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As COVID-19 vaccines progress, science and policy questions become more urgent

GSK-Sanofi deal underscores importance of tested technologies, manufacturing capacity in search for vaccine

The collaboration announced Tuesday between Sanofi and GlaxoSmithKline highlights the importance of bringing tested technologies and large-scale manufacturing capacity to the search for safe, effective COVID-19 vaccines.

The partnership, which combines the strengths of two of the largest vaccine manufacturers, also provides an opportunity to consider some of the practical aspects of moving from the lab to mass manufacturing.

For example, Sanofi (Euronext:SAN; NASDAQ:SNY) expects that two doses of its adjuvanted vaccine will be required to provide protection against COVID-19.

As vaccine candidates advance toward larger-scale efficacy tests, the need to address scientific and policy challenges is becoming more urgent.

Scientific questions that industry and regulators will need to answer quickly include how to determine the appropriate doses and regimens to be tested and how to design trials in ways that balance the need for speed with the time required to answer critical questions such as the length of protection a vaccine provides.

“Our role is to develop as quickly as we can a new vaccine and to scale up production capacity. But we can’t be alone in that fight.”

David Loew, Sanofi

Answering these questions exposes differences in preparedness among regions, as well as global gaps.

For example, while the U.S. has mechanisms in place to fund at-risk manufacturing, Europe and the rest of the world has not put these into place.

No one has determined how vaccines will be reimbursed or how to balance the needs for affordable access and the importance of creating predictable markets that give pharmaceutical companies confidence to invest in R&D and manufacturing.

And long before vaccines start rolling off manufacturing lines, the international community must determine whether and how they will be made available on an equitable basis to residents of poor countries.

The GSK-Sanofi agreement

Under Tuesday’s deal, GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) will contribute its AS03 pandemic adjuvant technology to Sanofi.

Although Sanofi is developing its own adjuvant, the company decided to partner with GSK to gain access to an adjuvant that has been proven safe and effective and for which there is large-scale manufacturing capacity in place.

AS03 has been demonstrated to reduce the amount of antigen required to make an effective dose, and to increase the efficacy of vaccines. It is used in GSK’s Pandemrix H1N1 pandemic influenza vaccine.

In addition to AS03, Sanofi will also test its COVID-19 vaccine with an adjuvant it is developing in-house, David Loew, the company’s global head of vaccines, told BioCentury.

“The GSK adjuvant has been tested on a very large scale in the previous H1N1 crisis and they can produce it at very large scale,” Loew said. “We are not as advanced yet with our own adjuvant."

He said the deal brings together two giants in the vaccines field, each with experience producing vaccines at scale.

The agreement is limited to the adjuvant; it does not include vaccine manufacturing or clinical trial support, Loew said.

GSK has also made its adjuvant technology available to other vaccine manufacturers, and has several collaborations involving COVID-19 therapeutics (see Figure).

Even with an adjuvant, Loew said Sanofi expects that a two-dose regimen will be required to provide immunity to COVID-19.


Proven technologies

Sanofi and GSK emphasized the importance of simultaneously developing multiple vaccines based on different technologies. They also stressed their commitments to meeting public health demands.

On a call with reporters Tuesday, GSK CEO Emma Walmsley cited both the need to try multiple vaccine development technologies because it isn’t known which will work, and the importance of having multiple companies manufacturing vaccines to meet expected demand.

GSK has determined that it can have the biggest immediate impact by making its adjuvant technology available; however, it is also reviewing options for developing its own vaccine, Walmsley said.

She noted that mRNA vaccine candidates, such as the vaccine Moderna Inc. (NASDAQ:MRNA) is developing, have gotten into clinical trials more rapidly than those based on more conventional approaches, but there is some uncertainty about mRNA technologies.

“We are seeing several mRNA candidates coming forward,” Walmsley noted. “They may get earlier visibility of results. These are new technologies that haven’t been manufactured at scale.”

“One of the important parts of this collaboration is our combined scale.”

Emma Walmsley, GSK

Sanofi is partnering with Translate Bio Inc. (NASDAQ:TBIO) to develop an mRNA-based COVID-19 vaccine.

“Messenger RNA is a promising technology; it’s very versatile and it can produce candidates relatively quickly,” Loew said. “It has, however, never been tested in large Phase III trials and there is also no registered vaccine available today using that technology. It remains to be seen what this technology can really deliver.”

The baculovirus expression platform Sanofi is using to produce its recombinant protein-based COVID-19 vaccine candidate has already been used successfully to manufacture its Flublok influenza vaccine. Ten million doses of Flublok have been injected into humans, Loew said.

Sanofi and GSK said they plan to start Phase I trials of the adjuvanted vaccine in 2H20.

The companies said they could “complete the development required for availability” by 2H21.

Clinical trials

That timetable assumes rapid successful completion of clinical trials. There are important issues to resolve before Phase II or III trials can begin.

Obtaining buy-in from regulators on surrogate endpoints could speed trials, Walmsley told reporters Tuesday.

While it is too early to say what endpoints will be required, it is likely that measures of immunological response and the durability of the immunological response will be included, "but I think ultimately the regulators will probably also want to see a clinical response,” Loew told BioCentury.

Sanofi hasn’t yet decided whether it will seek to have its vaccine tested in the WHO Solidarity master protocol, Loew reported. “If you go into the WHO master protocol, it adds complexity and you might not necessarily be able to move at full speed,” he said.

Manufacturing capacity

“One of the important parts of this collaboration is our combined scale,” Walmsley said. “Both companies have significant manufacturing capacity.”

Sanofi can manufacture 100-600 million doses annually of its COVID-19 vaccine in the U.S., Loew said.

Walmsley told reporters that in addition to its existing plants, GSK is considering creating new adjuvant manufacturing capacity in North America and Europe, including the U.K.

The U.S. Biomedical Advanced Research and Development Authority (BARDA) has already committed to funding preclinical development and a Phase I trial of Sanofi’s COVID-19 vaccine and the company is preparing to request funds for Phase II and III trials.

BARDA received funding in the Coronavirus Aid, Relief and Economic Security (CARES) Act to fund manufacturing of vaccines and therapeutics at risk prior to completion of trials.

In addition to its U.S. manufacturing capacity, Sanofi has a relationship with Unigen Corp., a contract manufacturer based in Japan. Unigen could manufacture a COVID-19 vaccine in greater quantities than Sanofi’s U.S. capacity; however, getting Unigen into the game could require external funding.

Funding for manufacturing outside the U.S. is less clear, Loew told BioCentury.

“There is a question on how Europe is going to start to get organized around” creating and funding vaccine manufacturing capacity, he said.

Europe doesn’t have an institution like BARDA that funds pandemic and biodefense product development and manufacturing.

“We have been saying to European institutions, to the commissioners of the European Union and also, for example, to some leaders of nations in Europe, that this is something which we think Europe will have to come together and start to think about and potentially establish in order to help as well to accelerate the development and the buildup of spare capacity,” Loew said.

Even with BARDA funding for the U.S., there is an urgent need for clarity about pandemic vaccine markets, according to Loew.

Determining what “kind of models can we build to share the risk of building up capacity at risk” is a “fundamental question which has not been completely resolved yet,” Loew said. “Governments are going to start realizing this. We will have to start to think about risk here in terms of building capacity, ordering raw materials and embarking on large-scale pharmacovigilance programs.”

Global collaboration and access

Walmsley also discussed the need for global cooperation. “At GSK we believe that tackling this virus urgently requires partnerships, a global approach, commitments to access, and an investment in long-term pandemic preparedness."

The company is committed to making vaccines developed through the collaboration affordable and available via mechanisms that offer fair access for all, Walmsley said.

“Overall, looking at the portfolio of our collaborations for COVID-19 vaccines, we do not expect to profit from them during this pandemic,” she said. “Any short-term profit we do generate will be invested in support of coronavirus-related research and long-term pandemic preparedness, either through GSK’s own internal investments or with external partners.”

Walmsley committed to ensuring access in developing countries. “Making our adjuvant available to the world’s poorest countries will also be a key part of our effort.”

Sanofi is also committed to ensuring global availability of its COVID-19 vaccines, but there are concerns that governments will prioritize the needs of their own citizens.

“As an industry we have said borders need to stay open,” Loew told BioCentury. “There should not be nationalistic behavior. We clearly encourage the free flow of goods and making sure that people who need [the vaccine] get access.”

He added, however, that “it’s going be tough if there is not enough [supply]. We will have to see how governments around the world react to such a situation.” The best way to ensure equitable access is for governments to help the industry scale up as quickly as possible, according to Loew.

One way to help industry scale up, Loew said, is to provide advanced purchase commitments. These are needed, he said, because no one knows how long the COVID-19 outbreak will last, whether there will be subsequent waves, or if it will become a seasonal event like influenza.

“If you don’t set up some sort of mechanisms in terms of advance purchasing and risk-sharing, I think we’re going to hurt ourselves in terms of getting to large-scale manufacturing in the shortest time possible,” Loew said.

“Our role,” he added, “is to develop as quickly as we can a new vaccine and to scale up production capacity. But we can’t be alone in that fight.”

Further analysis of the coronavirus crisis can be found at https://www.biocentury.com/coronavirus.

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