Slaoui on Warp Speed’s successes, limitations and lessons
Operation Warp Speed’s co-leader describes how the U.S. government helped move COVID-19 vaccines across the finish line in record time
Operation Warp Speed co-leader Moncef Slaoui describes how the U.S. government helped move COVID-19 vaccines across the finish line in record time.
Having helped create the fastest vaccine development programs in history, Moncef Slaoui has stepped down as scientific adviser and co-leader of Operation Warp Speed, the U.S. government’s initiative to develop, manufacture and distribute countermeasures to COVID-19.
Slaoui and Operation Warp Speed were introduced to the nation at a White House press conference on May 15, 2020. Standing in the Rose Garden, Slaoui called President Donald Trump’s promise to ensure that a COVID-19 vaccine would be developed by year-end “very credible.” Skeptics panned the assertion, noting that no vaccine against a novel pathogen had ever been discovered, tested, manufactured and approved in under four years and most took far longer.
While the authorization of two mRNA vaccines in December proved the skeptics wrong, Slaoui’s prediction at the Rose Garden press conference that “we will be able to deliver a few hundred million doses of vaccine by the end of 2020” turned out to be too optimistic by an order of magnitude.
The Warp Speed name has been retired by the Biden administration, but the operation’s successes in accelerating the development of safe, effective vaccines, as well as its failures to live up to expectations for both manufacturing capacity and administration of vaccines, will shape the U.S. COVID-19 response.
Warp Speed, which Slaoui calls “the Operation,” provided extensive hands-on assistance, including at-risk funding for manufacturing and testing of vaccine candidates from five companies: AstraZeneca plc (LSE:AZN; NASDAQ:AZN), the Janssen Pharmaceuticals unit of Johnson & Johnson (NYSE:JNJ), Moderna Inc. (NASDAQ:MRNA), Novavax Inc. (NASDAQ:NVAX) and Sanofi (Euronext:SAN; NASDAQ:SNY).
A sixth company, Pfizer Inc. (NYSE:PFE), opted to use its own resources to develop a COVID-19 vaccine. Warp Speed provided supply chain and logistics assistance and committed to purchase the vaccine, if it received emergency use authorization from FDA. Based on statements by Pfizer Chairman and CEO Albert Bourla after its vaccine was authorized by FDA, Pfizer did not consider itself part of Warp Speed.
BioCentury spoke with Slaoui on Jan. 15, exactly eight months after his appointment to Warp Speed was announced. The former chairman of R&D at GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) described how Warp Speed accelerated vaccine development. He predicted that the initial cohort of COVID-19 vaccines will remain effective in the face of mutations because of the structural biology of the virus spike protein.
“If the Phase III trials had failed, all the monies would have come from the U.S. government.”
Slaoui, who told BioCentury in September that he was not politically “aligned” with Trump, was stung by Biden’s Jan. 14 characterization of the vaccine rollout a “dismal failure.” The assertion, Slaoui said, is a “very harsh statement for an operation that has done something that nobody ever has done on Earth, which is to discover, develop, manufacture, and make available vaccines in less than a year and [has] immunized to date 11.5 million people.”
Slaoui acknowledged that administration of vaccines has been flawed, but defended Warp Speed’s decision to decentralize vaccine administration decision-making and implementation, a policy that the Biden administration is scrambling to reverse.
He also pointed to missteps in the development of COVID-19 therapeutics. The NIH-led ACTIV adaptive master protocol trials are excellent in theory, but implementation has been far too slow and cumbersome, Slaoui said.
One lesson from the COVID-19 experience, he said, is that the rush to develop mAbs led companies to rely on IV administration which is unsuitable for treating patients in the early stage of their disease, when they are not hospitalized. He added that in future pandemics, mAbs should be created as subcutaneous or intramuscular injectables from the start.
Even more importantly, R&D should focus on oral small molecule antivirals that can be administered as soon as patients are diagnosed, Slaoui said.
To be better prepared for future pandemics, Slaoui suggested that governments and industry should reconsider a proposal he made in 2016 for the creation of a BioPreparedness Organization, a permanent, independent entity dedicated to developing vaccines to protect against pathogens that could become mass killers.
“We are in a better place because we know mRNA is an unbelievably fast and unbelievably effective platform to make vaccines.”
Slaoui, who will serve as a consultant to the Biden administration, has returned to Medicxi, where he is a partner. Slaoui said 2021 will be a “huge proof of concept year” for two companies he chairs, Galvani Bioelectronics Ltd., a company formed in 2016 by GSK and Verily Life Sciences to develop and commercialize bioelectronic medicines, and SutroVax Inc., which is developing a pneumococcal pneumonia vaccine that could compete with Pfizer’s Prevnar 13.
BioCentury’s conversation with Slaoui, edited for clarity and length, follows.
BioCentury: What did Operation Warp Speed accomplish that wouldn’t have happened if it hadn’t been created, and how did it do it?
Moncef Slaoui: We have added value in two ways. One was with Pfizer, which was 90% to create the financial incentive for the company to take the risk. It was an arm’s length relationship where all of the financial risk was with Pfizer and all of the technical approach to the vaccine was with Pfizer and BioNTech, and we provided operational procurement support and distribution design support.
For the five other companies in the portfolio, there was a very different approach. The Operation was very much a hands-on and a day-to-day partner with the companies from inception all the way to today.
We published what we called tenets for the companies to adhere to as a requirement for receiving support. We took 100% or 80% of the financial risk in that we paid for the R&D activities and manufacturing leading to availability of vaccine doses. If the Phase III trials had failed, all the monies would have come from the U.S. government.
We engaged NIH network- associated clinical trial sites that represented between 20% and 40% of the clinical trial sites. We operationalized the clinical trials with the CROs, providing PPE, arranging for IT systems, shipping PCR machines to do the readouts of the samples, and defining the endpoints. Every single aspect, from technical details to the broad approach to the Phase I, Phase II and Phase III trials were discussed and agreed, with, frankly, the party that was taking the financial risk, which was the Operation, having the final say.
Pfizer did their manufacturing. For Moderna, we’ve been intimately involved in all operational aspects of the manufacturing, whether it was accessing and ordering raw materials or special equipment or bringing in particular machinery from abroad and supporting its installation.
With the other four companies, we used manufacturing sites for drug substance manufacturing that were part of a BARDA collaborative network. We have supported equipping manufacturing sites, hiring of talent, validation of day-to-day work leading to the scaling-up of the manufacturing processes, hand-in-hand with the technical teams from companies like Novavax or Janssen or AstraZeneca and the CMOs that are doing the manufacturing such as Emergent [BioSolutions Inc.] or Fujilabs [Fujifilm Diosynth Biotechnologies, the CDMO unit of Fujifilm Holdings Corp.].
BioCentury: The speed of the development and authorization has been pretty much spot on with what you said would happen, and although manufacturing has fallen behind, it’s ramping up. The administration of doses, getting them into people’s arms, is another story. Why has it been so bad and how does that get solved?
Slaoui: Administration has indeed been a lot less, two- to three-fold less [than Warp Speed had planned].
We decided to allocate vaccine doses to each state proportionate to its population, and then it is for each department of health within each state or jurisdiction to tell us where they want the vaccine doses allocated to the state to be shipped. We worked with them to identify 70,000 different addresses to which vaccine doses will be shipped. Prior to the approval of the vaccines, we shipped to those locations all the required immunization materials and PPE.
Then when the vaccines were approved, exactly the number of doses that they asked us for were shipped to those addresses. Our expectation, frankly, is that if you say, I want 900 doses of vaccine in this hospital, it is because you plan to immunize 900 people in that hospital. I think that’s a reasonable assumption. That’s not what happened.
What happened is I think a combination of the states realizing that it’s more complicated to vaccinate people [than they anticipated]. The healthcare talent and organization being overwhelmed by the surge in the pandemic must have played a role in the fact that that preparedness was not optimal. And maybe [there was] some level of vaccine hesitance.
We delegated to the states. I’m not saying this to put the blame on the states. I’m saying this literally to describe the situation.
“It’s going to be hard structurally for this virus to escape the polyclonal immune response induced by a vaccine.”
BioCentury: The question is, looking back on it and looking forward, was that the right decision?
Slaoui: I think for the U.S. healthcare system, that is the right decision, but maybe we should have given more support to the states.
It’s easy to say let’s put up a big tent, and we will immunize people there, but that’s not how we will immunize 300 million people. We will immunize 300 million people by having 70,000 sites immunizing a hundred people every day.
Only the states can know where to best put those sites and how to appropriately staff them.
BioCentury: How has the political environment affected the decision-making and the operations of Warp Speed?
Slaoui: As I repeatedly said, the Trump administration has not interfered at all with the discovery, development and manufacturing of vaccines. Once we started to have the distribution and immunization, I think we started to have, I’m not going to call it interference, but more participative input.
That was also in part triggered by enormous pressure from the media and from the Biden administration that has labeled the Operation as a “dismal failure.” In all objectivity, that is a very harsh statement for an operation that has done something that nobody ever has done on Earth, which is to discover, develop, manufacture, and make available vaccines in less than a year and [has] immunized to date 11.5 million people.
BioCentury: Are you concerned that SARS-CoV-2 mutations could make vaccines that are being manufactured now ineffective or less effective?
Slaoui: I think it’s going to be hard structurally for this virus to escape the polyclonal immune response induced by a vaccine.
The vaccine uses the full length S protein as a trimer, and really focuses its immune response against superstructures on the spike, and it’s much more difficult to lose all of them than for instance, with HIV, which has a discrete loop that can afford enormous changes in sequence. I think it’s going to be harder structurally for this virus to escape the polyclonal immune response induced by a vaccine.
It may take a long time and accumulation of many mutations that allow the virus to continue to use the three-dimensional structure of the spike to infect, but not to have changed it so much that even a polyclonal immune response against the whole structure doesn’t [recognize it] anymore.
Secondly, with this virus in particular, two arms of the immune system are important for protection, one is neutralizing antibodies, but the other is a cell-mediated immune response that clears virus infected cells either through secretion of gamma interferon or through direct killing of infected cells. When I see the level of protection after the first immunization with the Pfizer or Moderna vaccines two weeks after the first immunization, when there are almost no detectable neutralizing antibodies, it tells me that the cell-mediated immune response plays an important role.
That’s really important because the cell-mediated immune response recognizes linear epitopes on the full sequence of the S protein. There are many, many T cell epitopes there. The virus would need to mutate all of them to escape fully.
BioCentury: Monoclonal antibodies haven’t played the role that many people had expected. Is the technology unsuitable for pandemic response because of constraints on manufacturing and administration, or is it possible that these could be overcome now and especially for future pandemics?
“The true solution is to have an oral small molecule antiviral that you can give to all people that are exposed before the onset of any symptoms.”
Slaoui: For acute viruses you have the problem that you need to intervene very early in the disease after the infection, because most of the disease is actually an immunopathology.
The problem we have with the monoclonals, because they have been developed so fast, is that they’re delivered intravenously. That’s a big problem when you’re dealing with outpatients, particularly when the hospital facilities are overwhelmed by infected people, and you need to deal with people who themselves are infected.
I think the lesson is next time we have to go straight to a subcutaneous or intramuscular injectable formulation of a monoclonal to avoid that problem.
Also, the lesson is that the true solution is to have an oral small molecule antiviral that you can give to all people that are exposed before the onset of any symptoms.
BioCentury: What are the lessons from the COVID-19 experience for getting ready for the next pandemic?
Slaoui: I made proposals for what I called a bio-preparedness organization in 2016.
That conviction is even bigger now, and we are in a better place because we know mRNA is an unbelievably fast and unbelievably effective platform to make vaccines. We need to have the R&D facilities to be able to discover, develop, and start manufacturing at small scale of mRNA-based vaccines or live non-replicating viral vector vaccines very quickly.
The big problem is manufacturing. Nobody can have a big manufacturing facility sitting idle waiting for a pandemic. That is actually useless because an idle facility is not validated, and it doesn’t have the right trained talent.
What we need is to have a network of manufacturing facilities that are dedicated to manufacturing vaccines that have potential to serve in pandemics and do that all the time. This is part of the bio-preparedness proposal.
With mRNA or the live vector vaccine, we can discover vaccines from the list of WHO potential pandemic agents. We can design them, make them at small scale, show efficacy or relevant immune response in primates. We can scale up manufacturing quickly and manufacturer a million or two million doses, then store them and go to the next vaccine.
Because they’re manufacturing vaccines discovered against the list of potential pandemic agents, either we are lucky and the next pandemic is one of those agents we already targeted, in which case we have the vaccine, or if not, we have the team and the facility to immediately discover, develop and start large large-scale manufacturing of the vaccine.
The key is to have ongoing manufacturing, talent, capability and infrastructure that can be instantly refocused on a new objective. That is incompatible with an industrial setting or a commercial profit-making organization. Maybe it can be a public-private partnership of some sort.
BioCentury: What about clinical trial infrastructure? It has worked for vaccines, but for therapies it has been disastrous. There have been huge numbers of underpowered, poorly designed studies that are never going to produce actionable data. Is there a need for government to take control of clinical trials in an emergency?
Slaoui: I completely agree with you.
The vaccine took a centralized approach. We controlled it and that allowed us to not waste facilities, sites and talent in small trials that don’t give an answer. That did not happen for therapeutics. There were more than 400 clinical trials, most of which had no controls, so it was impossible to come to any conclusions.
Part of the answer was the ACTIV approach and what’s been called platform clinical trial designs, where you had one clinical trial protocol and a series of sites that would test different therapeutic candidates one after the other. It allows you to share control groups, to create a machine that can run very well once it has been well oiled.
The concept is very attractive. In practice, frankly, it didn’t work very well. It took forever to be set up, to be approved, to have each IRB agree. Moving from one drug to the next within the same platform trial required small changes and each time it took forever to have the approvals. But the principle of it, I think, is the way to go.
I remember having discussions with Janet [Woodcock, who led the therapeutics team at Warp Speed] when we were really frustrated with clinical trials. The problem is that trials use patients, facilities and talent that could be used for something else, so there’s a huge opportunity cost.
There is a big lesson there [about the need] to find a way that’s much faster than we have done trials this time, to have centralized clinical trials, and to have platform trials running as quickly as possible.