Serial infection after 3 vaccines. Intertefron gamma and MIS-C

sAgs, son !

Good afternoon/night, I hope the readers had a very good weekend, and wish you an entire good week. To avoid sending multiple e-mails per day I will cover a couple of papers in this post, and since they fit in posts covered before, they will be shorter in nature. To start, a very interesting paper.

Serial infection with SARS-CoV-2 Omicron BA.1 and BA.2 following three-dose COVID-19 vaccination

SARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have documented serial Omicron infections. We characterized SARS-CoV-2 humoral responses in a healthy young person who acquired laboratory-confirmed Omicron BA.1.15 ten weeks after a third dose of BNT162b2, and BA.2 thirteen weeks later. Responses were compared to those of 124 COVID-19 naive vaccinees. One month after the second and third vaccine doses, the participant's wild-type and BA.1-specific IgG, ACE2 competition and virus neutralization activities were average for a COVID-19 naive triple-vaccinated individual. BA.1 infection boosted the participant’s responses to the cohort ≥95th percentile, but even this strong "hybrid" immunity failed to protect against BA.2. Moreover, reinfection increased BA.1 and BA.2-specific responses only modestly. Results illustrate the risk of Omicron infection in fully vaccinated individuals and highlight the importance of personal and public health measures as vaccine-induced immune responses wane.

Responses were compared to those of 124 COVID78 19-naive vaccinees over the same period. Taken together with existing literature, our results suggest that vaccination provides limited protection against infection and/or reinfection by Omicron variants.

Unlike other papers that only look at “breakthrough or not” infection, this is one of the first papers to cover serial infection, meaning getting infected with a similar virus within a short period from the last infection. Here their cohort (group of people used in the tests) were infected with both BA.1.15 ten weeks after a Pfizer shot, and BA.2 thirteen weeks later, and their immune responses compared with unvaccinated.

In about merely 4 weeks, the immune responses after the infection, supposedly to last “months of protection” already fell to the average for a triple vaccinated individual. BA. 1 infection booster their immune response, but not enough to protect them from other sub-lineages (BA.2 and as we are about to experience BA. 4 and 5).

Per the literature so far, which I covered quite extensively, vaccination does not work to protect against infection, or reinfection, which will lead to problems. Now let us go dig a little into the paper.

RESULTS

Case participant SARS-CoV-2 vaccination and infection timeline. The participant was a frontline health care worker in their early 30s with no chronic health conditions. They received three doses of mRNA vaccine (all BNT162b2; 30mcg) in late December 2020, early February 2021 and late October 2021 (Figure 1A). All blood samples collected up to one month following the third immunization were anti-N seronegative.

In early April 2022, 13 weeks following the BA.1 infection (and 23 weeks following the third immunization) the participant experienced a different, more mild symptom profile compared to 166 their first infection, consisting of a sore throat, fever, body aches, headaches, and diarrhea. No change in sense of taste or smell was noted. The participant noted persisting weakness, fatigue and mental fog, as well as severe long-term, treatment-resistant shortness of breath triggered by mild activities or exercises.

The first bold part is a point I have made numerous times, add this to the pile of evidence on the difficulty the vaccinated have to mount a proper (detectable) immune response against the N protein.

The second paragraph is something a portion of people infected with Omicron experienced, regardless of vaccination status (I did it too!!!), and something you should expect to see at a larger scale with the new dominant variants (BA. 4 and 5).

The paper goes into lengths to measure the different levels of their chosen metrics which I won’t bother covering here, it just proves these points.

Nevertheless, despite BA.1 infection and BA.2 reinfection, the participant's virus neutralization activity against BA.1 at this time point, which represented the highest activity measured during the study, remained 4-fold lower compared to that against the wild-type strain one month following their third vaccine dose (Figure 1D), suggesting that the participant may remain at risk of additional Omicron infection

Together, these results confirm that the participant's humoral responses to wild-type and Omicron variants were broadly average one month post-third vaccine dose. Moreover, while BA.1 infection boosted Omicron-specific immune responses (highlighted by an increase in BA.1 and BA.2 Spike-ACE2 competition activities), BA.2 reinfection did not substantially augment these activities further but rather extended the duration of these responses.

Our results nevertheless illustrate the potentially limited ability of current vaccines to preven recurrent infections and symptomatic disease caused by Omicron variants.

The piece below has all the information you would need to further understand the mechanisms behind all this, so if you want a broader look and understanding, go read it all !!!

Reasons for Vaccine failure vs Omicron

Not to the second paper, and one I find more important, at least from my perspective. MIS-C mechanism, the piece below has further information and why it matters so much.

The pathway for MIS-C, Methylene Blue as protective supplement

B cells, BAFF and interferons in MIS-C

Multisystem Inflammatory Syndrome in Children associated with COVID-19 (MIS-C) is a late complication of pediatric COVID-19, which follows weeks after original SARS-CoV-2 infection, regardless of its severity. It is characterized by hyperinflammation, neutrophilia, lymphopenia and activation of T cells with elevated IFN-γ. Observing production of autoantibodies and parallels with systemic autoimmune disorders, such as systemic lupus erythematodes (SLE), we explored B cell phenotype and serum levels of type I, II and III interferons, as well as the cytokines BAFF and APRIL in a cohort of MIS-C patients and healthy children after COVID-19.

We documented a significant elevation of IFN-γ, but not IFN-α and IFN-λ in MIS-C patients. BAFF was elevated in MIS-C patient sera and accompanied by decreased BAFFR expression on all B cell subtypes. The proportion of plasmablasts was significantly lower in patients compared to healthy post-COVID children. We noted the presence of ENA Ro60 autoantibodies in 4/35 tested MIS-C patients.

Our work shows the involvement of humoral immunity in MIS-C and hints at parallels with the pathophysiology of SLE, with autoreactive B cells driven towards autoantibody production by elevated BAFF.

MIS-C, the systemic inflammatory response that kids might experience after a Covid infection is of high interest, not only because it affects mostly kids, but in my opinion, it is one of the underlying mechanisms of the severe inflammation and erratic immune responses we see in adults. Kids just react faster to anything, their immune systems are as they are, super active.

Here the authors corroborate the finding of another paper (in the piece above) where this severe, systemic inflammatory response is driven by Interferon Gamma but not Alpha or Lambda (λ, the reverse Y is lambda in case you didn’t know).

This work further points towards the humoral (antibody-based) immune response as the one driving this systemic inflammation, akin to the pathophysiology of SLE (systemic lupus erythematosus, a disease that I mentioned over half a dozen times). Other works analyzed MIS-C from a T-cell perspective so this one is fairly unique. They measure two specific markers, BAFF and BAFFR.

Naïve and transitional B cells are also highly dependent on BAFF for survival 28, however all MIS-C B cells had strikingly suppressed BAFF receptor (BAFFR) expression. This was true in all B-cell subsets, including naïve and transitional forms. These results are consistent with the similar situation observed in SLE and Sjögren syndrome, where high levels of BAFF are associated with decreased BAFFR expression on all B cell subtypes 29,30. This inverse correlation may be attributed to down-regulation of BAFFR resulting from chronic exposure to elevated BAFF levels, which was suggested to be mediated via unspecified post-transcriptional mechanisms 30.

In summary, our brief report highlights the dysregulation of humoral immunity with autoimmune bias in MIS-C and suggests a role of the BAFF-BAFFR axis, which warrants further exploration.

By measuring the levels of those markers, they found even more similarities with SLE, and even with Sjögren syndrome. To understand how meaningful the findings in this paper are, you should read the hypothesis. By the way, for clarity's sake, the name was just a meme, when we first came up with the hypothesis, the correct definition would be either Common Variable Immune Deficiency, or one I came up with, and describes pretty well. Paradoxical Acquired Immune Dysfunction. Because it is a dysfunction and not a deficiency.

Here is the piece in question.

Reverse AIDS Part III—Welcome to the Super Family

It is a shame they didn’t measure other specific cytokines and proteins, otherwise, they would have found surprising pathways. And for last, what could drive this response so much, in so many people, from infected to people who just got vaccinated (with wild-type Spike Protein) and never infected back in mid-2021?

Superantigens promote Staphylococcus aureus bloodstream infection by eliciting pathogenic interferon-gamma (IFNγ) production that subverts macrophage function

(The paper was later peer-reviewed and published recently here)

Staphylococcus aureus is a foremost bacterial pathogen responsible for a vast array of human diseases. Staphylococcal superantigens (SAgs) constitute a family of potent exotoxins secreted by S. aureus, and SAg genes are found ubiquitously in human isolates. SAgs bind directly to MHC class II molecules and T cell receptors, driving extensive T cell activation and cytokine release. Although these toxins have been implicated in serious disease including toxic shock syndrome, we aimed to further elucidate the mechanisms by which SAgs contribute to staphylococcal pathogenesis during septic bloodstream infections. As most conventional mouse strains respond poorly to staphylococcal SAgs, we utilized transgenic mice encoding humanized MHC class II molecules (HLA-DR4) as these animals are much more susceptible to SAg activity. Herein, we demonstrate that SAgs contribute to the severity of S. aureus bacteremia by increasing bacterial burden, most notably in the liver. We established that S. aureus bloodstream infection severity is mediated by CD4+ T cells and interferon-gamma (IFNγ) is produced to very high levels during infection in a SAg-dependent manner. Bacterial burden and disease severity were reduced by antibody blocking of IFNγ, phenocopying isogenic SAg deletion mutant strains. Additionally, cytokine analysis demonstrated that the immune system was skewed towards a proinflammatory response that was reduced by IFNγ blocking. Infection kinetics and flow cytometry analyses suggested this was a macrophage driven mechanism, which was confirmed through macrophage depletion experiments. Further validation with human leukocytes indicated that excessive IFNγ allowed S. aureus to replicate at a higher rate within macrophages. Together, this suggests that SAgs promote S. aureus survival by manipulating immune responses that would otherwise be effective at clearing S. aureus. This work implicates SAg toxins as critical targets for preventing persistent or severe S. aureus disease.

SAgs are the etiological agent of toxic shock syndrome where T cell activation caused by SAgs released from S. aureus triggers a systemic ‘cytokine storm’ that can lead to hypotension and multiple organ failure, and in some cases death. SAg activity has also been implicated in a number of other serious diseases including endocarditis, pneumonia and bacteremia

In the current study, we deployed targeted antibody depletion protocols that demonstrated, during bloodstream infection, SAgs target CD4+ T cells to produce pathogenic levels of the key cytokine interferon-gamma (IFNγ). IFNγ promoted enhanced disease severity and bacterial burden in the liver and excess IFNγ levels during infection appeared to perturb liver macrophage activity to promote the survival of S. aureus within these cells. This the first report of targeted SAg activity that manipulates host macrophages to support S. aureus growth during bloodstream infections.

“Wait, what the hell does a bacteria has to do with Covid, Spike protein and vaccines, and MIS-C, and everything else?”

It is not the bacteria, but the SuperAntigen. One of the most remarkable features of the Spike protein from Covid is its uncanny molecular similarity with staphylococcal enterotoxin B, known as SEB. One of the most powerful toxins and antigens in nature. To understand how meaningful the paper above is, you need to read the Reverse AIDS hypothesis.

It has been my opinion, based on extensive research and observation that most of the bad outcomes of both viral infection and vaccines are driven not solely by the design, the mRNA, or even the Lipid NanoParticles, these being horrible on their own. But by the antigenic sites and molecular mimicry (how similar to parts of other “things” parts of SARS-CoV-2 is), especially the SEB.

This paper describes very clearly a very similar immune response from the body to SEB, in ways that relate to the immune response towards the vaccines. Which leads us to the following.

JAMA @JAMA_current

Study suggests that multisystem inflammatory syndrome in children during the #Omicron wave was less severe than during the Alpha or #Delta waves of the #COVID19 pandemic.

ja.maMultisystem Inflammatory Syndrome in Children During SARS-CoV-2 Pandemic Waves in IsraelThis study examines outcomes of multisystem inflammatory syndrome in children during the Alpha, Delta, and Omicron variant waves of the COVID-19 pandemic in Israel.

One of the features of Omicron (and from my research one of the driving factors of Omicron Spike Protein not working as a vaccine target) is the fact that the SEB portion of the Spike Protein in the Omicron Spike was attenuated. It lost its potent immune activation profile, giving a broad immune response via other mechanisms.

I don’t know if there is interest from my reader in my covering papers non-related to SARS-CoV-2, but that paper is one of the most meaningful ones so far. It has a lot of the “answers” I was looking for, as in why some of the pathways that shouldn’t be activated, let alone go haywire, did.

While Omicron presents us with other problems, the best part would be that it lost the “nastiness” of old SARS-CoV-2. And of course, vaccinating children with wild-type Spike Protein will only lead to further problems and chances of this specific response when the children get a breakthrough infection with any Omicron variant.

Deep appreciation for all the supporters!