What's needed to prove a COVID-19 vaccine works—and are top players across 3 continents there yet?

In the global hunt for COVID-19 vaccines, all developers are throwing enthusiasm around about their candidates. Critics say they're too optimistic. So, what do scientists really need to demonstrate before we can call a shot effective?

It's not a short answer. Let's review the state of play.

Right now, three leading projects across three continents are catching most of the limelight. Chinese company CanSino Biologics was the first to push its adenovirus-based recombinant vaccine into phase 2 testing. Massachusetts biotech Moderna recently unveiled preliminary phase 1 data for its mRNA shot. And another adenovirus-vectored vaccine from Oxford University and AstraZeneca just nabbed $1.2 billion in funding from the U.S. government.

Having a vaccine ready as early as possible is crucial. “The first country to the finish line will be first to restore its economy and global influence,” former FDA commissioner Scott Gottlieb wrote in an article in The Wall Street Journal. However, despite the rosy picture companies—and countries—are painting, there are still hurdles ahead before any one meets the timeline of having a useable vaccine within a year and a half.

Vaccine development is a long process. After evaluation in test tubes and animals, a vaccine is tested in humans in a phase 1 trial, which is a small study that assesses safety and immune response to gauge its potential.

In a phase 2, scientists usually aim to find the optimal dosing and further understand a vaccine’s safety and immunogenicity in more healthy subjects. Given the urgency of a global pandemic, many are compressing the two phases into a continuous trial design.

Now, how have the three frontrunners been performing so far?

CanSino was first to post detailed phase 1 data in a peer-reviewed journal. According to a recent The Lancet study, the vaccine was generally well-tolerated in 108 healthy adults. All participants receiving three dosing strengths developed binding antibodies against the SARS-CoV-2’s spike protein.

More importantly, they developed neutralizing antibodies, as well as T-cell responses. While a binding antibody only binds to a specific antigen and tags it for potential destruction by other immune cells, a neutralizing antibody can keep a pathogen from infecting a cell by inhibiting its biological effects.

The problem with this vaccine? Like many gene therapies, it uses an adenovirus as a vector to carry the genetic information of the spike protein to trigger an immune response. Many people already have developed immunity against adenovirus. Theoretically, these people’s immune system can attack the vaccine's vector, dampening the effects of its protective payload.

RELATED: China's CanSino Bio advances COVID-19 vaccine into phase 2 on preliminary safety data

In the CanSino study, about half of the participants had high pre-existing neutralizing antibodies against the Ad5 vector. As the researchers noted, such adenovirus immunity “compromised” the immune response triggered by the vaccine.

Oxford University and AstraZeneca’s ChAdOx1 nCoV-19 candidate is also based on adenovirus. Results published on the BioRxiv (PDF) preprint site found that all vaccinated rhesus monkeys challenged with the coronavirus became infected, as determined by a swab test. But the researchers argue human tests are still warranted because the vaccine did ameliorate the disease. No vaccinated animals showed signs of viral pneumonia, compared to about two-thirds of unvaccinated monkeys.

On that point, a COVID-19 vaccine may resemble a flu shot. According to the CDC’s retrospective tally, seasonal flu vaccines are usually only around 30% to 40% effective at preventing infections at best, but they can help people get milder symptoms when infected.

However, as former Harvard Medical School professor William Haseltine noted in a Forbes article, levels of neutralizing antibodies in the animals appear to be low. That leads to a new question to which nobody has a definite answer right now: What kind of neutralizing antibody level is necessary to actually protect against the virus?

RELATED: It's too soon to assume success for Moderna's COVID-19 vaccine: analyst

Moderna recently said its mRNA-1273 elicited neutralizing antibodies in eight subjects “at or above” convalescent serum from people who had recovered from COVID-19. Problem is, we simply don’t know whether recovered people are protected from infection, or whether neutralizing antibody is a good marker to predict protection. For example, five sailors on the USS Theodore Roosevelt who previously appeared to have recovered later tested positive again.

“Currently, correlates of protection for a vaccine against COVID-19 are unknown, and the roles of the specific antibodies or T cells in building effective protection are not yet defined,” investigators in the CanSino vaccine study wrote in their paper.

Even if the level seen in convalescent serum is a good benchmark to draw correlations of immunity, the question remains as to how long such a response would last. Moderna said the convalescent blood was drawn “within a month or two after the disease.” But Evercore ISI analyst Umer Raffat questioned whether that’s an easier comparison. Convalescent antibodies may have hit higher levels early on and then dropped over that month or two.

Experience with two other coronaviruses, SARS and MERS, suggests that neutralizing antibodies can decline quickly in patients after recovery, whereas CD4 and CD8 T cells appeared to play an essential role in immunity, the CanSino researchers said.

For vaccines, the CanSino study team has only reported strong immune response within 28 days after vaccination and is following the vaccine recipients for at least six months to determine how that response fares over time.

The Moderna candidate and all other ongoing mRNA programs share one more uncertainty over their future: There is not a single mRNA vaccine approved anywhere in the world.

RELATED: AstraZeneca's COVID-19 vaccine enters phase 2/3 clinical trial

The questions could be answered by a large phase 3 study, in which scientists will measure infection rates directly rather than looking for clues from immune cells. But to do that, scientists need patients to be infected with the virus, so that a difference between the vaccine and a dummy shot can be determined. Ironically, that’s becoming more difficult now as strict social distancing requirements are in place and the number of new confirmed cases trends downward in many parts of the world.

“The challenge is, how do I ensure I have enough cases? If I go and vaccinate a lot of people, it doesn’t matter how many if there is no circulating virus,” Moderna’s chief medical officer, Tal Zaks, said in a conference call about the interim phase 1 results.

The Oxford-AstraZeneca program leader, Prof. Adrian Hill, expressed similar concerns. “At the moment, there’s a 50% chance that we get no result at all,” he told The Telegraph. “It’s a race against the virus disappearing,” he said.

CanSino knows all too well what that situation looks like. In 2017, the Chinese vaccine maker won domestic approval for its Ad5-based Ebola vaccine for emergency use without phase 3 data, as the filovirus quieted down in Africa.