The Shadow of COVID-19

The WHO declared the COVID-19 pandemic officially over in May 2023, but the disease continues to make media headlines. In the UK, for example, an outbreak of COVID-19 caused severe flight cancellations in late September at the country’s second biggest airport. In the US, cases are expected to rise over winter, which has triggered the government to re-introduce free at-home testing. Meanwhile, the EU is reportedly talking with Moderna about a new supply deal because of concerns over rising cases.

COVID-19 has sometimes been referred to as a “black swan” event, although this description is something that has irritated Nassim Nicholas Taleb (who coined the term “black swan” in his 2007 best selling book with the same title). He said, “black swan” should not be a “cliché for any bad thing that surprises us” and pointed out that many had predicted the dangers of COVID-19 in January 2020, but no action was taken. Perhaps smaller pandemics had lulled the world into a false sense of security.

“In recent years we’ve experienced SARS, MERS, and Ebola, but otherwise, the world hasn’t experienced a global health emergency on the scale of COVID-19 since the 1918 influenza outbreak,” says Drew Burch, Executive Vice President of Nucleic Acid Products at TriLink BioTechnologies. “We have learned how quickly a pandemic can begin and spread in the modern world.”

Although the world was unprepared for COVID-19, lessons appear to have been learned, with actions already being taken to prepare for the next pandemic, whenever and whatever it may be. According to researchers, the chance of a pandemic in any given year is around 2 percent, but climate change’s effect on animal habitats is also increasing the risk of zoonotic and mosquito borne diseases. Over 50 percent of infectious diseases have reportedly been aggravated by climate change. And that means that the world – and the pharma industry – must be ready.

Investing in preparedness
 

In June 2023, the European Commission struck deals with several European drug makers under its EU4Health program to reserve vaccine manufacturing capacity for up to 325 million doses per year in the case of a public health emergency. This network of capacity is called the EU FAB network and will, according to the EC, “close the gap between manufacturing and scaling up of vaccine production, while ensuring the capacity of the industry to produce life-saving medicines.”

So far, the manufacturing contractors involved include Bilthoven Biologicals, Laboratorios Hippra, CZ Vaccines and Laboratorio Reig Jofre SA, and Pfizer subsidiaries in Ireland and Belgium.

“I am extremely happy to hear that the EU has struck a deal with European drug makers to reserve the capacity to develop a vaccine for future global health emergencies. I’m also delighted to say that Bilthoven Biologics (the Netherlands), which is a subsidiary of Serum Institute of India, is one of the drug makers selected by the EC! The industry was not ready for the COVID-19 pandemic and the need to supply vaccines to the world, but lessons have been learned,” says Kedar Gokhale, Executive Director at the Serum Institute of India.

The deal has been welcomed by many in the industry. It should also be noted that companies outside of the network are also taking steps to be able to quickly increase production if required. Thomas Zimmer, Vice President of European Operations at ISPE, says, “It is impossible to know the modality or magnitude of the next pandemic, so we cannot predict if the reserve capacity is fit for use to receive the new process demands. However, the National Competition Authorities (NCAs) and EMA, based on Health Emergency Preparedness and Response (HERA) recommendation, have also started implementing proactive actions with marketing authorization holders to set up measures to increase their production. We also understand that the EC, EMA, and NCAs, in conjunction with manufacturing companies, will monitor demand and supply to anticipate and react to potential events.”

This monitoring and communication will be key to any future responses. Zimmer continues, “The COVID-19 pandemic revealed a lot of bottlenecks, but early actions could give enough time to have sufficient manufacturing capacity. EC actions are going in the right direction to provide the industry with relevant information on the demand, which allows better responses from manufacturers. This is similar to the existing arrangements for flu vaccines with a production to supply patients from September onwards. Since the pandemic, we have been informed that several fill-and-finish manufacturing sites have increased capacity and are available to supply. Emerging countries have also arranged the introduction of new capacity and facilities.”

Going local
 

For many countries, local production has become a key priority. COVID-19 drastically affected supply chains. Burch explains, “Organizations were able to prioritize and obtain supply for development, but restrictions between national borders stood in the way of obtaining necessary materials. In addition, backlogs in production equipment occurred, slowing down vaccine production.”

Prior to the pandemic, there had been a trend in the pharma industry towards a lean, just-in-time supply chain – much less effective in an emergency. “Just-in-time inventory is perfect when everything is business as usual,” says Burch. “However, in pandemic preparedness, you must plan for the unplanned and extend flexibility. For example, many companies now stockpile certain raw materials to provide flexibility. Since mRNA offers the opportunity to develop a new vaccine faster and uses a common set of raw materials regardless of the vaccine target, it can be a particularly valuable approach.”

It also became all too clear that some countries were better positioned than others to weather the challenge. Gokhale says, “During the pandemic, resource availability was a concern and building new facilities in a short time was not feasible. The main major lesson learned from the pandemic is that every continent should be ready with additional reserve manufacturing capacity at a different vaccine platform so that millions of doses can be rolled out quickly – and at affordable prices.”

Developing countries dependent on imports were extremely vulnerable to shortages of both medicines and medicine supplies. But even in territories with well-established and robust supply chains, like Europe, there were issues. Relationships between the UK and the EU became strained over supplies of AstraZeneca’s COVID-19 vaccine. When AstraZeneca came up short in its deliveries to the EU, the EU asked for doses of the vaccine to be sent from the UK – leading to a very public war of words and the EU threatening to block exports of vaccines to the UK.

“The pandemic strained international cooperation, which challenged supply chains and impeded the global health response,” Burch adds. “The EC’s involvement helps remove that roadblock by securing internal supply and infrastructure. However, it’s important to note that the capacity for responding to a pandemic depends on the drug that can be useful in that specific pandemic. Early in the pandemic, when we thought certain medicines might be useful, there was a scramble to address the capacity of those medicines. As it turned out, mRNA vaccines became the most popular approach, which drove the need for new production processes. In short, sometimes we can leverage existing capacity and sometimes we cannot. What we can do is try our best to be prepared for the unexpected. The good news about mRNA technology is that it can be adapted incredibly quickly to new pathogens.”

The promise of mRNA
 

The EU FAB network covers mRNA, vector-based, and protein-based vaccines, but mRNA is perhaps viewed by many as the golden child after COVID-19 successes. So great was the impact of mRNA that it led to the 2023 Nobel Prize in Medicine being awarded to Katalin Karikó and Drew Weissman, whose technology is used in the Pfizer/BioNTech and Moderna COVID-19 vaccines. Karikó and Weissman discovered nucleoside base modifications that allowed mRNA to be used in vaccines, as well as other therapeutics.

Burch says, “mRNA fully demonstrated its effectiveness and its speed of development during the pandemic; it was less than a year from the genetic sequence of SARS-CoV-2 to receiving emergency approval. As we progress out of the pandemic, we know we have the ability to design a response to a new threat quickly and adjust the regulatory pathways. The technology has not only been validated by governmental approvals, but also via the billions of people that have received the vaccine. A lot of capital and investment is now flowing into the mRNA sector.”

And the science of mRNA continues to advance. Burch points to new LNP and other delivery technologies, as well as capping innovations that are improving yields and speeding up manufacturing.

Zimmer agrees that mRNA has great potential: “mRNA has been a real game changer in the vaccines field. For many years prior to the pandemic, companies were testing mRNA anti-cancer drugs in low volumes. They were able to use this prior knowledge and technology for the pandemic. Now, the world of mRNA is continuing to develop products. Similar breakthroughs can be expected in other therapeutic sectors. In particular, the scope for mRNA cancer vaccines is vast, such as individualized mRNA cancer vaccines to target solid tumors.”

Burch adds, “An era of therapies based on an understanding of nucleic acids is underway, and mRNA has a huge role to play. The industry has witnessed incredible efficacy and safety, not only in the billions of people who have taken the COVID-19 vaccine, but in clinical trials for other infectious diseases, cancers, and other indications.”

Being ready
 

The drug development industry truly shined during the COVID-19 pandemic. Although there were challenges in supply chains and other areas, close collaboration between all stakeholders led to the development and deployment of vaccines across the globe in record timeframes – with millions of lives saved. 

Zimmer says, “Regulatory agencies worldwide demonstrated extreme speed and flexibility in approving new vaccines and treatments, while respecting all requirements for drug safety and quality assurance. Close collaboration and communication was essential to the pandemic response –  and will be for future pandemics and emergencies too.”

Following the COVID-19 pandemic, the world has a greater appreciation for innovation and science. And the industry, itself, has a greater appreciation for the importance of supply chains – and how much experience, reliability, and relationships all matter.

Although the European Commission’s initiative is a positive step in pandemic preparedness, it isn’t an automatic route to success. There’s still a great deal to discuss – and lead times to plan for. “The European Commission initiative shows the enormous cost and long lead times necessary to develop such strategies,” says Zimmer. “Multiple stakeholders (manufacturers, supply chain, regulators, and so on) must work together to develop business cases to achieve the goals. Some contract manufacturing organizations may have some capacity and could provide additional production capacity too. There is also a need to anticipate requirements for common components, such as vials, stoppers, and caps. Here, standardization of such components would be a great help. Increasing capacity by introducing more shifts is an obvious strategy; however, for aseptically produced injectable products, there will be a long lead time to train additional staff. Timescales like this need to be factored into future strategies.”

Preparing for a pandemic goes beyond looking for therapeutic interventions. Burch points out the need for greater knowledge in prevention tactics. “What can be done to avoid spreading the pathogen? Is it isolation, masking, or washing? The best course of action can vary depending on the pathogen and the mode of transmission. It is also important to consider the role of education and frameworks for international cooperation. When there is a lack of trust in the institutions, it is difficult to have successful widespread prevention or response.” 

Zimmer adds that we can also learn from other global health emergencies, such as drug shortages. “Drug shortages have been an increasing problem for years. We still don’t have the problems under control – in fact, it’s getting worse! However, a number of learnings have emerged: multi-stakeholder management is needed to ensure the complexity of the problem is understood, there are numerous root causes (it is never monocausal!), and there is not one simple solution. All of this can also apply to pandemic preparedness.”