Moderna’s patents stand in way of mRNA vaccine hub’s grand vision

Nestled away in an industrial corner of South Africa’s Cape Town is the Afrigen Biologics and Vaccines facility. Inside, a labyrinth of white hallways, hermetically sealed doors, and removable wall panels that allow for the easy entry and removal of equipment connect a series of sterile laboratories and preserve a range of air pressures — largely constituting the world’s first messenger RNA vaccine “technology transfer hub.”

The hub’s vaccine manufacturing suite is small — part of the also modestly sized Afrigen building, which sits on just over 1,000 square meters (10, 764 square feet). But it is home to a grandiose vision: the creation of a global network aiming to reshape pandemic preparedness in low- and middle-income countries.

“It looks very unassuming,” said Caryn Fenner, executive director at the mRNA hub. “But all of this,” she continued, pointing to a laminated map plastered on the hub’s entrance that outlines the maze of chambers, “is behind this facade.”

Companies within the hub’s network, known as “spokes,” are expected to flock to Afrigen for training on producing mRNA vaccines. While this includes COVID-19 vaccines, the technology is also intended to serve the broader purpose of allowing drugmakers to quickly pivot to producing vaccines for other emerging and existing diseases.

The hub was launched last year by Afrigen, the World Health Organization, the Medicines Patent Pool, the Access to COVID-19 Tools Accelerator, the COVAX initiative, the African Union, the Africa Centres for Disease Control and Prevention, the South African Medical Research Council, South Africa’s Department of Science and Innovation, and Biovac.

At its inception, the hub hoped to secure a technology transfer arrangement with a commercial manufacturer, such as Moderna, which is one of the companies that produces an mRNA COVID-19 vaccine. The pandemic marked the first time that this vaccine technology was approved for use globally. But Moderna declined to participate, forcing the hub to craft its own.

“We know mRNA is flexible, it is agile, and it is fast-moving. Having these [hub spoke] platforms across low- and middle-income countries brings a pandemic preparedness which we never had before. It actually changes the landscape,” said Petro Terblanche, managing director at Afrigen.

But standing in the way of this vision are Moderna’s patents on mRNA technology.

‘Just a nuisance’

“The mRNA intellectual property landscape is a nightmare,” Terblanche said. “If you look at the web of patents … it’s mind-boggling.”

To make the vaccine, Afrigen partnered with the University of the Witwatersrand, Johannesburg, which was already steeped in experience related to developing RNA therapeutics and mRNA vaccines. They used publicly available information, including the mRNA sequence of Moderna’s vaccine, to guide their efforts.

Moderna recently announced that it would never enforce COVID-19-related patents in 92 low- and middle-income countries. South Africa is not one of these, but the company told POLITICO that the hub is included in the pledge. Though well received, the pledge is limited to COVID-19-related patents, Terblanche said, adding that Moderna needs to put it in a written, legally binding commitment.

And still looming are Moderna’s patents in South Africa, which lay claim to the production of all mRNA vaccines in the country, Terblanche said.

“That will prevent us from working on any vaccine containing mRNA,” she said, apart from COVID-19 vaccines due to Moderna’s pledge.

This would block the hub’s efforts when its vaccines finish clinical trials and are set for commercialization, she said. According to Médecins Sans Frontières, “these patents could create legal risks of potential patent disputes for entities that acquire technologies from” the hub.

Terblanche said other national patent offices have rejected Moderna’s patents because the claims were too broad, but South Africa is “nonexamining,” meaning that filed patents are approved without scrutiny. Terblanche said she is concerned about countries that host the hub spokes also following lax patent practices, such that similar patents could block the hub’s work elsewhere.

“We don’t know because we need to work through layers and layers of data,” Terblanche said, adding that there is a need for a continentwide body to harmonize oversight of patent approvals in African nations.

Even with patents in place, governments can still issue compulsory licenses — which would allow vaccine production without a patent-holder’s consent. But this is a controversial process, and some countries don’t have strong national laws allowing it. Low- and middle-income countries have seen few cases in which compulsory licenses were used successfully, Terblanche said.

“Our preference is to select the key enabling patent-holders and to integrate the license with either collaborative agreements or voluntary license agreement,” she said, adding that voluntary licensing is “a much more constructive process.” The hub’s strategy is to develop its own intellectual property or license the necessary components for mRNA vaccines.

If Moderna formally includes South Africa in its pledge, then a waiver of some intellectual property restrictions on COVID-19 vaccines — as proposed at the World Trade Organization — would become less essential to the hub’s work. But a compromise that is currently being sought on that waiver proposal represents a “significant deviation from the original one,” Terblanche said, adding that there are concerns about the reduced value and difficulty of implementing the new version. Among other changes, the proposed compromise covers only COVID-19 vaccines, whereas the original also includes COVID-19 therapeutics and diagnostics.

While Terblanche said she supports a more encompassing waiver as a matter of principle, the compromise could still provide Afrigen with access to potentially valuable data currently sitting in confidential regulatory dossiers. This could fast-track the hub’s work and influence clinical design, she said.

Moderna plans to build its own mRNA factory in Kenya, which is also home to one of the hub spokes. “Will it be in competition with the spoke there? We don't know,” Terblanche said, adding that she hopes the company will collaborate with the hub in the country.

Moderna Chief Executive Officer Stéphane Bancel told POLITICO that working with the hub is “not a good use of our time” and that the hub is a “nice to have, not a must have.”

But for people across the African continent who experienced widespread COVID-19 vaccine inequity, the hub’s significance carries more weight, Terblanche said.

“If you were here and you were part of the void, you would have a different view. If you have a passion for low- and middle-income countries, if you really have a passion to change the landscape and drive a renaissance, you will have a different view,” she said. “For Stéphane Bancel, sitting in Boston, I can't believe that he could have a passion for something like this. And that's why this, for him, it’s just a nuisance. But we are in it. We are Africans. For us, it is a passion.”

At time of publication, Moderna hadn’t responded to requests for comment.

Work in progress

A chorus of drilling and hammering still echoes throughout the hub; it’s very much a work in progress. The development of its maiden COVID-19 vaccine is ongoing — and it still must face the scrutiny of immunogenicity and clinical trials. The hub is also waiting on equipment to arrive.

Afrigen, a young biotech company, became operational in 2016. Its first homes were small laboratory facilities rented from the South African Medical Research Council, with product lines including adjuvants — substances that help increase the immune response — and CBD capsules, as well as minerals and vitamins. The company started building its own facilities at the onset of the pandemic.

Eventually, it aims to support the full process of mRNA vaccine manufacturing — from the production of the drug substance to the bottling of millions of vials per year.

To make the mRNA substance, scientists at the hub cultivate E. coli before then extracting and purifying plasmid DNA, which is converted into mRNA. The drug substance is formulated into lipid nanoparticles that allow the mRNA to remain stable long enough to send a message to the body to make the spike protein of the SARS-CoV-2 virus, evoking an immune response. After time, it degrades and leaves the body.

“That is the safety of mRNA: It doesn't become incorporated into your body. … It breaks down,” said Fenner, the mRNA hub executive director.

The hub currently has 14 spokes, but that could rise to about 23, she said. Earlier this month, a team from a spoke in Indonesia traveled to South Africa to train, and a team from Bangladesh is next. Afrigen will hold the phase one and phase two clinical trials, while the spokes would host phase three and become commercial producers.

The South African Health Products Regulatory Authority still needs to accredit the Cape Town facility, which the hub aims to have done by the end of August. But the national regulator itself must receive “maturity level 3” status on a WHO scale that measures the quality of nations’ health regulatory systems. Without that status, the country cannot produce vaccine drug substances commercially, but the hub’s leadership said the country is on track to reach this level.

Tidal change

The silver lining to developing mRNA drug substance without Moderna is that the hub has now created a platform rather than a single product, Terblanche said. This could help keep the hub’s work financially sustainable, even if demand for COVID-19 vaccines eventually wanes.

“It takes longer, but … it's better,” Terblanche said.

After optimizing the process for producing mRNA drug substance and lipid nanoparticles, the hub essentially only needs to plug in the sequence for new vaccines — save some small tweaks, Fenner said. By contrast, the process of creating a live attenuated vaccine is lengthy, requiring the cultivation of cells.

“That is what gives you the flexibility and the faster turnaround time,” Fenner said.

The hub plans to put a variety of vaccines to the test — for diseases with existing vaccines needing upgrades and those still without any, including Lassa fever, Ebola, Marburg, tuberculosis, Chikungunya, dengue, hepatitis, measles, and HIV.

“I have absolutely no doubt that [the pandemic] is going to leave enduring change,” Terblanche said. “The hub is just one tiny, tiny component of a much, much bigger wave that's going through the globe.”