In the race for a Covid-19 vaccine, here come the tortoises

September 25, 2020 steven

The race is not always to the swift, as the cocky hare learned in Aesop’s classic fable, “The Hare and the Tortoise.” Those handicapping the so-called competition to develop Covid-19 vaccines would do well to keep an eye on the slower runners in this pursuit.

Corporate giants Sanofi and Merck, which got a relatively late start in developing Covid-19 vaccines, may seem far behind the frontrunners. But experts say they also have such deep experience developing and testing vaccine candidates, and producing vaccine at commercial scale, that both could well close the gap considerably in the months ahead.

Each is developing two vaccines, in partnership with others.

Saad Omer, a vaccinologist and director of the Yale Institute for Global Health, noted that some companies closer to the front of the pack lack Sanofi’s competitive advantages.

Cambridge, Mass.-based Moderna, for instance, has not yet brought a vaccine through the approval process and is now attempting to produce doses of a Covid-19 vaccine at a massive scale. It estimates it should be able to make between 500 million and 1 billion doses a year — an output target that would be daunting to even a seasoned manufacturer.

“Would you rather have … a company that has done scaled-up manufacturing under strict regulations and has substantial muscle memory of doing that?” Omer wondered, speaking about the appeal of a vaccine veteran. “That gives you some reassurance.”

Robin Robinson, the former head of the Biomedical Advanced Research and Development Authority, similarly noted that Merck, with its large global footprint, has experience conducting clinical trials around the world and significant manufacturing know-how.

“They can move fast,” he said.

A vaccine being produced by Pfizer in partnership with BioNTech appears poised to be the first to produce data that will show if it protects against Covid-19 infection. Moderna appears to be a close second, followed by a vaccine being developed by University of Oxford and AstraZeneca — the study of which is still on hold in the United States because of an adverse event in Britain — and Johnson & Johnson, which started its Phase 3 trial this week. Novavax, which also has yet to bring a vaccine to market, is currently running Phase 2 trials.

Sanofi and Merck are behind this group of five. But the race for a vaccine is not a winner-take-all situation. The world is expected to need vaccines from any number of manufacturers to curb the Covid-19 pandemic, and it’s likely that some that aren’t among the first to cross the finish line will have advantages the earliest vaccines do not.

“The best outcome for us is to have several across the finish line because the global need is tremendous,” said Luciana Borio, a former acting chief scientist at the Food and Drug Administration who is now vice president at In-Q-Tel, a not-for-profit investment group.

“Speed is just one parameter. And actually in the global scheme, it’s not the most important one,” said Borio, who stressed the need for safe and effective Covid-19 vaccines.

Sanofi and Merck are both known to prefer underpromising and overdelivering.

“We’re not a flashy, you know, press-release-everyday kind of company,” said Nicholas Kartsonis, who leads infectious disease clinical research for Merck Research Laboratories.

“We tend to be more conservative for our positions because we know the complexities and the challenges, especially for making vaccines,” said John Shiver, head of vaccine R&D for Sanofi.

Shiver initially estimated that it would take “several years” to develop and license a Covid-19 vaccine during a meeting with President Trump and other vaccine manufacturers at the White House in March. Trump appeared more taken with Moderna CEO Stéphane Bancel’s projection that his company could generate clinical efficacy data for a vaccine in mere months.

Moderna, along with Pfizer and BioNTech, are making messenger-RNA vaccines, which are far quicker to develop in the early stages than some of the more established vaccine constructs. While there is hope that with that great speed, mRNA vaccines will be the answer to newly emerging diseases in future, some experts question whether the technology is ready for a prime-time debut now. Much rides on how well the vaccines stimulate the immune system and how durable that effect is.

“In terms of making billions of doses, we’re probably a little premature for that to be as cheap and available at some of the other approaches,” philanthropist Bill Gates, whose Bill and Melinda Gates Foundation funded the science behind the RNA vaccine platform, told STAT in a recent interview.

“Five to 10 years from now, if things go well for that platform, it would be the primary and perhaps even the only response that we make here. So that timing’s a bit unfortunate,” Gates said.

One of Sanofi’s Covid-19 candidates is an mRNA vaccine, which it is developing with Translate Bio, a Lexington, Mass.-based biotech that has been developing therapeutics using mRNA. The company has a decade’s worth of experience learning how to manufacture mRNA to substantial scale, Shiver said, adding the partners believe they can make between 90 million and 360 million doses of this two-dose vaccine in 2021.

“The mRNA, for example, is a very interesting technology. That’s one of the reasons why we’re also pursuing that with a partner. But there are no licensed products with mRNA. No one’s ever made hundreds of millions of doses either before,” he noted, adding the Phase 1/2 trial for this vaccine is expected to start by the end of November.

Shiver said the earliest the vaccine might be approved — if it’s proven safe and effective — would be the second half of 2021.

Sanofi’s other vaccine is being developed using the same platform the company uses to make its Flublok vaccine. That’s a plus: There’s always a greater degree of comfort and confidence on the part of regulatory agencies when a vaccine is made using a platform that they are familiar with and that has an established safety record.

(Likewise, by the time Sanofi has data on its mRNA vaccine, it may be able to benefit from the regulatory agencies’ evaluations of Moderna’s and Pfizer’s vaccines, Omer noted.)

This Sanofi vaccine, called a recombinant protein vaccine, will be used with an adjuvant — a compound that boosts the immune system’s response — made by GSK.

A Phase 1/2 clinical trial — involving 440 subjects, large for an early trial — is already underway. Shiver said the company expects to have safety and immunogenicity data by the end of December. It also expects to have 100 million doses of the vaccine made by then — should the Food and Drug Administration start to issue emergency use authorizations for Covid-19 vaccines.

Shiver said Sanofi expects to be able to produce 1 billion doses of this vaccine in 2021. The vaccine is likely to require two doses — though the company is also testing a single dose.

Another advantage: This vaccine does not need to be shipped and stored at the ultra-cold temperatures of the mRNA vaccines, which makes distribution and administration easier.

One of the Merck vaccines is also being made using a platform that regulatory agencies already know. The vaccine is made by fusing genetic material from the SARS-CoV-2 virus, which causes Covid-19, onto a livestock virus that can infect people but does not sicken them. The vesicular stomatitis virus, or VSV, backbone triggers a rapid and robust immune response — and all research on the backbone to date shows it does it with a single dose.

It’s the same platform that was used to develop Merck’s Ebola vaccine, which has shown strong results. It has “not good and not very good, but outstanding efficacy” said Robinson, the former head of BARDA.

Merck is developing this vaccine in conjunction with IAVI — the International AIDS Vaccine Initiative — which is run by former Merck chief scientist Mark Feinberg.

Kartsonis noted Merck’s Ebola vaccine worked as well in the elderly as it did in young, healthy adults. That’s not a common feature of vaccines, and if the same is true for a VSV-vectored Covid vaccine, that would be a big selling point — given the elderly are at the highest risk from SARS-2. “There may be scenarios where this is a great vaccine for the elderly or a great vaccine for certain patient populations,” Kartsonis said.

Another potential plus: IAVI is working to see if the vaccine could be given orally. A vaccine that doesn’t need to be injected “would be the crown jewel of having a vaccine for this,” Kartsonis said.

This vaccine is not yet in clinical trials, though Merck expects to start them before the end of the year. The company said it is too soon to say when Phase 3 studies — the large studies that show if a vaccine works — could take place.

The second vaccine that Merck is making — in collaboration with its newly acquired subsidiary, Austrian-based Themis BioScience — is already in clinical trials. It uses an attenuated (weakened) measles virus as a vector with which to introduce genetic material from SARS-2 to the immune system. There are no licensed vaccines using this backbone, but clinical trials of a chikungunya virus vaccine using this approach show promise.

“Timing is important. Don’t get me wrong. It’s very important. But at the end of the day where we all want is a vaccine that highly effective, highly well tolerated and safe and is as durable as it can be,” Kartsonis said.

He and Shiver both expressed the hope that multiple vaccines will work and that others are approved before their companies’ products are ready for use. But both expressed a fair amount of confidence that as the Covid-19 market establishes itself, there will be some vaccines that perform better than others.

“The race has started. But I mean, how many marathon runners do you know in mile 1 win a race?” Kartsonis asked.

With other diseases, being fourth or fifth (or sixth or seventh) to market might make pursuit of a vaccine, even if promising, financially infeasible. But the global need for Covid-19 vaccine has introduced a whole new type of calculus to these considerations, said Omer.

“It’s not necessarily that the first vaccine is the one that establishes the market share,” he said. “Because the pie is so big.”

Source link