Therapeutics for the covid-19 pandemic fall into four broad categories: repurposed drugs, convalescent plasma, monoclonal antibodies, and vaccines. Each has its own role in responding to the pandemic, and each poses its own challenges.
New drugs need to go through extensive testing and take nearly a decade to get approval, said Walt. Therefore, the fastest way to help patients avoid severe disease is to screen the tens of thousands of drugs that have already been approved for effectiveness. Many thousands of compounds can be screened using robotics platforms and automated imaging systems that can read out the results of these assays. Remdesivir and dexamethasone, two of the drugs used for severe forms of covid-19, were both discovered using this approach.
As another example of a repurposed drug, Cheng mentioned a drug named acalabrutinib that could help patients moderate the immune response in the lungs. “I believe in science and innovation,” she said. “The more we know, [the more] we’ll come up with solutions.”
An unexpected aspect of covid-19 has been the unpredictability of the symptoms it causes, Walt added. “People react to it very differently. Some people have gastrointestinal issues. Some have neurological issues. One of the things that is just beginning to be discussed in the community is that we’re going to have this burden of recovering covid-19 patients as a long-term healthcare issue in this country and the world for the next generation.” Meeting the needs of this group will require
not just research but new therapies and other ways of helping disabled people. “We’re going to have to deal with these issues for a long time.”
Convalescent plasma has been a well-established treatment for some infectious diseases. Individuals who have recovered from infection and have developed antibodies to the infectious agent can donate blood, which can be transfused into severely ill patients so that the antibodies in the plasma will bind to the virus and neutralize it.
As early as March 2020, when the first few covid-19 patients had recovered, plasma was used as a last-ditch effort to save the most critically ill patients. This approach was approved by the FDA as a treatment under EUA, Walt noted, but it had not undergone randomized controlled studies.
As soon as proteins from the virus were identified and expressed using molecular biology, groups began to produce monoclonal antibodies that could bind to these proteins and prevent the virus from entering host cells. In principle, monoclonal antibodies have more predictable effects than does convalescent plasma because they are pure antibodies rather than a complex mixture that differs from one plasma donor to another, Walt explained.
Cheng noted that monoclonal antibodies can be used as a preventive option in people exposed to the virus, as well as to treat and prevent disease progression in patients already infected by the virus.
Soon after the covid-19 pandemic began, a massive global effort took shape to produce vaccines that would protect people from infection and disease. For example, observed Walt, the United States launched a multibillion-dollar program called Operation Warp Speed to produce large quantities of vaccine in record time—“months rather than many years, as has been the standard since vaccines were first developed.”
Vaccines take time to develop and to demonstrate that they are effective and safe. As is the case with new drugs, vaccines require a phase 3 trial where tens of thousands of people are enrolled to find
rare side effects that might not appear in smaller sample sets. As Walt pointed out, “We need to vaccinate a substantial fraction of the global population—billions of people—and in some cases two times billions of doses, since some of the vaccines will require multiple doses.”
A vaccine might cause a side effect in one in 10,000 people, but that would cause hundreds of thousands of people to experience side effects worldwide. Vaccines also can cause a particularly severe reaction called antibody-dependent enhancement, a rare but potentially deadly reaction in people who have been previously exposed to a virus. “This is not meant to scare you. It is just a reality check on why we don’t want to rush a vaccine to market that hasn’t been adequately tested in large cohorts.”
For covid-19, two types of vaccines have been tested. One is a synthetic vaccine that does not require culturing in eggs or growth in large bioreactors. For example, a synthetic vaccine might consist of RNA that codes for a viral protein that uses a host’s protein synthesis machinery to generate many copies of the protein, thereby causing an immune reaction to the protein.
The second type of vaccine is more traditional, such as a viral vector modified to contain viral proteins from SARS-CoV-2. AstraZeneca pursued such a vaccine, Cheng reported, called AZD-1222, through a collaboration with the University of Oxford. An adenovirus vector, which is nonreplicating in humans because of gene deletions, was bio-engineered to contain genetic materials for the virus’s spike proteins. Such a vaccine requires a biological manufacturing process that entails fermentation, infection, harvest, and purification, after which the drug substance is put into vials and packaged for delivery.
Early results from both types of viruses were promising. However, Walt noted, vaccine production immediately encountered the same problem as did diagnostics: the amount of vaccine required exceeded the world’s entire prepandemic vaccine manufacturing capacity. “It is an extraordinary engineering scale-up problem for both manufacturing and distribution,” he said. “Never before has the need for a vaccine been required of this magnitude.”
To meet production demands, companies were investing in new facilities even before positive data were available from clinical trials.
AstraZeneca, for example, was building new manufacturing capacity even as clinical trials of its vaccine were underway, said Cheng. “This speaks to the criticality of our engineers, who are not only working on developing the process but at the same time improving the process in rapid speed.”
Limits on production also raised the issue of who should get available vaccines first. Companies are not in a position to prioritize recipient groups for local governments, Cheng pointed out. Rather, they need to work with the governments that will decide on prioritization. In the United States, for example, AstraZeneca was working with the federal government, which would take delivery and decide how the vaccine should be distributed. “Fair and equitable access means that somebody has to make those calls.”
In his remarks during the forum, Paul McKenzie, chief operating officer at the global biotechnology company CSL Limited, went into more detail on the challenge of meeting production demands during the pandemic. As is the case for medical devices, diagnostics, and other kinds of therapeutics, preparing millions or even billions of doses of vaccines will require highly sophisticated advanced manufacturing platforms. Developing such platforms requires investment in the years before they are needed for a pandemic response, he said. “The combination of the platform and the underlying business processes serves as a springboard for our ability to fight in a pandemic situation.”
Engineering has a critical role to play in developing these platforms, McKenzie said. Because pandemics are unpredictable, scaling up production requires rapid engineering to address shortages of supplies and to accelerate time to market for critical supplies and products. Advanced manufacturing may involve using new techniques in ways that people have not considered before, such as when a distillery shifts from making distilled products to hand sanitizer. It may also involve leveraging an existing manufacturing process from a different industry. “Advanced manufacturing has been critical for our ability to be able to respond to covid-19.”
McKenzie pointed to four pillars of pandemic response, centered on people, processes, facilities, and distribution, and said that all four need to be well tuned to respond to a pandemic. People need to be flexible and accommodating so that their tasks can be repurposed around a new goal while maintaining production. The safety of people also has to be assured, particularly since they are likely to be doing something new and innovative.
Processes need to be thoroughly understood to expedite product development, even if they extend across multiple industries and sectors. “We are learning how to collaborate with government agencies and with other industries in ways that we’ve never thought of,” McKenzie observed.
The same applies to facilities, whether within a single sector or across multiple sectors. “A leveraged, collaborative environment across multiple industries is critical for our response in a pandemic,” he said, particularly for rapid manufacturing scale-up and increased manufacturing resilience.
Finally, McKenzie explained that distribution and supply chains “require different thinking from your normal manufacturing to be successful” in a pandemic. For example, many regulatory issues are involved in getting products from the factory to the point of use, such as those involved in administering a vaccine through hospitals, clinics, or retail outlets. Similarly, if a vaccine only needs to be cooled to the subfreezing temperatures of a typical cold chain, the infrastructure will be available in many parts of the world. But if it needs to be cooled to well below those temperatures, the distribution challenge is much greater.
Vaccine and therapeutic discovery, development, scale-up, and full-scale production require “whole of organization” involvement, said McKenzie. They also require working collectively with groups across the drug development and commercialization system, since no single company can handle a global response. Companies need to partner with others that may be competitors in other circumstances. They need to be able to “scale out” as well as scale up.
“All of us have had to rethink how we do day-to-day work to make sure that this pandemic vaccine—and future challenges like this—are well addressed,” McKenzie concluded. “The effectiveness of our global
response to covid-19 depends on engineers, medical professionals, and scientists across industries, nonprofits, and governments to tackle new challenges and work together in new and collaborative ways.”