Kristyn Feldman, Michael Le, Parul Rewari, Amit Pangasa, Cody Powers and Judith Kulich co-wrote this article with Michelle Choi.

 

Scientists across the globe are racing to develop a vaccine that could prevent further spread of a disease that has infected millions since the outbreak began in December. While vaccinating may be one of the most effective ways to slow the spread of the pandemic, vaccines have historically demonstrated slow development timelines, taking on average 10 to 15 years to develop. There is some hope, however, to believe that a COVID-19 vaccine could be developed in a record timeframe. Given the urgent need to develop a vaccine quickly, public and private institutions have engaged in a wide array of partnerships (such as Operation Warp Speed, the U.S. effort to make COVID-19 vaccines available to the public as quickly as possible), while regulators have shortened review timelines in order to hasten vaccine development.

 

A vaccine must hit a number of key milestones to successfully be administered to the general public. Investigators must first identify and test a target candidate in pre-clinical studies. Once human trials are initiated, safety and dosage are tested in earlier-stage studies before efficacy is tested in a larger sample. Investigators must design these pivotal studies so they are large enough to power the trial to demonstrate statistically significant measures of efficacy. Recruitment of volunteers for these studies must also consider how to demonstrate significant efficacy in subgroups of patients who will need the vaccine once approved, such as the elderly and pediatric populations.

 

Traditionally, these trials are conducted sequentially to mitigate risk. For COVID-19 vaccines, investigators have shortened the development timeframe by running trials in parallel, or conducting combined phase trials. In doing so, investigators may be faced with the challenge of designing larger trials with several arms to determine the appropriate dosage—including whether a booster dose is needed—and evaluate them in parallel.

 

The FDA recently issued guidance that serious adverse events should be monitored in participants for at least six months after trial completion, though it has not shared similar guidance for monitoring efficacy or for achieving emergency use authorization (EUA). However, the FDA did recently specify that a vaccine candidate should “prevent disease or decrease its severity in at least 50% of people who are vaccinated.” To demonstrate improved efficacy in a short timeframe, investigators may need to select trial sites with high infection rates, all while considering the volatility of transmission rates and how external factors such as policies regarding social distancing and travel may affect them.

 

In the case of the 2009 H1N1 pandemic, vaccine development took only six months as influenza vaccine technology had already been established at the time of the outbreak. Despite the quick development turnaround, production delays led to major shortages during the height of the pandemic. Moreover, the vaccine was contraindicated for the patients most likely to benefit from it, including children.

At least five manufacturers with advanced-stage candidates are targeting early 2021 for initial availability. Nearly all late-stage candidates are using novel virus technologies—such nucleic acid-based, viral vector-based, and recombinant protein vaccines—in efforts to develop a COVID-19 vaccine in a record timeframe. (Sinovac’s inactivated vaccine is one of the few exceptions.)

 

To meet reported timelines, each manufacturer will need to finalize trial sites, recruit about 30,000 participants for pivotal stage trials, demonstrate prevention of COVID-19 in its comparator arm, and receive EUA from the FDA—all in four to five months. While achieving such aggressive timelines is possible, it requires manufacturers to make quick decisions about next steps based on preliminary data from prior trials.

 

It’s in the interest of public health to “flatten the curve” as quickly as possible, yet the higher the infection rate around a clinical trial site, the higher the chance a vaccine can demonstrate effectiveness in a clinical trial, leading to potentially quicker vaccine approval. Given rapidly changing infection rates across geographies, manufacturers are posed with the challenge of predicting which sites will provide the fastest conditions to evaluate their vaccine candidates for the full duration of their trials. Variability across reported milestones may be therefore partially driven by differences in infection rates across clinical trial sites. For example, Oxford previously reported that depending on transmission rates at selected trial sites, it may be able to acquire enough data to understand efficacy and safety in anywhere between two to six months and be “ready to deliver" first doses as early as October. Vaccines under investigation in China and parts of Western Europe may potentially see longer timelines as case numbers have significantly dropped in those geographies.

Even while accounting for the fluctuating transmission rates, manufacturers may need to modify plans as their trials progress or new data become available. Moderna previously reported that interim efficacy data for its mRNA candidate could be available as early as Thanksgiving and a marketed vaccine could be available in early 2021. Though originally planning to initiate its pivotal trial on July 9, initiation has been delayed to later this month as a result of changes to the trial protocol. While Moderna was one of the first manufacturers to release details of its phase III trial design, these delays highlight some of the major challenges in this unprecedented and rapid development.

 

Manufacturers may also shorten development timelines through government contracts or in response to industry pressure. Johnson & Johnson, which originally planned to initiate human studies for its candidate in September, recently announced its accelerated plan to roll out its phase I/II trial in July and, pending preliminary results, begin a phase III study in September. The accelerated timeline may be a response to pressure from competing vaccines, or may be a response to being chosen as a part of Operation Warp Speed, which is aiming to achieve a 2021 milestone. This timeline, based on positive pre-clinical data and close interactions with regulatory authorities, underscores how quickly vaccine development timelines can shift.

 

The race to a vaccine for the public does not end at emergency authorization or approval: Sponsors must ensure that the appropriate infrastructure is in place for large-scale manufacturing and distribution while conducting ongoing post-approval studies. For today’s COVID-19 candidates, manufacturers will use existing infrastructure and manufacture large quantities of the vaccine at risk to avoid shortage issues like what was seen with the H1N1 vaccine in 2009. In tandem, they may need to conduct post-approval studies to test safety or efficacy in specific populations. For the pediatric population, this will be key to protecting them from the rare but concerning complications of COVID-19 being reported in this population, such as multisystem inflammatory syndrome.

 

The general public has its eyes set on the 2021 timeframe. These truncated development timelines—often with several clinical phases running simultaneously—provide hope that manufacturers can distribute a vaccine within the reported timeframes and represent a record-breaking coordination across researchers, manufacturers and regulators to quickly bring effective vaccines to the public. Although current anticipated timelines are optimistic, manufacturers may be equipped to reach this timeline by successfully achieving each of the milestones described above.