An earlier version of this article was first published in our Biotech Review of the year – issue 9.

With the cell and gene therapy industry growing at pace and the need for vaccines against COVID-19 still high, viral vectors are in high demand. However, they have been in short supply. Complex manufacturing methods, a shortage of manufacturing capacity and competition from vaccine manufacturers has led to manufacturing bottlenecks in the cell and gene therapy industry over the last few years. This, combined with renewed safety concerns over the use of adeno-associated virus (AAV) vectors has recently placed viral vectors in the spotlight.

In this article, we give a brief overview of viral vectors and what they are used for, examine what the shortages mean for developers of cell and gene therapies and take a look at what the future holds for this technology.

Viral vectors: the delivery system of choice

Viral vectors are made from viruses which have been engineered to be non-pathogenic (i.e. they will not cause disease in the patient) and are an essential component of many gene therapies, gene modified cell therapies and COVID-19 vaccines. The majority of gene therapies in human clinical trials in the UK (over 70% as of 2020) used a viral vector rather than a non-viral system such as a liposome or a polymer particle.

In basic terms, viral vectors are used to deliver genetic material into cells. Consider a protein replacement gene therapy such as Novartis Gene Therapies’ revolutionary product Zolgensma (onasemnogene abeparvovec) as an example of this technology in action. Zolgensma is a gene therapy used to treat spinal muscular atrophy (SMA); it works by delivering a new copy of the SMN1 gene (which codes for human SMN protein) into the cells of children with SMA. It does this by using an adeno-associated viral vector, AAV9, as a delivery system. You can imagine the AAV9 vector as a delivery truck. Packaged inside this delivery truck is the SMN1 gene. Once administered, this viral delivery truck takes its genetic cargo to its destination: the patient’s cells. Once inside the cell, the viral vector releases its genetic cargo and the new gene can begin its work (in this example, expressing human SMN protein).

There are many different types of viral vectors, each with distinct properties. Vectors can also be engineered to better target specific tissue types. By far the most commonly used type of viral vector in gene and gene-modified cell therapies are AAV vectors, which were used in over 80% of in vivo gene therapies in clinical trials in the UK in 2020.

Shortages

In recent years, there have been shortages of viral vectors which have led to bottlenecks in manufacturing cell and gene therapy products. Shortages even made mainstream news headlines in 2017 with a headline piece in the New York Times. Yet since then, there seems to have been little improvement and shortages of viral vectors are still a significant concern for gene therapy companies (particularly for newer entrants to the field who will likely not yet have long term contractual relationships with specialist CDMO manufacturers).

There are a number of issues which have led to these shortages. One of the most difficult issues to solve is the complex manufacturing process for producing viral vectors. Researchers have been keenly focussed on solving these manufacturing issues (including by seeking to standardise production and analytical methods), however there is still a long way to go.

The number of products in development which use viral vectors is also growing rapidly. There are over a hundred in clinical trials in the UK alone and many more in pre-clinical development.

Over the past two years, shortages have also been exacerbated by the COVID-19 pandemic. Not only are gene therapy companies competing for manufacturing slots at CDMOs (many of whom have been involved in the production of vaccines and treatments for COVID-19) but a number of the approved COVID vaccines also rely on viral vectors (including the Johnson & Johnson vaccine, which uses a modified human adenovirus vector and the AstraZeneca vaccine, which uses a modified chimpanzee adenovirus vector).

Commercial response and innovation

Gene therapy companies and manufacturers are acutely aware of the issues caused by shortages and the industry is reacting in a number of ways.

In the short term, CDMOs have been ramping up vector production and investing in expanding viral vector manufacturing capacity. Some CDMOs are expanding by building out their own facilities (such as Fujifilm, which announced in late 2021 that it would be investing £400 million to expand operations at its UK facility in Teesside, including a new viral gene therapy manufacturing plant). We have also seen some M&A activity such as the June 2021 acquisition of Vigene Biosciences (a specialist in viral vector-based gene delivery services) by multinational CDMO, Charles River.

For gene therapy companies who are focused on getting viral vector-based therapies through development and clinical trials and onto the market, the increased demand for vectors and the shortages mean that potentially difficult, long term strategic decisions regarding manufacturing need to be taken earlier than ever. Questions of when to partner with a CDMO or whether to bring viral vector production in-house have become increasingly important in a market where CDMOs are booking out manufacturing capacity years in advance and competitors are racing to be the first to bring potentially lucrative gene therapy products to market. Both options come with risks and advantages and which approach is right for a particular company will depend on many factors including company size, access to capital, stage of asset development and type of product. The potential inability to find an alternative CDMO partner if for one reason or another an initial relationship does not work out will also be an issue. This risk further highlights the importance of robust due diligence on any CDMO and we expect may also result in a focus on more practical remedies in contracts with CDMOs (as termination may not always be a realistic option without causing significant delays to development timelines).

The recent shortages have also led to an increased focus on the future of viral vectors. While they are currently the dominant form of delivery system for gene and gene-modified cell therapies, research is underway to find alternatives in the longer term (such as lipid nanoparticles which have found recent success in delivering mRNA). However, the search for alternatives is not driven entirely by shortages. There have also been some well-publicised safety concerns over the use of viral vectors. Viral vectors can themselves cause an immune response in patients with potentially serious side effects, including in the worst case, death. As a result, patients can generally only receive one dose of the relevant viral vectored gene therapy. The durability of current gene therapies is not well understood and so the inability to give a patient a second dose in the future, if effects of the first dose were to wear off, is potentially a significant downside of viral vector-based gene therapies.

A further downside of viral vectors is their limited size. Certain genetic conditions are caused by mutations in large genes (such as Duchenne Muscular Dystrophy which is caused by mutations in the dystrophin gene – the largest known gene). It is not possible to fit a full-length dystrophin gene inside a viral vector due to its size. Viral vector-based gene therapies in development for Duchenne Muscular Dystrophy therefore currently use a truncated form of the dystrophin gene. Clinical trials are ongoing so it is not known whether this will be a successful approach but it’s not difficult to imagine the potential advantages that would come with a delivery system which can take a larger genetic cargo.

Regulatory considerations

In addition to commercial considerations, with shortages of viral vectors anticipated, companies must consider the regulatory impact and obligations that may follow. In Europe, therapies involving viral vector technology are regulated as medicinal products. The Medicines Directive[1] imposes an obligation on the entity which holds the marketing authorisation for a product to notify the relevant competent authority of any anticipated shortages of that product. In theory, this notification should be made no less than two months before the shortage manifests itself on the market and there is an interruption in supply to patients. The purpose of this notification is to provide the reasons for the shortage and the notification must declare if the shortage is for reasons relating to the risk/benefit ratio of the medicinal product, for example, if the medicine is harmful or lacks therapeutic efficacy. This appears very relevant to the discussion of viral vectors given the recently publicised safety concerns.

Regarding safety, at the start of September 2021, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee met to discuss the toxicity risks of certain vector-based gene therapy products and it appears this is a pressing topic of discussion at present. This demonstrates that regulators are currently alive to, and considering, the safety concerns associated with this technology and we expect regulators in the UK and EU to be watching closely.

Our view

Shortages of viral vectors is an issue that has been simmering away for a few years. However, the convergence in the last two years of the COVID-19 pandemic (and the associated demand for manufacturing capacity driven by vaccines) and increased investment in the gene therapy sector has exacerbated the issue. Combined with safety concerns, limitations around repeat dosing and cargo size, and researchers focussing on alternative delivery mechanisms, some commentators are questioning whether the field will eventually move away from viral vector-based delivery systems for gene therapy. However, despite these issues, with so many viral vector-based therapies in clinical development, it seems likely that viral vectors will continue to be in high demand for a significant time to come. That being the case, gene therapy companies will continue to need to take early strategic decisions regarding manufacturing and forming strong relationships with key CDMOs is likely to become increasingly important. In light of the shortages, it is also crucial that companies remain aware of their regulatory obligations and we will watch with interest as the discussion over the potential toxicity of vector-based gene therapies continues.

[1] Directive 2001/83.