It’s rather uncommon that I encounter an antivaccine talking point early enough in its course that it hasn’t shown up in a post by one of the big antivaccine websites, such as the ones run by Robert F. Kennedy, Jr, Sherri Tenpenny, or Del Bigtree. This time around, this particular new antivaccine talking point seems to be mainly on Twitter. Have you heard the one about the spike protein and pulmonary hypertension? No? I’ll introduce you to it and then discuss why it’s really a stretch.
First, a few Tweets, not all from antivaxxers, as some appear to be from people worried about this claim being peddled by antivaxxers:
As an aside, actually, both the Pfizer and Moderna vaccines use mRNA that codes for the whole spike protein.
Dr. Richard Urso, it just so happens, is an ophthalmologist at Houston Eye Associates in Bellaire, Texas, who has been touting hydroxychloroquine for COVID-19. He told Fox News host Laura Ingraham last summer that he had been working with the drug for 30 years and has never had a patient with a heart issue. He’s also one of the so-called “America’s Frontline Doctors,” a group of quacks who have been promoting hydroxychloroquine to treat COVID-19 (which does not work) and continue to promote quackery. He’s also made the claim that the mRNA in the RNA-based COVID-19 vaccines (Pfizer and Moderna vaccines) can “permanently alter your DNA, a claim that requires an utter ignorance of some very basic molecular biology. So of course he’s going to peddle claims that the spike protein will cause pulmonary hypertension.
You’ll notice that all the Tweets above reference a single study about spike protein and the lung published in January. What is it with cranks taking two or three months to discover these sorts of papers? I’m reminded of the “Stanford” study that wasn’t from Stanford claiming that masks don’t work and cause harm, which was also published in January but didn’t bubble up in the COVID-19 crankosphere until the last month or two, and I’m told by readers that this study is showing up all over the place on Facebook and other social media sites, posted by antivaxxers as yet another example to claim that COVID-19 vaccines are dangerous.
So what are we dealing with. It’s a study (a brief review article/opinion piece, actually) published in Vaccines (Basel), an open access journal in the MDPI group of journals. Unsurprisingly, MDPI journals are pretty dubious, with MDPI having been listed on Beale’s list of predatory journals in 2013. It ultimately successfully appealed and was removed from the list. However, from my perspective, I have not trusted MDPI journals and would never publish in one. That doesn’t mean that this paper might not be a decent paper, but let’s just say that the chances aren’t good.
So what about the paper? It comes from two investigators, Yuichiro J. Suzuki from Georgetown University and Sergiy G. Gychka from Bogomolets National Medical University in Ukraine and is entitled SARS-CoV-2 Spike Protein Elicits Cell Signaling in Human Host Cells: Implications for Possible Consequences of COVID-19 Vaccines. Before I dive into the details, let me just say that rarely in my many years of reading scientific papers have I seen so few experiments cited in a review article do such heavy lifting to provide such weak evidence for a conclusion like the claim that the spike protein can cause pulmonary hypertension.
Before I go on, first, what’s pulmonary hypertension. I’ve been told that I sometimes assume too much knowledge on the part of the reader, forgetting that not everyone is a physician or a physiologist with sufficient knowledge to know what such a condition is. At its essence, pulmonary hypertension is high blood pressure in the lungs. The circulatory system is divided into two components, the pulmonary system, in which blood flows through the blood vessels in the lungs, picks up oxygen from the lungs, and then flows to the systemic circulation (the rest of the body) to deliver that oxygen to the tissues. The pulmonary vascular system is a much lower pressure system than the systemic circulation, which is why the right ventricle, the chamber of the heart that pumps blood through the lungs, is less muscular than the left ventricle, which pumps blood through the rest of the body. In any event, pulmonary hypertension can be caused by a number of things, including some types of congenital heart disease, connective tissue disease, coronary artery disease, high blood pressure, liver disease (cirrhosis), blood clots to the lungs, and chronic lung diseases like emphysema. The sequelae of pulmonary hypertension can be severe, including right-sided heart failure, hemorrhage in the lung, clotting, pulmonary artery dissection, and more. Let’s just say that pulmonary hypertension can be very bad.
As I’ve discussed a number of times, the mRNA-based COVID-19 vaccines use a mRNA codes for the spike protein, a very important protein in SARS-CoV-2, the coronavirus that causes COVID-19. Named because these are the proteins that give the characteristic appearance of “spikes” or “crowns” protruding from the virus, the spike protein, also called the S-protein or the S-glycoprotein because it has sugar residues attached to it, onto a receptor called ACE2. It is this binding that lets the virus get into the cell to do its virus thing and make more virus, ultimately killing the cell. The spike protein also appears to have a major role in some of the physiologic derangements associated with COVID-19. Spike protein has the following structure, borrowed from the paper.
The authors note about the current COVID-19 vaccines:
The remarkably rapid development of vaccines and therapeutics for COVID-19 in 2020 has been due to effective collaborations between governments and the private sector. On 9 November 2020, Pfizer and BioNTech announced that their mRNA-based vaccine candidate, BNT162b2, is more than 90% effective against COVID-19 . This was welcome news in that it revealed that effective vaccines may soon become available. BNT162b2 encodes the SARS-CoV-2 spike protein to elicit virus-neutralizing antibodies [9,10]. More specifically, it encodes the full-length spike protein of SARS-CoV-2 with two amino acids mutated to proline in the S2 subunit to maintain the prefusion conformation, while its sister vaccine BNT162b1 (also from Pfizer/BioNTech) encodes only the RBD of the SARS-CoV-2 spike protein, trimerized by the addition of a T4 fibritin foldon domain [9,10,11]. Clinical trials have demonstrated that neither BNT162b1  nor BNT162b12 [9,10] exhibit serious short-term adverse effects. On 10 December 2020, the results of a large clinical trial for BNT162b were published, showing that this vaccine conferred 95% protection in persons 16 years of age or older . Long-term consequences of these vaccines are, however, unknown.
Another promising vaccine, mRNA-1273 by Moderna, is also an RNA vaccine that encodes the full-length SARS-CoV-2 spike protein . Viral vector-based vaccines such as AZD1222 by AstraZeneca, which uses a non-replicating chimpanzee adenovirus vector , Ad26.COV2.S by Johnson & Johnson, a non-replicating adenovirus 26-based system , and Gam-COVID-Vac (Sputnik V) by Gamaleya Research Institute of Epidemiology and Microbiology , all express the SARS-CoV-2 spike protein. NVX-CoV2373 (Novavax), a recombinant protein-based vaccine , is also the full-length SARS-CoV-2 spike protein. These vaccines as well as many others under development [18,19,20] introduce the SARS-CoV-2 spike protein into our body, so that the production of antibodies and immunity against SARS-CoV-2 are stimulated.
So basically, different vaccine developers use slightly different versions of the spike protein, but they are all using the spike protein.
So how, you might ask, could the spike protein cause pulmonary hypertension? As I said, it’s a stretch, but let’s look at the paper. One thing you need to know (and that I’ve discussed multiple times), is that by design these vaccines don’t just keep making spike protein indefinitely. Indeed, in the case of the mRNA vaccines, even though mRNA is unstable and has a short half-life in the cell and manufacturers have chemically modified the mRNA to last longer, the production of spike protein is transient, a matter of days to weeks, not months to years or longer. Think of it this way at a very simple level: Why would the Moderna and Pfizer/BioNTech vaccines require two doses only three or four weeks apart if the vaccines kept churning out spike protein indefinitely? It’s not as though pharmaceutical companies or public health authorities would prefer vaccines that require two doses, given the number of people who might not get the second dose. “One and done” has many advantages.
Be that as it may, the authors pursue their hypothesis that the spike protein alone, without SARS-CoV-2, somehow injures cells in the lung. This is where I started to see the deception antivaxxers are pulling, and it’s very much the same as the deception pulled by that “Stanford investigator” who supposedly found that “masks don’t work.” Basically, this is not a research paper. It’s an opinion piece/brief review article that appears to summarize a small body of research.
It was found that the treatment of cultured primary human pulmonary artery smooth muscle cells (SMCs) or human pulmonary artery endothelial cells with the recombinant SARS-CoV-2 spike protein S1 subunit is sufficient to promote cell signaling without the rest of the viral components . Furthermore, our analysis of the postmortem lung tissues of patients who died of COVID-19 has determined that these patients exhibited pulmonary vascular wall thickening, a hallmark of pulmonary arterial hypertension (PAH) . Based on these results, we proposed that the SARS-CoV-2 spike protein (without the rest of the viral components) triggers cell signaling events that may promote pulmonary vascular remodeling and PAH as well as possibly other cardiovascular complications [21,22].
The first study is nothing more than a cell culture study coupled with a postmortem study of lungs first published last August, in which the authors combine observations to make the leap to speculation that spike protein alone can cause the problems seen in COVID-19. In the cell culture component, the authors treated the cells that line pulmonary arteries (pulmonary artery endothelial cells) and the smooth muscle that surrounds the endothelial cells with spike protein. Here’s what it found:
The treatment of human pulmonary artery smooth muscle cells or human pulmonary artery endothelial cells with recombinant SARS-CoV-2 spike protein S1 subunit (Val16 – Gln690) at 10 ng/ml (0.13 nM) caused an activation of MEK phosphorylation. The activation kinetics was transient with a peak at 10 min. The recombinant protein that contains only the ACE2 receptor-binding domain of the SARS-CoV-2 spike protein S1 subunit (Arg319 – Phe541), on the other hand, did not cause this activation. Consistent with the activation of cell growth signaling in lung vascular cells by the SARS-CoV-2 spike protein, pulmonary vascular walls were found to be thickened in COVID-19 patients.
This is the sort of paper that could only have been published early in the pandemic, with only four figures of its cell culture results showing a not particularly stunning finding, that the spike protein can induce a certain kind of cell signaling, MEK. I’m not going to go into detail, but it is important to know that some signaling proteins in the cell are activated to do their thing by having a phosphate group attached to them (being phosphorylated), and that activation of the signaling pathway that MEK is in causes a number of downstream functions, including cell growth and survival. In cancer, when these pathways are overactive, they can contribute to metastasis.
If you’re interested, here’s a nice little video explaining the pathway:
Basically, the finding reported is that the whole spike protein causes this signaling, and a fragment of the spike protein containing only the domain that binds to ACE2 does not. It’s an interesting result, but to leap from this observation to speculating that spike protein from vaccines might cause pulmonary hypertension years down the road is just that, quite a leap.
As for the second part of the paper, it is not at all surprising that people who die of COVID-19 would develop pulmonary hypertension and thickening of the walls of the pulmonary blood vessels. Severe COVID-19 results in acute respiratory distress syndrome (ARDS), a severe inflammatory condition that results in the lungs filling with fluid and inflammatory debris, leading to stiff lungs and impaired oxygenation and, yes, pulmonary hypertension. It’s also known now that the disease can involve the vasculature, particularly the pulmonary vasculature, with its inflammation. So it should be no surprise that those who die of the disease show signs of pulmonary hypertension on autopsy. To be fair, the authors did compare the lungs of patients who died of H1N1 influenza to those who died of COVID-19 and found that the pulmonary arteries were markedly thicker in the patients who died of COVID-19. It’s an interesting observation, but if there’s one thing that was observed early in the pandemic it’s that the ARDS caused by COVID-19 was like nothing critical care doctors had ever seen before.
That’s basically it. No, seriously. That’s it. There is no more, at least not from these authors. Sure, they do cite two other papers, one from 2005 showing that injecting mice with recombinant spike protein from SARS reduced the ACE2 expression and worsened acid-induced lung injury. The other paper is from December and reports that the full-length SARS-CoV-2 spike protein activated NF-κB (a signaling pathway I’m well familiar with) and AP-1 transcription factors as well as p38 and ERK mitogen-activated protein kinases. Again, you don’t need to know the details other than that these are survival and growth pathways, but also that this observation was not made in cells from the pulmonary vasculature, but rather from a cell line (A549) from the lungs and another (Huh7.5) from the liver. The relevance of this study to whether spike protein can cause pulmonary hypertension is questionable at best.
OK, now that’s it: One study by the authors, two observations, one involving spike protein and one involving actual viral infection, plus an old study of SARS spike protein. I say this because it needs to be emphasized that what the authors reported was in patients who died of infection with the whole virus, SARS-CoV-2. You have to separate the effects of full infection and the effect of spike protein alone, and the authors did not do this, other than as a prelude to speculation, starting thusly:
However, recent observations suggest that the SARS-CoV-2 spike protein can by itself trigger cell signaling that can lead to various biological processes. It is reasonable to assume that such events, in some cases, result in the pathogenesis of certain diseases.
Is it, though? Is it really? Again, the vaccines only produce spike protein transiently. They don’t do it in the context of a raging viral infection in which the virus is invading cells, using them to replicate, and then killing them all over the respiratory system (and in other organ systems). This doesn’t stop the authors:
Thus, it is important to consider the possibility that the SARS-CoV-2 spike protein produced by the new COVID-19 vaccines triggers cell signaling events that promote PAH, other cardiovascular complications, and/or complications in other tissues/organs in certain individuals (Figure 3). We will need to monitor carefully the long-term consequences of COVID-19 vaccines that introduce the spike protein into the human body. Furthermore, while human data on the possible long-term consequences of spike protein-based COVID-19 vaccines will not be available soon, it is imperative that appropriate experimental animal models are employed as soon as possible to ensure that the SARS-CoV-2 spike protein does not elicit any signs of the pathogenesis of PAH or any other chronic pathological conditions.
Notice how difficult to falsify this hypothesis is. The authors seem to be suggesting that the transient expression of the spike protein by existing COVID-19 vaccines over the course of, at most, six or seven weeks or so between two does of vaccine, will result in pulmonary hypertension years in the future. Again, this is not a case of spike protein circulating in the bloodstream in the context of a massive infection killing infected cells and causing a massive inflammatory reaction. It’s just spike protein being made and circulating at not very high levels compared to the local levels we would expect to see in the pulmonary vasculature.
What would we look for, though? Here are some of the symptoms of pulmonary hypertension:
- Shortness of breath (dyspnea), initially while exercising and eventually while at rest
- Dizziness or fainting spells (syncope)
- Chest pressure or pain
- Swelling (edema) in your ankles, legs and eventually in your abdomen (ascites)
- Bluish color to your lips and skin (cyanosis)
- Racing pulse or heart palpitations
So far, we have not seen a wave of these symptoms after COVID-19 vaccination. Given the transient time during which the spike protein is produced and the unlikelihood that, without a concomitant raging viral infection going on, spike protein can do much, if any, damage, I’d be willing to bet that years from now we won’t, either.
Basically, at its heart, the hypothesis that the spike protein from COVID-19 vaccines is toxic and will lead to pulmonary hypertension is implausible and has no good evidence to support it—and barely any evidence even to suggest it. It’s no wonder that antivaxxers find it very appealing, though. It very much appeals to their love of viewing vaccines as irredeemably toxic and dangerous. I’m just surprised it took them three months to pick up on this article.