A New Covid Vaccine's Trial Results Need a Dose of Realism
(Bloomberg Opinion) -- The U.K. government never said publicly why it abruptly pulled plug in September on its 1.4 billion-euro ($1.98 billion) contract for a new vaccine from Valneva SE, to be manufactured at a plant in Scotland. But Monday’s news that a Phase 3 trial of the French pharmaceutical company’s vaccine compared favorably to the Oxford-AstraZeneca Plc vaccine has brought fresh questions about that decision and the role this new vaccine might play in building Covid defenses.
The official reason for terminating the deal was that Valneva breached its agreement, though no specifics were given and Valneva disputed that. Some suspected it was a casualty of Brexit-related animosities. Valneva’s shares fell 42% on the news then, and rose by as much as 46% on Monday’s trial news.
What seemed clear was that the French pharma company’s product wasn’t really needed. Its vaccine was still working through late-stage trials at the time others were already being distributed. The long lead time for Valneva’s vaccine also made it a less attractive prospect. And the U.K. had plenty of supply coming from a range of other vaccines.
So where does the Valneva entrant sit in the vaccines lineup and where does it leave the U.K.’s vaccination efforts? Some answers here from Sam Fazeli, who covers the pharmaceuticals industry for Bloomberg Intelligence.
From the headlines, this looked like a slam dunk for Valneva — not only a successful trial but successful against the main vaccine in the U.K. Its headline claim is that the Valneva vaccine produces higher levels of neutralizing antibodies versus AstraZeneca’s shot. How important is that?
Valneva's claim is absolutely right; the trial showed a 1.39-fold higher level of neutralizing antibodies than the AstraZeneca vaccine in this trial. But the real question is how this matters when it comes to vaccine effectiveness. Is Valneva's vaccine going to provide better protection against an infection, symptomatic disease or hospitalization/death?
We would be able to answer that question if we had established “neutralizing antibodies” as a correlate of protection against all those different outcomes. But though there is some evidence that suggests this, it’s not yet clear. Interestingly, there is some data that suggests that about 50% of its efficacy against symptomatic disease may be attributable to neutralizing antibodies, with the rest likely coming from the so-called “cellular arm” of the immune system — the T-cells. What we don't know is whether that is the same for other disease outcomes, so we really can't say much more than what the Valneva trial reported.
How does Valneva’s compare to the Pfizer-BioNTech and Moderna vaccines? And what can we say now about the effectiveness of vaccines on offer generally, especially against delta and its new subtypes?
So this is where it gets really interesting. We do have comparative effectiveness data for the two mRNA vaccines versus AstraZeneca's shot, showing the mRNA vaccines to be more effective when it comes to prevention of symptomatic disease, but not hospitalizations or death. We also have data from the U.K.'s Com-COV trial, showing that Pfizer-BioNTech's vaccine induced 2.33 to 3.55 times more neutralizing antibodies than AstraZeneca's shot. So the 1.39 result may not actually show any increased protection unless you studied it in a massive trial.
As regards effectiveness against other subtypes, I expect antibodies generated by Valneva's vaccine to be reasonably good at neutralizing the delta variant as the challenge is less about the ability of the virus to evade the immunity provided by vaccines and more about its high transmissibility.
The Valneva vaccine isn’t an mRNA vaccine, which targets the virus’s spike protein, but more like a normal flu vaccine in that it uses an inactivated whole virus to draw an immune response. What implications does that have for the manufacturing process?
In theory, what that means is that there is a chance that the immune system reacts to other parts of the virus than just the spike protein. But we don’t know how important those are in providing protection against disease. We need more data before we can say whether other parts of the virus contribute much to immunity.
But it is unlikely that Valneva will ever manufacture the billions of doses that producers of the mRNA vaccines (such as the Pfizer-BioNTech one) and adenoviral vaccines (such as AstraZeneca) can produce. This is partly because of the need to grow relatively large quantities of live SARS-CoV-2 virus for the vaccine. It is also likely that making new vaccines based on novel variants could take longer than what the mRNA vaccines require, which is 100 days. Lastly, the fact that the virus has to be “grown” in cell culture raises the possibility that it acquires mutations that are not representative of the original virus, and so the immune response may be misguided. This happens with the flu vaccine, where the virus “adapts” to the cells, or chicken eggs, that it is grown in.
The Phase 3 trial was around 4,000 participants. What will be required to prove an efficacy difference — or an efficacy level to compete with the leading vaccines?
We touched on this earlier. If I am right, it could require a very large trial — involving tens of thousands of participants — to prove an efficacy benefit. And it's unlikely that Valneva would want to actually do such a trial as it would cost a huge amount, especially as it would need to look at all spectrum of disease severities.
And then there is regulatory approval. How long does that take normally?
Given that we already have a fully approved vaccine in the U.S. from Pfizer-BioNTech, and Valneva's vaccine was only compared with Astra's vaccine, which is not yet approved in the U.S., regulatory filing there based on the current data is out of the question for now. Filing in U.K. and Europe and wherever else the AstraZeneca vaccine is approved is possible, however, so long as the company solves its “final assay” required by all regulators. Every batch of any drug needs to be tested to make sure it’s what the manufacturer says it is — this is much tougher for vaccines where you are putting a whole load of dead virus in and don't really know what part of the virus is doing the key job, and whether the same amount is in each batch.
You’ve noted that the German pharma company CureVac NV and France’s Sanofi SA both abandoned efforts to win approval for their first-generation vaccines. If Valneva’s does make it through to approval stage, what do you see as its target market and how do you see pricing — would this be a nice earner for the company?
I believe the target market is most likely to be developing nations that are still very short of vaccine supply. But even there, if approval does not arrive in a timely manner, large volumes of mRNA and adenoviral vaccines with known effectiveness and side-effect profiles will be available in 2022.
As regards pricing and earnings impact, it all depends on which countries buy the vaccine. If it goes to developing nations, then by definition the price will be lower than the very rough estimate of 20 euros per dose for mRNA vaccines. It is very tough to guess which developed nations would want the vaccine given that it would be, at best, used in booster programs.
So it doesn’t sound like a must-have vaccine or one that changes the picture significantly. Has the U.K. lost anything by abandoning that contract in terms of its own vaccination and booster program?
The data from “mix and match” studies all suggest that the best thing to do is to give people who had the AstraZeneca vaccine a shot of an mRNA vaccine, which in the U.K. is likely to be the Pfizer-BioNTech shot, given the size of the government’s contracts with the companies. There really is no room for the Valneva vaccine in the current third-shot rollout in the U.K. given that it is unlikely to be approved before the year’s end.
This column does not necessarily reflect the opinion of the editorial board or Bloomberg LP and its owners.
Sam Fazeli is senior pharmaceuticals analyst for Bloomberg Intelligence and director of research for EMEA.
Therese Raphael is a columnist for Bloomberg Opinion. She was editorial page editor of the Wall Street Journal Europe.
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