How to Achieve Efficient Production “Acceleration” for the Scarce Herpes Zoster Vaccine?

Herpes zoster (commonly known as shingles, belt of fire, or snake wrapping around the waist) is an infectious skin disease caused by the reactivation of the varicella-zoster virus that lies dormant in the human nerve ganglia. It is characterized by clustered groups of vesicles. Over 90% of adults carry the varicella-zoster virus in their bodies. Herpes zoster can occur at any age, but the incidence significantly increases after the age of 50 due to a decline in immune function.


Recently, there have been frequent reports in the field of herpes zoster vaccine, attracting widespread attention in the industry. The development process of herpes zoster vaccine currently involves three main types: live attenuated vaccine, genetically engineered recombinant vaccine, and mRNA vaccine.  Changchun BCHT Biotechnology Co., Ltd. has become the first Chinese company to receive approval for the marketing of a herpes zoster vaccine, bringing good news to the potential high-risk population in China. The new mRNA technology has also been applied in the development of this vaccine. Currently, there are two types of herpes zoster vaccines on the market: live attenuated vaccines (Merck and Changchun BCHT) and recombinant glycoprotein E vaccines (GSK).


Live attenuated herpes zoster vaccine

Made from a weakened strain of the varicella-zoster virus (VZV), which causes chickenpox and shingles. After vaccination, the virus enters the body but cannot cause severe illness. The principle of this vaccine is to stimulate the immune system by introducing a weakened virus, enhancing the body's immunity against VZV and preventing the occurrence of shingles. If the virus reactivates, the immune system will quickly recognize and clear the virus, preventing it from causing shingles.

The Merck shingles vaccine (Zostavax), launched in 2006, follows this technology method. This method has low production costs and minimal side effects; however, it carries a residual toxicity risk and is not suitable for individuals with a weakened immune system.


Recombinant herpes zoster vaccine

Vaccines produced through recombinant DNA technology involve transfecting mammalian cells with antigen DNA to express the antigen, which is then purified from the cells. Shingrix, produced by GlaxoSmithKline, follows this technology method. The advantage of Recombinant herpes zoster vaccine is that they induce an immune response while avoiding adverse effects from other components of the pathogen. They can also be safely used in individuals with a weakened immune system.

Currently, the key recombinant glycoprotein E is used in herpes zoster vaccine with gene recombination. It undergoes fusion with Fc or recombinant expression, fermentation in CHO host cells, and a series of downstream clarification, filtration, and purification steps to obtain a high-purity target antigen. Finally, it is combined with the corresponding adjuvant to prepare the vaccine. Below, we will briefly introduce the purification method that can be used for different types of herpes zoster vaccines with gene recombination.

Overall, the preparation steps for herpes zoster vaccine with gene recombination can be simplified as shown in the flowchart below:

Figure 1: Process Flowchart of recombinant herpes zoster vaccine


The chromatography process for recombinant herpes zoster vaccines can be carried out using two different pathways, namely Fc-fusion protein or recombinant glycoprotein E.

Using the Fc-fusion approach for recombinant herpes zoster vaccines offers several advantages. Firstly, it can enhance the immunogenicity of the E protein by utilizing the Fc fragment. Secondly, the introduction of the Fc fragment allows the downstream purification process to utilize antibody purification techniques, making the downstream process relatively more efficient. Typically, a three-step chromatography purification process is employed. The Fc-fusion protein is first captured using Protein A, allowing for rapid purification and aggregation. Subsequently, further purification is achieved through techniques such as anion exchange, hydrophobic interaction, and molecular sieving.


Figure 2: Purification of recombinant herpes zoster vaccine: Fc-fusion protein



Affinity Capture (MaXtar ARPA): This step aims to quickly capture the target protein from the culture solution, making it a critical step. This step can remove a large amount of HCP, viruses, HCD, and components of the culture medium. The ligand of BioLink's MaXtar ARPA is a modified alkaline-resistant Protein A, which can withstand 0.5M NaOH for CIP. It has high flow rate, high capacity, and a dynamic capacity of >60mg/ml.


Anion Exchange Chromatography (MaXtar Q HR): In this step, not only impurities and aggregates can be removed, but more importantly, endotoxins and HCD can also be eliminated. The MaXtar Q HR matrix is a highly rigid modified agarose-based matrix, characterized by high flow rate, high capacity, and low back pressure.


Hydrophobic Interaction Chromatography (MaXtar Phenyl (HS)): The purpose of this step is to remove HCP and aggregates. The development of sample loading and elution conditions, as well as the selection of the resin, is particularly important for improving product quality in hydrophobic interaction chromatography. MaXtar Phenyl (HS) has high capacity and good resolution.

Molecular Sieve Chromatography (Geldex PG): For molecular sieve chromatography, high-resolution and easily scalable Geldex 75 PG and Geldex 200PG can be chosen as the resin materials.



Figure 3: Reference applications of Fc-fusion proteins

The chromatography process step for the target antigen, recombinant glycophorin E, is as follows: it can be captured using existing anion exchange chromatography, followed by hydrophobic interaction chromatography, and then purified using hydroxyapatite in steps 1-2:


Figure 4: Chromatography purification of recombinant herpes zoster vaccine

Anion Exchange Chromatography (MaXtar Q HR): For the recombinant E protein, MaXtar Q HR can quickly capture the target protein from the cell harvest, achieving the goal of enriching the sample.


Hydroxyapatite (CHT): The purpose of this step is to further control the impurity level. If aggregates cannot be controlled at a low level, it is recommended to use hydroxyapatite (BaronCHT type II) for development. Currently, BioLink can supply both type I and type II hydroxyapatite.



Figure 5: Spherical morphology and typical crystal structure of Hydroxyapatite


About BioLink

BioLink Biological Applied Technologies (Shanghai) Co., Ltd. is a group of technology-driven businesses that provides process solutions in the life sciences industry. It specializes in the research, development, and manufacturing of key process equipment and consumables for recombinant protein drugs, vaccines, antibodies, cell therapies, gene therapies, and other biopharmaceuticals. Its products include bioprocess upstream cell culture, disposable liquid handling and downstream chromatography, ultrafiltration, filtration, and other process units, as well as process development services. BioLink is committed to providing customers with high-quality, innovative products and solutions and strives to build an efficient, safe and competitive biopharmaceutical supply chain eco-system.

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