Hamidi Ahd, Hoeksema Femke, Velthof Pim, Lemckert Angelique, Gillissen Gert, Luitjens Alfred, Bines Julie E, Pullagurla Swathi R, Kumar Prashant, Volkin David B, Joshi Sangeeta B, Havenga Menzo, Bakker Wilfried A M, Yallop Christopher
Batavia Biosciences BV, Zernikedreef 16, 2333CL Leiden, the Netherlands.
Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Vaccine. 2021 Apr 8;39(15):2048-2059. doi: 10.1016/j.vaccine.2021.03.033. Epub 2021 Mar 18.
Despite solid evidence of the success of rotavirus vaccines in saving children from fatal gastroenteritis, more than 82 million infants worldwide still lack access to a rotavirus vaccine. The main barriers to global rotavirus vaccine coverage include cost, manufacturing capacity and suboptimal efficacy in low- and lower-middle income countries. One vaccine candidate with the potential to address the latter is based on the novel, naturally attenuated RV3 strain of rotavirus, RV3-BB vaccine administered in a birth dose strategy had a vaccine efficacy against severe rotavirus gastroenteritis of 94% at 12 months of age in infants in Indonesia. To further develop this vaccine candidate, a well-documented and low-cost manufacturing process is required. A target fully loaded cost of goods (COGs) of ≤$3.50 per course of three doses was set based on predicted market requirements. COGs modelling was leveraged to develop a process using Vero cells in cell factories reaching high titers, reducing or replacing expensive reagents and shortening process time to maximise output. Stable candidate liquid formulations were developed allowing two-year storage at 2-8 °C. In addition, the formulation potentially renders needless the pretreatment of vaccinees with antacid to ensure adequate gastric acid neutralization for routine oral vaccination. As a result, the formulation allows small volume dosing and reduction of supply chain costs. A dose ranging study is currently underway in Malawi that will inform the final clinical dose required. At a clinical dose of ≤6.3 log FFU, the COGs target of ≤$3.50 per three dose course was met. At a clinical dose of 6.5 log FFU, the final manufacturing process resulted in a COGs that is substantially lower than the current average market price, 2.44 USD per dose. The manufacturing and formulation processes were transferred to BioFarma in Indonesia to enable future RV3-BB vaccine production.
尽管有确凿证据表明轮状病毒疫苗在挽救儿童免于致命性胃肠炎方面取得了成功，但全球仍有超过8200万婴儿无法获得轮状病毒疫苗。全球轮状病毒疫苗覆盖率的主要障碍包括成本、生产能力以及在低收入和中低收入国家的疗效欠佳。一种有潜力解决后一问题的候选疫苗基于新型自然减毒的轮状病毒RV3株，在印度尼西亚，采用出生剂量策略接种的RV3-BB疫苗在婴儿12月龄时对重症轮状病毒胃肠炎的疫苗效力为94%。为进一步开发这种候选疫苗，需要一个记录完善且低成本的生产工艺。根据预测的市场需求，设定了每三剂疗程的目标完全生产成本（COGs）≤3.50美元。利用COGs建模来开发一种在细胞工厂中使用Vero细胞的工艺，以达到高滴度，减少或替代昂贵试剂并缩短工艺时间以实现产量最大化。开发了稳定的候选液体制剂，可在2-8°C下储存两年。此外，该制剂可能无需用抗酸剂对受种者进行预处理，以确保常规口服疫苗接种时胃酸得到充分中和。因此，该制剂允许小剂量给药并降低供应链成本。马拉维目前正在进行一项剂量范围研究，这将为所需的最终临床剂量提供依据。在临床剂量≤6.3 log FFU时，达到了每三剂疗程COGs≤3.50美元的目标。在临床剂量为6.5 log FFU时，最终生产工艺产生的COGs大大低于当前平均市场价格，即每剂2.44美元。生产和制剂工艺已转移至印度尼西亚的BioFarma，以实现未来RV3-BB疫苗的生产。
