Improving Vaccine Stability, Potency, and Delivery
Early input of formulation research is important since it may significantly reduce product development cycle times by avoiding the selection of labile candidates and screening out potential bad actors that may lead to high risk in later development and higher resource needs. Vaccine dosage form development requires a multidisciplinary approach to adequately address regulatory requirements (for healthy people and infants). Therefore, formulation research also involves awareness of additional technical and non-technical factors (see below) that will significantly influence the selection of the final vaccine dosage form for commercial use. To obtain a safe, efficacious, stable, and scaleable vaccine dosage form for commercial use, the vaccine has to be designed with a formulation containing only pharmaceutically acceptable excipients and/or adjuvants [16], with enhanced stability and/or potency, and with suitable or optimal delivery device and packaging components. In addition to understanding the strengths and weaknesses of the vaccine antigen, adjuvant, and excipient systems, the formulation research should also include the efforts from some or all of following areas: Safety Assessment to evaluate safe use of novel adjuvants and excipients to ensure that only safe components are considered in the formulation design (e.g. excipients that have been approved for human use and do not cause allergic reactions), Procurement to determine the availability of GMP suppliers for candidate components, Clinical Research to provide information or guidance on optimal dose, volume, pain management, and the route of administration, Marketing to provide information on market preference and distribution management, and Engineering to look into process parameters and scale-up factors, as well as Packaging Technology to determine the availability and compatibility (stability and machinability) of candidate container-closure systems and delivery devices.
A designed vaccine formulation must be characterized by using the actual time and temperatures used to define the shelf-life and storage conditions for the "real-time stability" of a vaccine. The stability of an optimally-designed vaccine dosage form should be defined by a thorough examination of the formulation at various storage temperatures with appropriately developed stability- and activity-indicating assays. It is also necessary to carry out stability studies under accelerated and stressed conditions since they help determine limits and tolerances of the products regardless of their usefulness in predicting the stability under actual storage conditions. The designed vaccine should also possess sufficient tolerability to stresses from various processes, including vaccine bulk and final container product handling, storage, and shipping. Such stresses include temperature, humidity, light, agitation, residual sterilizing agents, and exposure to various surfaces of process equipment and container-closure systems. Such tolerability would allow the designed formulation to tolerate various challenges during formulation/fill process development at the manufacturing scale.
The main objective of formulation process development is to design an overall process to manufacture the vaccine product from bulk drug substance to drug product, and all the way to final container product in laboratory scale, and to transfer the designed process to pilot and manufacturing scales. One question generally asked is "is the formulation compatible with a large scale (scaleable) formulation process that is controllable and reproducible?". The pilot and manufacturing scale processes should be able to produce the vaccine product with desired homogeneity and acceptable lot-to-lot consistency in addition to the designed composition, stability, and potency. Two of the most common problems faced during formulation process development includes the stress of high shear forces generated during engineering processes during manufacturing and the impact of various surfaces of the process facilities and equipment, as well as process temperatures/timing.
The approach to improve the stability, potency, and delivery of vaccines can be very different for various types of vaccines (e.g. liquid vs. lyophilized) and is highly dependent on the specific type of antigen present. The antigens include live-attenuated or inactivated virus or bacterials, such as inactivated polio and hepatitis A viruses, recombinant proteins such as hepatitis B surface protein expressed in yeast, and polynucleotides such as plasmid DNA, as well as polysaccharide or peptide antigens conjugated to an antigen carrier. From live-virus vaccines to recombinant protein vaccines, the simplicity of the vaccine generally increases but the technical complexity of developing such vaccines generally increases significantly [2]. Differences in the chemical, physical, and biological properties of the different types of antigens demand that the major techniques employed for vaccine preformulation research, dosage form design, and formulation process development be significantly different.
A common issue that arises in developing vaccines with a delivery and/or sustained release systems is the compatibility of the various components of the system. For example, most antigens would be damaged during the process of manufacturing a microsphere delivery system for microencapsulation due to organic solvent exposure and agitation, unless precautions are taken by adding an excipient such as a surfactant during the microsphere manufacturing process. Without such special protection, antigen activity loss and poor vaccine preparation reproducibility could be significant problems.
Recombinant Protein Vaccines
Before the 1980s, vaccines were typically live-attenuated or inactivated virus and bacteria-based vaccines. Advancements in molecular biology and genetic engineering in the late 1970s enabled scientists to clone genes and express proteins in foreign host cells, which opened the way for production of large quantities of recombinant proteins. The first recombinant protein vaccine for human administration, a second-generation hepatitis B vaccine using recombinant DNA-derived hepatitis B surface antigen (HBsAg), became available in 1986 [18-20].
Compared to traditional vaccines, current recombinant protein vaccines generally have much longer shelf-life, better thermal stability, and simpler system and composition. Furthermore, recombinant vaccines possess well-defined physical and chemical characteristics and are safer than live-virus vaccines. The stability and well-characterized biophysical/biochemical properties of recombinant antigens allows most recombinant vaccine dosage forms to be designed as parenteral formulations stored in liquid form. However, compared to traditional vaccines, the technical complexity of recombinant vaccine development is significantly greater [2,21,22]. In addition, recombinant vaccines normally give lower immunogenicity than live virus vaccines and need an adjuvant, delivery system, and/or carrier to augment the immune response [22]. A three-dose vaccination regimen is generally required to approach a full protection.
Formulation approaches to enhance the stability of recombinant protein antigens include optimizing buffer conditions (pH and ionic strength), introducing stabilizing excipients, minimizing surface interaction, and modifying the antigen chemically, physically, and/or biologically. The technical challenge of enhancing vaccine formulation stability increases as the approach changes from buffer control to excipient addition, to surface protection, and to antigen and/or adjuvant modification. The stability enhancement of formulated antigen-adjuvant vaccine drug substances/products can also be achieved by controlling antigen-adjuvant interactions and by optimizing inactive ingredient compositions and doses. To ensure the stability of the vaccine dosage form during manufacturing, shipping, handling, and storage, all of the above approaches should be re-enforced to meet the challenges of agitation/shearing force, temperature, light, and facility exposure.
Enhancing the potency of a recombinant protein vaccine product is normally achieved by introducing an adjuvant or immnuostimulator, enhancing antigen intrinsic stability and activity through formulation approaches, and/or improving vaccine delivery. The most commonly used adjuvant in commercialized vaccines is aluminum compounds, aluminum hydroxide, aluminum phosphate, and aluminum hydroxyphoshate. Aluminum adjuvants have been used for nearly 60 years with well-established efficacy and safety profiles [23]. In recent years, a wide range of novel adjuvant development through preclinical and clinical studies has resulted in the invention of various promising adjuvants or immunostimulators, such as MF59, QS21, MPL, CpG, OM174, and ISCOM [24-27]. A selected novel adjuvant or immunostimulator must be able to enhance either humoral or cellular immunity or both. As a result, less recombinant antigen is needed for a standard vaccine or the low-responders respond effectively without increasing the antigen dose. In addition, the adjuvant must be stable and manufacturable to meet the need for vaccine production and storage. The adjuvant supplies also need to be consistent lot-to-lot and better inexpensive. Furthermore, it is required that the adjuvant has an acceptable safety profile and is biodegradable.
Controlled or sustained-release technology can be used for recombinant protein or subunit vaccine delivery and offers the potential of further improving the efficacy of conventional vaccine formulations by optimizing the temporal and spatial presentation of the antigens and adjuvants to the immune system. The existing recombinant protein vaccines usually need multiple injections to receive the required level of immune response for full protection. One of the major issues concernin
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