As coronavirus works its way through humanity, the path to normalcy becomes murkier rather than clearer. Herd immunity appears to be much more easily achieved than originally thought. At the same time, reports from a former COVID epicenter, Italy, suggest the virus may be weakening.

Absent these encouraging trends a third path, vaccine-based immunity, is a time-proven way to combat deadly infectious diseases. Many questions remain though: How effective will COVID-19 vaccines be? Vaccines against polio and other childhood diseases have saved millions of lives, but the track record for influenza vaccines is quite spotty, with effectiveness ranging year to year from around 60% to as low as 19%, with viral mutations making last year's vaccines obsolete.

How safe will a COVID-19 vaccine be, especially given the fivefold-compressed development timelines? And finally, how many doses will be required and how expensive will an effective global vaccination program be? Absent natural immunity, billions of doses may be required to achieve herd immunity. In a best-case scenario, with COVID-19 persisting for years but natural immunity dominating, global health systems will still require hundreds of millions, if not billions, of doses, even if only at-risk demographics are vaccinated.

As of July 15, 2020, more than 150 candidate vaccines for COVID-19 are currently under development and 23 are in clinical trials. Most of the companies already beyond the starting gate have one thing in common: a vaccine discovery and development platform with some degree of prior success and regulatory exposure.

“You need a plug-and-play platform or you’re not in this particular game,” says Sean Tucker, Ph.D., Chief Scientist at Vaxart, whose development platform has been employed for vaccines against influenza and norovirus.”

Vaxart’s COVID-19 vaccine has been selected for a non-human primate challenge study funded by Operation Warp Speed, a U.S. program that hopes to deliver 300 million doses of COVID-19 vaccine to Americans by January 2021. According to Vaxart, their vaccine is the only oral vaccine under Warp Speed consideration.

The vaccine consists of a non-replicating adenovirus that expresses one or more COVID-19 protein antigens. Critically, it also carries a genetic construct that instructs cells not to process the antigens as food—the vaccine target is immune system cells in the gut—but as an invading pathogen.

Oral drug delivery holds numerous advantages over injections, among them improved stability, easier formulation, and vastly less costly administration. Tucker sees the potential for mailing doses to patients, who can take the vaccine on their own schedules and without the dreaded injection. “I don’t always take the flu vaccine because I often don’t have the time. An oral vaccine that comes in an envelope or box eliminates that issue.”

Vaccine development platforms that are already familiar to regulators sidestep some toxicology testing, which for vaccines can take up to one year. The Vaxart antigen presentation method is already well characterized in both animals and humans. As Tucker explains, toxicology tracks to the vaccine platform, so formal toxicity studies of well-characterized platform-plus-antigen are often unnecessary. “Without that advantage though, you could not get into the clinic fast enough to respond to this pandemic. The question becomes how to pick the viral antigens you know very little about,” Vaxart has already demonstrated safety and effectiveness for respiratory pathogens. “We had to take guesses with COVID-19, but we weren’t completely in the dark.”

Uncertainty squared

Marianne Stanford, Ph.D., VP for R&D at vaccine and immunotherapy firm IMV, identifies three issues in developing vaccines under current pandemic conditions: the pandemic itself, scientific uncertainty, and timelines.

To those who might ask if people are still working in physical labs the answer is “yes” but with qualifications. “Developers face the need to work effectively in laboratories while following public health guidelines, for example social distancing.”

After conquering the space-and-distancing issue, developers face a serious gap in acquiring and putting into practice the type and depth of knowledge normally needed to produce and distribute a new vaccine. “It’s like flying an airplane while you’re building it, in our case running and optimizing assays as we’re designing them, and all in a knowledge vacuum,” Stanford adds. “Researchers are publishing up to four thousand papers per week on COVID-19, but in an effort to disseminate information widely and quickly much of that work is not peer-reviewed. You have to look at every result critically.”

Uncertainty also involves the virus’s natural history, how it is transmitted, and what constitutes immunity. “We have no idea what the correlate of protection for a vaccine will be,” Stanford tells Biocompare. Vaccine developers typically rely on biochemical yardsticks to quantify effectiveness. For the flu, it’s the HA antibody titer. “We don’t have that data yet for COVID-19. We assume it will likely be an antibody response but it’s unclear from previously infected patients what the levels should be.”

Compressed timelines mean that studies that normally take place sequentially occur in parallel in ways that Stanford says “have never been conceived as feasible before. We have succeeded in adapting and even thriving in that environment, but it has not been easy.”

Supply considerations

Since so much global economic activity hangs on overcoming COVID-19, potential vaccines must not only be safe and effective, they must become available while they are still relevant, that is before herd immunity kicks in. Vaccine development programs take up to 15 years. “That timeline must now be compressed to a year or two,” notes Nathalie Charland, Ph.D., Senior Director for Scientific and Medical Affairs at Medicago.

Charland echoes the significance of having a development and manufacturing platform already in place. “Everyone was expecting the next pandemic to be an influenza strain but surprise! It was a coronavirus. Regardless, our plant-based expression system allowed us to switch rapidly from flu to COVID, and produce a virus-like particle [VLP] vaccine candidate rather quickly.”

This approach has two main advantages. VLPs can never become infectious (as was the case with an early polio vaccine) because they lack the capacity to replicate. Plant-based antigen expression eliminates concerns of pathogen carryover (e.g. from adventitious viruses), and as a production platform is much simpler. Purification entails the usual unit operations of filtration, ion exchange chromatography, and other validated purifications suited to virus preparations. “Yet the process doesn’t require live viruses at any stage, only the genetic sequence of the protein we want to express,” Charland adds. The “virus-like” qualities further duplicate, to some degree, the virus’s physical presentation.

The vaccine product itself is formulated as a solution and packaged in a vial, as with most injected medicines.

Medicago began a phase 1 dose-escalating study of its vaccine candidate on July 14, and is planning a phase 2/3 trial for October. During the initial study Medicago will examine two adjuvants individually (GlaxoSmithKline’s “pandemic adjuvant” and Dynavax’s CpG 1018™). To the question of supply and availability, Medicago claims the ability to produce 100 million doses annually by the end of 2121, and up to 1 billion doses upon completion of a commercial manufacturing facility in 2023.