Aashish Dhakal
Vaccine development is a lengthy, expensive process. Attrition is high, and it typically takes multiple candidates and many years to produce a licensed vaccine. Because of the cost and high failure rates, developers typically follow a linear sequence of steps, with multiple pauses for data analysis or manufacturing-process checks. Developing a vaccine quickly requires a new pandemic paradigm, with a fast start and many steps executed in parallel before confirming a successful outcome of another step, hence resulting in elevated financial risk. For example, for platforms with experience in humans, phase 1 clinical trials may be able to proceed in parallel with testing in animal models.
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As soon as China announced that a novel coronavirus had been identified as the cause of the Wuhan outbreak, Coalition for Epidemic Preparedness Innovations (CEPI ) contacted its partners that were developing Middle East Respiratory Syndrome (MERS) vaccines or working on novel platforms. With the potential for further financial support, they and others began vaccine development as soon as the first gene sequence was posted, and development is proceeding quickly. Modern’s mRNA-based SARS-CoV-2 candidate entered a phase 1 clinical trial on March 16, less than 10 weeks after the first genetic sequences were released; the first phase 1 trial with a no replicating vector-based vaccine has regulatory clearance to start phase 1 studies in China. Other phase 1 trials of nucleic acid vaccines are expected to start in April.
For some candidates, additional clinical trial material for phase 2 studies is being manufactured now; proceeding rapidly beyond phase 2 trials means manufacturing will need to be scaled up to commercial levels before substantial safety and immunogenicity data are available. Building manufacturing capacity can cost hundreds of millions of dollars. Furthermore, for novel platform technologies, most of which are unlicensed, large-scale manufacturing has never been done, so facilities capable of producing large quantities of product must be identified, technologies transferred, and manufacturing processes adapted, all without knowing if the vaccine candidate is viable.
It’s far from certain that these new platforms will be scalable or that existing capacity can produce sufficient quantities of vaccine fast enough. It’s therefore critical that vaccines also be developed using tried-and-true methods, even if they may take longer to enter clinical trials or to result in large numbers of doses.
Conducting clinical trials during a pandemic poses additional challenges. It’s difficult to predict where and when outbreaks will occur and to prepare trial sites to coincide with vaccine readiness for testing. In addition, if multiple vaccines are ready for testing in the second half of 2020, it will be important not to crowd sites or burden countries and their ethics and regulatory authorities with multiple trials, as happened with Ebola therapeutics during the 2013–2016 outbreak.
Moreover, in a high-mortality situation, populations may not accept randomized, controlled trials with placebo groups; although other approaches that address such concerns may be scientifically feasible, they’re typically not as fast, and the results can be harder to interpret. This problem can sometimes be overcome by comparing outcomes with early vaccination versus delayed vaccination, as in the “The Ebola Phase III vaccine trial in Guinea” . One possible way forward would be to test several vaccines simultaneously in an adaptive trial design using a single, shared control group, so that more participants would receive an active vaccine. This approach has advantages but can be logistically and statistically complex, and developers often avoid trials that may generate head-to-head comparative data.
Although as many as several million vaccine doses may become available as a by-product of development, in a pandemic situation, once vaccine candidates are proved safe and effective, doses must be manufactured in large quantities. Though some high-income countries may pay for development and manufacture with their own populations in mind, there’s no global entity responsible for financing or ordering vaccine manufacture. Discussions with global stakeholders about organizing and financing large-scale vaccine manufacturing, procurement, and delivery are under way.
Finally, pandemics will generate simultaneous demand for vaccines around the world. Clinical and serologic studies will be needed to confirm which populations remain at highest risk once vaccines are available and could form the basis for establishing a globally fair vaccine-allocation system. Some Group of Seven countries have already called for such a global system, whose planning must start while vaccine development proceeds.
Though it’s unlikely, if the pandemic appears to abruptly end before vaccines are ready, we should continue developing the most promising candidates to a point at which they can be stockpiled and ready for trials and emergency authorization should an outbreak recur. A global financing system that supports end-to-end development and large-scale manufacturing and deployment, ensures fair allocation, and protects private-sector partners from significant financial losses will be a critical component of future pandemic preparedness.
