Self-Proclaimed inventor of mRNA vaccines, Robert Malone, misrepresents an excellent vaccine study
The gist: Robert Malone is among hundreds of scientists who contributed to the effort to make mRNA vaccines possible, having done some important early experiments that helped to prove the concept. However, Malone has distinguished himself on the basis of being a prolific source of vaccine misinformation and wants more or less sole credit for the invention of mRNA vaccines as a concept, even though he had no role in the central ideas that make our current mRNA vaccines possible and continues to advocate for a different class of mRNA vaccines that has already failed clinical trials for a lack of efficacy (and it managed to cause similarly unpleasant side effects with even lower doses of mRNA than Pfizer/BioNTech and Moderna/NIH’s vaccines). Puzzlingly, Malone describes at length (falsely) why the mRNA vaccines we currently have are bad- while also claiming to have invented the concept (this always confuses me- I don’t know). Most recently, a substack post of his has gained attention describing a study that changes our understanding of how mRNA vaccines work. We had previously thought that the mRNA and antigen generated by mRNA vaccines disappeared quickly, as this is what experiments had shown. Röltgen and colleagues recently showed that this might not be true in humans, as mRNA and spike protein could both be detected even as late as 60 days after vaccination in the lymph nodes (the headquarters of the immune system for lack of a better analogy), and spike protein even briefly showed up in the blood of vaccinees (but we’ve seen that before). While that finding might sound alarming, it actually helps to explain a great deal about why the immune response to the mRNA vaccines is so excellent and why they work so well. The persistence of these antigens in the lymph node allows for antibodies to continue to evolve to cover new variants and bind to the spike protein even better, and, if it were to disappear rapidly, that process would stop. However, more important than that is the fact that this doesn’t change any of the fundamental safety data we have to date, which are extremely clear: the vaccines are safe and effective- not 100% safe, nor 100% effective (nothing is), but far, far safer than COVID-19. Always remember: mechanisms for how things work in science are stories we tell ourselves to make sense of our observations and that is very valuable- but the most important things are the observation themselves. We do not observe evidence of harm from the presence of spike proteins from mRNA vaccines alone and the fundamental question of whether or not it is worthwhile to be vaccinated is not changed by these data. The power of Röltgen and colleagues’ data is that it may one day be used to help make even better, even more effective vaccines- but it in no way reverses or challenges the safety data we already have supporting that the vaccines are safe and effective. In fact it only serves to help us understand why this is so.
Robert Malone recently posted an article on his substack that is gaining traction discussing a really excellent paper that I thoroughly enjoyed, except he misrepresents numerous parts of the paper and its findings to make things sound scary when they’re not.
Who is Robert Malone?
An abridged summary of key historical events in the development of lipid nanoparticles for mRNA delivery. Malone played a role in the highlighted discovery in 1989. He was not responsible for nucleoside modification of mRNA (2005) which is central to the effectiveness of mRNA vaccines currently available for COVID-19 and was not involved in the projects that gave rise to either the Pfizer/BioNTech or Moderna/NIH vaccines. Figure 1 from Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021). Lipid nanoparticles for mRNA delivery. Nature Reviews Materials. doi:10.1038/s41578-021-00358-0
This is probably the best question to start with, and the answer is complex, though I do promise to consider the merit of Malone’s arguments on their own basis rather than him as a person. I mention this only because I think this context is important. Malone frequently refers to himself as the inventor of mRNA vaccines, but speaking frankly, there is no definition of the term “inventor” that I am aware of under which I think Malone would qualify. Also, before going forward, I think it’s very important to clarify that no one invented mRNA. There are hypotheses around the origin of life that suggest that RNA was the first molecule that gave rise to life, which makes it, at least, billions of years old. As it happens, mRNA itself has a very convoluted history as a subject of research. The details of its discovery and the question of who deserves credit for that discovery is discussed at length here. As for mRNA vaccines, the story there is also complex.
So, what of these COVID-19 mRNA vaccines? Principally there are a few parts to the mRNA vaccines. The first part is the sequence. The sequence of SARS-CoV-2’s spike protein were uploaded in January 2020 by a Chinese team, and a team at the Vaccine Research Center at the NIH subsequently deduced how to modify that sequence to make the spike protein a better antigen, for which Jason MacLellan and colleagues are generally credited (this approach was used in multiple vaccines including Pfizer/BioNTech’s, Moderna/NIH’s, Novavax’s etc). Another aspect to the sequence is the use of modified nucleosides that prevent the innate immune system from recognizing the mRNA (if this occurred, it would suppress production of the spike protein encoded by the mRNA and therefore any ability to make a good immune response against it)- an achievement generally attributed to the efforts of Kariko, Weissman, and their collaborators. The other matter of interest is the lipid nanoparticle. The concept of the lipid nanoparticle as a delivery vehicle for mRNA dates back to 1978, predating the work at Vical which included Malone. Malone does indeed have several patents relating to nucleic acid vaccines, but, critically, the lipid nanoparticles used in the vaccines are distinct from those patented by Malone. Malone’s place in history is among the hundreds of scientists who contributed to the critical work that made mRNA vaccines possible, in part as a middle author in a publication which proposes nucleic acid vaccines as a concept (though it’s not clear to me whether or not it was the first publication to do so). This is not to say that his work was unimportant- he did carry out some key experiments. It is worth noting however that the self-proclaimed inventor of mRNA vaccines has four publications on nucleic acid vaccines indexed on Pubmed, of which a single one describes original research (the rest are reviews) and none of which describe candidates that made it into human trials. In contrast and for the sake of example, Drew Weissman, who worked alongside Katalin Kariko and essentially made the paradigm of mRNA vaccination viable (by no means alone in that effort but indulge me for a moment in this overly reductive foray), has 65 indexed publications about mRNA vaccines (to the best of my ability to tell- you can see the inputted query), most of which ARE his own original research- and yet even he does not go around proclaiming that he is the inventor of mRNA vaccines. That’s because the effort involved hundreds of scientists and no single one of them can claim to be the inventor.
Nonetheless, getting an accurate account of what his precise role was in the history of things will likely prove impossible without some kind of detailed investigation by a third party, per the Tangled History article in Nature:
Malone contends that Verma and Vical struck a back-room deal so that the relevant intellectual property went to Vical. Malone was listed as one inventor among several, but he no longer stood to profit personally from subsequent licensing deals, as he would have from any Salk-issued patents. Malone’s conclusion: “They got rich on the products of my mind.”
Verma and Felgner categorically deny Malone’s charges. “It’s complete nonsense,” Verma told Nature. The decision to drop the patent application rested with the Salk’s technology-transfer office, he says. (Verma resigned from the Salk in 2018, following allegations of sexual harassment, which he continues to deny.)
Graphical Abstract from Röltgen et al., Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination, Cell (2022), https://doi.org/10.1016/j.cell.2022.01.018
Irrespective of what Malone’s true place in history is in the matter of mRNA vaccines, nothing changes the fact that he is actively spreading disinformation about the vaccines and the paper he is currently misrepresenting on his substack is no different. Let’s dig into the study in question and compare what it finds with what Malone claims it finds.
The Paper
The paper in question (hyperlinked in the heading) is a piece of fantastic science involving many collaborators across multiple institutions and its findings are actually very well summarized in the graphical abstract which you can see at the right. Firstly, a central focus of the paper was how the immune response, specifically the antibody response, elicited by infections compared with those elicited by vaccination. What is mentioned nowhere in Malone’s substack piece is that consistently for nearly every vaccine evaluated and most prominently for the Pfizer/BioNTech vaccine, vaccination produced an antibody response that had significantly broader coverage of variants than infection did. Alpha and Delta infections outperformed the vaccines in immunity against Alpha and Delta respectively (some slight advantages against the Kappa and Epsilon variants for Delta as well), but overall the vaccines show significantly broader recognition of variants. Another key finding is that among patients who die of COVID-19, lymph nodes reveal a lack of structures called germinal centers (more on what this means shortly), while they are abundant in recipients of mRNA vaccines. Truthfully these are the most consequential findings from the paper, in my view, but the ones that will likely be of most interest to most people have to do with the finding that mRNA and spike protein are both persistent within the lymph node following vaccination, which is in contrast to prior data suggesting that this would not be the case.
There is no appreciable difference in the lifetime of mRNA based on nucleoside modifications. Figure S3b Parr, Callum J C; Wada, Shunsuke; Kotake, Kenjiro; Kameda, Shigetoshi; Matsuura, Satoshi; Sakashita, Souhei; Park, Soyoung; Sugiyama, Hiroshi; Kuang, Yi; Saito, Hirohide (2020). N 1-Methylpseudouridine substitution enhances the performance of synthetic mRNA switches in cells. Nucleic Acids Research, (), gkaa070–. doi:10.1093/nar/gkaa070
Malone initially asserts that it’s very surprising to see the spike protein and the mRNA being expressed so persistently. I agree that it’s unusual that the mRNA is found to last as long as it does. At one point I did research on riboswitches (genetic elements in bacteria that regulate their gene expression made from RNA that can sense the presence of certain metabolites) and the precautions that you have to take in handling RNA are so extensive so as to not degrade it that I actually was skeptical that mRNA vaccines as a concept could work. This is largely related to the fact that RNAses, enzymes that degrade RNA, are everywhere, including throughout the human body, probably as an antiviral defense mechanism. But Malone goes on to take things a bridge too far when he asserts that this must be due to nucleoside modification that prevents the mRNA from being degraded, citing this paper. It’s not an implausible hypothesis but the linked paper does not support this claim. In fact it directly refutes it:
We then examined the cellular degradation rate and transfection efficiency of EGFP mRNAs with different modifications and found no significant differences among the mRNAs, suggesting the enhancement does not stem from these parameters (Supplementary Figure S3B, C).
The nucleoside modification in mRNA vaccines is key to their efficacy and effectiveness. N Engl J Med 2021; 385:1436-1438
The rate of degradation of the mRNA is approximately the same irrespective of nucleoside modifications. What the paper does show is that nucleoside modified mRNA is much more efficient in inducing production of the encoded protein than unmodified RNA. When designing mRNA vaccines, there are a few key considerations about the sequences. Because mRNA within the cell can have a lifetime measured in minutes, one of the goals is to make it last as long as possible, which comes about through sequence modification meaning the RNA must have a sufficiently long poly-A tail (100-150 bases), appropriate selection of untranslated regions (UTR) for the target cell type, and should avoid complementarity to host microRNAs which can drive degradation of the mRNA. For the record, nucleoside modification is likely key to the effectiveness of current mRNA vaccines as CureVac’s vaccine used unmodified nucleosides with lackluster results (though admittedly this is not the only difference between CureVac’s platform and those of Pfizer/BioNTech and Moderna/NIH). Ironically, Malone later gives a full-throated endorsement of CureVac’s technology because (I can only infer) it is closer to the work his patents include.
Let’s unpack the significance of this persistence of spike protein and mRNA and the possible implications it has for human health. Upon discussing the spike protein, Malone offers a lengthy quote that erroneously claims:
Key properties of B-lineage cells via Figure 10.9 from Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. Boca Raton, FL: CRC Press; 2016
Initially in the course of an immune response, there is a burst of antibodies made from plasmablasts and short-lived plasma cells. The short-lived plasma cells, as their name implies, die. This results in a decline in antibody levels. A minority of cells may go on to become long-lived plasma cells. Mainly, these cells populate the bone marrow in survival niches where they receive support from a number of other cells of the immune system, but they have also been noted to survive for decades in mucosal tissues like the gut. Memory B cells can be rapidly recalled upon encountering an antigen to differentiate into antibody-secreting cells, including long-lived plasma cells, to clear infectious threats upon a re-encounter. However, unlike the plasma cells, memory B cells can adapt to give rise to clones that cover new viral variants that may have emerged since the last encounter. This forms a second wall of immunity that works in concert with constant antibody production to protect the host.
the mechanism of mRNA vaccines does not resemble that of any so-called “traditional vaccines,”
This is completely untrue. The mechanism of mRNA vaccines is actually extremely similar to that of any live attenuated vaccine such as MMR. In the case of those vaccines, live attenuated viruses encoding the antigens infect your cells and divide in them for a limited number of times and cause your own cells to make copies of viral antigens- precisely like the mRNA vaccines do. The difference is that mRNA vaccines circumvent a lot of thorny issues relating to live attenuated vaccines like the potential to revert to virulence, the inability to give them to immunocompromised people, and in the case of some of those vaccines, the potential for horizontal transmission.
the spike protein is inherently pathogenic
This is a repackaging of the claims that the spike protein is “toxic” which I have addressed before in detail here. Like other work discussed in the linked blog post, this study also finds that the spike protein may be briefly be present in the blood of vaccinees and then quickly disappears over a matter of days. This study adds that within the blood, the spike protein is covered in antibodies (at least by the time of the second dose for sure) which limit its ability to do anything we might be concerned about (indeed, even with the superantigen hypothesis for the spike protein, neutralizing antibodies do in fact protect from superantigens). Furthermore, the spike protein of the mRNA vaccines is a prefusion-stabilized spike, and thus cannot readily fuse cell membranes. This quality is proposed to directly relate to the pathogenicity of different variants of SARS-CoV-2.
incorrectly claims that antibodies against the spike protein are not very good at preventing infection or transmission
This is explicitly shown to be false with macaque models wherein high levels of antibody do in fact stop infection and therefore transmission, and in fact antibodies against spike protein are the most robustly demonstrated means to prevent infection and transmission. There is also considerable data showing the effects of mRNA vaccines in reducing transmission, even during the periods of Delta and Omicron predominance, and this is even seen in households which are high-risk for transmission because of high exposure among members in shared spaces. We actually have a great deal of insight into this matter from studies of post-vaccine infections such as this one. In truth, and the study Malone discusses does support this, the immune response elicited by mRNA vaccines is NOT waning. Memory B cells against the spike protein continue to increase even 9 months after vaccination. Why then do we see more post-vaccine infections as time after vaccination goes on? The answer is in fact in the antibodies. While antibody levels are high, through mechanisms that are not completely clear, they are able to leak into the upper respiratory tract where SARS-CoV-2 initiates infection and block it by binding to the spike protein and preventing the interaction with spike and ACE2. Over time, the short-lived plasma cells initially elicited by the response to the vaccine die off, and we become susceptible to infection once more. However, the memory B cells we gain from vaccination are prepared for variants and can be rapidly recruited in a matter of 3-4 days to fend off and substantially limit infection in concert with other key actors of the immune system like T cells. Because of this, there is a significant effort among researchers currently to develop mucosal vaccines that will generate persistent immunity in the upper airway including several candidates in advanced clinical trials. In the interim however, non-pharmaceutical interventions will continue to be necessary to help control transmission. One really interesting version of this is called “prime and spike,” which so far only has preclinical data but in that data was shown very clearly to be superior in protection from infection by SARS-CoV-2 than intramuscular mRNA vaccination alone and furthermore showed that the immune response from the mRNA vaccine could be pulled in even with a distantly related spike (in this case from SARS-CoV-1) to elicit extremely broad local mucosal protection. Another potential strategy was also recently described with an adenovirus vector encoding S1 (the top part of the spike protein), N (nucleocapsid), and RdRP (RNA-dependent RNA polymerase) administered intranasally, which also showed superior protection to an intramuscular strategy alone. Such a vaccine would depend much more on T cells for protection and interruption of transmission though rather than B cells and antibodies as the value of antibodies against N and RdRP are not established whereas the value of T cell responses against them is (here and here, for example). In the interim, booster doses can help to boost baseline antibody levels by adding to the pool of long-lived plasma cells and provide a burst of antibodies when well timed, such as right before or in the middle of a surge, wherein they can significantly help to curb transmission by reducing the chance of infection.
Malone subsequently misrepresents the data once more to claim that the authors’ note that the antibody response from mRNA vaccines favors IgG rather than IgM and IgA to mean that none are made and then misrepresents the role of each of these types of antibodies. Both IgM and IgA have roles in mucosal protection but this is not the whole story. Firstly, it is overwhelmingly secretory IgA that exerts mucosal protection, and not monomeric IgA that circulates in plasma. Increasing plasma IgA levels does NOT increase IgA in the mucosa- that IgA has to be produced by antibody-secreting cells within the lamina propria of the relevant mucosal tissue. Secondly, IgM is the first antibody isotype every B cell makes in its development and it must then undergo class switching to other isotypes (like IgG) as part of its development. Nonetheless, class switching to IgA is observed in vaccinees (and as I said, their antibodies always have to transition through an IgM stage). Per the publication:
The relative absence of IgM and IgA responses suggests a potent effect of the vaccine formulation in driving early and extensive IgG class-switching, potentially as a result of the reported T helper type 1-polarized CD4+ T cell responses stimulated by vaccine components (Lederer et al., 2020; Lindgren et al., 2017; Pardi et al., 2018).
T helper type 1-polarized CD4+ T cell responses are the type that are classically associated with effective immune responses against viruses (like SARS-CoV-2! The target of this vaccination approach) and intracellular bacteria.
We are not off to a promising start.
The cyclic re-entry model describes how we develop high affinity antibodies. See text for summary. Figure 10.11 from Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. Boca Raton, FL: CRC Press; 2016
Malone then argues that the clinical trials should have measured the spike protein expression in vaccinees blood from the start. I don’t think that’s necessarily an invalid opinion but frankly given the urgency of getting vaccines as quickly as possible, adding extra assays of unclear value to the list of things to do doesn’t seem like the best use of resources, though that was examined in preclinical data with a luciferase-encoding mRNA surrogate which showed that most of the signal from the luciferase is gone in a matter of about 9 days. This is based on data in rats given the equivalent of massive doses in comparison to humans and it is a different protein so it might not translate directly. It could be that something about spike inherently makes it last longer than luciferase but it’s hard to know for sure.
Laidlaw, B.J., Ellebedy, A.H. The germinal centre B cell response to SARS-CoV-2. Nat Rev Immunol 22, 7–18 (2022). https://doi.org/10.1038/s41577-021-00657-1
So the result is surprising, but is it bad? Immunologically, it’s actually probably very, very good. To explain why, I present: the cyclic re-entry model. The cyclic re-entry model explains how it is that we develop excellent antibody responses. In short, there is a structure within the lymph node called a germinal center, established by cells called T follicular helper cells (TFHs). It is filled with centroblasts and centrocytes (types of B cells), T follicular helper cells, and follicular dendritic cells. The germinal center is split into a light zone and a dark zone. In the dark zone, B cells will undergo a process called somatic hypermutation, wherein they rapidly mutate the DNA (completely randomly) encoding their immunoglobulin protein (antibody) resulting in random changes to binding affinity to the target antigen. From there, they will migrate into the light zone where they will test the affinity of their immunoglobulin against antigen, which is picked up by follicular dendritic cells. The authors in fact note:
Spike antigen localized in a reticular pattern around the GC cells, similar to staining for follicular dendritic cell processes (Figure 7B).
Suggesting that this spike protein is in fact being picked up by follicular dendritic cells and facilitating the germinal center reaction. B cells that bind the most tightly are able to get help from TFHs. Therein they may receive signals to differentiate into a long-lived plasma cell, memory B cell, or be sent back to the dark zone for another round of somatic hypermutation. The B cells that prove not to be good at this will die from neglect. So this is an ingenious Darwinian mechanism we have evolved to generate excellent antibodies, and it’s self-evident that the longer the process goes on for, the more high quality antibodies we will generate. But there’s a key point here: to be able to test the affinity of an immunoglobulin against antigen, you need to have antigen in the germinal center. It turns out that in some people there is evidence of antigen within the germinal center even 30 weeks later. As above, one publication has found that the memory B cell compartment specific to spike protein keeps stably expanding even 9 months after vaccination suggests it lasts even longer than that. Throughout this process, vaccinees are generating antibodies to variants that do not even exist yet, but might one day, so that we can be armed and ready for them. So, the finding of spike protein in the lymph nodes even 60 days later is not something I find concerning (I might be a bit concerned if the spikes were instead in e.g. the intestinal epithelium, but even then we have to lean on pharmacovigilance data). The finding that the mRNA persists for as long is surprising, however. Still, the mRNA is nucleoside modified to not be inflammatory (although in the lymph nodes that might not even be a bad thing) and it can’t do much on its own, so while I am surprised and impressed, I also don’t find this to be a safety concern. At most the worst thing that I can imagine happening is the mRNA inside the lymph node, outside cells, can be picked up by some cell in the lymph node (although that’s pretty unlikely because naked RNA doesn’t really just get spontaneously picked up without some delivery vehicle like a nanoparticle or a virus), make some more spike protein, and facilitate continued evolution of antibodies in the lymph node. Scott Boyd, the lead contact on the paper, is of the same opinion, as he explicitly notes on his Twitter. I would remind any readers that we can’t really prove negatives in empirical science so the best we can ever say is we do not see evidence of a phenomenon (e.g. a given safety issue). For a detailed review of the germinal center response in COVID-19 and in vaccination, this one is excellent.
Malone also takes out of context a passage describing that vaccinees had spike protein concentrations in plasma higher than those of severely ill COVID-19 patients. He also includes a quote that notes that recipients of mRNA vaccines also have antibody levels as high as those of patients with severe COVID-19 (and antibody levels against SARS-CoV-2 due to COVID-19 track with disease severity). Conceivably, this could be attributed to the dose of spike protein produced within individuals, and it ties together with some neat findings that delayed interferon and neutralizing antibody responses correlate with worse outcomes. It’s probable that among patients with severe disease, the delayed response results in essentially unimpeded replication of SARS-CoV-2 for a time until the dam therein bursts, and releases a massive flood of SARS-CoV-2 antigens, including spike. At that point the immune system scrambles and tries to address the infection with a massive response. This is also consistent with findings of genetic and acquired defects in viral sensing pathways and interferon signaling among those who have severe and fatal COVID-19. As noted by the authors of the paper however, the spike protein in the blood is transient, and unlike the vaccinees, the COVID-19 patients have… COVID-19. SARS-CoV-2 has about 30 additional proteins trying to ensure the virus’s evolutionary success and thwart the action of the immune system- the vaccine has just one and by itself it doesn’t do a good job of helping SARS-CoV-2 without the others to make function SARS-CoV-2. In this context, there isn’t an infection that urgently needs to be purged. Furthermore, the major cell type that is responsible for taking up the lipid nanoparticles seems to be the dendritic cell, which are known to have this quirk of releasing extracellular vesicles to carry out antigen presentation, and this likely accounts for the spike protein’s presence in blood. An animal study has had a similar finding and shows that these vesicles work as vaccines. This is intriguing because, in a minority of people, a mucosal antibody response against the spike protein is detected following mRNA vaccination, and this could offer up an explanation for why, but that’s speculation on my part.
Here’s the thing: at every stage of the clinical trial process, safety of the vaccines is being monitored. If you claim the spike protein is itself inherently harmful and sufficient to cause disease, the disease should be manifesting in the vaccinees. It very clearly isn’t and it wasn’t in the trial participants either. I think to some people that might seem like a cop-out response, but it really isn’t. The truth is that biological phenomena are way too complicated for us to have detailed understandings of precisely what is happening- mechanisms are the stories we write to make our observations make sense. But you know what that means? The observations (or lack thereof) are the most important thing. The reality is that across billions of doses and 2 years of clinical data, no significant safety issues for mRNA vaccines are apparent (other than myocarditis which is mostly limited to certain demographics, rare, generally self-limiting though still serious, and still does not make vaccines less safe than COVID-19; incidentally Malone has also made a number of false claims about this on Joe Rogan’s show and Science Versus has an excellent podcast episode explaining why what he says is wrong or lacks context in detail). The pharmacovigilance data will always be our most powerful tool for understanding vaccine safety. We can offer up good rationalizations of why it looks one way or another but at the end of the day, the only thing that matters is whether or not we can see a real safety issue, and we can’t. That leaves two possibilities: it doesn’t exist, or it’s too rare for us to detect, both of which are strong endorsements of the safety of mRNA vaccines. You can come up with mechanisms to make anything sound plausible (look at Malone- his substack post is full of mechanisms that sound plausible and yet they fall apart under the slightest scrutiny) but the actual outcomes data always, always, always matter most.
Coda: Imprinting
Imprinting is noted in the title of this paper and you may have heard it go under the more sinister and frankly inappropriate name “Original Antigenic Sin.” While I will discuss the matter in detail in a subsequent post (it is too complicated not to give it its own post), I think it pertinent to leave the matter to Scott Boyd, lead contact on the paper, to explain:
As a concern, imprinting is showing up a lot in the discourse after animal trials are showing that Omicron-specific mRNA vaccines do not appear to confer an advantage over mRNA vaccines encoding the ancestral spike, which some are taking to mean that the vaccines cannot effectively elicit strong anti-Omicron responses. Available human data however, suggests that this is not true. Firstly, breakthrough infection has been shown by multiple studies in humans to enhance the breadth of the immune response against Omicron as well as non-Omicron variants much more closely related to the ancestral virus. Secondly, Omicron-specific responses do show up even after the second dose of the Pfizer/BioNTech mRNA vaccine, though they do take a bit longer to appear. Over time, the antibody response against the spike protein seems to shift to different regions and it becomes more concentrated against the receptor-binding domain (RBD) where Omicron’s spike differs so substantially from that of the ancestral variant. The third dose of ancestral spike appears to shift it even further to be able to cover Omicron as well. But we will have definitive clinical trial data on the question soon enough, so in the interim, patience- and boosters for all.
