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Editor of Pharmaceutical Technology Europe
Vaccine development is inherently challenging; however, in light of the COVID-19 pandemic, innovations have been prioritized, leading to accelerated development processes.
Vaccines are known to be hugely important in maintaining global public health and minimizing the impact of infectious diseases worldwide. Despite their worth, vaccines are subject to intense scrutiny, and, due to the fact that they are intended for large patient populations—including healthy patients and infants—the assurance of their safety, prior to approval and administration, is of paramount importance.
According to recent market research, the vaccines market is expected to grow at a compound annual rate of 14.7% for the forecast period of 2020–2026 (1), the growth of which has been accelerated by the recent COVID-19 pandemic. “Heightened by the recent COVID-19 outbreak, vaccine innovation has become a top priority worldwide,” confirms Elham Blouet, strategic portfolio manager, Roquette—a specialist in plant-based ingredients and provider of pharmaceutical excipients.
“In recent years, a paradigm shift has been observed in the way vaccines are being developed,” says Smruti Phadnis, biopharma marketing manager at Agilent. “The focus on disease-causing pathogens has been well integrated with intensive studies on human immunity. This research has opened doors to allow advances against complex noncommunicable diseases as well as cancers. However, inherent challenges, such as antigen selection and genetic diversity, need to have a broader immune response that includes T-cell protection, and alternative routes of vaccine delivery still exist during vaccine development.”
A constant challenge facing pharma companies developing vaccines is the wide range of potential pathogens that could cause serious illness, explains Kai Lipinski, chief scientific officer of Vibalogics. “Great strides have been made over the years to develop and commercialize effective vaccines for a wide range of infectious diseases,” he adds. “However, there are still particular illnesses that remain difficult to prevent or treat, such as HIV, malaria, norovirus, tuberculosis, and Zika virus.”
Particularly when trying to develop vaccines for difficult to treat illnesses, development obstacles can arise due to the inherent properties of the responsible organism, Lipinski continues. “Organisms displaying high rates of antigenic shift, such as RNA viruses including influenza and even the recent coronavirus (COVID-19), pose one such challenge,” he notes. “Antigenic shift of organisms yields frequent new variants, which develop very quickly, subsequently requiring surveillance, identification, and recomposition of the modified vaccine antigen or strain, often with a seasonal cyclicality.”
As vaccines are derived from pathogens, there are myriad antigen or target types to identify and select for development, emphasizes Phadnis. “Each type has its own degree of safety and efficacy,” she says. “To add to the complexity, non-live vaccines need to be combined with adjuvants (carriers) to induce immune response and slow release. Target/antigen selection is complicated further by genetic diversity across strains, including post-infection evolution and geographic variability.”
A key challenge in vaccine development for Anissa Boumlic, head of global vaccine and plasma segments, bioprocessing, within the life science business at Merck KGaA, is the fact that there is not a singular manufacturing template available to be widely used. “Manufacturers need to adapt constantly to tackle new pathogens and, sometimes, under tight deadlines,” she says. “A number of processes need to be optimized to increase scalability, robustness, efficiency, and cost. Additionally, formulations of certain vaccines need to be improved to increase efficacy and stability while ensuring patient safety, and facilitation of distribution and access.”
Lipinski concurs that, in addition to the challenges associated with vaccine candidate discovery, companies need to develop vaccines that are stable, can be stored, and administered in a variety of climates to ensure widespread distribution and use. “For example, emerging countries often lack appropriate facilities for vaccine storage at sustained sub-zero temperatures at or near the point of treatment, which can pose issues in launching vaccination programs that require cold-chain storage,” he says. “With this in mind, developers are challenged to devise vaccine formulations capable of being stored and transported at temperatures that don’t restrict their widespread use. Formulations must also allow for in-use stability, in the brief window between removal from storage and administration. They must be able to remain stable in tropical environments, where temperatures might exceed 30 °C.”
“Lyophilization or spray drying of vaccines can provide stability during transport and introduce alternate vaccine administration routes,” continues Phadnis. “Packaging is also heavily impacted by liquid vaccines. Durability of glass vials at very low temperatures and permeability of plastic vials has complicated the packaging decisions as well.”
Since the beginning of the pandemic, the bio/pharma industry has been under pressure to produce stable formulations for effective vaccines in accelerated timescales, Blouet asserts. Moreover, the drive for a COVID-19 vaccine has occurred during a period of increased basic scientific understanding, such as in genomics and structural biology, supporting a new wave of vaccine development and production, she says.
“As well as bringing about much needed innovation in a historically conservative field, [COVID-19] has also raised questions about whether conventional vaccines—developed by attenuating or inactivating the respective pathogen—are enough in today’s landscape. Although mostly successful in the past, these established methods may not always be suitable or even feasible in outbreak situations because they simply don’t allow for the fast response required,” Blouet reveals.
There are numerous tools that have been developed to help accelerate vaccine development, and novel technologies and platforms are emerging. “Manufacturing platforms, such as viral vectors, virus like particles, and messenger RNA, allow a reduction in process development time once established,” Boumlic remarks. “Systematic methodologies such as design of experiments (DoEs) and quality-by-design (QbD) have demonstrated the ability to increase process robustness and scalability.”
Processing has been simplified through the implementation and availability of single-use and filtration technologies, Boumlic continues. These tools have enabled an increase in speed of development and are easy to use. Boumlic also notes, however, that flexibility in scale, technologies to manufacture different modalities, more process simplification, and modernization are areas that require improvement still.
According to Phadnis, in addition to single-use technologies, automation for high throughput and robust analytical assays are necessary for rapid turnover during development and manufacturing of vaccines. “Automation technologies can speed up vaccine research as well as the manufacturing process by efficiently reducing manual errors. Automation also gives the flexibility of scaling up or down depending on the external demand. Simultaneous high-throughput workflows supported by robotic automation can swiftly generate consistent data across samples and users,” she says.
Using robust analytical assays for the characterization and validation of vaccine components, and to measure potency, are critical for inducing immunogenicity, Phadnis emphasizes. “Right from antigen selection and functionality testing at laboratory level to its final manufacturing, an integrated workflow of several analytical methods is required to ensure efficacy and safety of the vaccine,” she notes. “Innovations in mass spectrometry (MS) and capillary electrophoresis (CE) combined with in-line detection methods, such as high-performance liquid chromatography (HPLC), provide high sensitivity, selectivity, and accuracy for multidimensional analysis of samples. This innovation aids robust monitoring and control of key attributes of vaccines during development and enables a quick and reliable decision-making process during product development and manufacturing.”
For Blouet, the critical role of functional excipients, specifically cyclodextrins, is gaining interest for those in vaccine development seeking to overcome formulation challenges and produce a safe and efficacious vaccine quickly. “Cyclodextrins are a family of oligosaccharides produced from starch using enzymatic conversion,” she states. “2-hydroxypropyl-beta-cyclodextrin (HPβCD), in particular, is reaching into therapeutic biologic processes, final formulations, and delivery of vaccines, and is being used in some promising new areas where work is still at a very early stage.”
“To shorten formulation development timelines, accelerated temperature predictive modeling is key,” adds Lipinski. “However, this requires robust and well-designed analytical assays to assess a formulation’s performance.”
Both physical and chemical stability of vaccines are ongoing formulation challenges, notes Blouet, particularly given the novel technologies being employed and demand for increased shelf-life for convenience and cost-efficiency. “Physical and chemical instabilities may lead not only to the loss of biological activity, but also potentially to the formation of products that detrimentally affect toxicity and immunogenicity,” she says.
Using adenoviruses as an example, Blouet highlights that a “robust formulation, with precise optimization of buffer type, pH, and specialized excipients, are critical to ensure stability over a wide range of conditions. But options for addressing stability challenges in adenoviral vector formulations are limited to those few excipients approved for parenteral use.” Here, she emphasizes the utility of HPβCD, which is already approved for existing commercial formulations.
“At the same time, a key challenge in recombinant subunit vaccines is their stabilization for delivery,” Blouet continues. “These are typically protein-based and very few approved excipients are available to formulators working in this area.” Again, she emphasizes HPβCD as a potentially useful excipient to stabilize subunit vaccine proteins.
“Certain vaccines are less stable than others depending on their inherent properties,” specifies Boumlic. “For example, viruses or mRNA can be degraded through the process and a number of approaches need to be considered to minimize product loss—gentle purification, specific reagents, degradation inhibitors, stabilizers, delivery vehicles, and so on.”
It is imperative that the stability of process intermediates, or the product matrix as it moves through the manufacturing process, be understood and addressed, emphasizes Lipinski. “As downstream purification processes can span multiple days, a vaccine that is sensitive to the process itself, or cannot be subjected to freezing due to freeze-thaw processes, will present complications or limitations,” he says. “Developers must link drug substance and drug product manufacture, often within one facility, or within the limitations of the stability of the fresh (unfrozen) product, which can pose issues with often desired manufacturing flexibility.”
Combinatorial platform excipient banks can be used to speed up formulation development while overcoming stability issues, Lipinski states, which involves developing each vaccine in the same design space to optimize stability while reducing time-to-market. “Vaccine technology platforms (materials, processes, formulations) can also be used to minimize the development time for new products, as this approach offers considerable advantages where one universal formulation creates efficiencies that can be utilized across new products minimizing changes and allowing for a more predictive development paradigm,” he adds.
QbD and DoE-based principles, supported by orthogonal analytical methods, are significant when optimizing and streamlining the assessment of formulation stability, Lipinski remarks. “As an example, using physicochemical analytical methods to assess formulation performance as an indicator for infectious titer in the case of live-attenuated vaccine development can potentially reduce development timelines,” he says. “If sufficient knowledge is not available in-house to perform formulation stability studies to a high standard and with minimal delay, collaboration with experienced [outsourced service providers] is vital.”
The majority of commercially available vaccines are formulated as liquids, which, if kept in cold temperatures, can maintain their potency for about three years, asserts Phadnis. “However, freeze-thaw cycles can lead to immediate loss of potency,” she stresses. “Alternate formulations such as lyophilization and spray drying are being considered for alternative administrative routes as well as for ease of distribution and stability of the vaccines. However, dehydration needs antigen-protective excipients such as a combination of amino acids and glucose derivatives to replace the water molecules.”
“The route of administration has a significant impact on the development pathway of a vaccine,” Lipinski asserts. “Oral vaccines, such as those utilized for poliomyelitis or rotavirus, offer a number of advantages when it comes to development compared with parenteral products.” However, oral administration is not suitable for all vaccine candidates.
Administering vaccines nasally can also provide advantages over the more traditional parenteral approach, such as the avoidance of needles, ease of administration, and convenience for respiratory diseases, Lipinski continues. “One further delivery device being utilized is the micro-needle-based vaccine,” he says. “This [route] overcomes patients’ syringe needle anxieties while providing further benefits in its ease of use, and lack of cold chain distribution and storage need, due to its solid-state nature. This technology can also be self-administered by patients. However, sufficient production capabilities and capacities for such products are not available yet.”
The majority of vaccines are delivered intramuscularly with other routes including subcutaneous, intradermal, oral, or nasal, confirms Boumlic. The administration route of choice is determined by the type of vaccine being developed (i.e., whether the vaccine is adjuvanted or not) and whether the efficacy versus side effects can be balanced, she adds.
“The route of administration will influence the process to meet the associated safety requirements or to trigger sufficient immune response. For instance, injected vaccines will need to be sterile, and this can impact process design and cost efficiency,” Boumlic says. “Certain vaccines will need to be injected in high quantities to be efficacious and, therefore, this will impact the dimensions of the process (more volumes to handle, more scalability challenges). Messenger RNA vaccines need to be delivered in lipid nanoparticles to remain protected and be translated to antigens.”
The route of vaccine administration is dictated by the formulation and potency requirements, notes Phadnis. “Technologies that enable lyophilization, spray drying, and use of inert stabilizers in the form of lipids and nanoparticles are being developed for ease of administration and distribution of the vaccines,” she reveals. “A careful optimization of stabilizers as well as different formulation parameters during the first stage of vaccine product development should be done along with antigen screening and validation.”
“A glaring constraint with injectable delivery systems for large-scale vaccine programs is a complete reliance on cold storage, which directly escalates operational costs and diminishes market reach,” emphasizes Blouet. “For example, to ensure that each patient benefits from the injectable vaccine, meticulous logistical planning is required to successfully maintain the cold chain at every step, often involving collaborations with supply chain partners.”
The COVID-19 pandemic has presented industry with significant and unprecedented challenges in terms of vaccine development; however, opportunities have also arisen. “Historically, vaccines took about 10 years of development to reach the market and were mostly restricted to affected areas,” states Phadnis. “With the COVID pandemic, we have seen a paradigm shift in shortening the vaccine development process to less than a year. mRNA vaccine technology to make highly potent and safe vaccines was a breakthrough during this pandemic. This technology was implemented for the very first time in commercial vaccines.”
Additionally, the fact that the pandemic has raised questions about whether or not conventional vaccines are sufficient in today’s landscape has challenged developers to push the boundaries of vaccine development, Blouet notes. “Rapid development and accelerated large-scale vaccine manufacture are both critical factors in outbreak situations, key to combatting pandemics and protecting individuals worldwide by getting solutions to market faster,” she says. “To get vaccines to market quicker and overcome complex formulation challenges, more developers than ever are moving away from traditional vaccine development models.”
For Boumlic, the pandemic has demonstrated the requirement of standardized vaccine manufacturing and has highlighted the need for expanded capacity to ensure biopreparedness. “A clear trend is the development of platforms that can be easily adjusted for new targets. Using recent technologies, such as viral vectors and mRNA, single-use technologies and tapping into contract manufacturing organization capacity has also been beneficial to increase productivity and will shift vaccine development and manufacturing in the future,” she says.
“One key development that has proven useful during the pandemic and will change the way we operate in the future is the creation of vaccine platform technologies,” concurs Lipinski. “The advantage of such a platform approach, in the example of adenoviral vector platforms, is that the different vaccine products are, with the exception of the disease-specific transgene, the same. This shortens the production timeline for a number of reasons, as the producer cell bank and expression technology are already in place and the vaccine design tools and manufacturing infrastructure are already established. Moreover, formulation and stability data are available from products previously developed with the same platform technology.”
Furthermore, collaboration by all stakeholders has been highlighted as crucial during the COVID-19 pandemic, Lipinski emphasizes. “Greater collaboration should continue into the future. Not only will it support national governments in preparing for future outbreaks, but it will also allow knowledge-sharing between businesses and academia to devise the technology and infrastructure needed to develop treatments more quickly,” he says.
“As mentioned before, the inherent challenges would remain as different pathogens emerge,” Phadnis concludes. “However, the rapid development of the COVID vaccines and their usefulness to control the pandemic has given us hope for a better future in vaccine development.”
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1. Global Market Insights, Vaccines Market Size by Age Group (Pediatric, Adult), by Disease (Cancer, Hepatitis, Pneumococcal Disease, DTP, Dengue, Influenza, Human Papilloma Virus, Meningococcal Disease, Polio, Rotavirus), by Technology (Conjugate, Live, Inactivated, Recombinant, Toxoid), Industry Analysis Report, Regional Outlook, Application Potential, Price Trends, Competitive Market Share and Forecast, 2020–2026, Market Report (October 2020).
Felicity Thomas is the European editor for BioPharm International.
Vol. 34, No. 5
When referring to this article, please cite it as F. Thomas, “Overcoming Vaccine Development Challenges,” BioPharm International 34 (5) 2021.