SARS-CoV-2

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Neutralizing ground

Hopes are high for the Covid-19 molecular antibodies heading into clinical trials.

Crystal structure of SARS-CoV-2 receptor binding domain in complex with human antibody CR3022

Before, or maybe after, we get vaccinated against Covid-19, millions of us eventually may get another biologic drug for the coronavirus, made of synthesized proteins known as monoclonal antibodies (mAbs). Clinical trials are underway for many mAbs created to treat the disease, and many of these studies could yield results quicker than vaccine trials because the mAbs are given right to people who have the virus.

Some background:

We don’t yet have direct public evidence that any Covid-19 vaccine candidate works in humans. We do have evidence that the vaccines produce significant amounts of “neutralizing antibodies”—proteins churned out by immune system B cells that can slow or stop an infectious disease. In this case, the proteins bind to the SARS-CoV-2 virus’s spike protein, the molecular crowbar by which the virus enters cells.

People who survive the disease carry these neutralizing antibodies in their blood, at least for a while. That’s the mechanism behind “convalescent plasma” transplants, using blood from these recovering patients.

Convalescent plasma transplants have been widely used for more than a century for diseases that lack drugs and these transplants are generally considered safe if not necessarily effective. So in addition to the turbocharged global march toward Covid-19 vaccines for prevention, dozens of clinical studies are looking at convalescent plasma.

The jury is still out on how well this approach will work. And as with any blood transplant, the logistics are tough, the supplies are limited and each transplant will work a little differently.

But mAbs that act as neutralizing antibodies may offer a better route.

Dozens of mAb drugs have been approved, mostly for cancers. And we have an astonishing toolkit for precisely designing and testing these biological beasts, and churning them out in volume. So labs in academia and pharma have been rapidly developing Covid-19 mAbs: plucking out B cells from survivors’ blood, analyzing the antibodies these cells produce and how well they work to shut down SARS-CoV-2 infection, testing huge volumes of mAb variants, optimizing their neutralizing characteristics and coming up with the best candidates for clinical trials.

Last week in a webinar hosted by The Scientist, James Crowe of the Vanderbilt Vaccine Center and Joseph Jardine of the Scripps Institute and the International AIDS Vaccine Initiative (IAVI) outlined two round-the-clock initiatives that led to mAb candidates, described in Nature and Science.

The main goal is treating patients with Covid-19. But both groups also hope the drugs will guard other groups at high risk, such as the elderly.

Aside from maybe arriving months earlier, how will mAbs compare to vaccines in preventing Covid-19?

As with vaccines, the biggest question may be how long mAbs remain effective.

In Covid-19 patients, levels of neutralizing antibodies drop off fairly quickly. “That’s concerning; it’s not what you’d like,” says Jardine. The hope for survivors (and people who receive vaccines) is that B cells will remember the threat and ramp up production of neutralizing antibodies again if needed, which seems likely but apparently isn’t proven.

In contrast, mAbs simply don’t last indefinitely. Jardine commented that if they are suitably tuned up, these drugs might deliver protection for three to six months or so.

Crowe suggested, however, that mAbs might actually work longer than vaccines, noting that two of his group’s mAb candidates hung on surprisingly well when tested in rhesus macaques. These drugs probably also will perform well among the elderly, whose immune systems often struggle to produce suitable flows of antibodies.

Moreover, mAbs may come with fewer safety concerns. “Vaccines are pretty complicated, and they have complex safety profiles,” Crowe said. “Antibodies generally have a very high safety profile.”

Both researchers predicted that the newfound ability to quickly whip up targeted mAb drugs and test them in the clinic also may prove invaluable for other infectious illnesses.

“Antibodies increasingly will be a major part in the future of preventing and treating infectious diseases,” Crowe declared.

Jardine emphasized IAVI’s goal to bring mAb technology into lower and middle-income countries (LMICs) as well. “If we can make this viable for LMICs with Covid-19, we should be able to use it for other things like HIV,” he said.

Top, crystal structure of the business end of SARS-CoV-2 bound to a human antibody

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Herd on the street

Could previous exposure to other coronaviruses offer some protection against SARS-CoV-2?

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Talking with vaccine experts for a Knowable story, I keep hearing about the huge gaps in what we know about SARS-CoV-2. It differs from most better-known coronaviruses in many ways, among them its ugly trick of spreading from people showing no symptoms. Scientists are struggling to understand how SARS-CoV-2 immunity works, including the roles of the antibodies targeting the virus that are created by our innate immune system and of the protective cells such as T cells that are activated by the adaptive immune system.

One puzzle is why cases dropped off so quickly in some of the worst-hit areas such as Spain, since studies that measure antibodies to the virus seem to indicate that, even today, relatively low numbers of people have been infected there. That may well be  because in some of those infected the antibodies never hit expected levels and/or don’t last long, worrisome scenarios that get a great deal of attention. Another potential factor, which I first saw courtesy Mayo Clinic’s Vincent Rajkumar, is that exposure to other coronaviruses such as colds might help to defend some of us. This hypothesis is backed up by evidence in Cell, Science Immunology and elsewhere that T cells are already geared up to react specifically to SARS-CoV-2 in some probably small fraction of people who haven’t been exposed to the virus. Even if this hypothesis turns out to hold some truth it should change nothing in our defenses against the pandemic. But let’s hope for a glimmer of light here.

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What’s ‘safe enough’ for a Covid-19 vaccine?

Understanding the risks and benefits in the first lines of defense against the pandemic.

NIAID SARS CoV2

Covid-19 vaccines are being developed by the dozen.  In the best of all possible worlds, these would all be highly effective, with minimal side effects, since we need to treat people by the billions.

In the real world, in the Moderna Therapeutics phase 1 clinical trial, we know that a healthy 29-year-old fainted after receiving a second dose. He was given the highest dosage of the mRNA vaccine candidate, which has been dropped from the phase 2 trial now launching.

Infectious disease experts remain cautiously optimistic about the vaccine in lower dosages. They wish, however, that Moderna would be more transparent about its early clinical results—avoiding the mere brief upbeat press release.

“What we would have preferred to do, quite frankly, is to wait until we had the data from the entire Phase 1 — which I hear is quite similar to the data that they showed — and publish it in a reputable journal and show all the data,” National Institute of Allergy and Infectious Diseases head Anthony Fauci told STAT’s Helen Branswell.

Given that Moderna has been awarded almost half a billion dollars of federal funding for the effort, such public reporting doesn’t seem too much to ask.

As the biotech and dozens of its peers ramp up to test their various vaccines among tens of thousands of volunteers, we also want to boost the public discussion about what to expect from whichever treatments eventually are approved.

A vaccine’s effectiveness will only be reliably known once a sufficiently large number of people in the trials eventually become exposed to the virus. But my non-expert guess is that the tricky part of vaccine approvals will not be about effectiveness, given the bluntness of our other medical defenses.

Instead, the biggest issue may be safety: What’s good enough to give the billions of the rest of us?

There’s limited safety evidence from other coronaviruses; there are no approved vaccines for SARS  (severe acute respiratory syndrome) or MERS (Middle East Respiratory Syndrome). Moderna has worked on a MERS vaccine but not pushed it along into the clinic.

The company, and some of its rivals, have taken mRNA vaccine candidates for other types of viruses into phase 1 trials. Among them, a Moderna study of a Zika vaccine is underway. Additionally, the company has reported positive results for earlier studies of vaccines against pandemic avian H10N8 and H7N9 flu viruses. None of the trials, Moderna says, saw any vaccine-related serious adverse events.

But what does that tell us about covid-19 vaccines?

Maybe annual flu vaccines will give the best guidance on how we balance risks and benefits. Glancing over papers that review each flu season’s results, I was struck by how the authors focus almost exclusively on vaccine effectiveness (yes, a huge problem!) rather than safety.

Of course, that’s not because safety issues are irrelevant in flu vaccines. Instead, these issues have become well understood over the decades—and addressed by intense focus at every step of design, manufacture and delivery. The results are very low rates of risk among vaccine recipients—for example, about 1.6 cases in a million suffer anaphylactic shock.

Given months rather than decades of experience with covid-19, vaccine risks are under a particularly intense global spotlight. Moderna’s planned phase 3 trial will “very carefully look at safety, even more so than is done in a regular trial,” Fauci told STAT.

In this imperfect world, particularly with anti-vaxxers so loud, we will need an informed consensus about what will be “safe enough”.*

 

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Sending the messengers

If mRNA vaccines for Covid-19 prove themselves, manufacturers may ramp up production surprisingly quickly.

jigsaw2Speculation time: Let’s imagine that Moderna’s messenger RNA vaccine for Covid-19, already in clinical trials, is effective enough for approval. And/or the mRNA candidate from BioNTech, which might begin trials this month. And/or one of the candidates from CureVac or Translate Bio or many other groups feverishly working on mRNA vaccines.

True, no mRNA vaccine candidate has ever been generated in large numbers. So how could we scale up to the billions of doses that the world needs yesterday?

CureVac says it can manufacture millions of doses by this summer. Moderna has built an enormous, fully digital, fully operational, very impressive plant in Norwood, Massachusetts.* The other players are making suitably serious plans.

But beyond that, let’s remember that mRNA medical technology is radically different and one key difference is that it lends itself to extremely fast and flexible manufacturing. It’s built around synthesizing DNA and RNA rather than growing the infinitely idiosyncratic cells in traditional biotech factories. The bioreactor that generates the actual antiviral response is the patient’s body, so the amounts of active ingredient in an mRNA vaccine are almost unimaginably tiny.

And unlike traditional biotech factories, mRNA facilities are designed to rapidly switch between multiple products.

So: When and if one of these mRNA vaccines proves itself, is there any technical reason that all of these companies could not switch their production lines to churn out that one? **

* On April 16th 2020, the Biomedical Advanced Research and Development Authority (BARDA) announced funding up to $483 million for Moderna to ramp up. “Plans now call for producing millions of doses in the fall, tens of millions next year.”

** Sanofi plans to make the Pfizer/BioNTech mRNA vaccine, as of January 26 2021.

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Moderna’s vaccine dream machine

How a messenger RNA drug became the first novel candidate to take on the COVID-19 pandemic.

 

In the world of vaccines, this was crazy fast.

The SARS-CoV2 coronavirus was sequenced on January 7. Scientists at Moderna and the National Institute of Allergy and Infectious Diseases (NIAID) selected a vaccine target on January 13. By February 7, Moderna had a vaccine candidate. After some safety testing, on February 23 the company shipped this “mRNA-1273” vaccine to the NIAID, which is now recruiting for a first clinical trial.*

Moderna is a pioneer of messenger RNA (mRNA) drugs, designed to generate exquisitely tailored therapeutic proteins within each patient’s body.

As you recall, the central dogma of molecular biology is that DNA makes RNA that makes protein. The mRNA drug candidates created by Moderna and a few other biotechs tap into those natural steps.

Once researchers design the desired therapeutic proteins, manufacturing for an mRNA drug starts with a DNA template for those proteins. The DNA is treated with a suite of biological players to generate mRNA. Next, the mRNA is purified and put inside a lipid nanoparticle built to slip inside cells. After quality controls, you get an injectable drug. Once it’s injected, the patient’s own cells churn out proteins that attack the disease—in the case of Covid-19, by mimicking the deadly disease to alert the immune system.

No mRNA drugs have been approved, but there’s a real chance they will become that rare beast, a genuine revolution in medicine. That’s what Juan Andres, chief technical operations and quality officer, told me last summer when I visited the company’s giant facility in Norwood, Massachusetts for a Nature story on flu vaccines.

Traditional biotech drugs go after extracellular proteins, because the drugs can’t enter cells. But mRNA drugs open the possibility of producing proteins inside the cell. Moreover, unlike gene therapies, “we are not touching the DNA,” Andres said. “We are not touching the hardware of the body.”

mRNA drug manufacture and delivery are also stunningly efficient, at least in theory. You’re not using cells at all, so you don’t need the giant bioreactor vats in traditional biotech factories. In fact, the main bioreactor in the Norwood plant was roughly the size of my home’s hot-water heater.

Unusually for a biotech startup, even one as well-heeled as Moderna, the company invested heavily to achieve fully integrated production, starting with raw materials, at  Norwood. “We produce the active product ingredient, which is basically mRNA itself,” Andres said. “We formulate it, we fill into vials, we finish it, we do the quality control and we ship it into clinical sites.”

So one of Moderna’s potential manufacturing advantages is speed—especially crucial for vaccines for seasonal flu or for epidemics, where the clock is always ticking (or rather, alarms are ringing loudly). The technology also may offer other major benefits, eventually, in product quality, scalability and cost.

And mRNA drugs just may end up addressing a broad spectrum of medical need. Moderna is examining many opportunities for treatment, among them personalized cancer vaccines and localized regenerative medicine.

But the company’s most advanced programs are in preventive vaccines. So far it has chalked up positive results in phase 1 clinical trials for six vaccines, among them a cytomegalovirus vaccine combining no fewer than six mRNAs that has moved into a phase II trial.

Good safety signals from these early vaccine studies encouraged NIAID to launch the mRNA-1273 trial even before the vaccine was tested in animal studies.

It will be many months before trials can prove safety and efficacy for mRNA-1273, if indeed they do.

The desperate global need drove both quick funding for the novel vaccine from the Coalition for Epidemic Preparedness Innovations (yes, not the CDC) and the supercharged development. “There was a huge amount of motivation,” Andres commented at a Moderna online forum last week. “I have not seen this kind of energy anywhere before.”

* Volunteers received first injections on March 16.

Images courtesy Moderna.