One of the ways in which this pandemic will be looked back on as a pivot point will (almost certainly) be in the use of mRNA vaccines. It seems clear at this point that these have come through spectacularly against the coronavirus: every new study of their effects in the broad population just adds to the efficacy story, and safety concerns have been minimal. We are extremely fortunate that this is the case – never forget that. The huge amount of work that’s gone into this platform over the years paid off at just the right time for us to quickly get such therapies into human trials, and what’s more, they worked when they got there. That’s not always the case – never forget that, either. Vaccines for infectious disease have a historic two-out-of-three failure rate in the clinic (which is nonetheless the lowest such failure rate by far compared to all other drug development areas!) We had a substantial leg up on the current virus because of all the work that went into SARS and MERS, but even so we’ve seen coronavirus vaccine failures from large, well-resourced, extremely competent outfits like Merck, Sanofi, and GSK. There is a timeline in which this happened to everybody, and I’m glad I’m not living in it.
Now that we’ve seen this, though, there is naturally going to be a big push for the mRNA platform as a whole. Moderna and BioNTech are of course good companies to watch for such developments. The first of these will surely be continued targeting in immunology. That’s because systemic mRNA dosing is still a real problem – you get far more effect if you can use the technology to leverage the power of the immune system, which is just what a vaccine does, rather than try to soak the whole body in it as a therapy all its own. I wrote here about some recent BioNTech work directed at multiple sclerosis, so today let’s see what Moderna is up to.
The weeds are not growing up around them, that seems clear. This press release updates several long-running efforts of theirs, and you can see the effect of a big infusion of money, capacity, and clinical confidence. Their first update is on mRNA-1345, a vaccine candidate for RSV (respiratory syncytial virus). That one is of special concern in infants and also in the elderly, and there is as yet no vaccine. That’s not really for lack of trying – people have been working on such candidates for many years, but it’s a challenge. This 2020 review estimates that there are 38 candidate vaccines in development (!), and it is clear that (a) not all of these are going to work in the first place, or surely not to the same degree, and (b) the market will end up dominated by whichever of these many candidates can truly stand out in efficacy, ease of administration, and safety.
Moderna is obviously betting that theirs can. They’ve had previous swings at this target (mRNA-1777), but the Phase I data they’re presenting now indicate that the 1345 vaccine leads to much higher levels of neutralizing antibodies, with no safety concerns yet. The fifty-microgram dose seems just as good as the 100-microgram one, so far. This is just a first look in a small number of young adult patients, and there are many more groups being tested, but so far, so good. As with all vaccines and all drug candidates, Phase II is where the bat will make contact with the ball (or not!), and that efficacy data is still some time in the future. There will likely be other RSV candidates before various regulatory authorities (or even approved) by the time Moderna is ready to make its case, and the story will also be how well their candidate compares.
The release also updates data on their cytomegalovirus vaccine (mRNA-1647). CMV is quite common – over half of adults in the US have already been infected, most of them without much incident. The big concerns are pregnant women and immunocompromised adults (especially organ transplant recipients) for which the infection can mean real trouble. This is another area where vaccine work has been going on for a long time, and there are some significant challenges. CMV is a huge virus, and codes for over two hundred proteins, a ridiculously large number by viral standards. Which of those are the best candidates as vaccine antigens, and how are you sure about that? Right.
Moderna’s candidate actually was the first mRNA vaccine candidate to go into a human Phase II – it made it in just as the pandemic was gathering earlier last year. The interim data show a strong neutralizing antibody response, and the company is moving on with one of the doses (100 micrograms) to a Phase III study in women 18-40. That one will produce preventative data, obviously the key for the whole effort.
The company also has a longrunning flu vaccine program, and that’s a tough place to work in. The existing vaccines hover around 50% efficacy – far better than nothing, but plenty of room for improvement – and the influenza viruses themselves are notoriously good at rearranging their surface proteins season by season. As an aside, we should be very, very happy that the coronavirus does not have these abilities (and no, it’s not going to acquire them suddenly – they’re built differently from the start). One real advantage of the mRNA platform would be shorter lead times for vaccine production. If the damn flu is going to change every time around, which it is, we’d be better off tracking the strains in closer to real time to match vaccine antigens. The Moderna press release says that they heading into Phase I with “multiple candidates”, and they they hope to come up with combination vaccines against flu, SARS-CoV-2, RSV and human metapneumovirus (hMPV) all at once. This is a very worthy goal, but it’s obviously going to take a while.
Finally, Moderna has also had a longtime interest in the HIV vaccine field, and if you want to pick a tough area to work in, that’s the place to be. As the world knows, decades of work have yet to yield a useful vaccine in this area. But over the past thirty years, a great deal of effort has identified several broadly-neutralizing antibody types, featuring rare but powerful binding modes that remain active across many different viral strains. Moderna is going into a range of Phase I trials around their candidate mRNA-1644, partnered with the International AIDS Vaccine Initiative (IAVI) and the Gates Foundation. IAVI and Scripps recently saw good results with the induction of such broadly-neutralizing antibodies, and the hope is that mRNA-1644 can be optimized even past that. This is going to also take a while, but overall the bNAb approach is the most promising HIV vaccine news around. Moderna has another approach being developed with the NIH, mRNA-1574, a multiple-antigen vaccine that will also be moving into Phase I this year.
That’s a lot of trials! I’m glad to see the company moving so quickly and aggressively. They’re clearly putting the money and momentum from the coronavirus vaccine work to good use. And remember, this is just the clinical trial end of things, the tip of the spear, and there is surely a good deal going on preclinically that we’re not hearing about. I wish them, BioNTech, and all the other mRNA immunology developers every success. The acceleration of work in this area is one of the few real silver linings of the pandemic.