The vaccine relies on a novel technology that hasn’t been used at scale yet.
On Monday, the Associated Press reported watching the first safety tests of a vaccine against SARS-CoV-2, the coronavirus that recently spread into a global pandemic. Considering we didn’t even know the virus existed five months ago, this represents remarkable progress. But the technology that allowed such rapid development is relatively untested at the scale we’d need for a global vaccine.
How to make a vaccine quickly
Most vaccines use viruses or bacteria that are either treated so that they are unable to reproduce or damaged in a way that ensures that they reproduce very poorly. These vaccines are generally very effective, as they expose the immune systems to many of the proteins normally made by the pathogen, thereby ensuring a robust immune response. The downside, however, is that you have to be able to isolate and manipulate the bacteria or virus, and then you have to grow and purify it at scale. This means a significant amount of time is needed to build up a production stock for widespread use.
Many viruses, however, have a limited number of proteins on their surface that the immune system typically responds to. For these viruses, it’s possible to focus on the genes for these proteins, either cloning them into a harmless virus or producing large quantities of the proteins themselves. This still involves challenges with large-scale production but avoids the steps involved with isolating the pathogen and figuring out how to grow large quantities safely.
The new vaccine has been developed using an approach that simplifies matters even further, allowing development to start as soon as the genome of the virus is sequenced. And as we’ve seen, that can happen less than a month after we become aware that there’s an outbreak.
It all goes back to basic biology. Proteins are made by cells by translating the sequence of a molecule called a messenger RNA, which is typically transcribed from a gene on the organism’s chromosome. A virus directs a cell to make its proteins by creating messenger RNAs from its own genome and getting the cell’s systems to translate those into proteins.
The new approach to vaccine-making hijacks this approach. It involves making lots of copies of the messenger RNAs the virus uses to make the proteins on its surface and then packages them into a vaccine. Upon injection, these copies get inside a person’s cells and cause them to start making these viral surface proteins. Without the rest of the virus, however, these proteins are harmless. And should the actual virus come along, the person’s immune system will already have been exposed to its proteins and mount a vigorous defense.
All this can be done as soon as the sequence of the virus is available, which allows scientists to identify the genes that encode its surface proteins.
Some chemistry problems
If messenger-RNA technology were actually as simple as that description, we’d probably already be using it for vaccines. But there are a number of hurdles that make this more challenging than it seems. First, our bodies typically interpret RNA outside of cells as an indication that something’s wrong: it’s typically either an indication of a virus, or a cell that has been damaged and leaking its contents. So lots of proteins are made that efficiently break down RNA.
A second issue is that RNA molecules are highly charged, which makes it extremely difficult to get RNA molecules across the neutral, fatty membranes of a cell. The company that has developed the vaccine, Moderna, has taken a path used by a number of other companies, including CureVac, the company that the Trump administration reportedly expressed interest in purchasing. The process involves encapsulating the RNAs in tiny pouch of fat, which will protect it from the environment. At a certain rate, these pouches will fuse with the membranes of cells, placing the messenger RNAs inside the cell where they can direct the production of virus proteins.
This approach has been under testing for a while, since there are plenty of useful things you can do by getting RNAs into cells, including substituting for damaged genes or shutting harmful genes down. But these have generally gotten to the stage of small-scale testing; Moderna itself cautions that none of its vaccines have gone past Stage II clinical trials, in which the focus is on whether the vaccine elicits any kind of an immune response, rather than a careful examination of effectiveness.
This is a significant caveat to something that will need to be produced at a scale that’s appropriate for the global population. We’ve not needed to do that with messenger-RNA-based therapies before, and there will undoubtedly be some problems in scaling the technology up.
That said, it’s a testament to the flexibility of the approach that a vaccine could be made ready for small-scale production in a matter of months. And both the company and the National Institutes of Health, which assisted in its development and is running the trial, did an impressive job of getting all the requirements for a clinical trial in place on an accelerated schedule.
The trial will be run out of Seattle’s Kaiser Permanente Washington Research Institute and will focus on identifying doses that are tolerated without side effects. It will enroll 45 healthy adults between the ages of 18 and 55. At this stage of testing, there are no control groups; everyone enrolled will get the vaccine, and the test population is small enough that we’re unlikely to get valuable information on protective effects.
Phase II trials will focus on determining whether the vaccine elicits an immune response and should begin within a matter of months if there are no safety issues during Phase I. Moderna indicates it is already preparing doses for the Phase II trials, as well as ensuring it has the facilities needed to scale up production dramatically if needed.
As noted above, other companies, both in the US and elsewhere, are also developing vaccines in parallel, some of which are getting close to ready for testing. Further out, vaccines developed using more traditional methods are undoubtedly in the works.