What it will take to meet CEPI’s 100-day vaccine goal for the next pandemic
A vaccine library, Coca-Cola machine-type manufacturing options, and some immunology lessons from the cancer field
A vaccine library, Coca-Cola machine-type manufacturing options, and some immunology lessons from the cancer field.
As CEPI looks to prepare for the next pandemic, it has set a lofty goal to reduce to 100 days the time from sequencing the pathogen to a regulatory submission of a vaccine. But meeting that mark will require invention of technologies that don’t yet exist, layered on top of step changes in almost all stages of the process from day one to 100.
It may also require a scientific shift in vaccinology away from the focus on neutralizing antibodies, towards a broader recruitment of the immune system, catching up with advances made in immunology that other fields, notably cancer, have already embraced.
The Coalition for Epidemic Preparedness Innovations is not waiting for this pandemic to be over before preparing for the next one. It launched a plan on March 10 to raise $3.5 billion for its five-year plan for the 100-day goal, but wants $1 billion of the sum now to expedite COVID-19 vaccine R&D for a second wave of products, in particular to battle the rise of variants of SARS-CoV-2.
CEPI will issue a request for proposals before the end of March that will focus on broadly protective strategies against betacoronaviruses.
For COVID-19, vaccine development took 314 days, from the release of the SARS-CoV-2 genetic sequence on Jan. 10, 2020 to the first submission of Phase III data on a COVID-19 vaccine for regulatory review — the Cominarty mRNA vaccine from Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX), submitted to FDA for an emergency use authorization on November 20.
The 100-day goal is predicated on a vision of a library of partially prepared vaccines against at least 25 virus family representatives, plug-and-play manufacturing with a global footprint, and international cohesion on regulatory policies that can shave time and uncertainty from the process of vaccine development.
“There needs to be a solution to fast and effective and convenient that doesn’t exist yet on the technology side.”
The success of the last year was not happenstance but was built on advances in multiple diseases and fields as well as “directed and motivated science,” said CEPI CEO Richard Hatchett, speaking at a press conference launching the plan. “10 years ago, this would have been science fiction,” said Hatchett.
According to Mathai Mammen, global head of R&D for at the Janssen Pharmaceutical Cos. unit of Johnson & Johnson (NYSE:JNJ), the future vision should involve a rapidly synthesizable, developable technology that can be handled by the world’s distribution channels. And it will take human ingenuity to solve the problems of the current platforms or come up with a new one.
“There needs to be a solution to fast and effective and convenient that doesn’t exist yet on the technology side,” Mammen told BioCentury.
The seeds of these advances are in the mRNA platforms that proved their worth in COVID-19. While there are leaps that need to be made in assay development and manufacturing, there are lessons from adjacencies such as immunology and templates from other industries that could pave a path.
The bigger challenge may not be scientific or technical but human — gaining agreement among global developers and regulators on uniform protocols and requirements to support global approval.
Melanie Saville, director of vaccine research & development at CEPI, told BioCentury CEPI thinks there’s a lot of room to expedite the process if the core components are all in place.
The idea is, “You can just come and plug in the new target and hit the ground running,” said Saville. That requires “having the infrastructure, having protocols ready for emergency use clinical trials, and really teasing out every tiny detail in terms of time that you can cut out.”
Assays and sophistication
CEPI wants to build a library of vaccines against 25 virus families most likely to pose a threat to humans, based on work from the Global Virome Project. Translating this to the 100-day goal will require a slate of preclinical assays that add both reproducibility and sophistication to the current tools.
The strategy is broadly based on an approach first described by NIH’s Barney Graham that involves selecting prototype pathogens representative of each virus family from an antigenic and mechanistic standpoint, said Rajeev Venkayya, president of the Global Vaccine Business Unit at Takeda Pharmaceutical Co. Ltd. (Tokyo:4502; NYSE:TAK), who is also a board member at CEPI.
“Once you identify that prototype pathogen, you go after it with every tool you have at your disposal to understand all of the surface proteins, all of the non-structural proteins, basically all of the potential targets that you could use for a vaccine approach,” Venkayya told BioCentury.
Graham, deputy director at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID), was unavailable for an interview.
“There will probably be a lot of innovation on the mRNA platform to understand why it doesn’t work for certain targets.”
Venkayya said the process begins by screening with monoclonal antibodies and identifying which epitopes on the surface are the most attractive, then identifying which of those antigens is capable of eliciting a set of antibodies that neutralize the virus. “Then that becomes your construct that you plug into whatever platform you're going to use, whether it's mRNA or a nanoparticle or a DNA construct in a vector vaccine,” said Venkayya.
“Then you need the ‘surround sound’ — the enabling science that is necessary to do the preclinical work to give you confidence that you have something that's actually going to work in humans,” he added, which involves creating animal models that don’t yet exist.
CEPI is developing reference standards that can be used by researchers globally to compare across different assays — a feature that hampered early COVID-19 readouts where even though manufacturers were all employing antibody neutralization assays, they used different protocols. The organization has built a centralized laboratory network for COVID-19 immunology assays that it is expanding to enable free testing for developers.
Mammen believes the vaccine field needs to expand its focus, which has been heavily concentrated on inducing neutralizing antibodies and effector CD8+ T cells. Other types of antibodies are important, he says, and vaccine developers should be looking to harness additional types of T cells that can help clear infected cells, as well as NK cells, and memory T and B cells that lead to a durable response.
“We have extremely sophisticated immunology, yet the vaccine industry measures T cell responses,” said Mammen.
In immunology broadly, and in immuno-oncology, three types of assays are routinely used that could benefit vaccine research: bespoke assays such as specialized T cell assays, single-cell sequencing, and flow cytometry. Others that are under way include proteomics and metabolomics, which he expects to become mainstream in the foreseeable future.
“Over the next 10 years we will figure out the science in order to have a protective vaccine, have higher efficacy and higher likelihood to get to a full immunological characterization of what happens when you poke someone’s arm,” said Mammen.
The current pandemic may yield useful information on how different types of immune cell responses relate to protection. Though developers of the first COVID vaccines focused on neutralizing antibodies, the vaccine pipeline holds several candidates designed to elicit broad cellular immunity.
J&J’s vaccine, COVID-19 Vaccine Janssen (Ad26.COV2.S), showed in the Phase I/IIa trial robust CD4+ responses that skewed towards type 1 helper T cells, in addition to robust CD8+ T cell responses, as reported in the NEJM.
Inovio Pharmaceuticals Inc. (NASDAQ:INO) also showed in a Phase I study that a DNA vaccine, INO-4800, can induce CD8+ and CD4+ memory T cells. And a primate study published in Nature in December showed CD8+ T cell responses can be sufficient to confer protection when antibody responses are absent.
In addition, Adaptive Biotechnologies Corp. (NASDAQ:ADPT) has produced serological tests for T cells, which Mammen called “a good sign on the commercial level that people are paying attention to both antibodies and cells.”
mRNA springboard: chemistry beats biology
There’s broad agreement that mRNA platforms, or next-generation versions, provide a solid basis for future vaccine development.
Venkayya and Mammen tie this directly to the manufacturing advantages the modality confers because of its chemistry-based synthesis.
“If you were to repeat the experiment that we did over the past year of taking multiple platforms and putting them against this target and repeat it 100 times, I believe what you’d find is that the mRNA platform would consistently perform the way it has, or close to the way it has, but you’d see very wide variability across the other platforms because of this risk that comes with the biology,” said Venkayya.
“That’s the promised land, because you can envision modular mRNA vaccine manufacturing platforms all over the world.”
Traditional vaccine approaches require growing viruses or viral antigens in culture, developing complicated assays and monitoring what’s being made, “not just the end product, but along the way,” which presents three dimensions of complexity that create a lot of risks and extend timelines, said Venkayya.
With an mRNA platform, the process parameters can be worked out ahead of time because changing the sequence is unlikely to change the dynamics of the manufacturing process.
Mammen agrees that mRNA supports faster development because “there’s no culture, you’re synthesizing with chemicals.”
He and Venkayya acknowledge that next-generation versions such as self-amplifying mRNA are likely to emerge, and that mRNA likely won’t work for all scenarios. “There are some targets where no vaccine approaches really work, like HIV, malaria is borderline, and TB — we don’t have anything. So mRNA of today is not the answer to everything,” said Venkayya. “There will probably be a lot of innovation on the mRNA platform to understand why it doesn’t work for certain targets,” he added.
Mammen also sees opportunities for innovation on the lipid nanoparticle that could make it more stable and a good adjuvant, “meaning that even in a single dose, you get a great immune response that’s not cleared so fast.”
Still, Mammen thinks the ideal format will require innovation beyond the available toolbox. He doesn’t rule out another modality coming “out of the blue,” or a process to create a protein adjuvant very fast that doesn’t require a biological process but is synthesized. “But my point is, it doesn’t exist today.”
Manufacturing meets The Real Thing
CEPI’s Saville said a core aspect of the 100-day vision is a robust manufacturing process that is easily scaled. Beyond that is the absolute requirement for access, so that populations around the world can receive the vaccines.
The extension of the 25-vaccine library is a plug-and-play manufacturing system that has pre-optimized conditions built in.
Venkayya’s analogy is the Coca-Cola machines with hundreds of different beverage combinations in a single machine. “That’s the promised land, because you can envision modular mRNA vaccine manufacturing platforms all over the world.”
“It really does open up the possibility of regional and national self-sufficiency for pandemic preparedness and immunization,” added Venkayya.
He believes there’s potential to leapfrog traditional vaccine technologies in parts of the world new to vaccine manufacturing, in particular for mRNA-based products. “It’s easier for a country that has never manufactured vaccines before to get in the game with a chemistry-based approach to vaccine manufacturing.”
The groundwork needs to be created, however. “It’s not enough to just drop a machine into a building and say you can now make vaccines.” In addition to “people and training,” he said there needs to be competent regulatory authorities, a supply chain, and the facilities need be GMP-certified.
Venkayya said the biggest risks in manufacturing he sees are in the time to transfer manufacturing processes from one facility to another as they hand off to a partner. “There’s always talk of IP being the barrier to this kind of technology transfer but it’s not. It’s that it takes time and you need scale to be able to replicate a manufacturing process.”
Another risk is that the process can be hard to replicate, which circles back to testing issue. The problem is that the vaccine itself is hard to characterize, meaning if you switch out components in the manufacturing process, this could change the efficacy or safety, which is hard to detect without additional clinical trials.
Connecting regulators and ironing out differences, in many cases nuances, is critical for the global vision CEPI is advancing.
“The idea of having a single label that can be used on a vaccine wherever they are around the world would be something that would have a huge advantage for the rollout of vaccines,” said Saville.
CEPI has a regulatory advisory group that brings global regulators together to discuss issues and look for potential solutions. According to Saville, there’s much more regulatory convergence than in the past, but there are often variations on “smaller things.”
“Regulators have different opinions as to how to do things, how to label things, that adds complexity,” said Saville.
She said that vaccine regulations are “baked into the law” of each country, or region such as with the EMA, but there are also usually emergency-use provisions that allow flexibility. The goal is to apply that flexibility to reduce duplications of processes, multiple submissions and multiple questions, all of which slow down development.
Similarly clinical trial networks need to be built throughout the world, said Saville, a point illustrated by the SARS-CoV-2 variants that are coming from different geographies. A common protocol for different regions would also speed up the timeline for development. “You’re using the same principles in that protocol, and therefore you’re collecting good quality data, irrespective of where you’re doing a trial around the world,” said Saville.
To date, CEPI has commitments of €120 million ($142.6 million) from Germany, NOK200 million ($23.3 million) from Norway and C$30 million ($24 million) from Canada. Since its founding in 2017, CEPI has garnered backing from about 30 sovereign states in addition to the European Commission, USAID, the Bill & Melinda Gates Foundation and the Wellcome Trust. Private sector entities and the UN Foundation COVID-19 Solidarity Response Fund have also supported CEPI.