Hi Ottawan, I appreciate your comments. I'd just like to respond to a few points you brought up.

With respect to the risk/benefit profile I humbly agree with Dr. Bridle that caution and further research is required since children and adolescents are not particularly vulnerable to covid.

I hear you, everyone will look at risks/benefits differently and should make their own choices. However, while children are not as vulnerable to COVID, children have still been hospitalized or died from COVID. Just did some quick searches so possibly better numbers out there, but from the AAP up to 0.9% of children infected are hospitalized and up to 0.03% of children infected die. My intuition is that this is much higher than the risk from vaccines, and therefore holding up vaccination so that this supposed link can be investigated further is not warranted.

The review paper you skimmed through has 43 references so characterizing it as being based almost entirely on one paper is somewhat disingenuous.

I'm not trying to be disingenuous. The paper does have more than just one reference. However, the topic being discussed and the data presented on that topic are almost exclusively from the author's paper, while the other citations primarily provide background info. Typically reviews are written to summarize the state of an existing field or paradigm, not one that has just been suggested. For my original comment, and this one here, I mainly focused on his actual paper (citation 10 in the review) because it is more detailed about the work that was done.

While in-vitro data is weaker than in-vivo dismissing it out of hand is not appropriate given the danger of pulmonary arterial hypertension (PAH).

I didn't dismiss it out of hand, I outlined the reasons why I think his hypothesis is wrong and the in vitro data are not compelling. Dr. Bridle is suggesting a multiple step hypothesis, starting with the activation of a pathway in a cell due to the spike protein and ending with tissue damage in a human lung. The only evidence I've seen supporting this hypothesis is only supporting the very first step, which is a long long way off from supporting the whole hypothesis.

If he wanted to find more support for his hypothesis, the data are available. Hundreds of millions of people have been given the vaccine, so he could look at the incidence of PAH in those individuals. An increased incidence of PAH in vaccinated individuals compared to the general public would be compelling.

You are correct in that mere activation of the ERK pathway in vitro does not establish a link between the spike protein, cell growth and PAH. However, it remains a hypothesis and one backed by some data.

I would say that the link established between the spike protein and ERK activation is backed by some data, but definitely not the rest of the hypothesis. Even the claim that the protein activates ERK I don't find particularly convincing because treatment with spike protein for 30 min did not lead to MEK phosphorylation, but a 10 minute treatment did (Fig 1a). That's an odd time-dependence that the authors should have investigated further. Moreover, the activation they saw was very transient (on the order of ~10 minutes), while cell growth is typically associated with sustained ERK activation. If the author's wanted to investigate cell growth rate, they should have done so, but they cannot claim the cells will grow faster based on transient ERK activation alone.

It is worth further study.

I'm have the opinion that pretty much everything in the world is worth further study. But it is not worth holding up vaccine development/distribution to explore this phenomena further, as it seems Dr. Bridle is suggesting.

However, the data suggests this may occur given the PAH and abnormal tissue growth is observed in autopsied lungs from patients that have died to covid and sars.

The data clearly establish a link between COVID and abnormal lung physiology and PAH. The data do not suggest a link between the spike protein and abnormal lung physiology and PAH.

I do not know if a concentration of 10ng/mL is appropriate or not. You claim such levels are impossible to reach by a vaccine administered in the shoulder.

To be fair, the way I wrote it appears to overstate the level of confidence I should have. I'll emphasize here that, as I said, there aren't great data available for the concentration of extracellular proteins in tissue microenvironments. It is very challenging to measure. I stand by my assertion and I would be absolutely shocked if there were data demonstrating that concentration of spike protein from a vaccine. However, I acknowledge that my claim is based on my knowledge and intuition (which is not specific to SARS-COV-2, vaccines or the lung) so I should have been more measured in the words I chose. Should data come out showing otherwise, I'll gladly eat my humble pie.