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BLOG: COVID-19 Vaccine Hopes and Hurdles

Cobra Biologics has been fortunate to be given the opportunity to work with two novel vaccine candidates against COVID-19, utilising the company’s knowledge and experience in the production of plasmid DNA and viral vaccines. This blog aims to give a short introduction into the different types of vaccines that are in use, including the platform approaches relating to these two candidates and to highlight some of the potential manufacturing and administration challenges relating to the production of a vaccine to address a worldwide pandemic of the scale we are facing.


We are currently in the middle of the most severe pandemic for a hundred years; in less than 4 months COVID-19 has spread across the entire globe, infecting millions of people killing tens of thousands and bringing the global economy and national and international travel to a standstill. Whilst drastic measures such as social distancing and isolation may break, or reduce the chain of infection within specific communities, they will not prevent the potential for re-emergence of the virus in the future.


Vaccination is Key


The only accepted long term solution to prevent further outbreaks is through immunisation against COVID-19 involving mass vaccination on a global basis. This requires the development of a safe and effective vaccine that can be manufactured and administered across all the countries of the world. Whilst vaccines have been developed against seasonal, endemic, emerging diseases, and pandemic flu, we have not faced the scale that the current COVID-19 outbreak presents. The breadth of challenges not only in terms of the timelines, but also the scale of production required and the number of people to be vaccinated makes this a unique task and there are now over 40 vaccine candidates in development, with at least two in clinical trials.


The first point to make with regards to vaccine development is that, whilst they have been produced for many years and have saved millions of lives, giving protection for a wide range of diseases both bacterial and viral, the development of a successful vaccine is not a given. There are still many diseases, such as HIV, where despite massive efforts we still don’t have a vaccine. The second is that vaccines are unique in that they are given to healthy patients on mass to prevent future illness, rather than to treat specific patients with an existing condition hence heightening the stringent demands on safety.  Thirdly, as they often need to be administered to large population groups, many with constrained healthcare budgets, vaccines must be produced at large scale and at low cost. Finally, to ensure high levels of take up of the vaccines, supply chain and routes of administration must be kept as simple as possible.


Drilling Down the Options


Vaccines are not a singular type of product and come in multiple forms; early vaccines for diseases such as polio were based on the developed whole virus or bacteria which were weakened strains of the pathogen. These can be very effective, giving long term immunity but carry the risk of vaccine related infection. An alternative approach is to produce vaccines from inactivated forms of the pathogenic organism itself. This approach is much safer than using a live vaccine, and is used for several vaccines including the flu, but does not always give long term immunity and therefore requires re-vaccination.  Both approaches present a number of technical hurdles in terms of developing safe and effective vectors, including the handling of potential hazardous vectors at scale in production facilities. This approach can be further developed with the purification of the inactivated antigens to increase product safety.


More recently we have been able to characterise viruses at both a genetic and a chemical level; achieved in a matter of weeks for the coronavirus that causes COVID-19. These insights have allowed for the development of vaccines based on immunogenic elements of the pathogen, producing recombinant proteins vaccines based on elements of the virus’ protein capsids, this has enabled synthetic sub-unit, conjugate and Virus Like Particle (VLP) vaccines, which offer safer vaccines and the potential for producing multiple component containing antigen epitopes (sometimes greater than 10, such as the Hepatitis B vaccine).  However, these types of vaccines are time consuming to produce and have complex manufacturing processes both for the active vaccine product and formulation, especially multi-component vaccines, with de-novo manufacturing processes required for each vaccine and potentially each component of the vaccine product.


An alternative approach to this is to seek development and manufacturing processes that are “platform” in nature, both in terms of development and manufacturing which can build on existing approaches and knowledge. One method for platform processes is that of gene therapy where the therapies are delivered as genetic material and the patients’ cells produce the desired product rather than then being introduced as pre-made materials. This concept has led to the development of nucleic acid-based vaccines, which were first developed over 20 years ago. Initial products were largely based around the plasmid DNA and adenoviral vectors and more recently RNA based vectors.


Nucleic Acid-Based Vaccines


The initial DNA vaccine candidates were developed largely against diseases such as HIV and TB. Disappointingly, the initial promise could not be translated into successful clinical outcomes. However, work has continued into the development of potential vaccine candidates including studies on the development of vaccines against certain coronavirus diseases, SARS (Severe Acute Respiratory Syndrome) and MERS (Middle Eastern Respiratory Syndrome) where some level of success has been seen.


Adenoviral vectors have been developed for a number of years, whilst initial studies were with human adenoviral vectors, many current studies including those performed by the Jenner Institute are with chimeric chimpanzee-based vectors, as these avoid the issues of immune responses from patient previously exposed to human adenoviruses. These vectors have been developed against a wide range of diseases including Ebola, Zika, MERS and SARS and a number of clinical studies have been performed on over 1,000 patients including infants and children to demonstrate their safety and efficacy. The potential for the use of generic delivery vectors has allowed groups like the Jenner Institute to optimise the vector design with regards to best possible expression of genes to maximise immune responses, vector infectivity and productivity. It also speeds up pre-clinical development in that selected vaccines candidates can be constructed in a matter of weeks as all that is required is the construction of gene sequences which is very rapid and cheap.


Rapid Response


From a manufacturing perspective, as the manufactured vectors are essentially delivery vehicles of the gene of interest, they can be produced through standardised production platforms.  As with the development of the vaccine candidates themselves, manufacturing platforms can be developed and optimised independently and ahead of the selection of a vaccine candidate. From a clinical safety perspective these vectors have already been used in large animal and human clinical studies, and there is significant clinical experience and knowledge of these vectors, giving confidence with regards to safety and the potential to generate protective immune responses. Overall this allows for a rapid response to emerging diseases, not only with respect to the development of vaccine candidates but also in the establishment of large-scale production of vectors once vaccine candidates have been shown to be effective; a critical factor with regards to COVID-19.


Unprecedented Need


The rapid need for a COVID-19 vaccine is unprecedented, only comparable to pandemic flu vaccines, where it is possible to produce vaccines utalising existing egg-based production platforms. For pandemic flu, however, the rate of infection and severity of the disease was significantly less, with no where near the societal or financial impact. The manufacturing, distribution and administration of vaccines at a global scale presents enormous challenges. For example, the plans developed for a pandemic flu estimated a need for 4.9 billion doses to be manufactured per year. The requirements for COVID-19 vaccines are likely to exceed this number.   Therefore, looking at potential vaccine candidates and the ability to produce billions of doses with the subsequent rapid distribution and administration will be essential. Success will depend on several factors including the potency of the vaccine in terms of quantity of antigen required and the ability to achieve protection with the productivity and the scalability of the production platforms being used.


Additionally, to be able to produce billions of doses of vaccine it will be necessary for manufacturing to be performed simultaneously across multiple sites and locations. To achieve this, manufacturing processes need to be transferable, robust and will preferably not require highly specialised facilities or be restrained by complex supply chains and raw material needs.  Whilst these vaccines are still in development it is possible, from previous studies for similar coronavirus vaccines such as SARS and MERS, to make estimates based on dose levels and current productivity levels for comparable products, to predict the potential manufacturing scales required.


A Question of Capacity


For DNA Vaccines, dose levels vary, but doses as low as 0.67mg have been reported. Such a dose would relate to approximately 670g of DNA per million patients, which equates to 300,000 doses (or 300 doses/ L). To dose the population of Sweden would require 6.7Kg (or 33,500L fermentation broth) and for the UK for 32.5kg (or 162,500L fermentation broth). To put this into context the largest reported batch scale for plasmid production is in the region of 200g from a 1000L fermenter. Therefore, without significant investment in manufacturing capacities, DNA vaccines may be restricted to use with smaller groups such as healthcare workers.  When we look at the production of adenoviral vectors, it likely that doses will be in the region of 1-2x1010 vp/ml, this equates to approximately 0.2-0.4ml of cell culture based on current productivities. It should therefore be possible to produce between 4- and 8,000,000 doses from a 2,000L scale bioreactor. This would equate to 2.5 batches (at a 2000L scale) to vaccinate the whole of the population of Sweden and about 16 batches for the UK. Adenoviral vector production also has the advantage that it can be produced more readily at scale in single use systems which will allow for duplicate facilities to be established.


Lifelong Protection?


One final aspect when looking at the viability of vaccine candidates is patient compliance. This is a critical area for vaccines in order to achieve herd immunity whereby the spread of a disease can be contained if a sufficiently high proportion of individuals in a population are immune to the disease and therefore can act as buffers between unvaccinated individuals and an infected person.  So ideally, the supply and the administration of the vaccine needs to be simple, especially for areas with less developed healthcare systems. For a DNA based vaccine, whilst it is possible to treat via direct injection, an increasing amount of studies have used electroporation (effectively using a small electric charge on the skin to promote uptake of the DNA into cells). These systems seem to work well, but the question does arise of how you would administer these vaccines to large populations if electroporation devices were required at all the clinical sites. The adenoviral vaccines pose a different problem in that whilst they can be directly injected into patients, they are genetically modified organisms (GMO). Whilst we have seen a big increase in the numbers of GMOs being administered as vaccines and gene therapies, these have all been performed in specialist clinical  centres and not the ubiquitous doctors’ surgeries or pharmacies where you normally have vaccinations. Therefore, this issue will also need to be addresses especially in countries which have highly conservative approaches to genetic modification of organisms.


Whilst in an ideal world, it would be possible to give lifelong protection through a single vaccination against COVID-19, this may not be possible and in reality it is likely that long term manufacturing capability will need to be established across the globe to ensure that protection against COVID-19 is maintained.


In summary, both the plasmid DNA and adenoviral vaccine approaches offer real potential for the development of a safe and effective vaccine against COVID-19. Given the magnitude of the challenge that COVID-19 represents in scale and time, there is not going to be an ideal solution, and multiple vaccines will need to be adopted to start bringing the spread of this disease under control and allow societies, the economy, and travel to return back to the ‘normal’.

 

Author: Tony Hitchcock, Technical Director

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