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Pfizer/BioNTech. Moderna. Johnson & Johnson. AstraZeneca.

These are the marquee names that spring to mind when you think of the vaccine companies at the forefront of the global fight against Covid-19. And for good reason: together they have manufactured the majority of the estimated 7 billion-plus Covid vaccine doses administered to date around the world.

But as regulators in the U.S., Europe, and around the world mull the most responsible way to expand vaccine eligibility to an even larger share of their populations — including to younger children, as the Food and Drug Administration (FDA) and Centers for Disease Control (CDC) have done this month by greenlighting Pfizer’s vaccine for kids 5 to 11 years of age — it’s time to confront an uncomfortable reality: The global health community still doesn’t know which of the hundreds of Covid vaccines currently in clinical and preclinical development are truly “the best.” That’s a shortcoming governments and the global health system need to address if they are to ensure that the next pandemic doesn’t knock the world on its heels to the extent the novel coronavirus has done.

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Of the 128 Covid vaccines currently being clinically tested (21 of which have been cleared for use in general populations), Pfizer, Moderna, J&J, and AstraZeneca manufacture just four, according to the latest World Health Organization (WHO) data. Russia’s Sputnik V jab is being distributed in 39 countries with dozens of other markets potentially on the horizon; Sinovac and Sinopharm, both of China, have delivered nearly half of the world’s vaccine doses to date; Bharat Biotech in India won WHO emergency use approval for its Covid shot earlier this month.

These are just a handful of the other companies with vaccines that are being given to people in many low- and middle-income countries. Another 194 candidates are in preclinical development in labs or being tested in animals.

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These companies and their products are largely unknown outside of the life sciences industry, some academic institutions, and government-backed public health centers. But just because massive, globally established pharmaceutical companies and universities have fueled the world’s vaccine supply to date doesn’t mean they have created the best ones. Other vaccines may prove to be more effective, or safer, or more appropriate for a certain coronavirus variant or among certain age groups in the coming years as the march of SARS-CoV-2, the virus that causes Covid-19, is slowed and it becomes endemic.

To be clear, I am not denigrating the safety and effectiveness of the most common and widely used Covid-19 vaccines. But as with so many other facets of public health, the pandemic has turned a glaring light on a long-festering problem: There is no unifying framework for what makes a vaccine “best.” This shortcoming inevitably leads to R&D and manufacturing imbalances down the line as dominant pharmaceutical players leverage their access to institutions and capital to leapfrog the vaccines-that-might-have-been.

The first essential step in addressing this failure is establishing a working definition of what constitutes “best” in vaccine development. Key data points to consider will include safety and effectiveness across coronavirus variants; short-, medium-, and long-term immunity; safety; and overall real-world health outcomes.

Should the level of neutralizing antibodies produced by a vaccine and their staying power be the metric by which it is judged? Should one vaccine be prioritized in certain geographic locations over another because different demographics respond to various jabs in different ways? Those questions need answers.

Randomized clinical trials, the gold standard for sniffing out effective medicines, conducted early in the development process must be paired with monitoring real-world evidence for an evolving virus, like the data being collected in the 427 ongoing observational Covid-19 studies the WHO has tracked so far. Head-to-head clinical trials that compare one vaccine directly against another have their uses as well, but don’t address the underlying dilemma of defining exactly which qualities you’re looking for in a vaccine. And with hundreds of vaccine candidates, it’s simply implausible to conduct head-to-head studies of all of them.

The focus, then, must be on ensuring that the vaccines most likely to be best are supported early. That requires a level of consensus on critical issues such as proper endpoints and goals, whether a vaccine is keeping people out of the hospital or preventing breakthrough infections, as well as more consistency in clinical trial enrollment, such as whether or not a study assesses a jab in children ages 5 to 12 rather than ages 5 to 11.

Beyond those clinical fundamentals, vaccines for Covid-19 or future infectious disease threats cannot reach their full potential without adequate investment and funding mechanisms guided by science. The vaccines that have been granted approvals or authorizations to date have been the best funded, either through government programs such as Operation Warp Speed or private funding, while other candidates have stalled for lack of access to capital that can facilitate a quick manufacturing ramp-up to meet the moment’s need.

If the same kind of global emergency were to emerge again, the system for advancing vaccine candidates currently in place would be no better — and perhaps would be even worse — without gargantuan ad hoc measures like Operation Warp Speed at play. By default, the current pandemic response has revealed a system where finance is a proxy for “best,” as if it was a betting market, rather than letting science guide resource allocation.

There is currently no set of mutually recognized guidelines by which to rationalize investment in global vaccines, even though the U.S. will accept WHO “recognition” of a vaccine as sufficient for immunized travelers wishing to come into the country. But there is no prospect of the European Union, the United Kingdom, the U.S., and countries around the world working together “next time.”

This is not a sustainable dynamic if we are to prevent, or at the very least mitigate, the public health catastrophes of tomorrow. Global health experts at the WHO and beyond had been warning that the world is fundamentally unprepared for such a calamitous event years before Covid-19 reared its head. And there has been a common theme in critiques of the existing vaccine infrastructure: There must be a mutual recognition around the world of rationalizing investment in vaccines of the future to outsmart yet-unknown pathogenic foes.

Some of the world’s leading health organizations, such as the Coalition for Epidemic Preparedness Innovations (CEPI) and think tanks such as the Peterson Institute for International Economics, have already proposed common-sense improvements to the vaccine discovery, development, and evaluation process that can also make a tangible difference in manufacturing and distributing vaccines down the line. These are “portfolio” approaches meant to take a vaccine through its full life cycle, from discovery to real-world deployment. For instance, Peterson’s Reinhilde Veugelers, a professor in the department of management, strategy, and innovation at KU Leuven in Belgium, penned a report in March on the level of public and private investment necessary for both discovering and identifying the best vaccines in future pandemics and making sure they are effectively distributed across the globe.

“Because of the high risks associated with research projects, and the high social cost of failure, we need multiple vaccine candidates and technologies simultaneously. Public resources should especially support (or at least not bias against) the early stage, riskiest projects, which offer the greatest promises for big breakthroughs. Risks can be managed by diversifying and staging grants,” she writes.

Veugelers goes on to note that this portfolio approach, which will almost inevitably mean government support for programs that will eventually fail, necessitates proactive investment at both the cheaper, early developmental stages and the far costlier long-term prospect of mass vaccine production and distribution.

GAVI, the International Vaccine Institute, and CEPI laid out concrete steps on how to make sure promising vaccines are effectively distributed in an unpredictable pandemic environment in an article in the journal Nature Medicine:

  • Standardize labeling of vaccines so they can be interchanged across countries and regions;
  • Use date of production rather than expiration so shelf life can be tracked;
  • Adopt three-dimensional bar coding to allow critical information to be updated;
  • Employ standard indemnification and liability language that provides protection for manufacturers;
  • Create no-fault compensation mechanism for serious adverse events related to vaccine administration;
  • Harmonize regulations.

Pharmaceutical innovation requires constant reinvention and the ability to adapt to shifting circumstances while carrying forth the lessons learned from previous shortcomings. The world faces a tough set of choices on how to change existing structures of pandemic preparedness and vaccine development if it is to ward off the next worldwide threat. And that conversation must begin with the acknowledgment that the status quo cannot ensure a different, better outcome in the coming years and decades.

Mike Rea is a biopharmaceutical industry and innovation expert, a senior fellow at the Milken Institute’s FasterCures center, and the CEO of IDEA Pharma and Protodigm.

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