Michael Yee: Hi. Thanks. Good morning. A couple of follow-up on the flu vaccines and also a PCV question for Stephen. I guess could you clarify €“ do you have a hypothesis around why these strains were not non-inferior and what the ramifications are for that, either for this flu vaccine, but also for the infection study, and what that would mean for combinations? So first of all, just to clarify what’s going on there with the B strain, the ramifications for flu vaccine? And then my second question is on PCV. Obviously, we are excited about the adjuvant data. There is also a competitor reading out in metastatic melanoma this summer, so I wanted to understand how we should compare and contrast that and if you could walk us through how to think about metastatic and what competitors might show? Thank you.
Stephen Hoge: Thank you, Michael for both questions. So, first on the flu, on the B, we are still looking into the data, and we are going to develop a more complete picture of what we think happened in the influenza B immunogenicity study. I would note a couple of things that are important. The first is these are active comparator studies. And so when you look at non-inferiority on zero conversion or titers, it’s important to note that we are going at the standard-dose influenza vaccine active comparator. And between the Phase 2 study and the Phase 3 Southern Hemisphere study, there were changes in the composition of those active comparators and the comparator use, and so that can drive some difference. The second thing I would note is that they were different populations, and so we went from a Northern Hemisphere to a Southern Hemisphere.
And obviously, that can drive some differences in background history of influenza illnesses. But the third and perhaps maybe most relevant is we did expect that the influenza B neutralizing titers were lower. As you remember, we shared with the Phase 2 data about a year ago. We did have lower neutralizing HAI titers for the influenza B strain. And for our older adult influenza vaccine, we thought that was acceptable because at the end of the day, our goal was only to achieve non-inferiority, not to demonstrate superiority. Whereas for the influenza A strains, we really wanted to maximize those neutralizing titers and potential for benefit because influenza A really is what drives the illness in older adults, which is our first generation product.
So, we did focus heavily on the influenza A. We were aiming at non-inferiority on the influenza B. And as you said, we did not make non-inferiority on those, and we will continue to pull apart the reason as to why. But we have already identified an update that would allow us to improve immunogenicity against the Bs to the extent that that is important going forward, not just in younger populations but perhaps from an overall regulatory perspective. And so we have made that update, we are actually going to be evaluating that in the clinical study very shortly here. And we expect that we will be able to address that lower immunogenicity that we saw on the Bs quite quickly. But as I said a moment ago, what really matters is efficacy and efficacy against influenza disease.
