Today will be a mixed bag of some sort, it does feel like I am playing Shin Megami Tensei. Good news, neutral news, “bad” news, not exactly bad but rather evidence we needed.
Repeated Omicron infection alleviates SARS-CoV-2 immune imprinting
The continuous emergence of highly immune evasive SARS-CoV-2 variants, like XBB.1.5 and XBB.1.16, highlights the need to update COVID-19 vaccine compositions.However, immune imprinting induced by wildtype (WT)-based vaccination would compromise the antibody response to Omicron-based boosters. Vaccination strategies that can counter immune imprinting are critically needed. In this study, we investigated the degree and dynamics of immune imprinting in mouse models and human cohorts, especially focusing on the role of repeated Omicron stimulation. Our results show that in mice, the efficacy of single Omicron-boosting is heavily limited by immune imprinting, especially when using variants antigenically distinct from WT, like XBB, while the concerning situation could be largely mitigated by a second Omicron booster. Similarly, in humans, we found that repeated Omicron infections could also alleviate WT-vaccination-induced immune imprinting and generate high neutralizing titers against XBB.1.5 and XBB.1.16 in both plasma and nasal mucosa. By isolating 781 RBD-targeting mAbs from repeated Omicron infection cohorts, we revealed that double Omicron exposure alleviates immune imprinting by generating a large proportion of highly matured and potent Omicron-specific antibodies. Importantly, epitope characterization using deep mutational scanning (DMS) showed that these Omicron-specific antibodies target distinct RBD epitopes compared to WT-induced antibodies, and the bias towards non-neutralizing epitopes observed in single Omicron exposures due to imprinting was largely restored after repeated Omicron stimulation, together leading to a substantial neutralizing epitope shift. Based on the DMS profiles, we identified evolution hotspots of XBB.1.5 RBD and demonstrated the combinations of these mutations could further boost XBB.1.5's immune-evasion capability while maintaining high ACE2 binding affinity. Our findings suggest the WT component should be abandoned when updating COVID-19 vaccine antigen compositions to XBB lineages, and those who haven't been exposed to Omicron yet should receive two updated vaccine boosters.
I recently wrote about how a lot of scientists, researchers, public health officials (and especially the ones responsible for the sorely state of mRNA technology right now) between the lines of their writings, wish and hope breakthrough infections could “overwrite” the early immune imprinting induced by primary exposure to the Wuhan Spike (virus or vaccine, but mostly pertinent to the vaccine).
As months of evidence, evidence that I covered in my Substack, demonstrated pretty early on that vaccination with the original Spike induced a profound fixation of the immune system towards the Spike Protein at the cost of proper immunity towards everything else. Authors replicate real-world observations by vaccinating mice with many of the variants that circulated since Delta using CoronaVac, and any mice previously vaccinated with the original Spike had poor neutralizing response towards the newer variants and poor response towards even boosting with the “new spike proteins”.
They also repeated these tests using mRNA and achieved similar results, demonstrating the strong imprinting from primary exposure to wild-type (Wuhan) Spike, so the first immune response still heavily affects the boosting response, the only way they could equate the immune response and somewhat circumvent the imprinting was with higher dosage and repeated vaccination with mRNA, but in their own words “although this strategy might be practical in the real world due to safety concerns”.
The next section was using groups of vaccinated and unvaccinated, and regardless of immunization status, one breakthrough infection wasn’t enough to alleviate the immune imprinting, but two (with different variants) were, my rather simplistic observation is that you need somewhat distinct variants (immunogenic distant) for the immune system to adapt and overcome the primary imprinting. Yet, unvaccinated fair better at overcoming this imprinting than the vaccinated, precisely because of how potent the Spike used in the vaccines is. Both Alpha and Delta had a very strong imprint on any person not infected to that point.
I will leave you with the closing remarks of the authors.
The degree of immune imprinting might be different between mRNA and inactivated vaccination. Recent studies have shown that subsequently exposed to Omicron twice after two doses of WT based mRNA vaccines still produce significantly low levels of Omicron-specific antibodies, despite the enhanced neutralization breadth against BQ.1.1 and XBB variants 37,38. Additionally, individuals who have received two doses of mRNA vaccines and experienced two rounds of Omicron infection also have low levels of Omicron-specific antibodies 37. This indicates that mRNA vaccines may 345 generate a stronger immune imprinting effect compared to inactivated vaccines, potentially due to its stronger primary humoral immune response . However, a head-to-head comparison is needed for validation.
This begins to put to rest some of the talking points of the other side of the conversation (the anti-this vaccine side), and also helps to explain some of the changes in the immune system of the vaccinated. Our immune system is much more complex and resilient than most give credit to.
Based on my observations and all the research (public and private) I have done, I will stand by my assertion that each infection, regardless of how “mild” the variant has become, has a cost, perhaps a minimal cost from both an immunological and physiological perspective, but long-term, repeat infections will tally up in many forms, and the secondary hits will still be never-ending dynamic.
The best approach for anyone healthy or not so much would be to supplement whatever you are comfortable with (special attention to antioxidants) after each infection. Fasting is still your best tool, and so is a low-carbohydrate diet (regardless of supplementation) for long-term health and avoiding any of the worst long-term outcomes. To my point of long-term (months to years) effects of infection, I will bring up the following Substack where we analyze and discuss the shift in the microbiome after a mild infection, with good attention towards Omicron infection, the one below is a direct “fix” to it.
The following is something I and many others suspected, a direct impact of vaccination on the gut microbiome by the vaccines, but the surprising aspect is each vaccine had a different impact, it affected different families of microbes. For the last few years, the gut microbiome has been getting increased attention from an immunization standpoint since not only it impacts your immunological response against any sort of (natural) infection, but also vaccination.
It is interesting to note the individual microbial diversity changed gradually after each dose of the ChAdOx vaccine, and a total difference between the ChAdOx and BNT (mRNA) was observed. The authors also go on to measure the impact of the microbiome on creating an immune response toward the vaccination, similar to the differences in impact, each vaccine is modulated by different microbes but there are a few “hints” on said changes. The most pertinent is the fact that each group of “higher responders” always had more abundance of microbes related to specific pathways and nutrients, of main interest, the ones responsible for tryptophan. So in a crude way, tryptophan metabolism and where its metabolic pathway finds itself inside each person dictates a portion of the entire cascade. The following paragraph is pertinent to future research.
Although riboflavin (B2), niacin (B3), and vitamin C intake may be beneficial owing to their positive correlation with bacteria enriched in high responders (the genus Romboutsia and the species Eubacterium LT907848_s and Romboutsia timonensis), these nutrients also correlated positively with bacteria enriched in low responders (M. indica). Because each nutrient can influence several bacteria differently, the effects of diet on microbiota and vaccine immunogenicity should be interpreted with caution.
Niacin is a major part of the Tryptophan metabolic pathway.
The next is another “good news” in certain ways.
Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis
I would like to add that what is described here is what I came to understand as a “subset” of patients, Long Covid (PASC) is an umbrella term for a myriad of post-infection sequelae, I think this distinction should be made clear by anyone covering the subject, but would be helpful for researchers to describe as such in some paper within this subject.
Immune Adsorption/Apheresis is “old tech” given a breath of fresh air recently since the only change was how we can now make very specific “filters” for specific proteins, worth reminding this is also a treatment for ameliorating IgG4-Related Diseases, and many other autoimmune conditions.
I can personally attest B1-AdR autoantibodies are present in some Long Covid patients, but as the cohort (group of patients) in this paper, the most common autobodies are towards the other receptors, and often the case, of fatigue, brain fog, and other symptoms have the presence of 3 of the described antibodies here.
The treatment has a perceptible improvement on all the most common biological markers for Long Covid, including the level of autoantibodies, inflammatory proteins, and ROS (oxidative stress is one of the biggest drivers of everything one can observe on Long Covid, and the persistent production of ROS creates many feedback loops). 70% of the more than 1000 people treat in many centers with similar treatment reported significant improvement of the symptoms (and people who messaged me from Germany and had the change also had improvement). The symptom amelioration can last months sometimes.
Bringing this to your attention since I know there are many people with Long Covid needing help, and this is a way for them to take steps towards recovering their health and normal life.
Something out of the scope of this research, but that provides me leeway to both comment on and write a substack about it is the latent infection aspect of it all, in regards to autoantibodies and SARS-CoV-2, it is a complex, multifaceted relationship, fairly contextual and double-edge in nature, and the underlying cause for a sizable part of many of them is latent infections, and not only that, certain common infections (both bacterial and fungal) when left uncontrolled can “aid” the development of these autoantibodies.
Since so many people ask me for my suggestions, the Substack below has a lot of my suggestions and particularly my “stack”, just use control/command+F and the words “starting point” for the suggestions. A stopgap while I work on the Short Guide for Health and Recovery, the simplified version of everything I wrote so far.
There is new important information in regards to long-term damage caused by the vaccines, but it is too depressing so I will leave for tomorrow (and search my notes for ways to remediate them besides the usual supplements I suggest).
Thank you for your support, it helps with my research efforts and time invested.
Thanks for this article. I found it easier to read too, not sure if you attempted to make your writing more simple or understandable...
Thanks for bringing to our attention the cost of multiple infections.
Wifey finally had covid at Xmas and hasnt been fully better since. SHe has had a rash on her bullybutton that antibiotics get rid of for like 2 days but then its back.
She finally got a swab from doctor and it just came back as CULTURE ++ Staphylococcus aureus +
Scanty'Streptococcus species.
Fungal infection I think.
My problem is She wont take your vitamins or fast, she thinks theyre unhealthy and put a tax on your liver etc.(she has Latent Hep B and active TB 4 years ago)
You called it JP - the fungal infections and lowered immune systems!