CIDRAP unveils roadmap for advancing better coronavirus vaccines

Gloved hand selecting vaccine vial

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Before the COVID-19 pandemic, the warning signs for newly emerging and deadly coronaviruses were already flashing bright red. Researchers were still working on SARS-CoV studies in 2012 when the even deadlier MERS-CoV arrived on the scene in the Middle East, repeatedly jumping from camels over the years and sparking large healthcare-related outbreaks.

As scientists track the rapidly changing SARS-CoV-2 evolution, others are testing and sequencing animal samples to sift out the ones that might pose the next threat to humans. Taken together, the developments have led to a stark realization: The vaccines that worked so well to cut severe illness and death during COVID-19 aren't enough to protect people from the current virus, which has become a moving target, or the novel coronaviruses that will certainly follow.

To help jump-start the search for better vaccines, the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota today released the Coronavirus Vaccines Research and Development (R&D) Roadmap (CVR), a strategy to develop broadly protective vaccines—suitable for use in all world regions—to tackle both threats. Armed with $1 million in support from The Rockefeller Foundation and the Bill & Melinda Gates Foundation, CIDRAP pulled together an international collaboration of 50 scientists who mapped out a strategy to make the new vaccines a reality.

Michael Osterholm, PhD, MPH, CIDRAP's director and professor at the University of Minnesota, said COVID-19 taught the world a hard lesson, that it must be better prepared, and rather than waiting for a fourth coronavirus to emerge or the arrival of a dangerous SARS-CoV-2 subvariant, the time to act is now. "If we wait for the next event to happen before we act, it will be too late."

Research scientist
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CIDRAP publishes CIDRAP News, but its news service operates independently of its research and policy efforts.

A heavy lift by a driven scientific team

Bruce Gellin, MD, MPH, a CVR steering group member and chief of public health strategy at The Rockefeller Foundation, said there's an urgency to carve out what to do next. He said the push for a more broadly protective vaccine needs to be some sort of equivalent to Operation Warp Speed (OWS), a public-private partnership that accelerated the development, production, and distribution of COVID-19 vaccines in the United States.

He emphasized that an approach like OWS shows what can happen when people put their mind to it with a process that's a lot of work, but done in a metered way.

If we wait for the next event to happen before we act, it will be too late.

CIDRAP Director Michael Osterholm, PhD, MPH

The key goal is to protect people when they need it, Gellin said. Alongside making the case for urgency, the CVR clearly describes the next steps, with each goal supported by milestones and dates—details that are also useful for policymakers and funders, he added.

The grant was announced last April, and by October the group had already released a draft version for public review and comment. Osterholm said the CVR approach draws on a similar roadmap strategy CIDRAP has used for other projects, including a recent game plan for improving seasonal flu vaccines and developing a universal influenza vaccine.

For the CVR, the path has been complicated by a maze of scientific questions that still need to be answered and by the fact that scientists and policymakers who helped with the CVR are still grappling with the demands of the pandemic itself.

Osterholm said the CVR group was blessed by the level of support from the research community. "We literally had people working at all hours of the day—this was a heavy lift," he said. "We had to summarize work that had never been summarized before."

Five key topics, from bat sampling to investments

The CVR crystalizes key barriers and gaps and lays out specific steps for advancing broadly protective coronavirus vaccines. The team organized its work into five topic areas: virology, immunology, vaccinology, animal and human models for vaccine research, and policy and funding. The full 92-page report is available on CIDRAP's website, and a summary version of it was published today in Vaccine.

In a related commentary in the same issue of Vaccine, Margaret (Peggy) Hamburg, MD, former Food and Drug Administration (FDA) commissioner who serves as chair of the NTI / bio Advisory Group, and Greg Poland, MD, CVR task force member and director of the Mayo Clinic's Vaccine Research Group, wrote that the first-generation COVID-19 vaccines are safe and have done a remarkable job at preventing serious disease. There are down sides, however, including notable reactogenicity for some, short duration of protection, and technical requirements that make them difficult to deploy to remote or low-resource settings.

Hamburg and Poland said the strategy of chasing the latest subvariant and offering frequent booster shots isn't sustainable. "Next-generation vaccines may offer additional benefits such as new methods of delivery—transdermal patches, oral or intranasal vaccines—which are easy to distribute and apply, stimulate mucosal immunity, and potentially block transmission," they wrote.

The two lauded the work that public health groups, manufacturers, and scientists are already doing to advance new vaccines, but they noted that the information is typically siloed. "The CVR recognizes and capitalizes on building bridges between these various sectors and is aimed at reducing barriers and duplication and improving efficiencies," they wrote.

Next-generation vaccines may offer additional benefits such as new methods of delivery—transdermal patches, oral or intranasal vaccines—which are easy to distribute and apply, stimulate mucosal immunity, and potentially block transmission.

Margaret Hamburg, MD, and Greg Poland, MD

Failure to act now puts lives and economies at catastrophic risk, Hamburg and Poland said. "No one will do this for us; we must do it together, and the roadmap provides the action steps and timelines to get us there."

Knowledge gaps and other challenges

Developing better vaccines first depends on a better understanding of the global distribution of coronaviruses, and the CVR sets out a plan for coordinated and sustained efforts to collect them and to characterize the full range of reservoirs in wild and captive animals. The results will help scientists pick the viruses to include in broadly protective vaccines.

Linfa Wang, PhD, a member of the CVR task force and zoonotic disease scientist at Duke-NUS Medical School in Singapore, said the task is an enormous one that will require long-term commitment and international collaboration. "The coronavirus diversity in bats is so great that we even don't know how much we really know about them."

Another challenge is the rapid evolution of coronaviruses, clearly evident from the variants of concern that result from human infections and a process that also occurs in animals, he said. "It is therefore not enough to do animal surveillance for coronaviruses at one time point; longitudinal surveillance is key."

Little brown bat
University of Illinois, Steve Taylor / Flickr cc

Useful information can only come from active and transparent international collaboration, Wang said. "As the cliché says, viruses recognize no borders, and neither do bats!"

Another tough challenge spelled out in the CVR is the need to better understand the body's immunologic response to both infection and vaccination, especially to identify the factors that promote long duration and broad protection. Teasing out correlates or markers of protection will help speed the development of coronavirus vaccines that use different approaches.

"Improved understanding of the role of immune imprinting from prior infection and vaccination will be critical to advance new vaccine R&D," the group emphasized in the CVR.

Vaccine options, R&D issues

In the in-depth section about vaccines, the group tackled a range of issues, from sketching out ideal profiles of what next-generation vaccines would look like to weighing the extra complexities of developing and making a broadly protective vaccine.

Improved understanding of the role of immune imprinting from prior infection and vaccination will be critical to advance new vaccine R&D.

CVR authors

In the Vaccine summary, the CVR group raises the possibility of making a universal coronavirus that could be stockpiled and used as needed. However, they also described a "tiered approach," starting with a variant-proof SARS-CoV-2 vaccine, then working up to vaccines that protect against broader coronavirus families, starting with sarbecoviruses and working up to betacoronaviruses, then all four genera.

Also, the CVR outlines clinical trial challenges, such as how to compare vaccines with each other and the need to navigate thorny issues preexisting immunity and immunity in participants.

Given that research and development is a main theme, the CVR explores animal models, and even controlled human trials, that could help speed clinical development.

Dan Barouch, MD, PhD, a CVR task force member and professor of medicine at Harvard Medical School, said, "This was a fantastic and open collaborative process among many scientists, physicians, and stakeholders." He also directs the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center.

This was a fantastic and open collaborative process among many scientists, physicians, and stakeholders.

Dan Barouch, MD, PhD

He added that the consensus document is a blueprint on the scientific gaps that need addressing to protect against COVID-19 and future pandemics. "The challenge now will be to enact this proposed plan."

Digging into policy and financing

In the section on policy and financing, the group said a big challenge is shrinking support for large-scale vaccine investments, now that the emergency phase of the COVID-19 pandemic has mainly passed. They also identified lack of corporate incentives, uncertainty around public demand for a broadly protective vaccine, and the feasibility of expanding vaccine production capacity as other tough issues to address.

One milestone for addressing financing issues is establishing value assessments or cost-benefit analyses for the next vaccines, starting with variant-proof SARS-CoV-2 vaccines. Another is to convene a stakeholder meeting to look at strategies for building a reliable marketplace and financial model for developing and producing broadly protective coronavirus vaccines.

On April 20, the CVR team will hold a 1-hour scientific webinar that will be open to the public.

In a press release from the University of Minnesota, Gellin, who has led several federal vaccine initiatives and has been a technical advisor for groups including Gavi, the Vaccine Alliance, COVAX, and the World Health Organization, sounded an optimistic note. "Time and time again, we have seen that investment in science brings solutions. The COVID-19 pandemic galvanized the research community and advanced vaccine R&D efficiently and through broad collaborations."

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