The Last Mile: COVID-19 Vaccine Developers Prepare to File for Emergency Use Authorizations

As winter approaches, a second wave of COVID-19 infections has hit Western Europe and the southern and western United States with brutal force.In a keynote presentation at the annual Galien Foundation Forum on Oct. 30, 2020, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), noted that SARS CoV-2 had exploded in an “unprecedented manner” not seen since the Spanish flu of 1918. On the day of the Forum, 8.9 million cases of COVID-19 were reported in the US, and the death toll had reached 227,2000, 20% of the global total, noted Lynne Zydowsky, PhD, president and co-founder of Alexandria Summit, who moderated the session on COVID-19 vaccine development.

The increasingly urgent need for vaccines and treatments has slashed development timelines dramatically. Clinical research projects launched in late July are already in Phase III. Currently, according to the World Health Organization, 42 COVID-19 vaccine candidates are in clinical development and another 151 are at the pre-clinical stage. So far, Moderna, AstraZeneca, and Pfizer-BioNTech are on track to deliver the first doses of their target vaccines during the first quarter of 2021, and perhaps even sooner.

Applying knowledge gained from coronaviruses past

They, and other vaccine developers, have drawn from years of past experience studying coronaviruses, starting with outbreaks of severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012, noted Fauci. Teams at NIAID have worked closely with companies, notably Moderna. in early clinical work on its target vaccine, mRNA-1273.

At the forum, two pharma CEOs whose teams are now in Phase III, the last lap in the race to develop a COVID-19 vaccine, shared insights on the road ahead as well as challenges they’ve met and are overcoming: Stéphane Bancel, CEO of Moderna, whose target vaccine is under development with the collaboration of the US NIAID, in partnership with the US Operation Warp Speed program, and Paul Stoffels, MD, executive vice president and chief scientific officer for Johnson & Johnson Pharmaceuticals (J&J), whose COVID-19 vaccine candidate is currently in Phase III. J&J had briefly paused its clinical work in October to investigate possible connections to adverse effects after a trial subject became ill, but has resumed its work full speed.

According to Bancel, whose company was founded 10 years ago to commercialize a non-cell-based platform based on messenger RNA (mRNA) technology, COVID-19 vaccine development has benefitted from previous work on MERS. “We had worked on a few emerging pathogens that we all thought could come back,“ he noted. That knowledge came in handy in early January 2020, after the novel coronavirus was identified in Wuhan, China. After the virus’ genetic sequence was published, Moderna teams studied its structure closely, using 3-D modeling to confirm that the spiked protein, which had also been targeted by the company’s previous MERS vaccine, was the best bet for developmental focus, Bancel told attendees.

“On January 13, we wrote down the experimental vaccine design; within 42 days we shipped product to the National Institutes of Health; and, in early March, we began to work with Dr Fauci and his team on Phase I,” he told attendees.

mRNA, a scalable platform
Bancel believes that mRNA, which is also being used by Pfizer and BioNCell in their COVID-19 vaccine candidate, will make development of future vaccines easier.

“If our COVID-19 vaccine gets to the finish line in the next month or so, it will be an incredible de-risking for the entire mRNA platform. The next product will use the same chemistry to make the mRNA, the same manufacturing process in the same rooms operated by the same people and use the same formulation around the mRNA to get it into the cells,” he said.

Calling mRNA an “information molecule,” Bancel noted that the technology being used to make its COVID-19 candidate is basically the same that the company used for its Zika and cytomegalovirus (CMV )vaccines. “You just adapt to the biology of each individual virus,” he said. The end goal, he said, is training the recipient’s immune system so that, if a person is infected, it will create antibodies to neutralize the virus. With CMV, for instance, six different mRNAs were needed to make six different proteins, he noted.

“What is really hard with this technology is getting it to work safely,” he said, a fact that has driven Moderna to spend “a few billion dollars” on the project so far, and to step up collaboration with Big Pharma and academic labs, including Dr. Fauci’s teams at NIAID.

J&J applied lessons learned from Ebola

J&J, meanwhile, has applied knowledge gained developing vaccines for Ebola and Respiratory Syncytial (RSV) viruses, to the new COVID-19 vaccine. “We used human adenoma vector (Ad26) for the Ebola virus,” said Stoffels, noting that the vector has been optimized over the past six years to maximize immunogenicity and antibody and immune response, and has been used to vaccinate more than 100,000 people so far, generating a large volume of safety data.

J&J’s trial is one of the largest, with 60,000 participants, but previous clinical experience with the vector allowed the company to speed up preclinical and clinical work, Stoffels said. “We optimized the vector during the first three months of the year, then did animal work. Phase I and II studies began in mid-July and continued through mid-September, while the Phase III study is now underway, he said.

Pausing the work briefly in October merely reflected best clinical practices, Stoffels said. "You pause the study to learn and discuss with experts before moving forward," Stoffels said, emphasizing the importance of protecting participants in clinical studies.

On the manufacturing side, cell-line optimization was crucial to improving the vaccine's manufacturability, Stoffels explained. “We can produce a billion doses of vaccine using a cell line that works. In addition, stability has been optimized to levels of 2-8 °C for distribution. This is very important for distribution in countries within the developing world,” he said.

Clinical trials reflect demographics

Optimizing clinical trial recruitment has been crucial. In the US, members of minority groups have been disproportionately affected by the virus, Bancel said, which underscores the need to include more people from these groups in clinical trials. Insufficient representation could not only affect results, but also limit public trust in the vaccine, he said.

Both Moderna and J&J have included more ethnically diverse subjects in their clinical trials. For J&J, that meant locating half of its 60,000 subjects in the US, and the other half in Latin America and Southern Africa at 180 centers throughout the world.

Moderna, whose clinical trial involves 30,000 people in the US alone, hit the pause button on its clinical studies in September to ensure that the right demographics were in place. Since then, presence of African American subjects has doubled to 10%, and that of Latin American people has grown to 20%, Bancel said.

Another key step to achieving diversity was including more mature subjects (i.e., aged 65 or older), across all different ethnic groups, in the study. Moderna’s clinical trial makeup is now consistent with the US population and includes people at higher risk of developing the disease (eg , older people with diabetes or heart failure), Bancel said.

Moderna’s decision to limit trials to the US had more to do with the company’s size at the time than anything else, since the company only had 800 employees in the spring (a number that has since grown to 1200).“We’ve discussed this issue with global regulators, and, while we may need to run some small studies in a few Asian countries, other countries are very comfortable with data from the US,” he said.

Dosing: efficacy and manufacturability concerns

Dosing has been another key question for developers to address. Depending on how long the novel coronavirus persists, booster dosages will likely be needed over the next few years. Moderna has opted for a two-dose approach, where J&J has stayed with the single-dose strategy that it used with the Ebola vaccine. So far 25,000 of the Moderna trial’s 30,000 participants have received second shots of the target vaccine.

“When we looked at the data, we always saw a higher antibody level and longer period of protection by giving a second booster shot,” explained Bancel. AstraZeneca also decided to move from one dose to two doses in its Phase III COVID-19 vaccine work, he mentioned.

“It’s not easy to manage the logistics dictated by vaccinating people twice, but we needed to ensure the highest efficacy we could, especially for the elderly,” said Bancel. Results so far have shown the vaccine to result in similar levels of neutralizing antibodies in both elderly and younger age groups. “That consistency is very important. For some vaccines you see a big drop between young and elderly.In this case, with the elderly accounting for 80% of all COVID-19 deaths, it was crucial,” Bancel said.

Manufacturing plans and just-in-time distribution

“We agonized last Spring about whether to go with 50- or 100-mL doses,” Bancel recalled.The smaller size would have been better for manufacturing, and Moderna’s own manufacturing department had advocated that approach. Ultimately, the need to optimize efficacy drove the company to opt for the larger dose, Bancel said.

The company plans to submit the data required for an Emergency Use Allowance (EUA) by the end of November, when it expects to have its first interim results, he said.

Bancel also noted that FDA guidance for COVID-19 vaccine development has been clear, setting a goal of at least 50% efficacy and at least 30,000 participants in Phase III, with a 50/50 split between subjects receiving target vaccine and those getting placebo. “This clarity avoided guesses and higher risk,” he said.

The company has already been filing parts of the chemistry, manufacturing, and controls (CMC) application so that the detailed documentation required (a stumbling block for many companies along the "critical path" of drug development) will not delay development. “We expect data for the EUA to be filed by the end of November to early December,” he said.

Moderna has also prepared its vaccine distribution plans. “Working with Operation Warp Speed, we are on track to have at least 20 million doses made before the end of the year, and 100 million doses by the first quarter of 2021,” says Bancel, noting that trucks will stand ready to load and start shipping immediately pending receipt of EUA approval.

When asked whether the novel coronavirus might become like the influenza virus and call for a new vaccine to be developed each year, both Bancel and Stoffels emphasized the need for additional booster capacity. “We hope that this virus won’t be like the flu, but we need to understand that [this pandemic] won’t be over in six to twelve months. We will have to protect people for two to three years, until the virus can be eradicated, Stoffels said, emphasizing the need for stakeholders in the industry to learn together. Based on what happened with Ebola and Zika, he is confident that COVID-19 can be eliminated within three years.

Role of CDMOs and collaboration with the government

Rapid development has emphasized the need for scalable manufacturing platforms and experienced contract development and manufacturing organization (CDMO) partners, said Bancel. Moderna had the advantage of having a head of manufacturing who had previously led manufacturing at Novartis, he said, and also partnered with the CDMO, Lonza Pharma & Biotech, early on. Last spring, the CDMO started working with Moderna in GMP-scale production suites in the US and in Switzerland, which will manufacture supply outside of the US.

Collaboration has also been critical with fill/finish and handling suppliers, Bancel said. Moderna had to pay suppliers more for additional products and equipment up front, to assuage any concerns that they might have about potential development failure. “We have been so thankful for government help, and particularly the help of Operation Warp Speed, which saw to important details, including the shipment of some pieces of equipment by military escort to production sites,” he said.

COVID-19 vaccine development has built on a foundation set by strong ties with government agencies such as the US Defense Department’s Biomedical Advanced Research and Development Agency and the National Institutes of Health, as well as regulators, said Stoffels. Of particular help was the fact that Moncef Slaoui, head of scientific operations at Operation Warp Speed, has extensive experience in vaccine and pharmaceutical research and development. “This has allowed us to streamline decision making,” said Stoffels.

Never again: lessons learned

The industry is learning painful lessons from the COVID-19 pandemic that must inform global scientific and government strategies in the future, panelists agreed. “We need to invest in the critical scientific knowledge required to prepare for the future, not just with vaccines, but with therapies, better diagnostics, and improvements in the entire primary healthcare system. This must not happen again,” said Stoffels.

Bancel believes that developers need to come up with “what if” scenarios for the world’s 20 most dangerous pathogens likely to come up in the future. He also stresses the need for improved manufacturing. “We need to build ‘never again’ plants that will be capable of making human-grade clinical material in a matter of 40 days,” he said.

Both he and Stoffels agree that the issue of pandemic preparedness needs to be viewed as a top strategic security issue. “If governments can spend billions of dollars on nuclear weapons hoping never to use them, what should keep them from spending a fraction of that to prevent diseases like COVID-19?” he reasoned.

So far, though, the level of collaboration seen in developing vaccines has been unprecedented and deep, said Stoffels. In an industry noted for secrecy and strong competition, this spirit bodes well for the development of future vaccines and therapies at a time when the need for them is growing exponentially. Development timelines may never be the same.