Covid-19 spurred a historic vaccine R&D effort. What does it mean for future pandemics?

In the historic campaign to vaccinate the world against Covid-19, Corbevax was far from the first vaccine to reach the market. While the first mRNA shot became available 326 days after the SARS-CoV-2 virus was sequenced, the journey of Corbevax — which has so far gone into the arms of 75 million kids in India and recently won approval for adults — spanned about 600 days.

But Peter Hotez, one of its co-inventors, believes it could’ve played out differently if his team had received more funding and there was a smoother regulatory path.

“That could have been probably cut in half had we had the support to move faster,” said Hotez, the co-director of the Texas Children’s Hospital Center for Vaccine Development.

There was good reason to go faster. The mad scramble for life-saving shots exposed the stark disparities between the vaccine haves and have-nots. Corbevax, a patent-free vaccine based on older but proven technology, can be affordably produced and distributed to lower-income countries.

The Corbevax story is relevant to a bigger question as the world attempts to strengthen vaccine research and development infrastructure to go even faster and more equitably distribute vaccines. Vexing scientific, regulatory and manufacturing challenges must be solved ahead of the next pandemic, public health experts and advocacy group representatives said in interviews.

The Coalition for Epidemic Preparedness Innovations, or CEPI, which launched in 2017 in the wake of the Ebola outbreak in West Africa, has proposed what it calls a moonshot goal of spurring a vaccine against a new pandemic-causing pathogen in 100 days. The initiative is known as the 100 Days Mission.

Melanie Saville

Melanie Saville, CEPI’s executive director of vaccine R&D, reckons the group would’ve been “laughed out of the room” if they had told people before the Covid-19 pandemic that a vaccine would arrive within 326 days – but already there’s a path to going faster.

“If you actually put everybody’s innovation together from Covid-19, we already probably could shave off two months by looking meticulously at every step of the process,” she said, citing a CEPI analysis based on interviews with companies, international organizations, regulatory agencies, academia and the media.

To get to 100 days, though, much more needs to be done. The key is to do as much of it upfront as possible, she added, during so-called peacetime, much like decades-long RNA research ushered in the first Covid-19 vaccines.

James Anderson

“The ecosystem is the result of decades of work, particularly some of the new technologies like the mRNA vaccines, and the viral vector vaccines,” said James Anderson, executive director of global health at the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA). “Those didn’t just come out of nowhere.”

Yet perhaps more crucially, experts emphasized the importance of coordination — to fund the right mix of projects, to keep track of how many vaccines can be produced and by whom, to reach consensus on regulations that balance speed and safety, and to put in place frameworks for transferring vaccine technology to local manufacturing sites.

“We have the capabilities to do this differently,” said Luciana Borio, former National Security Council director for medical and biodefense preparedness and current senior fellow for global health at the think tank Council on Foreign Relations. “We’re not asking to, you know, build new capabilities necessarily. There’s a lot that we already have that we just have to make better use of.”

The science — and funding it

In March of 2020, as he was just starting work on what would become Corbevax, Hotez flew to Washington, DC, and testified before Congress on infectious diseases and coronaviruses — particularly the one that just cropped up on American soil weeks prior.

Peter Hotez

Donning his signature bowtie, Hotez recounted how his team had set out more than a decade ago to make a coronavirus vaccine after the deadly SARS outbreak in China illustrated the enormous toll that this family of viruses could take on humanity.

It was a major scientific challenge to sidestep a potential safety problem that’s long been known about respiratory virus vaccines — the paradoxical phenomenon of immune enhancement, where vaccinated people get a worse-than-usual infection after contracting the virus. Together with academic collaborators, the scientists at Texas Children’s Hospital figured out that if they take just one tiny piece of the coronavirus, specifically a subunit in the spike protein called the receptor binding domain, and put it in a vaccine, they get protection without the dangerous immune enhancement.

As it turned out, the biggest challenge was financial.

“We had it manufactured but then we could never get the investment to take it beyond that,” he explained to lawmakers. “So that was really unfortunate because we had the vaccine ready to go but we couldn’t move it into the clinic because of lack of funding.”

Maria Bottazzi

When Hotez and his co-director, Maria Elena Bottazzi, dove into SARS-CoV-2, they ran into the same bottleneck again. While multiple vaccine developers got multibillion-dollar contracts from the US government to advance candidates, the Texas Children’s Hospital team turned to private funders — including, famously, Tito’s Handmade Vodka — to raise a meager $9 million.

The money would’ve helped them move faster into early-stage non-human primate testing, he said. It also would’ve helped foot the bill on shipping yeast strains that produce a key ingredient of the vaccine, setting up cell production facilities and honing technical know-how. That way, companies in lower-income countries could make the vaccines and begin testing them sooner.

“You don’t want to make the mistake of demonizing the pharma companies, because they do a lot of innovation, and they provide a lot of vaccines,” Hotez said. “But it’s gone too full tilt in favor of the multinationals at the expense of the (low- and middle-income country) vaccine producers and their academic partners.”

For those immersed in vaccine R&D, the astonishing efficacy of mRNA vaccines was unexpected. After years of development, the technology made its debut amid some of the most chaotic times, offering a near-miraculous weapon against the coronavirus and saving countless lives.

Still, there’s much to unwind about the intricacies of the technology. And the engines that came up with some of the world’s leading Covid-19 vaccines are still humming along today. On top of subvariant-specific boosters, Pfizer, Moderna and BioNTech each laid out varying programs to tackle pathogens that could spark major threats in the future; they declined interviews for this story. Others have poured major investments into mRNA, from the WHO’s mRNA hub in Africa to Japan’s $2 billion initiative. Just days ago, CEPI unveiled a $140 million plan to beef up SK bioscience’s mRNA prowess in South Korea.

Luciana Borio

“Part of the success for the mRNA vaccines that were produced in the US have to do with the way the protein was designed, and the mRNA sequence was designed to create a very specific spike protein that was highly stabilized in its conformation, in the right conformation,” said Borio, who’s now also a venture partner at ARCH. “So it still takes, you know, sophisticated science and know-how to be able to design these vaccines.”

As big of a role as it played in the current pandemic, though, mRNA won’t be a singular solution, experts largely agree.

“I think there’s still plenty of room for improvement,” said Saville of CEPI. “But we shouldn’t think it’s the only platform; it is really there for speed. We cannot say for the next pandemic, whether that is the right platform or not.”

From whole inactivated virus vaccines (the most common type in China) to viral vector vaccines (such as the ones from J&J and AstraZeneca) to nanoparticle vaccines (one of which, from SK bioscience, just got approved in South Korea), choices abound — and each one comes with its own advantages and tradeoffs.

As one alternative, the Corbevax vaccine, based on older protein subunit technology, can be easily produced and stored, fitting into existing infrastructure in lower-income countries.

“Indonesia, Brazil, elsewhere, all make their own recombinant hepatitis B vaccine,” Hotez said, which is a type of protein subunit vaccine. “So any delays on the front end are more than made up on the back end.”

Peter Dull

Then there’s the issue of delivery. Peter Dull, who supports clinical development of vaccines at the Gates Foundation, pointed to the recent shift in attention to inhaled vaccines, which would target immune responses in the mouth and nose. If the priority is to reduce transmission and not just risk of severe disease and death, this type of nasal vaccine may be preferred to intramuscular ones.

“I do think educating ourselves and educating our stakeholders around what the goals of the next pandemic will really guide the types of vaccines that we’re going to drive for,” he added.

But equally important, if not more, is basic research on what molecule to put in a vaccine to stir up a protective, yet safe, immune response. In the case of SARS-CoV-2, scientists already knew to target the spike protein — the corona in coronavirus — and it appeared that both full spike protein or the smaller receptor binding domain worked. For other priority pathogens, that’s not always so clear. In some cases, Dull noted, scientists also don’t fully understand what type of immune response would predict protection — whether immunity would be driven mainly by antibodies or T cells — which could complicate the search for the right antigen.

Even with pathogens for which scientists have a good grasp of which antigens to use in vaccines, there is still room to explore alternative strategies in vaccination.

Adolfo García-Sastre

With coronavirus and influenza, existing vaccines need to be updated regularly because the antigen being targeted can disappear when the virus mutates. Adolfo García-Sastre, director of the Global Health and Emerging Pathogens Institute of Icahn School of Medicine at Mount Sinai in New York, has for years been working on a universal flu vaccine that would protect against any flu strain. That means searching for an antigen that is conserved no matter how much the virus mutates to make a vaccine that stands ready to battle a flu pandemic.

Yet, in weighing a product that needs to be updated but is sure to bring in revenue each year, versus one that’s potentially better but hasn’t been tested and will be extremely expensive to test in late-stage trials, most companies still decide the universal vaccine work is too risky, García-Sastre said.

“There is a lot of interest, I think that helps to maintain the work,” he said. “I don’t think it has accelerated the work.”

On the platform side, companies could contribute to future vaccine R&D just by “advance investments in versatile technologies” even if not directed at pandemics, said John Billington, GSK’s head of commercial pipeline and health security, policy & advocacy. Moderna and BioNTech, after all, were more focused on cancer and flu vaccines specifically before jumping into Covid-19.

Biological E, the Indian vaccine maker responsible for steering Texas Children’s Hospital’s Corbevax through animal testing and clinical trials, has been muscling up not just in recombinant protein vaccines but viral vector and mRNA, said Vikram Paradkar, the head of Biological E’s vaccine division.

“You can’t create a stagnant company who will just respond to a pandemic. You require a vibrant, fully functional company that produces and has expertise in vaccines, is state of the art, is familiar with all aspects of vaccine technology,” he said. “And that company will come to the forefront when a new pandemic will hit.”

The hurdles

Say that scientists crack the recipe for a vaccine. Say they understand the pathogen. Say they line up prototype vaccines. There’s still a ways to go: testing in animals and then humans. All the while, the 100-day clock would be ticking.

One of the biggest speed bumps in developing Corbevax arose when the shot was ready for large-scale trials. By that time, it was nearly impossible to find participants in the country who hadn’t been exposed to the virus or vaccines.

Instead of traditional efficacy trials, the Biological E team wanted to do immuno-bridging studies, which measure whether a vaccine is working via a simple blood test.

Vikram Paradkar

“In July, August ‘21, when we were ready to start our Phase III trials, we had a lot of uncertainty as to how to conduct these trials,” Paradkar said.

UK regulators advised the immuno-bridging trials, which ultimately led to approval in India. But it would be months before the WHO came out with detailed regulatory guidelines on how to run those studies. In such studies, researchers infer, rather than directly measure, vaccine efficacy by comparing the markers for immune response, such as antibodies, to those in previous efficacy trials.

While experts largely applauded health regulators worldwide for being agile during the Covid-19 pandemic, they say it’s necessary to continue having conversations to codify those special arrangements so that next time around, they will have a better idea of what to do and won’t have to figure as much of it on the fly. And there’s always room for improvement.

For one, regulatory agencies around the world had varying requirements for clinical trials and vaccine authorization submissions.

“There’s no international cooperation for approval of vaccines, basically,” Garcia-Sastre said.

“A lot of time is spent with specific dossiers for a specific entity,” added Lyn Morgan, senior director of public affairs at Sanofi. “And really, it’s not something that’s tenable in the case of a pandemic.”

Ideas for potentially cutting down regulatory barriers run through the entire life cycle of a vaccine, and it begins at the very first step.

Morgan noted that when outbreaks originate in countries that ratified the Nagoya Protocol on Access and Benefit-sharing, it could take time even just to negotiate the sharing of genetic data on newly emerging pathogens because some countries have strict rules on sharing any benefits coming from the use of genetic resources — even genetic sequences. Without data on the pathogen causing an outbreak, researchers can’t get to work putting together a vaccine.

“I think what would need to be done if, for example, that 100 Days Mission was to be something that could ever be realistic, we’d need to uncouple that access from any benefits and see it under a different angle,” Morgan said.

Moving down the process, others say it would be helpful for regulators to have guidance and recommended protocols ready on clinical trial design — something the Biden administration just started working on — and decide which studies can be done a priori. As an example, Biological E’s Paradkar said data like toxicology, pharmacokinetics and vaccine stability could be generated using an existing platform even if the pathogen is still unknown.

Regulators might even consider allowing vaccine deployment before full-fledged approval and outside traditional clinical trials — but only when the pathogen is extremely dangerous and researchers are familiar with the vaccine platform being used, have already banked sufficient safety and efficacy information and are only making a slightly different vaccine. As Saville points out, that’s exactly what regulators already do with flu vaccines that are updated each year.

“If you waited for efficacy data, it will be too late,” she said.

The flexibility considerations could extend all the way down to requirements on labeling and packaging, Morgan noted. As it sought regulatory approvals in Europe, Sanofi had to go through the same serialization process on outer packaging and placing specific barcodes as normal times.

“Additional complexity in packaging lines can be complicated by multiple downstream packaging units in the context of a global pandemic where there are numerous distribution channels within and outside of the European Union,” Morgan wrote in a follow-up email. “We believe regulators should explore how this could be handled differently.”

Rethinking regulatory processes can be a delicate exercise, Saville acknowledged.

“We have to recognize that we’re not always in a crisis situation,” she said. “We’re really talking about situations where there’s a highly deadly, highly transmissible virus, where you can go at great speed, because the benefit of doing that outweighs that, you know, the devastation that would happen otherwise.”

And no matter how much flexibility, there are certain principles that should never be compromised, Borio argued — such as randomized clinical trials, even if it’s a simplified trial.

“We have to remember that it’s — we always say, oh, we could have been more flexible because this succeeded. This product is so good. We should have made this decision a long time ago,” she said. “But there are a lot of products that did not work out. And we wouldn’t have known if we hadn’t done the studies.”

Getting shots where they’re needed

Stavros Nicolaou

For Stavros Nicolaou, group senior executive of strategic trade at Aspen Pharmacare, the past two years of trying to make a Covid-19 vaccine in Africa, for Africa has been nothing short of a roller coaster.

Aspen was contracted to fill vials with J&J’s single-dose vaccine and, much to its pride, the company completed the task in six months and readied commercial production.

“We carried almost the hopes of South Africa and Africa on our shoulders, in a sense,” said Nicolaou, as those doses were originally expected to go to Africa at a time the continent struggled to secure vaccine supply.

The South African manufacturer has often been hailed as a bright example of regional manufacturing, with the idea that if manufacturers are distributed around the world rather than centered in one place, more players could physically produce the vaccines once they’re tested and ready to go — and manufacturing can take place closer to the outbreak, saving any time taken in moving vials around.

Having a globally distributed network also means countries that have less bargaining power wouldn’t be beholden to the mercy of wealthy nations or companies.

But as Aspen’s experience suggests, having a facility in place won’t be enough if it doesn’t get integrated into the broader pandemic response effort.

The first batch of drug substance that Aspen received from another J&J contractor, Emergent BioSolutions in Baltimore, turned out to be contaminated, and Aspen had to throw it out. J&J then arranged for Aspen to fill vaccines using ingredients from Leiden, Netherlands, instead — which triggered a fight between the African Union and the European Union over where the finished vaccines should belong.

Although the tension ultimately subsided, Aspen took it as a clear lesson that a contract arrangement wasn’t sufficient to guarantee vaccines. Without control over other parts of the production and distribution process, it was vulnerable to global supply chain issues and international dynamics. At the urging of African health leaders, Aspen struck a deal with J&J to officially license the vaccine, which gives it rights to brand and distribute the vaccine. Aspen named the shot Aspenovax.

“What the pandemic taught us is that solidarity goes out the window when you’re in the midst of a pandemic, and it’s each man to himself, it’s like ‘Hunger Games,’” Nicolaou said. “You cannot depend on your neighbor, or the next continent. So unless you have your own capability and capacity to produce vaccines, you will find yourself at the back end of the queue.”

And yet, Aspen has still not received a single order for Aspenovax.

A “complex set of circumstances” is in play, said Nicolaou, who’s been trotting the globe speaking at conferences and advocating for reforms in the way that organizations in charge of vaccine purchases make decisions. In the case of Covid-19, the drop in demand for vaccines is a factor, but it doesn’t fully explain the situation.

Compared to bilateral deals between one manufacturer and one country, he said, multilateral procurement is more efficient because it can achieve economics of scale; by and large, most of the procurement around the world is happening through these global agencies.

Collective purchase blocs such as COVAX — the vaccine buyer and distributor directed by CEPI, Gavi and the WHO — represent another mechanism that experts say should be in place before future pandemic strikes, in order to lessen the risk that companies are taking by developing vaccines amid significant uncertainties.

But Nicolaou noted that these agencies don’t currently have provisions for supporting local manufacturing or compelling them to buy from regional manufacturers. In a recent communiqué, a group of African leaders urged Gavi and its partners to commit to purchasing at least “30% of all vaccines produced by the continent for global consumption.”

“Unless these procurement agencies start procuring from African companies, we’re not going to sustain the capacities or the capabilities,” Nicolaou said, adding, “We have made significant investments both in capacity and personnel. You know, these are skilled people that you train over a period of time. I’m afraid if we don’t get an order, you lose a lot of that.”

Public health advocacy groups have had some progress reframing the R&D challenge not just as one of speed and efficiency, but making sure “vaccine doses get to countries and populations when they want them, in the way they want them,” as Courtney Carson, senior program officer, policy & advocacy at Pandemic Action Network put it.

“But, you know, still a lot of the proof is in the follow-through,” she said.

Following through

Despite backing by the G7 countries, CEPI has yet to raise the full $3.5 billion it sought to implement its five-year vision for the 100 Days Mission. Governments and philanthropic foundations have so far pledged only $1.5 billion toward the goal.

Courtney Carson

“We’re certainly headed back towards the neglect phase of the panic and neglect cycle, around pandemic preparedness,” Carson said, especially with competing and compounding crises including climate change, the war in Ukraine as well as economic and energy crises.

Ultimately, vaccines are part of a holistic response needed to combat pandemics, including surveillance — it took 45 days after China first reported cases of suspicious pneumonia for the WHO to declare it a public health emergency of international concern, after all — diagnostics, protective equipment as well as treatments. International cooperation depends in large part on governments and political leaders.

“Even beyond that, we shouldn’t lose sight of the need to make sure that what happens after that 100 days is also lined up and ready to go,” Anderson, of the trade group IFPMA, said. “Otherwise, we will lose time in the rollout phase.”

Still, the next time around, many more groups will have had some institutional memory — good or bad — working on a vaccine at unprecedented speed.

“This has been, in some ways, a democratizing experience,” said Dull, who organized training for a range of companies around the world about designing early-stage clinical trials for their vaccines.

One thing is certain: There will be more pandemics. And her group at CEPI, Saville said, will probably respond to outbreaks that will just disappear. Yet to her, it’s not necessarily a problem, because scientists will learn from those experiences and gather more information to help discern what is most likely to be a full-fledged pandemic.

“Some of the times we’re gonna get that wrong,” she added. “But that’s, I’m afraid, emerging infectious diseases for you.”

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