Merck

疫苗生产:工艺开发和专业知识

疫苗是针对病原体和其他传染病的最具成本效益的卫生干预措施之一,每年可挽救数百万人的生命,同时改善无数其他人的生活质量。但是,全球需求的增长给疫苗生产商带来了严峻的挑战。每种新的病原体或疾病爆发都会增加所需的疫苗类型和制造方法的种类,从而无法建立可提高整体有效性、安全性和经济性的可靠的处理模板。制造商必须开发出可扩展生命科学范围的定制方法,同时以高效和经济的方式加快具有迫切需求的疫苗生产。

从制造角度来看,许多因素都对加快疫苗生产和实现性能目标至关重要。这些因素包括可预测的规模扩大、优化的上游生产率、强大的杂质去除能力、最大限度提高下游回收率、临床应用速度、患者的安全性以及合规性。实现过程的改进可以为以下所述的所有疫苗开发平台带来益处,但该过程需要创新的技术和高水平的应用专业知识。


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Virus-Based Vaccines

病毒疫苗

By attenuating viruses to render them harmless while retaining their immunogenic profile, virus-based vaccines offer quick immunity, activate all phases of the immune system, and provide durable long-term immunity. The manufacturing process for each viral-based vaccine (VBV) is different, dictated by virus shape, size, nature, physico-chemical behavior, stability, and host specificity. An important challenge is to keep the attenuated virus live while maintaining the infective potential of the viral vaccine throughout downstream processing and formulation, until it is administered to healthy individuals. 

 

Virus-like particle (VLP) vaccines

A virus-like particle is a biological nanoparticle consisting of the protective protein shell of a virus without its genome. Mimicking the overall structure of virus particles but lacking infectious genetic material, they represent an appealing model for vaccine development. VLPs can be produced by methods such as mammalian cell culture, insect cell culture, and bacterial and yeast-based systems. While these systems can result in good production yields, purification requires particular attention. The challenge is to develop a scalable upstream process, together with clarification steps and effective purification, while ensuring product quality and reproducibility.

Vira vector vaccines

Viral vectors are a promising platform for vaccine development, inducing cell-mediated immunity against complex diseases such as Ebola, RSV, COVID-19, and other emerging threats. They also offer quick-response potential to repurpose a single virus production template for multiple diseases. However, viral vector processes can pose challenges: improving yield to meet patient demand, maintaining biosafety testing standards for product characterization, potency and safety, as well as streamlining time-consuming production to enhance commercial readiness and accelerate therapy to-market. Manufacturers that overcome these challenges can capitalize on viral vector platform opportunities, while improving the response to global health challenges. 

Plasmid DNA Vaccines

Plasmid DNA (pDNA) is an important component of viral vector or vaccines therapies. pDNA is also used as the starting material for mRNA vaccines.

These circular DNA molecules can be used as therapeutic transgene, to code for the viral capsid or as the vaccine itself. DNA vaccines have been approved for use in animals and have been developed against the SARS-CoV-2 virus.

mRNA Vaccines

mRNA vaccines are rapidly developing vaccine type and have clearly demonstrated that they are opening a new era in vaccinology. Nucleic acids are based either on DNA formed from a fermentation process and, on messenger RNA (mRNA), which are synthesized in in vitro systems. They induce or promote an immune response against a large number of potential pathogens. These RNA vaccines are growing in popularity because of their quick turnaround time and cost-effective production of large quantities in the event of an outbreak or pandemic. They are also resilient and offer long shelf life under a variety of storage conditions.

Conjugated polysaccharide and bacterial vaccines

Conjugated polysaccharide (CPS) vaccines are used globally, particularly in children and the developing world. They offer lifesaving protection against a variety of bacterial infections, including pneumonia, Haemophilus influenzae type b (Hib), and meningitis. Because polysaccharide antigens are not very immunogenic in their native state, chemical conjugation with an immunogenic carrier protein is a critical step. CPS vaccine production requires a complex, multi-step downstream purification process that can pose severe challenges for manufacturers under pressure to maximize yield and reduce costs. To keep CPS vaccines affordable for developing countries, state-of-the-art technologies and process design are essential for fast, cost-effective production that also meets specifications.

    Toxoid and whole bacteria vaccines

    Toxoid and whole bacteria vaccines induce immunity in a similar manner as CPS vaccines, which also utilize inactivated toxoids or bacteria via chemical conjugation. While these platforms are generally regarded as safe, there are process-related challenges with endotoxin removal and, as with any process, the goal of optimizing recovery and yield. Such challenges must be overcome during process development and implementation in order to assure high-quality product.