In Vivo: 医療用医薬品・医療機器産業の経営層向けニュース
By Deanna Kamienski 06 May 2021
During Q1, biopharma merger and acquisition value reached $34.8bn and drew in $35bn in potential deal value (PDV) from alliances...
10 major COVID-19 vaccines have now been authorized worldwide, but the production challenge remains formidable.
The development of the first COVID-19 vaccines in 2020 was undoubtedly one of the greatest ever achievements of the biopharma sector and its partners, with the first vaccines discovered, tested in Phase III trials and granted emergency use authorization in less than 12 months.
This has transformed expectations about how fast a vaccine can be developed, condensing the work of 5-10 years into just one.
What makes these achievements even more remarkable is that it was the first time vaccines had been brought to patients using these platforms – messenger RNA (mRNA) in the case of both Pfizer/BioNTech and Moderna, and a chimpanzee adenovirus vector-based vaccine from Oxford University and AstraZeneca.
Similar adenovirus vector-based vaccines developed by Johnson & Johnson, and Russia’s Gamaleya Institute and China’s CanSino have also been authorized, with very few vaccines in this category having been marketed before.
Meanwhile a number of vaccines using the more established inactivated virus platform have been developed and launched by China (two from Sinopharma, one from Sinovac) and from India’s Bharat Biotech (see Exhibit 1).
While this diversity of approach was seen as vital to de-risk global efforts, the mRNA vaccines have emerged as the best performing technology so far in terms of manufacturing output, as well as their clinical efficacy. (Pfizer Rose To The COVID-19 Challenge And The Stars Aligned)
This technology also looks best placed to respond to the emerging threats posed by new variants of SARS-CoV-2, and look set to become the go-to technology for any future infectious disease pandemics.
Nevertheless, there is more to the COVID-19 manufacturing challenge than adopting new technologies. It is also bringing home the realization that closer collaboration and investment on pandemic preparedness – between countries, between the private and the public sector and indeed between companies – is vital if this pandemic is to be ended as quickly as possible.
In 2021, the attention of the world has turned to how to scale-up manufacturing to take on arguably the most difficult stage of the challenge: rapidly producing enough doses to treat the majority of the world’s 7.6 billion population.
So just how many doses must be produced in 2021 and into 2022 to beat the virus? A recent virtual Chatham House meeting on this once-in-a-generation challenge brought together global vaccine leaders from the Coalition for Epidemic Preparedness Innovations (CEPI) and global industry trade organization the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), data analysts Airfinity and other key stakeholders.
In the accompanying discussion document, Towards Vaccinating The World, the organizations set out in detail many of the challenges ahead.
Estimates of the percentage of the population required to meet the much-discussed ‘herd immunity’ vary, but a working estimate is 70%, or about 5.5 billion people worldwide. That means that at least 11 billion doses of a two-dose regimen will be required (though J&J’s vaccine is administered as a single dose vaccination).
Once the need for revaccination and booster jabs are factored in, global demand for the vaccines could range anywhere between 10 and 14 billion doses this year.
To put this into perspective, current annual production of all vaccines in the world is about 5 billion doses. That means a huge step change will be required this year to scale-up production to meet demand.
The Chatham House document calculates that all the global vaccine companies involved in the field are aiming for a collective production target at the top end of this 2021 forecast, 14 billion doses.
This goal looks ambitious, because as of 22 March, only a fraction of that – 448 million people – have received one or more doses so far. Meanwhile, no more than 1 billion doses have been manufactured in total so far.
There are encouraging signs that this goal can be met, however. The US will very soon be reaching the point where it has surplus vaccine stocks and can start to engage in international efforts to donate doses around the world. But barriers remain – both in problems sourcing raw materials and building facilities and infrastructure, but also political obstacles, included the much debated ‘vaccine nationalism.’
Leaders in global public health and vaccines, like CEPI and the Bill and Melinda Gates Foundation want 2021 to be a turning point for the world, and an opportunity for greater forward-thinking and international co-operation on pandemic preparedness and rapid response vaccine development and manufacturing.
But for now, biopharma companies are focused on honoring their multi-billion-dollar advance purchase agreements (APAs) with governments around the world. Those governments are themselves are under pressure to get vaccines into the arms of their populations and help break the chain of infections and severe disease which is still resulting in thousands of lives lost around the world every day.
In December, Moderna’s CEO Stéphane Bancel commented to the MIT Technology Review: “Imagine the people making cars in the 1920s. If someone had said ‘I want a billion cars,’ the answer would have been, ‘What are you talking about?’ None of us were ready because no mRNA vaccines have been approved before, but now we are building the infrastructure to make a billion doses.”
AstraZeneca and Oxford University have set themselves the most ambitious target in terms of volumes of vaccines in 2021, aiming to produce up to 3 billion doses worldwide. This will be done via a network of partners, including India’s Serum Institute, the world’s biggest manufacturer of vaccines.
However, it is the mRNA vaccine companies that have made the best start to the delivery of doses. The Chatham House document stated that these account for around 45% of vaccine production to date.
Perhaps the clearest picture comes from Europe, where the European Commission is embroiled in an ongoing row with AstraZeneca about lower-than-expected volumes of vaccines in the first quarter of 2021.
Meanwhile the Commission increased its orders from Pfizer/BioNTech and Moderna. AZ’s agreement is to supply it with 400 million doses by the end of the year, but may struggle to achieve this, whereas Moderna has expanded its deal to 420 million doses by year end, and Pfizer aims to deliver 500 million doses, with an option to raise this to 600 million doses.
There are undoubtedly many factors which have influenced these contrasting performances, including, perhaps, AZ’s leading commitment to supplying low- and middle-income countries. But some inherent advantages of mRNA platforms over other technologies look to be coming to fruition.
Zoltán Kis, a research associate in the Future Vaccine Manufacturing Hub at the Centre for Process Systems Engineering based at London’s Imperial College, said the success of the two leading mRNA vaccines in manufacturing has been astonishing. “These platforms have shown that they are capable of making vaccine candidates far quicker than older technologies. And this has been done even before these platforms have been validated. It is the first time they have been used at scale, and they still managed to come out ahead of the game.”
What has been the key to the success of the mRNA process so far?
The core reason lies in the fact that the mRNA vaccine production process is largely chemical in nature rather than biological processes the other platforms rely on.
First, a plasmid DNA template for the mRNA drug substance is produced via biological fermentation, and then an enzyme-catalysed in-vitro transcription process produces the mRNA drug substance that codes for the desired protein, in this case the SARS-CoV-2 spike protein.
The raw mRNA must then be made biologically active via chemical processes called capping and stabilization. The fragile mRNA needs to remain intact inside the body long enough to penetrate into cells where it can pass on its instructions to produce the spike proteins. This is achieved by encapsulating it within lipid nanoparticles (LNPs).
These LNPs are made up of a blend of cholesterol and cationic or PEGylated lipids. The mRNA is then encapsulated within this LNP shell via a microfluidic or nanofluidic mixing operation. Once the mRNA drug substance is formulated into LNPs, it then undergoes fill-and-finish as well as quality assurance and quality control, in much the same way as other vaccines.
The beauty of the mRNA vaccine process is that it uses the patient’s own body to ‘manufacture’ the antigen – simply passing on the instructions for generating the spike protein to cells, which the immune system then identifies and generates antibodies against.
This is in contrast to the other technologies where either an inactivated version of the virus itself, a protein subunit fragment, or another (inert) virus is used to carry in the instructions.
That allows mRNA vaccines to bypass the complexities of growing a cell culture, as required in these other platforms, such as AstraZeneca’s viral vector-based vaccine. “You have living cells [in the bioreactor] which you have to keep happy, so that they can produce the virus It's not an easy task, they have to be kept in a happy state to produce the virus, and things can go wrong with a huge population of cells,” noted Zoltán.
mRNA vaccines also have the clear advantage of being more easily scalable compared to cell based vaccines: if you optimize the process at the lab scale in a viral vector production, for instance, this has to be reproduced from scratch at commercial scale, where the mixing process, temperatures and pressures are all different at this larger volume.
However, the mRNA vaccines have not been without their own pinch points.
In early March, Stéphane Bancel gave evidence to the European Parliament’s health committee, which wanted to know how production could be ramped up to meet the EU’s requirements.
He described how vulnerable vaccine manufacturing was in its start-up phase, and how one faulty pump set its EU manufacturing back by weeks.
“The team… worked day and night to replace the pump, but because we have to make medicine, safety and quality is non-negotiable. And the regulators, rightly so, asked us to document that the pump was being used in accordance to what the product was designed for,” he explained.
There are plenty of other bottlenecks, and shortages of key raw materials for the vaccines, including a shortage of the LNPs, a vital ingredient.
Strengthening defenses against COVID-19 and reducing the risk of future coronavirus pandemics, by optimizing current vaccines, addressing variants of concern, developing next-generation COVID-19 vaccines, and initiating the development of broadly protective or universal coronavirus vaccines.
Developing vaccines for known threats, to include completing the development of vaccines for Chikungunya, Lassa Fever, Nipah and MERS, advancing the development of vaccines against Rift Valley Fever, and completing additional clinical trials to broaden the populations eligible for the Ebola vaccines.
Working to compress vaccine development timelines to 100 days by optimizing the capabilities of rapid response platforms including mRNA, preparing clinical trial networks to respond rapidly to new threats, working closely with global regulators to streamline regulatory requirements, and linking manufacturing facilities to enable rapid production of pandemic vaccines.
Producing a library of prototype vaccines and other biological interventions against representative pathogens from critical viral families. The “library of prototype vaccines” would allow rapid adaptation if related viruses emerge.
Establishing global networks for lab capacity, assays, and preclinical models that are critical for rapid vaccine development and developing arrangements with existing national or regional clinical trial and manufacturing networks.
Supporting the efforts of low- and middle-income countries to take full ownership of their national health security by developing the infrastructure and expertise to conduct epidemiological and clinical studies, support technology transfer, and establish national and regional vaccine manufacturing.
Another likely advantage of the mRNA vaccines is the ability to keep evolving the production process. Once again, this contrast with cell-based vaccine production, where once a good yield is reached, the process tends to become fixed and cannot be altered without having to start again from scratch.
Nevertheless, timelines today are on average 90 to 120 days for the manufacturing and control of a single batch of COVID-19 vaccine, whatever the technology – mRNA, viral vector, or recombinant protein.
But the mRNA technologies are expected to pull away from competitors in this respect – helped by the hefty profits these vaccines will make in 2021 that can be reinvested. At Pfizer-BioNTech the partners have launched ‘Project Light Speed’ to reduce production time of their mRNA vaccine from 110 days to 60 days.
Meanwhile, there are plenty of other companies developing their own mRNA platforms aiming to compete with and outperform these incumbents.
These include CureVac, working with GSK, and Sanofi with Translate Bio, both aiming to develop a next generation of COVID-19 vaccines. Researchers in South Korea are developing a mRNA vaccine platform that can be lyophilized using liposome-based technology, which would address the Achilles heel of the technology, its need for ultra-cool transportation and storage.
Included in this are Zoltán’s colleagues at the UK government funded Future Vaccine Manufacturing Hub. A team led by Robin Shattock is working on a self-amplifying mRNA vaccine platform, a potential next generation platform against new variants, and future pandemic threats.
Other ambitious efforts to transform manufacturing could arrive in the next few years. These include a link-up between CureVac and Elon Musk – the man behind Tesla and Space X – with the aim of creating ‘RNA microfactories,’ miniaturized facilities able to make vaccine production mobile and cut down logistical challenges.
“There's definitely potential for disruption, because [mRNA] is such a transformative technology,” said Zoltán. “Someone like Elon Musk has a track record of changing industries, so these approaches could really change how vaccines are being made in the future.”
At the same time, innovation in viral vectors should not be written off. Experts also predict advances in this technology – not only to support more efficient vaccine manufacturing but also to support cell and gene therapies which rely on the platform. Key to this will be the development of more stable producer cell lines for viral vector production, with numerous specialist companies investing in the field, such as US-based Center for Breakthrough Medicines and UK-based Oxford BioMedica.
One major remaining concern is the impact of so-called ‘vaccine nationalism’ on the availability of raw materials and finished doses creating extra scarcity in COVID-19 supply chains.
While it is only natural for countries to seek to organize supply chains during a pandemic, overly restrictive moves can deprive other nations of valuable materials.
Just one example of this arose recently when The Serum Institute of India (SII) raised concerns about US president Joe Biden invoking the country’s Defense Production Act (DPA). This restricts the export of products which might be needed for domestic manufacturing, and prioritizes the US government orders over foreign buyers.
SII manufactures vaccines for Novavax and AstraZeneca, and its chief executive, Adar Poonawalla, said his company was experiencing shortages because of a US ban on specialized bags and filters, cell culture media and other equipment, as well as raw materials needed for vaccine production.
Global health leaders are looking to learn from COVID-19 and want to prepare the world for the next potential pandemic.
CEPI is calling for an international alliance and says the world must invest now in novel vaccines and biologic countermeasures, while linking these investments with commitments to equitable access.
It is calling for a further $3.5bn in funding for its work so that it can begin work on a five-year strategy to keep one step ahead of emerging epidemic and pandemic diseases.
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