况下大大提高现有设施的生产，从而促进为数亿患有这种疾病的人更直接地广泛使用整个PfSPZ疫苗。

DESCRIPTION: Malaria causes >250 million clinical cases and ~1 million deaths annually, is responsible for >1% loss of GDP in Africa and is a serious concern for travelers and military personnel. A highly effective vaccine is desperately needed and radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ) and non- attenuated PfSPZ with chloroquine chemoprophylaxis (ChemoProphylaxis with Sporozoites, CPS), administered by mosquito bites, induce the most efficacious (>90%) and long lasting (10-28 months) protection against malaria in humans. In its most recent clinical trial, Sanaria's PfSPZ Vaccine, consisting of radiation attenuated, aseptic, purified, cryopreserved PfSPZ, protected 6/6 (100%) of volunteers 6/9 subjects who received the highest and second highest dose of PfSPZ intravenously (IV), unparalleled in the history of malaria vaccine development. PfSPZ Vaccine will undergo rigorous testing during the next year in clinical trials targeting individuals in the U.S., Germany, Tanzani, Mali, and Equatorial Guinea towards licensure in ~4 years for mass administration elimination campaigns in Africa and prevention of malaria in travelers. Also, based on the demonstration that Sanaria's non-attenuated, infectious PfSPZ (PfSPZ Challenge) can infect 100% of volunteers in Europe and the US, PfSPZ Challenge in conjunction with chemoprophylaxis is Sanaria's 2nd vaccine product, PfSPZ-Chemoprophylaxis (C) Vaccine (Vac) (PfSPZ-CVac). The accelerated path to licensure requires scale-up efforts to meet projected market needs. Although the absolute number of PfSPZ required/yr will depend on the numbers of PfSPZ/dose, and the numbers of PfSPZ that can be obtained per mosquito, we anticipate soon needing to process 10^7, then 10^8 and finally >2x10^8 mosquitoes/yr. Manual dissection of 10^7 mosquitoes/yr is achievable with a 2-fold expansion within our current manufacturing facility however, automation can facilitate a further 5 to 10-fold increase (5x10^7 -10^8 mosquitoes/yr) in throughput within the same physical space. In contrast dissection of 10^8 mosquitoes per year by hand will require sizeable expansion in order to house a hugely expanded dissector taskforce. Modeling of projected cost curves also indicates that the price of the vaccine will drop progressively with each increment manufactured only if automation is put in place, but not with manual-dissection. In fact after processing the first 10^7 mosquitoes, the cost/vial of vaccine drops >50%. Based on preliminary development of automatable prototypes we propose to construct the first integrated automated mosquito microdissection system (AMMS) and fine-tune performance parameters and materials compliance for high throughput cGMP processing at an industrial scale. Successful completion of these goals will put Sanaria's manufacturing progress on track with its clinical development and commercialization plans, allow for greatly enhanced production from current facilities without a need for significant expansion and thereby facilitate more immediate widespread use of a whole PfSPZ vaccine for the hundreds of millions who suffer from this disease.