Biopharma looks to deliver on COVID-19 vaccines and other promising therapies.

Biopharma Gets Back to “New Normal” Business

Can lessons learned during the pandemic pay off in shorter development timelines?

Boosting Drug Development

J&J rollouts out initial vaccine supply; Industry expedites vaccine production

Merck to Produce J&J Vaccine

LabVantage Solutions announced three enhancements to its laboratory information management systems (LIMS) offerings in a virtual press conference on March 8, 2021, part of Pittcon 2021.

The company has added validation to three of its subscription-based software-as-a-service (SaaS) LIMS for regulated sectors, including the pharmaceutical industry. LabVantage Pharma, LabVantage Biobanking, and LabVantage COVID-19 LIMS now offer SaaS validation.

Evidence of validated control provides a record that the software is held to a set standard for data integrity and control and the responsibility rests with the vendor.

Customers pay an annual subscription fee to access the LabVantage LIMS, electronic laboratory notebook, laboratory execution system, and scientific data management system. Validated software updates are implemented by the company. A vendor-validated SaaS LIMS allows customers to expand the system to other locations, subsidiaries, and partners, the company reported.

The company also announced the launch of LabVantage Analytics, a self-service advanced analytics solution that allows users to explore, analyze, and visualize LIMS, enterprise, and external data for business insights. The offering integrates with the LabVantage LIMS platform

LabVantage Analytics enables laboratory managers and business colleagues both inside and outside the lab control of LIMS data together with relevant business and external data.

The tool analyzes structured and unstructured data from different sources, combining data ingestion, pre-processing, storage, analysis, and visualization into one application. Customizable dashboards and LIMS data reports enable users to access needed information.

In a third announcement, the company reported that LabVantage LIMS 8.6 has been designed and tested to optimum cybersecurity standards. The company has adopted SonarQube to scan source code for potential vulnerabilities; the use of Atlassian’s Jira software to track code and increase the visibility of security issues during development; and partnering with a third-party cybersecurity organization to test the software.

LabVantage LIMS features configurable security protocols and permissions that meet the requirements of the US Health Insurance Portability and Accountability Act, and the EU’s General Data Protection Regulation. Encryption is included in multiple stages and the company reports that it has been proactive in ensuring security through penetration testing and other activities to combat cyberattacks.

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Validation for SaaS LIMS, advance analytics, and cybersecurity features announced during Pittcon virtual press conference.

LabVantage Announces Product Enhancements

on March 2, 2021 that, in collaboration with Health Canada, it has published the full clinical data set that was reviewed as part of the authorization of the Moderna COVID-19 vaccine. Publication of data is part of EMA’s efforts to be transparent in its authorization of COVID-19 vaccines.

“With the publication of the data package for Moderna’s COVID-19 vaccine, we are publishing the clinical reports that we assessed in support of the authorisation of this vaccine, and going forward, we will continue with this open data approach for all other COVID-19 vaccines,” said Emer Cooke, EMA’s executive director, in a press release. “EMA and Health Canada’s joint commitment to openness and transparency will support global research, allow for public scrutiny and reinforce society’s trust in COVID-19 vaccines as mass vaccination campaigns continue to be rolled out across the EU, Canada and the rest of the world.”

The published data are available on EMA’s clinical data website and Health Canada’s Public Release of Clinical Information portal. EMA stated that clinical data for the Pfizer-BioNTech vaccine will be published soon.

The European Medicines Agency and Health Canada have published clinical data used to support the authorization of Moderna’s COVID-19 vaccine.

Clinical Data on Moderna COVID-19 Vaccine Published

A united effort between federal agencies is underway to combat COVID-19 fraud that ranges from the sale of misbranded drugs claiming to treat COVID-19 to products claiming to prevent the virus. The situation is being monitored by FDA’s COVID-19 Fraudulent Products Task Force. Operation Quack Hack has resulted in hundreds of these products being removed from the marketplace, and FDA has sent more than 120 warning letters to various companies selling these fraudulent products. Fake vaccines have also been reported for sale.

“Consumers should know the COVID-19 vaccines that the FDA has authorized under Emergency Use Authorization cannot be sold online. Legitimate COVID-19 vaccines are being distributed for free. Unfortunately, the agency is aware of reports of unauthorized websites and listings on online marketplaces purportedly offering COVID-19 vaccines for sale. When such online listings are found by or reported to the FDA, the agency notifies the online marketplaces, who can then remove the listings. We are also aware of emails sent to consumers featuring the FDA logo, advising consumers to call a phone number to schedule a vaccination. If consumers are contacted directly by someone who says they are from the FDA about a COVID-19 vaccine appointment, it is a scam,” said Judy McMeekin, Pharm. D., associate commissioner for Regulatory Affairs, in an 

FDA is asking the public to help by being alert about COVID-19 fraud schemes. Resources to help consumers protect themselves from fraud can be found on the 

The agency is working to identify and obstruct scammers looking to profit from the pandemic.

FDA Protects Consumers Against COVID-19 Scams

on March 4, 2021 that its human medicines committee (CHMP) has begun a rolling review of the Sputnik V (Gam-COVID-Vac) COVID-19 vaccine. The review is based on results from laboratory and clinical trial studies that indicate the vaccine triggers the production of antibodies and immune cells. The rolling review will look at data as they become available and will continue until there is enough evidence to support a formal marketing authorization application. The usual standards for effectiveness, safety, and quality will be assessed by the agency for the vaccine, according to EMA.

Sputnik V (Gam-COVID-Vac) was developed by Russia’s Gamaleya National Centre of Epidemiology and Microbiology. EMA states that the vaccine is made up of Ad26 and Ad5 adenoviruses that “have been modified to contain the gene for making the SARS-CoV-2 spike protein; they cannot reproduce in the body and do not cause disease. The two adenoviruses are given separately: Ad26 is used in the first dose and Ad5 is used in the second to boost the vaccine’s effect.”

The European Medicines Agency has begun a rolling review based on laboratory and clinical studies of the Sputnik V (Gam-COVID-Vac).

Rolling Review of Sputnik V COVID-19 Vaccine Begins in Europe

Many COVID-19 treatments and vaccines use glass vials and stoppers as their container closure system (CCS), and supply of these components may become constrained, according to FDA. Because of this, manufacturers may need to update approved applications to make changes to CCS components. FDA, therefore, 

 on March 4, 2021 providing recommendations for reporting and implementing changes to COVID-19 CCS components that consist of glass vials and stoppers for parenteral sterile drug products and biologics.

“In response to this public health emergency, FDA will consider risk-based approaches to facilitate implementation of chemistry, manufacturing, and controls (CMC) changes to a CCS in an effort to mitigate the disruptive effect of the COVID-19 pandemic. These measures may include, but may not be limited to, recommendations for adjustments to submission content and reduction in reporting categories for CMC changes,” the guidance states.

The guidance discusses regulatory approaches to CMC changes and common changes to glass vials and stoppers. The guidance also discusses risk-based tools for implementing CCS changes and comparability protocols.

The guidance document provides recommendations for reporting and implementing changes to container closure system components consisting of glass vials and stoppers for sterile drug products.

FDA Publishes Guidance on Changes to COVID-19 Container Closure Systems

The European Commission (EC) has launched a structured dialogue aimed at gaining a better understanding of global medicines supply chains and to identify potential causes and drivers of vulnerabilities.

Bringing together actors of the pharmaceuticals manufacturing chain, public authorities, research communities, health professionals, and patient organizations, the dialogue is one of the flagship initiatives of the EC’s Pharmaceutical Strategy, which was adopted in November 2020. A particular focus of the dialogue will be the development of production capacity for critical APIs, raw materials, and medicines in the European Union to ensure better preparedness for future pandemics, and will serve to put forward a set of policy recommendations to address the identified vulnerabilities by the end of 2021.

The launch event was opened by Margaritis Schinas, EC vice-president, with Stella Kyriakides, EC commissioner for Health and Food Safety, and Thierry Breton, EC commissioner, Internal Market, acting as moderators of the roundtable discussion with stakeholders. The Portuguese Presidency was represented by Marta Temido, the country’s minister for Health, and the European Parliament was represented by Dolors Montserrat and Nathalie Colin-Oesterlé—both ministers of the European Parliament.

The EC has launched a structured dialogue aimed at gaining a better understanding of global medicines supply chains and to identify potential causes and drivers of vulnerabilities.

EC Launches Structured Dialogue to Address Medicines Supply Vulnerabilities

A recent survey by SwedenBIO—a national non-profit association—has demonstrated a major upswing in the Swedish life science industry. The results of the survey were revealed in a March 2, 2021 press release.

The survey targeted pharmaceutical development companies with operations in Sweden and found that a vast majority (80%) of those surveyed are planning on expanding with new hires in the coming year. Additionally, when comparing with survey results from a year ago, it was revealed that there was increased confidence in projecting future growth with 62% of those surveyed expressing a more positive view of projections now.

“The positive outcome of our follow-up survey is very encouraging for the future,” said Helena Strigård, director general, SwedenBIO, in the press release. “The results also confirm our belief that involvement with other global life science hot spots opens more opportunities for collaboration and drives growth. We have, in fact had several fruitful interactions with similar organizations in regions internationally, including California. Furthermore, the fact that overall, the disturbances due to COVID have been limited and that numerous Swedish companies have re-focused their development towards COVID-related tests or treatments, underscores the strength of the industry as a whole and how creative and dedicated our life science industry experts are.”

Further information about the survey and a special investment conference being held in April 2021 can be found on SwedenBIO’s website.

A recent survey by SwedenBIO has demonstrated a major upswing in the Swedish life science industry. 

Survey Demonstrates Upswing in Swedish Life Sciences Growth

Merck (known as MSD outside the United States and Canada) will receive up to $268 million from the Biomedical Advanced Research and Development Authority (BARDA), US Department of Health and Human Services, to adapt and make available some of the company’s manufacturing facilities for the production of COVID-19 vaccines and medicines.

On March 2, 2021, the company announced multiple agreements with BARDA and Janssen Pharmaceuticals, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson (J&J), to support the manufacturing and supply of J&J’s single-dose COVID-19 vaccine. Merck will produce drug substance, formulate, and fill vials of the vaccine at US facilities.

Biden Administration invoked the Defense Production Act 

to equip the Merck facilities for this “historic manufacturing partnership” of two pharmaceutical giants, a White House spokesperson said.

“We are steadfast in our commitment to contribute to the global response to the pandemic as part of the remarkable efforts of the entire medical and scientific community,” said Mike Nally, executive vice president, Human Health at Merck, in the press statement. “This funding from BARDA will allow us to accelerate our efforts to scale up our manufacturing capacity to enable timely delivery of much needed medicines and vaccines for the pandemic.”

“At Merck, we have a rich legacy in vaccine manufacturing and look forward to combining our expertise with Johnson & Johnson to help increase supply and expand access to authorized SARS-CoV-2/COVID-19 vaccines,” said Sanat Chattopadhyay, executive vice president and president, Merck Manufacturing Division, in the statement.

anssen COVID-19 vaccine received Emergency Use Authorization from FDA on Feb. 27, 2021 

and initial supplies of vaccines shipped on March 1, 2021.

Merck discontinued development of two COVID-19 vaccine candidates

, when studies showed the immune response was inferior to levels following natural infection. The company announced plans to focus research and production capabilities on two COVID-19 therapeutic candidates.

With funding from the federal government, Merck will expand capacity to produce J&J’s COVID-19 vaccine.

Merck to Manufacture J&J Vaccine

AstraZeneca has announced, in a March 2, 2021 press release, that the mass rollout of its COVID-19 vaccine has begun via the COVAX initiative. These first steps by the company in the distribution of the vaccine to low- and middle-income countries will fulfill its efforts to provide broad and equitable access.

So far, shipments of the vaccine have been dispatched to Ghana and Cote D’Ivoire with more expected to begin arriving in the Philippines, Indonesia, Fiji, Mongolia, and Moldova shortly. Vaccine shipment allocations have been made according to the COVAX Allocation Framework, which determines volume per participating country based on several factors, such as readiness and national vaccination plans.

“These first steps towards fulfilling our broad, equitable, and no-profit emergency response to the pandemic mean millions of people, irrespective of their country’s income level, will soon be protected against this deadly virus,” said Pascal Soriot, CEO, AstraZeneca, in the press release. “This is a moment of great pride for us at AstraZeneca and I am extremely grateful to our partners including Gavi, CEPI, and Oxford University for their hard work and dedication in order to make this humanitarian ideal a reality for many millions of people around the world.”

“Global, equitable access to COVID-19 vaccines is only possible when the public and private sectors work together,” added Seth Berkley, CEO, Gavi, in the press release. “When we launched the Gavi COVAX Advance Market Commitment in June 2020, our first Agreement was with AstraZeneca. Nine months later, the first doses are already being delivered to those that need them most. This is the beginning of COVAX’s effort to end the acute phase of the pandemic, not the end, but we can all take strength from this moment and I thank AstraZeneca and the University of Oxford for their support and partnership at every step of our journey.”

AstraZeneca has announced that the mass rollout of its COVID-19 vaccine has begun via the COVAX initiative. 

AstraZeneca Progresses Rollout of COVID-19 Vaccine to Low- and Middle-Income Countries

WuXi AppTec announced on March 2, 2021 that it has acquired OXGENE, a UK-based contract research and development organization focused on the design and development of scalable gene therapy technologies.

Under the terms of the acquisition, OXGENE will become a fully owned subsidiary of WuXi Advanced Therapies (WuXi ATU), WuXi AppTec’s cell and gene therapy contract testing, development, and manufacturing organization (CTDMO) business unit, WuXi Apptec said in a company press release. OXGENE will be WuXi ATU’s first facility in Europe and will work to enhance WuXi ATU’s abilities to transform the development, testing, manufacturing, and commercialization of cell and gene therapy products while accelerating their time to market.

“OXGENE is proud to have invented a range of next-generation platforms that address the complexities of viral vector manufacturing for gene and cell therapies,” said Dr. Ryan Cawood, founder and CEO of OXGENE, in the press release. “We are excited to join the team at WuXi ATU and to work together to scale up our technologies as a combined business, which will strengthen and broaden our service offerings for customers, improving by orders of magnitude the scale and cost of bringing cell and gene therapies to market. The benefits will be significant for the industry and for patients worldwide.”

“We are delighted to welcome OXGENE to WuXi ATU,” added Dr. David Chang, CEO of WuXi ATU, in the press release. “By combining WuXi ATU’s world-class cell and gene therapy CTDMO platform with OXGENE’s innovative capabilities, we will be able to provide transformative solutions for our customers. This business combination represents a significant step in our ongoing effort to enable our customers and partners worldwide to deliver more effective and accessible advanced therapies to patients globally.”

Under the terms of the acquisition, OXGENE will become a fully owned subsidiary of WuXi Advanced Therapies, WuXi AppTec’s cell and gene therapy contract testing, development, and manufacturing organization business unit.

WuXi AppTec Acquires OXGENE to Increase Cell and Gene Therapy Offerings

Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.

For a vaccine to be effective, the components of the disease of interest that provide protection from disease (an antigen) must be incorporated or present in the candidate and induce a strong and appropriate immune response in the vaccine. Viral vaccines specifically can be classified into ‘classic or traditional vaccines’ and include attenuated/killed virus. Recombinant vaccines include subunit, virus-like particle (VLP), conjugate, and viral-vectored vaccines. Genetic vaccines include messenger RNA (mRNA)/DNA. Alternatively, vaccines can be classified into live and non-live vaccines, which is important when considering safety profiles.

Traditional vaccines and viral subunit/proteins directly elicit an immune response without the need for cellular transcription and/or translation of genetic material. Genetic vaccines use part of the virus’ own genetic code (either mRNA or DNA) to instruct cells to make a viral antigen that will stimulate an immune response. Viral-vectored vaccines allow selection of a non-disease causing, and in some cases, a replication-deficient virus to be used to carry and deliver the antigen of interest to the vaccine and offer a mixture of advantages and disadvantages of live and non-live vaccines.

Traditional vaccines have a long track record of safety and efficacy. They have been shown, according to Charles Christy, head of commercial solutions for the Ibex Dedicate at Lonza, to effectively treat global diseases and eradicate disease burden, or even eliminate diseases (polio, smallpox).

The immune response is triggered immediately with this type of vaccination; however, the body also has to fight the full viral or antigen load, which may facilitate adverse effects (e.g., feeling under the weather following the flu vaccine), notes Thomas Becker, site quality director for Recipharm.

The potential exists for adverse effects because live viral vaccines are attenuated by genetic mutation of the wild-type, disease-causing virus, either by passaging the virus through cells, eggs, or animals or purposeful deletion of sections of the viral genome, explains Kelly Lyn Warfield, vice president of vaccines research and development within Emergent BioSolutions’ Vaccines Business Unit. “For selection and use of live, attenuated viral vaccines, caution must be applied due to potential safety issues in immunocompromised individuals (i.e., primary immunodeficiencies, patients on immunosuppressant treatment, HIV-infected people, and sometimes the very young or old), since this type of vaccine has the potential to replicate in an uncontrolled manner, spread to other individuals due to shedding of the vaccine, or revert to a virulent (disease-causing) form,” she says. “Care must be taken, therefore, to select a candidate that has an appropriately balanced replication profile to maintain an acceptable safety profile but that can also induce a potent immune response,” Warfield adds.

To modulate the immune response and to increase the duration of the immunization, Becker says that the entire vaccination program may have to be applied in several doses, which can be inconvenient for patients. Live viral vaccines may also be challenged with stability issues and require frozen temperatures to remain viable and potent.

Similarly, a viral vector-based vaccine can cause an immune response to the viral vector itself in addition to the antigen of interest for which it is delivering the nucleic acid, according to Gregory Bleck, vice president of research and development at Catalent Biologics. “This issue can make repeated dosing difficult, since with additional dosing, the patient’s immune system may clear the viral vector before it has an opportunity to insert the nucleic acid into a cell for antigen production,” he observes.

There are a multitude of approaches for non-live viral vaccines that can be based on whole, killed organisms; purified or recombinant proteins; VLPs; or genetic vaccines, notes Warfield. “In contrast to live vaccines,” she comments, “non-live vaccines pose no risk to immunocompromised individuals and cannot spread or potentially cause disease.” Development of purified or recombinant proteins, VLPs, and genetic vaccines, however, requires knowledge of the protective antigens, including their identities and possibly structures, to ensure proper and robust immune responses, she adds. In addition, some protein-, VLP-, and killed virus-based non-live vaccines require addition of an adjuvant to improve their immunogenicity due to their non-replicating nature.

Genetic vaccines are different because they contain only a small part of the virus’ genome and cause cells to produce the desired antigen(s). Typically, the RNA or DNA sequence that instructs the human cell to produce the viral antigen(s) intended to trigger an immune response is formulated in a lipid nanoparticle that can enter the human cell after vaccination, according to Becker. He adds that because the human cell produces the antigen itself in order to produce the immune response, a smaller dose of vaccinating agent is required for genetic vaccines when compared with traditional vaccines.

Some people consider viral-vector vaccines, in addition to those based on DNA and RNA, to also be genetic vaccines, because the genome fragment is embedded within a virus that usually cannot multiply itself in the human body, but once inside the cell directs the cell to produce the viral antigen.

In the case of DNA-based vaccines—either plasmid/naked DNA- or viral-vector-based—explains Bleck, the cell that takes up the DNA will transcribe the DNA into mRNA, and then the mRNA will be translated into the protein-of-interest, which will be an antigen from the virus. In the case of mRNA vaccines, the transcription step is already completed, so the cells that take up the mRNA only need to transcribe the mRNA sequence into the protein-of-interest. Viral vector-based vaccines utilize the engineered virus to insert the nucleic acid encoding the viral antigen into the cell, where that molecule is then subsequently transcribed to mRNA and translated into the protein-of-interest.

DNA- and RNA-based genetic vaccines have been impeded by the ability to appropriately deliver the nucleic acids intact and to the correct site within the body or a particular cell type, according to Warfield, but this issue has more recently been overcome with the development of novel, improved delivery formulations such as more effective lipid nanoparticles.

Importantly, although they are considered genetic vaccines, the DNA of the human cell is not impacted by the vaccine, and Becker notes that antigen production only continues for a short duration before the RNA or viral vector are eliminated from the body. As a consequence, though, the immune reaction (and potential adverse effects) occurs in a more modulated and delayed manner, Becker asserts. “As a result, to achieve complete immune protection and to increase its duration, a prime boost dosing regimen in two consecutive vaccinations with the same or a different vaccine may be applied, which is what we’re seeing in the mRNA COVID-19 vaccines,” he says.

Indeed, while genetic vaccines hold much promise, they have not yet been widely commercialized. This situation has started to change with FDA granting Emergency Use Authorizations to the mRNA vaccines from Pfizer-BioNTech and Moderna for COVID-19 in late 2020 and approval for the viral-vector vaccine for Ebola from Janssen (Ad26.ZEBOV) followed by a second dose of MVA-BN-Filo from Bavarian Nordic, also in 2020.

Development and manufacturing advantages for genetic vaccines

What makes genetic vaccines so attractive is the potential to establish platform solutions that allow the rapid development of a range of vaccines against emerging infectious diseases based on a scalable novel core technology platform. “The process to develop and produce genetic vaccines is highly similar from one to the next, so we have already a lot of information from other vaccine projects that have used the same platform. This saves valuable time and energy when starting the development of a vaccine against a new disease,” explains a company spokesperson from Janssen Infectious Diseases & Vaccines.

The design and development of traditional vaccines is fairly complex. Most importantly, the best way to propagate the virus or its antigen needs to be newly developed in each and every case, Becker stresses. For killed or attenuated viruses, a mechanism must be explored and established that kills or lowers the infectious potential of the virus, without destroying it, so that the ability to generate the immune response remains. If this is not achievable, the traditional vaccine route is blocked for these viruses. For conjugated or VLP vaccines, the appropriate carrier substance or partner molecules also need to be explored and then combined with the antigen in the formulation process.

“While historical knowledge can be applied in the attenuation or formulation process, each case requires developmental activities to some extent. The more similar the new virus is to existing organisms, the easier it will be to use existing processes, reducing the amount of development time required. This is particularly true when creating vaccines for new mutations of known and treatable viruses such as flu,” Becker remarks.

“Traditional vaccines can take years to develop because they rely on the actual virus or viral proteins grown within eggs or cells,” Bleck agrees. “Viral proteins are developed and manufactured in cell-based expression systems, and they require time to generate a clonal cell line expressing the protein-of-interest and then optimize the manufacturing process so that it can be reliably scaled-up to clinical and commercial scale.” Traditional vaccines based on cell culture are also manufactured using large stainless-steel equipment, which is slower to scale up and requires longer construction timelines, Christy adds.

In addition, traditional vaccines are usually ranked as requiring an elevated biosafety level, and manufacturing facilities therefore need to comply with a higher level of biosafety requirements. “Such capacities may be limited worldwide, especially in pandemic situations, and facilities that are usually used for the manufacturing of ‘normal’ drug products cannot be used. Moreover, the virus propagation or the production of the antigens are biochemical processes that need to be run under controlled conditions and that may take a long time (weeks to months),” Becker observes.

Genetic vaccines, on the other hand, can be designed more rapidly and deployed as soon as the genetic sequence has been identified. The DNA product can be quickly expressed and scaled-up to clinical or commercial scale, Bleck adds. In the case of mRNA vaccines, the DNA precursor can then be transcribed in an 

 process that does not require the same long development timelines; for viral vector-based vaccines, the base systems are already established and the gene that encodes the antigen of interest only needs to be substituted into the vector backbones to start the process. Subsequent engineered viral production is performed using well-established manufacturing techniques.

As an example, Christy notes that Moderna went from sequence selection to shipping the first manufactured batch of the clinical drug product in 42 days. In addition, Lonza was able to scale up, build, and commercialize the Moderna vaccine in its Visp, Switzerland facility in only eight months, compared to the two to three years (or more) usually required to build a new cell-culture facility. This speed was also made possible by Lonza’s pre-investment Ibex Dedicate in a manufacturing complex and supporting infrastructure that was pre-primed and ready for fit-out, according to Christy.

“Part of the reason for this speed is that no cell bank or viral seed bank needs to be developed; this time-consuming task is often required for traditional vaccines,” says Christy. “Secondly,” he continues, “the dose for genetic vaccines is very low compared to traditional vaccines; an mRNA dose of 30–100 µg is being utilized. Such low doses require smaller facilities, which can be equipped with single-use (SU) technology, resulting in a faster scale-up and facility implementation.” Similarly, viral vaccines can be produced in small SU bioreactors, with 1000-L vessels sufficient for producing millions of doses.

“Theoretically,” adds Richard W. Welch, vice president of development services for Emergent BioSolutions’ CDMO Business Unit, “once a process and testing have been developed for a genetic or platform-based vaccine, that same process and the majority of the release assays can be used for any vector or antigen. For more traditional vaccines, each process and set of release assays must be developed separately.”

More specifically, the level of development effort required for platform-based vaccines is often substantially less than for more traditional vaccines from a chemistry, manufacturing, and controls perspective, Welch explains. “This decreased level of process and method development results in a substantial reduction in cost, and more importantly during a pandemic, the time from determination of identity and sequence of the target antigen or antigens sequence to clinical production and release of clinical trial material.”

Moreover, the biosafety level category for genetic vaccines usually is lower than for traditional vaccines. “The majority of these vaccines may not even require biosafety measures during production at all, merely the same techniques as those used for other biopharmaceutical products,” notes Becker. As such, facilities that produce “normal” biopharmaceutical drug products can be used also for the manufacturing of these vaccines.

In addition, Welch observes that a genetic- or platform-based approach can also avoid other potential delays for clinical production. “If a site has already manufactured, tested, and released that type of genetic or platform vaccine, then the equipment is in place and qualified for any vaccine that platform can support. Materials and suppliers are already qualified, and materials specifications are already developed and set. Often, long lead-time items with long expiry dates can also be held in stock, decreasing the time necessary to order, release, and supply material to the manufacturing or QC [quality control] suites,” he says.

However, Becker points out, genetic vaccines are a much younger class of drug product compared with traditional vaccine techniques. “The knowledge level for some of the required production techniques, such as the formulation of lipid nanoparticles, is still limited within the pharmaceutical industry. We can expect to accrue even more valuable knowledge over time to further enhance the effectiveness and efficiency of these vaccines,” he states.

Easy to modify in response to virus mutations

Viruses naturally mutate, and the longer they are in circulation and the more transmission that occurs, the more opportunities they have to develop mutations that enable resistance to established antigens. Depending on the mutations, the impact can range from minimal to substantial for traditional vaccines, according to Welch. Traditional flu vaccines offer an existing case where the seasonal variation has minimal to no impact on the production process. However, substantial mutations or changes in strains with increased potential for infection can result in substantial changes.

“If the mutation or shift in strains cannot be produced using the existing process, such as an avian flu not being able to be produced in eggs, then inactivated and attenuated vaccines could potentially require completely new starting strains or production platforms, which would essentially require anything from substantial to complete redevelopment and validation of the manufacturing process for the new strains,” he says. The same could hold true for protein-based or recombinant protein-based.

Because genetic vaccines trigger their immune response via a fragment of the virus genome, they will continue to provide an effective immunization route as long as the gene sequences in those particular fragments remain unchanged or display minimal mutations, according to Becker.

If the mutation is more significant, genetic vaccines also have the advantage of being extremely easy to modify. “That is the beauty of genetic vaccines; they represent a platform approach with a central technology (adenovirus, liposome particle mRNA, or other) that can be readily modified by inserting a new genetic sequence for rapidly response to virus mutations or even novel viruses (e.g., other coronaviruses),” Christy asserts.

The DNA template just needs to be modified to encode the new variants, and manufacturing of the updated vaccine can typically continue with very few, or no modifications to the process, Bleck notes. The existing body of knowledge about related virus strains facilitates the location and isolation of the relevant gene sequence, Becker says. Bleck adds, however, that the new vaccines still need to be evaluated in detailed clinical studies to confirm that the new mutated epitopes do not elicit unwanted immune responses in patients.

Like with traditional vaccines, developers of genetic vaccines must ensure sufficient process and product understanding to meet FDA, European Medicines Agency (EMA), and other regulatory guidelines, and they face scalability issues moving from early clinical phase to late clinical phase and commercial. “One key difference for genetic vaccines,” asserts Welch, “is that if the technology is a true platform approach, these issues only have to be worked out once for multiple indications.”

Companies, however, still need to define how much volume should be manufactured in order to meet demand and ensure that they—or their manufacturing partners—have the capacity to scale-up operations to meet the necessary peak volume. Genetic vaccines, while faster to develop than proteins, are still biologic products that require cell culture and sophisticated technology for development and manufacturing at both clinical and commercial scale, according to Bleck.

In a pandemic, adds Christy, the key challenge is manufacturing at risk during ongoing clinical trials. Further, the production scale-up to deliver hundreds of millions (if not billions) of doses places an enormous strain on the supply chain. Becker points out that currently there is only limited global capacity for biopharma production, some of which is required for existing drug and vaccine products. In addition, both traditional and genetic vaccines require filling under aseptic conditions, further reducing global capacity.

Genetic vaccine approaches have been contemplated for nearly 30 years, but until recently, Warfield says, they had been challenged by the need for large doses to induce mild to moderate immune responses, the instability of the nucleic acids (particularly with RNA candidates), and the inability to efficiently deliver the nucleic acids to targeted tissues or cells.

The recent success of the Pfizer-BioNTech and Moderna mRNA vaccines demonstrates that these issues have been overcome at least to some degree, but Warfield believes further improvements will need to be made for continued and future success of this class of vaccines. She highlights a need for the reduction of costs for raw materials and manufacturing processes and improvements in stability to reduce the need for storage at low or extremely low temperatures, which can create supply-chain challenges.

“The lower stability of genetic vaccines is definitely the major challenge when it comes to widespread adoption of this new technique,” Becker agrees. Formulation of the lipid nanoparticles required to protection of mRNA vaccines from degradation can be challenging, however; the correct ratio of lipids, proteins and nucleic acids is needed to form the nanoparticle, in addition to any additional excipients, adjuvants, etc., according to Bleck.

In addition, genetic vaccines may only undergo a limited number of freeze-thaw cycles, and thus the bulk vaccine should be filled into vials immediately after the formulation process is completed. In addition, he notes that the filling process should be followed immediately by visual inspection and label and pack operations. “With this in mind, the size of a batch, which is processed in one run, may be limited in order to shorten the exposure of the vaccine to room temperature,” he comments.

Because genetic vaccines are so new, there is also a need for careful short- and long-term monitoring and understanding of side effects to assist in the development of next-generation candidates that are potentially safer with less untoward effects, Warfield adds. “Achieving understanding and approval of the safety and efficacy profile of genetic vaccines by the general public, and especially amongst those with existing vaccine hesitancy, will be required for efficient and broad acceptance of genetic vaccines in the future for a larger set of pathogens outside the current COVID-19 pandemic,” she continues.

Overall, Christy observes that as with any new technology, genetic vaccines will progress through a maturation curve. Equipment and production processes must be optimized and standardized so processes can be made robust and scalable and global supply can be achieved at acceptable costs. He also stresses that the human capital factor must not be neglected. “The availability of trained, regulatory-compliant GMP manufacturing staff and quality control and quality assurance personnel is a critical success factor,” he says. Much investment in facilities will be needed as well, which during the COVID-19 pandemic been supported by numerous government and private partnerships.

A similar challenge common to all vaccines is the delivery of a safe and efficacious dose to patients. “Full focus on SISPQ (safety, identity, strength, purity, and potency) is common to all medicines. However, for genetic vaccines, this means developing a whole new battery of analytical methods, especially around purity and potency,” Christy states. “Methods exist, but these generally are research-based techniques (such as sequencing, infectivity, transfection assays), and they need to be fully developed to be robust, validatable, GMP-compliant, and able to be routinely implemented across multiple sites (globally for both drug substance and drug product),” he says.

Methods for genetic sequencing and product release, adds Bleck, require specialized expertise and equipment not required for traditional vaccines. In addition, he notes that for mRNA-based vaccines, their instability relative to most proteins will typically expand the scope of stability studies required.

The shortened timelines for manufacturing of genetic vaccines, Becker comments, also means that with currently accepted analytical methods, analysis results for intermediate production materials, such as formulated bulk product or product in filled but unlabeled vials, are not available at the time of processing. “This situation results in an increased risk that non-conforming product may undergo further value-adding manufacturing steps before being identified and discarded,” he says.

Because genetic vaccines are still a relatively new class of treatments, there is significant potential for further development. Primary opportunities revolve around the selection of more appropriate excipients, observes Welch. Work is ongoing to improve the target product profiles of genetic vaccines to improve their stability, Christy adds. “Formulation development with a range of stabilizers offers the potential to improve both the temperature stability and the shelf life of such vaccines,” he states.

In some cases, Welch believes that the use of existing or novel drying technologies will improve the stability of genetic vaccines. Becker agrees that transferring liquid formulations into lyophilized products can potentially improve thermal stability and reduce the need for cold-chain handling. Recipharm’s site in Wasserburg, Germany, for instance, successfully developed and implemented a lyophilization cycle that can freeze-dry a COVID-19 mRNA vaccine. “Initial results indicate that the lyophilized product has a significantly improved thermal stability profile in comparison to the liquid formulation,” Becker says.

The need for formulation improvement, however, creates its own challenges for vaccines being used to treat emerging infectious diseases, especially in the case of pandemics, where speed is of the essence, according to Welch. “Opportunities to increase stability that involve substantial revision of the final formulation may require additional and extensive clinical trials to establish efficacy and safety along with revalidation of the drug product production process.”

While there are many advantages to genetic vaccines, there are also many reasons why traditional vaccine approaches will continue to be used. “Traditional vaccines have been on the market much longer than genetic vaccines and, in most cases, can currently be made at a significantly lower cost,” Bleck. “Over time,” he adds, “these technologies have evolved to adapt to changes in the viruses that they protect against. In addition, if necessary, multiple antigenic proteins in certain ratios and configurations can be expressed to get the correct epitopes produced for a neutralizing immune response, which is currently difficult to achieve in genetic vaccine formats. Furthermore, getting adjuvants to work effectively with genetic vaccines can also be difficult.”

Traditional approaches might be preferential when preclinical animal studies indicate that an effective vaccine requires the presentation of an antigen or antigens in a complex structure that cannot be engineered or can only be effectively and reproducibly done using the entire infectious agent, a company spokesperson from Janssen Infectious Diseases & Vaccines says. In addition, when the protective antigens are not known for an emerging pathogen, traditional approaches incorporating the entire pathogen (live or killed viral vaccines) may be required until a firm understanding of protective immune responses are established, Warfield notes.

Furthermore, Becker points out that traditional approaches allow the combination of vaccination agents for different diseases, which may not be possible for genetic vaccines for the foreseeable future, as they are less robust. “With this in mind,” he says, “traditional vaccines may be more appropriate not only to address a wider variety of mutations of one virus type in one vaccination, but for routine vaccination programs against different diseases.”

Finally, Warfield notes that killed virus, protein, and VLP vaccines potentially have the advantage of more temperate storage requirements compared to some live virus- and genetic-based vaccines, which can be particularly important in remote areas and developing countries that lack the necessary cold-chain infrastructure.

But genetic vaccines are creating real excitement

The arrival of the new class of genetic vaccines heralds an exciting time in vaccine development, asserts Becker. “This new technology offers a number of promising routes to help us not only enhance infectious disease prevention, but to progress the fight against other serious diseases, such as cancer,” he says. The fact these vaccines can be manufactured in standard multi-product facilities, rather than on specialist sites, will also enhance efficiency for pharmaceutical companies and offers greater scope for maximizing vaccine production capacity in the event of future pandemics.

Process and product regulations for genetic vaccines and viral-vectored vaccines still have to mature, however, as the technologies thus far have only recently produced commercially viable products that have been approved by stringent regulatory agencies like FDA and EMA. “Our expectation is that both technology regulations and platform regulations will evolve over the next several years,” says a company spokesperson from Janssen Infectious Diseases & Vaccines.

As more genetic vaccines become available, Welch envisions a shift to their use not only for pandemics, but also for existing and emerging infectious diseases. “Such as shift could enable companies to decrease time and cost, at least for manufacturing development, from inception to market,” he notes.

New advances in mRNA vaccines and other novel vaccines may indeed mean that we are entering into a new “golden age” for vaccines, according to Christy, but with the caveat that important work remains to be done to ensure global access, adequate capacity, and ease of administration, as well as education to ensure widespread uptake. He also notes that effective vaccines have yet to be developed for many well-known viruses, and more than 80 emerging viruses have been identified since 1980, with two novel viruses appearing every year. “Despite recent successes, much remains to be achieved to protect humanity,” he insists.

In addition to novel genetic vaccine technologies, Christy is excited about mucosal vaccines that aim to boost local immune memory and effector responses at the point of entry of pathogens and mRNA vaccines in development as cancer vaccines, intra-tumoral immune-oncology therapies, and localized regenerative therapies. Other cancer and T-cell vaccine are in development to treat antibody evasive viruses, and existing vaccines are being re-developed to provide better protection and coverage.

“Ongoing global pre-investment by governments, private foundations, and other groups will be needed to drive further advances in technology, manufacturing capacity, and infrastructure that will enable effective response to epidemics/pandemics going forward,” Christy concludes.

Cynthia A. Challener, PhD, is a contributing editor to 


Vol. 34, No. 3
March 2021
Pages: 10–17

When citing this article, please refer to it as C. Challener, "Genetic Vaccine Platforms Demonstrate Their Potential, "

In a pandemic, genetic vaccines offer several advantages over traditional approaches.

Genetic Vaccine Platforms Demonstrate Their Potential

Generic small-molecule pharmaceuticals transformed the industry when they were introduced to the United States in the 1980s, slashing costs and making more drugs accessible to more patients. According to IQVIA, they saved the US healthcare system some $313 billion in 2019, and have cut costs by $2.2 trillion since 2009 (1). 

Decades later, as the cost of biologics became a larger factor in rising healthcare costs, biosimilars (similar but not chemically equivalent to their name-brand references) were introduced with similar cost-cutting intent. However, their acceptance in the US has been slow. FDA established a pathway for biosimilars approval in 2010, with the Biologics Price Competition and Innovation Act (BPCIA), but it took five years for the agency to approve the first biosimilar. The next few years saw relatively few biosimilar approvals and intense battles over intellectual property, yet IQVIA found, biosimilars still saved the US healthcare system $2.2 billion in 2019 and $4.5 billion in four years (1).

In 2019, a year in which policy experts and former FDA Commissioner Scott Gottlieb (a strong advocate for biosimilars) openly debated whether or not to “throw in the towel” on the whole biosimilars concept, FDA wound up approving 10 new biosimilars (

. Today, 29 biosimilars have been approved in the US, and IQVIA expects biosimilars to gain $80 billion in sales and generate $100 billion in healthcare cost savings through 2025 (2).

Table. Biosimilar Approvals in the United States.

So far, most biosimilars development has focused on oncology; supportive therapies used with other treatments; and anti-inflammatories, but in 2020, under the BPCIA, FDA’s approval pathway changed for 90 reference products, including insulin. Although they aren’t technically called biosimilars, these transitional biologics, originally submitted as new drug approvals (NDAs) under the US Food, Drug, and Cosmetic Act 505 b(2), must now be submitted as biologics licensing applications (BLAs) under the BPCIA 351(k). A number of companies, including Mylan and Biocon, are actively developing therapies in this area.

Improving the outlook for biosimilars has been FDA’s Biosimilars Action Plan, rolled out in 2018 to improve the internal agency review process and encourage innovation. On the legislative side, H.R. 133, which became law at the end of 2020 (3), set requirements designed to prevent delays in biosimilar commercialization. Among other things, it calls for patent data transparency, requiring that patent information and expiration data be published in FDA’s Purple Book, which is now an open-access online database (4). 

In 2020, FDA also clarified distinctions between regular biosimilars and interchangeable types (5), which require additional clinical testing but could be used to replace innovator drugs in patient prescriptions without informing the prescribing physician. So far, none of the biosimilars approved by FDA has gained interchangeable status, but developers can now submit applications for interchangeable status only, or two-part applications for both biosimilar and interchangeable status.

Despite all the advances that have been made to help stimulate biosimilar development, hurdles remain. Most significant is the large number of patents that innovators have filed to delay the introduction of biosimilars. Of the 29 biosimilars approved for use by FDA, only 19 can currently be sold. The impact of the name-brand “patent thicket” is particularly evident with adalimumab biosimilars, anti-inflammatory treatments similar to AbbVie’s Humira. In the European Union, eight such biosimilars are available. In the US, six have been approved, but none will be available until 2023 (6), as a result of agreements that each developer reached with AbbVie.

In 2019, a third-party payor representing US labor union members and insurance firms launched a class action anti-trust suit against AbbVie, which had applied for more than 100 manufacturing and formulation patents for Humira years after it had been introduced. The suit alleged that AbbVie and the biosimilars developers had blocked competition. In 2020, however, a judge dismissed the case, which could set a precedent for the future (7).

Clearly, the costs of entry to the biosimilars market are considerable. Amgen has invested more than $2 billion on 10 biosimilar candidates since 2010 (8). However, biosimilars development is starting to pay off for more companies. Pfizer, for example, which had three biosimilars approved in 2019, saw its fourth quarter 2020 biosimilars income increase by 80% from the previous year (9). Increased competition among biosimilars manufacturers, and pressures on innovators to reduce costs, may finally achieve the goals originally envisioned for biosimilars, as they move into their sixth year in the US.

 1. Association for Accessible Medicines, “2020 Generic Drugs and Biosimilars Access and Savings in the US,” 

 2. M. Aitken, M. Kleinrock, E. Muñoz, “Biosimilars in the United States 2020-   2024: Competition, Savings, and Sustainability,” 

 2. US Congress, H.R. 133, The Consolidated Appropriations Act of 2020, 

Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability

Biosimilarity and Interchangeability: Additional Q&As

 5. I. Gherghescu, M.Begoña Delgado- Charro, ”The Biosimilars Landscape: An Overview of Regulatory Approvals by EMA and FDA,”

 6. R. Gervase, J.Miller et al. “AbbVie’s Enforcement of its ‘Patent Thicket’ for Humira,” 

 8. T. Hagen, “Pfizer’s Biosimilars Earnings Soar,” 

When referring to this article, please cite it as A. Shanley, “Biosimilars Hit Their Stride,” 

Despite the persistence of the patent thicket, and slow uptake by the medical community, biosimilars are positioned for growth in the US.









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