Walkthrough: "Delayed Induction of Noninflammatory SARS-CoV-2 Spike-Specific IgG4 Antibodies Detected 1 Year After BNT162b2 Vaccination in Children" (July '24)
TL;DR: New study.Not only do young kids get class switched by engineered mRNA COVID-19 jabs, but they show a greater IgG4 response than adults and only need 1 dose +1 booster to potentially screw over their immune priming for life, along with the risk of developing organ damage through fibrosis if they progress to full, untreated IgG4-RD. No one knows how likely this is, as we are sailing into uncharted waters.
Any extracts used in the following article are for non-commercial research and educational purposes only and may be subject to copyright from their respective owners.
Hat tip to Dr Alberto Rubio-Casillas for sharing this study. I thought I was beyond being shocked and disgusted by the callous disregard of all safety and ethics considerations over the last 4 years. This is especially poignant when it concerns our children.
Quite rightly, those who abuse kids are seen as the lowest scum of society. If personal morals don’t check behaviour in this arena, nothing is out of bounds. “I didn’t know” or “I was only following orders” didn’t cut it at Neurenberg, and it doesn’t now. The silence is deafening, and the gaslit parents, with the odd exception, remain mystified or don’t speak out.
The final version by Kobbe et al. was published in “The Pediatric Infectious Disease Journal” on 30th June. I was considering including it in “IgG4 class switching and Immunoglobulin G4-related aortitis - Part III”, but that review draft is already long enough, and this study doesn’t directly relate to macrophages.
We know from case studies in Part I and Part II that, due to fab-arm exchange (half-antibody exchange), Spike-induced IgG4 Abs can generate bispecific antibodies with affinities for non-viral, human tissue antigens too.
The generation of memory B-cells can put the recipient at lifelong risk of IgG4-RD, as self-antigens can never be eliminated for obvious reasons. All we can do is monitor and treat the symptoms or try to suppress IgG4 Abs using drugs such as corticosteroids (CSs).
You will see frequent references to one of these called “prednisolone”. This is quite a powerful drug, and some need to keep taking it at low levels for years to prevent a flare-up. Common side effects include restlessness, weight gain, and irritability.
In 2018, Healthline posted slides of some of the stranger side effects, collected from community Facebook groups.
As you can see, you really don’t want to be taking this stuff long-term, and it doesn’t always stop IgG4-RD, it just slows it down. Other meds are frequently needed due to lack of efficacy. Plus it puts you at elevated risk of other nasty pathologies including:
Allopathic osteoarthritis.
Diabetes.
Cardiovascular disease.
Cancer.
I wrote about the dangers of CSs here, the mantra being: “use the lowest dose of steroids for the shortest period”.
The objective of this Substack is to help raise awareness of the risk of vax-induced IgG4-RD in children. This is so that medical professionals are more likely to make a more timely and correct diagnosis. They can then start them on the appropriate treatment, hopefully before too much organ damage has occurred.
Discussion
“Delayed Induction of Noninflammatory SARS-CoV-2 Spike-Specific IgG4 Antibodies Detected 1 Year After BNT162b2 Vaccination in Children”1
It’s quite a short paper, you can read the full version here, by open access.
Abstract
Humoral immune responses after BNT162b2 vaccination are predominantly composed of immunoglobulin (Ig) G1 and IgG3 subclass antibodies. As previously described in adults, S1-specific and receptor-binding domain–specific IgG4 levels increase significantly 1 year after the second BNT162b2 vaccination in children 5-11 years of age. Understanding mRNA vaccine–specific IgG4 responses in all age groups is crucial as more mRNA vaccines will reach licensure in the coming years.
As is usual to get published, there is a positive spin to this paper and no criticism of mass-injecting children with an experimental gene technology they never needed and had almost no clinical safety or efficacy data for, certainly not long-term.
The recent release of the RKI protocols showed that, as many of us suspected at the time, science, safety, efficacy and ethics got pushed aside in order to push these clownworld measures.
The ultimate goal was to coerce as many as possible into taking engineered mRNA products in return for a little freedom, whilst furthering the WEFs jackboot ideology.
The Child Catcher: classic bait and switch
Karl Lauterbach. In 2021 he was designatedFederal Minister of Healthand promoted a COVID-19 vaccine mandate for healthcare workers.
As is typical with paying protection money to the Boyz, once they got what they wanted the price went up, and freedom had to wait.
Key takes
I know that too much of a red-pill approach is likely to get you blacklisted. But even so, this is quite vomit-inducing:
The new technology of mRNA-based vaccination proved to be one of the most important tools to fight the SARS-CoV-2 pandemic, allowing safe and effective mass vaccination, saving millions of lives and opening the possibility of developing wide-ranging future therapeutics.1
Some four years after stage 2 and 3 trials were conducted we still don’t know all the effects of engineered mRNA on the body. The full body count will take decades.
The number of vax-related IgG4 papers must be approaching 20 by now, but sadly all these arrived long after the vax had been mass-administered, and still is.
You now need 9 DeathVax™ doses to earn a “fully vaxxed” smiley badge. More are in the works of course, and no amount of safety or efficacy data is ever enough to prompt a recall of this democidal product line.
It’s the Wild West out there, and you are on your own, safety-wise. There is practically no regulator, unless it’s to restrict something safe, cheap and effective like ivermectin.
Remember that, if they try again with a bird flu scamdemic or any other new drug. Suspect everything to be unsafe and ineffective as the default position until proven otherwise over a long period. They lost our trust years ago, and have done nothing to try to earn it back.
We all need to be our own MHRA now, the official one is just a gold-watch wearing pharma rep:
The cretinous chasing of subvariants never worked and never could. Even a “safety-can-go-to-hell” hundred-day vaccine approach can never keep up with a constantly mutating virus. And these are just the variants common enough to move the needle. Antibodies-schmantibodies, they keep pushing this BS.
Variant-watch latest, as at 1st July:They now need to landfill the current vials and start preparing batches for KP.3, or the one after that. See my Back to the Future themed Substack for how Ralph knew what was coming.
The strong association of SARS-CoV-2 spike–specific antibodies with protection against COVID-19 and the detailed knowledge gathered by the research community about humoral immune responses after repeated mRNA vaccination has recently been reviewed in detail.2
Meanwhile, some features induced by mRNA vaccination still need further investigation, among these the unusual induction of immunoglobulin (Ig) G4 antibodies.
In general, the protective humoral response after 2 doses of BNT162b2 or mRNA-1273 is composed predominantly of IgG1 and IgG3 subclass antibodies, both capable of mediating effector functions such as antibody-dependent cytotoxicity, phagocytosis and complement activation via their fragment crystallizable (Fc) region.2,3
Ignoring CD4+ & CD8+ T-cells, IgM, IgA mucosal & complement system immunity etc., they are citing studies here to the effect that you need antigen-specific Fc engagement by antibodies to protect against infection by variants.
Remember that for later.
Real-life data and passive and active immunization studies in mice suggest that the engagement of the Fc region with Fc gamma receptors is required for vaccine-induced antibody-mediated protection against infection by antigenically distinct SARS-CoV-2 variants of concern, including Omicron strains.3,4
Previously, it has been reported that 5- to 11-year-old children vaccinated with a 3-fold lower vaccine dose (BNT162b2, 10 µg) mount a lower magnitude of total antibodies at 2-4 weeks after the second vaccination compared to adults.5
3-fold less Abs than an adult, but more neutralising potential against variants?
In the same study, the analysis of Fc receptor–binding properties by Luminex revealed that children mounted similar levels of Fc receptor–binding antibodies compared to adults. This finding suggests a qualitatively superior Fc antibody functionality that may contribute to the protection against variants of concern and attenuation of COVID-19 in this younger age group.5
They then discussed class switching and the Irrgang paper2, which I don’t need to repeat here.
What is new is their assessment of IgG4 induction in kids by vaccination. It wasn’t a high-powered study (14 children), but the findings are consistent with other papers:
To determine IgG4 induction following BNT162b2 vaccination in children 5-11 years of age, we measured SARS-CoV-2 spike subunit 1 (S1)–specific and receptor-binding domain (RBD)–specific IgG subclasses by a bead-based multiplex immunoassay in 14 healthy children [median age, 8.5 (interquartile range [IQR], 6.4–10.0) years; 6 (43%) girls, 8 (57%) boys;
They all had 2 doses. The time between doses was 27-28 days and IgG4 was evaluated from blood samples taken on the day of dose 1; after 5 weeks; and after 1 year:
The children were vaccinated with 2 doses of BNT162b2 vaccine (10 µg, Corminaty, BioNTech/Pfizer), with a median interval of 27.5 (IQR, 27–28) days between doses. Blood was collected on the day of the first dose (V1D0), as well as 5 weeks [V2D35; median, 35.5 (IQR, 30–45) days] and 1 year [V2M12; 350.5 (IQR, 344–364) days] after the second dose.
2 of the kids were not naive to infection, which in adults is very protective against IgG4 class switching:
None of the participants had more than mild postvaccination reactions. In 2 children with a history of mild COVID-19, evaluation of humoral and cell-mediated immune responses confirmed previous SARS-CoV-2 infection.
Remember how the “… children mounted similar levels of Fc receptor–binding antibodies compared to adults”, and this is protective against infection by variants? Well, despite the risk to their health of cancer, cardiovascular disease, neurological disorders, autoimmune disorders etc. it was for nought, as they all got infected with Omicron regardless.
You can only call this a success if immunosuppression is your metric, as in “mild symptoms”. HIV also has “mild symptoms” at first due to a second-rate immune response. This doesn’t mean that a virus isn’t causing a lot of sub-clinical harm to your organs or hematopoietic stem cells3, and even mild symptoms may be associated with cognitive deficits months after recovery4, no doubt due to bioweapons motifs borrowed from HIV.
With the emergence of the Omicron variant, all children became infected with no or only mild symptoms by the time of long-term follow-up (V2M12) and showed respective positive hybrid immunity responses (for more information see Figures, Supplemental Digital Content 2-3, https://links.lww.com/INF/F657; https://links.lww.com/INF/F658).
Note:
An excess of one isotype of IgG may lead to a deficiency in another. This is particularly the case with IgG4, as it not only displaces other isotypes but can neutralise them too.
Any deficiency may lead to recurrent infections or disorders like chronic obstructive pulmonary disease (COPD) or bronchiectasis in children5 (a long-term condition with widening of the airways and excessive mucous build-up).
It is atypical for a child to have elevated IgG4. If anything a deficiency would be expected, until aged about 10:
The IgG in the bloodstream is 60-70% IgG1, 20-30% IgG2, 5-8% IgG3, and 1-3% IgG4. IgG1 and IgG3 reach normal adult levels by 5-7 years of age, while IgG2 and IgG4 levels rise more slowly, reaching adult levels at about ten years of age.
Each subclass serves predominantly (but not exclusively) a slightly different function in protecting the body against infection. For example, IgG1 and IgG3 subclasses protect against toxins from bacteria such as diphtheria and tetanus, and against viral infections. In contrast, IgG2 predominantly protects against the polysaccharide (complex sugar) capsule of certain disease-causing bacteria such as Streptococcus pneumoniae and Haemophilus influenzae.
Individuals with IgG subclass deficiency are defined as having recurrent infections, persistently low levels of one or more IgG subclasses, and normal concentrations of total IgG, IgM, and IgA. IgG2 or IgG3 deficiencies are the most common IgG subclass deficiencies. Since IgG1 comprises 60% of the total IgG level, having a deficiency of IgG1 usually drops the total IgG level below the normal range, resulting in hypogammaglobulinemia.
Because IgG4 does not reach adult levels until the age of 10 years, a diagnosis of IgG4 deficiency should not be made in young children. In addition, it may also be undetectable in the serum of many healthy adult individuals, and therefore low IgG4 alone is insufficient evidence of an antibody deficiency disorder.
From: “IgG subclass deficiency“ by the Immune Deficiency Foundation
The children’s antibody response 5 weeks after the second BNT162b2 vaccination was dominated by the IgG1 and IgG3 subclasses, which subsequently decreased over time.
As above, deficiencies in IgG2 put them at increased risk of pulmonary infections:
By contrast, IgG2 and IgG4 levels were relatively low at week 5 after the second vaccination and increased in frequency until the late follow-up for both S1 and RBD (Fig. 1A and B), as also observed in our adult cohort.10
Most concerning, IgG4 levels kept climbing up to the 12-month cutoff period. More recent studies show that both boosters and breakthrough infections, even from new variants, keep recalling IgG4 Abs from memory B cells. It’s a long-term immune priming that is not easily broken:
Specifically, S1- and RBD-specific IgG4 antibody levels increased significantly 1 year after the second vaccination compared to baseline (Fig. 1C and D).
As reported by Buhre et al8 for adults, we observed higher IgG4 levels in infection-naive children at the time of first vaccination compared to the previously infected individuals although the small number of participants hampered statistical calculations.
A log scale on the Y-axis, C and D shows that even the 2 prior-infected children had abnormally elevated anti-S1 and anti-RBD IgG4 Abs at both 5-week and 1-year time points. I read this as a sustained, approximately 10-fold increase in serum IgG4.
The sustained sub-optimal IgG2 response to Spike S1 stands out (A, orange):
From: “FIGURE 1: Longitudinal IgG subclass composition of spike-specific antibodies following BNT162b2 vaccination in children. A and B: Subclass composition of (A) S1- and (B) RBD-specific IgG subclasses at baseline (V1D0), 4 weeks (V2D35) and 1 year (V2M12) after the second vaccination. Boxplots indicate median, IQR and min-max range. Dots represent individual study participants. C and D: Longitudinal dynamics of (C) S1- and (D) RBD-specific IgG4 induction. Connecting lines indicate data points belonging to the same study participant. All data points are reported as median fluorescent intensity (MFI), measured by the Bio-Plex 200 system. Fourteen children [median age, 8.5 (IQR, 6.4–10.0) years] received 2 doses of the mRNA-BNT162b2 vaccine (10 µg, Corminaty, BioNTech/Pfizer) with a median interval of 27.5 (IQR, 27–28) days; blood was collected on the day of the first dose (V1D0), as well as 5 weeks [V2D35; median, 35.5 (IQR, 30–45) days] and 1 year [V2M12; 350.5 (IQR, 344–364) days] after the second dose. Two individuals had been infected prior to V1D0 (indicated by black circles in C and D), and all previously uninfected children experienced breakthrough SARS-CoV-2-Omicron infection until V2M12. Statistical comparisons between V1D0, V2D35 and V2M12 are only shown for IgG4 subclasses, irrespective of statistical significance. Comparison over time within either the S1 or RBD group was done by the Kruskal-Wallis equality-of-populations rank test, followed by Dunn’s test, Bonferroni-adjusted for multiple comparisons (*P < 0.05; **P < 0.01; ***P < 0.001; and ****P < 0.0001). ns indicates not significant.” Source: https://journals.lww.com/pidj/fulltext/9900/delayed_induction_of_noninflammatory_sars_cov_2.959.aspx
“Somatic hypermutation” and “memory responses”. This is not good if it’s priming your child to recall IgG4 antibodies for an indefinite period, especially to Self. And it’s one of the reasons there has never been a successful HIV vaccine:
It remains unclear how the specific subclass kinetics with delayed IgG2 and IgG4 induction by mRNA vaccination, here first described in children, affects long-term immunity.
A study by de Jong et al performed immunophenotyping and sequencing of peripheral blood mononuclear cells from young children and adults to investigate sequential IgG subclass switching.
Their findings suggest that an accumulation of specific IgG2- and IgG4-expressing memory B cells occurs with age, is associated with increasing levels of somatic hypermutation and might represent a marker for an efficient generation of memory responses.9
We hope that our observation will stimulate more studies on both similarities and differences of immune responses in adults and children, for example, regarding switching of IgG subclasses and functionality of vaccine-induced antibodies.
From failed attempts to make a HIV vaccine:
… Comparison of antibody functionality showed that RV144 induced highly functional IgG3, whereas VAX003 after seven protein immunizations elicited mono-functional antibodies with high levels of IgG4.38IgG subclass switching from highly functional antibodies to IgG4 may pose a new challenge for HIV vaccines as multiple immunizations and vaccine regimens may generate durable antibody responses but antibodies may not be of the highly functional IgG1 and IgG3 subclasses. Factors that determine subclass contribution to total IgG are not fully understood but adjuvants, antigens, vaccine dose, route of administration, age, and vaccine production methodologies could play a role.39 Decreased IgG3 and increased of IgG4 and IgG1 subclasses were observed in RV305, a follow-up study in which RV144 uninfected volunteers who received all vaccinations 6–8 years earlier were boosted with ALVAC-HIV/AIDSVAX B/E or AIDSVAX B/E alone or ALVAC-HIV alone.40,41
In all three HIV-1 trials, the antibody responses observed a typical saw-tooth pattern and were poorly sustained over time. Conflicting results have been observed42,43 but none match the long duration of antibody responses observed with other common viral and vaccine antigens.44It is hypothesized that plasma cells are imprinted with a predetermined lifespan based on the magnitude of B cell signaling that occurs during the induction of an antigen-specific humoral immune response.45 Moreover, additional AIDSVAX B/E, two late boosts given 8 years post last RV144 vaccination of the ALVAC-HIV/AIDSVAX B/E combination or AIDSVAX B/E alone (RV305) did increase IgG1 and IgG4 but not IgG3 subclass antibodies.40,41
From: “Comparison of Antibody Responses Induced by RV144, VAX003, and VAX004 Vaccination Regimens” (2017)
A hypothesis for Spike-induced class switching I proposed6 was that the Galectin-3 fold of the S1-NTD is largely responsible, just as Gal-3 was the primary antigen in patients with IgG4-RD. See here and here:
From: “Figure 4. Heat map demonstrating differential protein binding of PaCa2 cell lysate by mAb clones #1 and #2. Scale reflects log2-fold change divided by isotype control. Background was determined using an isotype control. Galectin-3 was identified as the antigen with the highest binding affinity for both mAb clones.” Source: “Identification of Galectin-3 as an Auto-Antigen in IgG4-Related Disease”(2018)
Envelope glycoprotein GP120 was suspected with the HIV vaccines. There are GP120 motifs on Spike S1 too, but they are associated with less immunogenicity than the galectin-fold NTD site due to them being glycoslylated7.
The authors from our new paper discuss other possibilities, and it doesn’t exclude persistant vaccinal expression of Spike + Gal-3 in the lymph node GC’s:
It has been proposed that persistent germinal center responses in lymph nodes, either specific to lipid nanoparticles or spike-antigen, or freely circulating spike-antigen in the priming phase of the immune response after mRNA vaccination, might drive IgG4 class switching.2,13
One potential explanation is the important role of cluster of differentiation 4 + T follicular helper (TFH) cells in establishing long-term immunity elicited by this new vaccine type.14
TFH cells are also described as involved in regulating IgG4 class switching and the pathogenesis of IgG4-related diseases.2,15
Factors deemed important in this process include TFH localization related to the germinal center, its differentiation, functionality and age-related tempering of inflammation, as well as its control by cytokine signals, T cell antigen receptor stimulation and costimulation.16
It’s a bit late now to admit you don’t know and for all those who were poisoned by contaminated products, but it’s not too late to recall the existing lines from the market, (hint: MHRA):
Understanding the role and interplay of these regulatory factors will be crucial to design safe and effective vaccines for all age groups in the future.
In summary, we report on increased spike-specific IgG4 levels in children 1 year after BNT162b2 vaccination, such as the effect observed in adults. While our study does not allow to predict effects on population level due to the small cohort size, it gives insight into the longitudinal dynamics of the spike-specific IgG subclass composition in children.
IgG4 responses should gain more attention in health and disease, especially in the context of mRNA vaccination. Understanding the unusual mechanism triggering IgG4 production is crucial, as more mRNA vaccines are currently under development and could hit the global market soon.
Other studies
It would be useful for the study to have included unvaccinated, SARS-CoV-2 exposed controls for comparison. I can help them with this.
In September 2023 Joshi et al. published: “Infants and young children generate more durable antibody responses to SARS-CoV-2 infection than adults”9:
Not only do the naturally immune generate a nicely balanced set of long-term IgG1, 2 & 3 Abs, but IgG4 remained at baseline levels, and a really useful mucosal IgA antibody response was mounted:
From: “Figure 1. Infants/young children generate durable antibody responses to SARS-CoV-2 antigens following infection. IgG (A–C) and IgA (D–F) antibodies reactive to SARS-CoV-2 spike (A and D), spike receptor-binding domain (RBD) (B and E), and the spike N-terminal domain (NTD) (C and F) were measured in duplicate by an electrochemiluminescent multiplex immunoassay and reported as arbitrary units per mL (AU/mL) as normalized by a standard curve. Longitudinal antibody titers of SARS-Co-2-infected infants/young children (n = 23) are plotted over days post positive PCR result. The dotted line represents the limit of detection, defined as the mean value pre-infection + 3SD.” Source: https://www.cell.com/iscience/fulltext/S2589-0042(23)02044-8
From: “Figure 4. Anti-spike IgG subclass distribution in infants/young children and adults. The concentration of anti-spike IgG subclasses was measured at an early (30–140 days post infection, red) and late (250–375 days post infection, blue) time points. (A) Early and late time point samples from the infant and adult donors chosen to assess the antibody subclass distribution. (B) Concentration (ug/mL) of anti-spike IgG1, IgG2, IgG3, and IgG4 antibodies at early and late time points in infants and adults. Statistics were calculated using two-tailed Mann-Whitney test. ns – not significant, ∗p < 0.05, ∗∗p < 0.01.” Source: https://www.cell.com/iscience/fulltext/S2589-0042(23)02044-8
The second study is a preprint by Nziza et al., also from 2023: “Humoral profiles of toddlers and young children following SARS-CoV-2 mRNA vaccination”10
They administered 25 μg of Moderna’s mRNA-1273 COVID-19 vaccine to 18 infants and toddlers, aged 6 months to 5 years, and compared immune responses to those of adults who took the higher, standard 100 μg dose.
I know what you are thinking, eugh, and I have thoughts on this too, and they aren’t for writing down, but the data is worth presenting as it’s been published.
Timepoints were comparatively short, which is quite commonly used if you expect data that perhaps doesn’t support claims of safety or efficacy:
“… before vaccination (V0), 1 month (V1) after first dose of mRNA-1273 vaccine, 2 months (V2) after the first dose of mRNA-1273 vaccine, in addition to 1 months after the second dose, 6 months (V6) after the first mRNA-1273 vaccination in addition to 5 month after the 2 doses, as well as 1 month after boosting (post-boost).”
Extracting C to E from figure 1, we see that the type of immune response most useful to prevent infections by respiratory pathogens was significantly reduced, compared to adults: IgGA1 and FcαR (the Fc receptor for IgA) for mucosal immunity.
IgM is mainly found in lymph fluid and blood, and is the first antibody secreted by the adaptive immune system in response to initial exposure to a foreign antigen. IgM got obliterated. In other words, vaccinated toddlers and infants allow the virus to proliferate somewhat to a higher viral load than would be the case with natural immunity. They would be prone to reinfections for months as a consequence.
There’s also the small matter of class switching being initiated. The higher IgG4 response is notable and alarming:
Extract from: “Fig. 1. mRNA-1273 vaccination induces a strong humoral immunity in children less than 5 years old. Antibody levels and functionality were measured in the plasma of children less than 5 years old and adults, 2 months after vaccination… (C) ADCP, ADNP and ADCD against Spike and RBD WT. (D) Heatmap shows the univariate comparison between SARS-CoV-2-specific antibody response in children and adults. Difference between the median of Z-scored MFI data are represented, where the color corresponds to the group that has the highest antibody response. (E) Breadth score was calculated by categorizing each antigen response as positive or negative, with positive response defined as 6 standard deviations above the mean of the COVID-unexposed controls, then calculating the percentage of positive Spike and RBD variant antigen responses for each secondary. Non-parametric Mann-Whitney U-test was used to calculate statistical significance, followed by Benjamini-Hochberg correction for multiple testing. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.” From: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104253/
Figure 4:
Blue = vaccinal response; Pink = infection response.
I’m sure they included this to try to show equivalence, but D exposes the ugly reality.
With zero priming for viral N protein, you are at a huge disadvantage compared to the naturally infected. Vaccine escape becomes much easier if the entirety of your defences are focused on one particular variant of Spike antigens alone, and not the rest of the virus, which mutates at a relatively slower pace.
Vaccine-specific Spike-Omicron induced IgG4 also stands out, along with a highly impaired IgG1 response to Delta (D). These kids will be at the mercy of the next variant entering circulation.
Epic fail:
From: “Fig. 4. Distinct antibody response between vaccination and natural infection in children under five. Antibody response was measured in the plasma of children 1 month after vaccination or diagnosis (on average). (A) Total IgG, IgG1, IgG2, IgG4 and IgG4 against Spike and RBD WT. (B) FcyR2A, FcyR2B, FcyR3A and FcyR3B binding against Spike and RBD WT. (C) ADCP, ADNP and ADCD against Spike and RBD WT. (D) Heatmap illustrates the difference between the median of Z-scored MFI data of the vaccinated and infected groups. Non-parametric Mann-Whitney U-test was used to calculate statistical significance, followed by Benjamini-Hochberg correction for multiple testing. *p < 0.05, **p < 0.01, ***p < 0.001.” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104253/
If you are curious about IgG4 changes over the 5 months I can’t answer that, as they conveniently excluded such data:
From: “Fig. 2. Strong impact of mRNA-1273 vaccination on antibody response overtime. Antibody levels (A), binding to FcyR (B) and function (C) against Spike WT was analyzed in children at different timepoints: before vaccination (V0), 1 month (V1) after first dose of mRNA-1273 vaccine, 2 months (V2) after the first dose of mRNA-1273 vaccine, in addition to 1 months after the second dose, 6 months (V6) after the first mRNA-1273 vaccination in addition to 5 month after the 2 doses, as well as 1 month after boosting (post-boost). Connecting lines represent identical individuals that were followed over time, and statistical differences were calculated between 2 consecutive timepoints. Wilcoxon signed rank test was used to calculate differences between timepoints for paired data. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104253/
Checking the supplementary data, their heatmaps showed the strongest IgG4 response was in the vaccinated under 5’s, and varied by group.
Extract from: “Fig. S2. mRNA-1273 vaccination induces strong humoral immunity in children less than 5 years old. Heatmap shows antibody function, antibody levels and FcR binding against SARSCoV-2 antigens among children (n=9) and adults (n=13), 2 months after vaccination. Data were zscored across columns and each row represent a different individual.“ Source: https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-024-45181-7/MediaObjects/41467_2024_45181_MOESM1_ESM.pdf
In Fig. S4. the top grid is an IgG4 heatmap for the 8 vaccinated, the bottom grid of 13 from infection. One vaccinated infant was significantly affected:
Extract from: “Fig. S4. Different antibody response in children less than 5 years old after SARS-CoV-2 vaccination versus infection. Heatmap shows antibody function, antibody levels and FcR binding against SARS-CoV-2 antigens among vaccinated (n=13) and infected (n=8) children. Data were z-scored across columns and each row represent a different individual.“ Source: https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-024-45181-7/MediaObjects/41467_2024_45181_MOESM1_ESM.pdf
Theory vs Reality: Why should we care about IgG4 in children?
Elevated IgG4 is clinical, objective evidence of possible disease. But can children get IgG4-RD? After all, it’s normally a disease associated with older adults, typically around retirement age. A brief literature review provides clues here.
Our first of 3 papers is from 2015, by Corujeira et al. The titles tell you a lot. As with adults, many cases go undiagnosed, unrecorded, and without appropriate treatment. One can only guess how paediatric clinics will cope with the inevitable influx of difficult cases, sooner or later:
“Severe IgG4-Related Disease in a Young Child: A Diagnosis Challenge”
(Emphasis mine)
Abstract
Immunoglobulin G4-related disease (IgG4-RD) is an increasingly recognized syndrome that can appear with multiple organ involvement, typically with tumor-like swelling, lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, and elevated serum IgG4 concentrations. We report the case of a 22-month-old female child with failure to thrive and recurrent respiratory tract infections since 8 months of age. Physical examination was normal except for pulmonary auscultation with bilateral crackles and wheezes. Laboratory tests revealed elevated erythrocyte sedimentation rate, and elevated serum IgG and IgG4 with polyclonal hypergammaglobulinemia.
“The mediastinum is the part of the chest that lies between the sternum and the spinal column, and between the lungs. This area contains the heart, large blood vessels, windpipe (trachea), thymus gland, esophagus, and connective tissues.”
Thoracic CT and MRI showed multiple mediastinal lymphadenopathies and a nodular posterior mediastinal mass in right paratracheal location with bronchial compression. Initial fine needle aspiration biopsy was compatible with reactive lymphadenopathy but after clinical worsening a thoracoscopic partial resection of the mass was performed and tissue biopsy revealed lymphoplasmacytic infiltrate and increased number of IgG4-positive plasma cells and a ratio of IgG4/IgG positive cells above 40%. Glucocorticoids therapy was started with symptomatic improvement, reduction in the size of the mass, and decrease of serum IgG4 levels after 6 weeks. There are very few reports of IgG4-RD in children. Long-term follow-up is necessary to monitor relapses and additional organ involvement.
Figure 1 (a) Coronal T2 MRI: complex nodular posterior mediastinal mass infiltrating the right hilum; (b) axial T2 MRI: bilateral mediastinal and hilar lymphadenopathies.
Figure 2. Mediastinal mass biopsy showed reactive lymph nodes presenting follicular hyperplasia with germinal centers and plasmacytic infiltrate ((a) H&E stain, 40x; (b) immunohistochemical stain for IgG, 400x; (c) immunohistochemical stain for IgG4, 400x).
There are very few reports of IgG4-RD in children and only one in a 15-year-old boy with lung involvement to our knowledge [14]. IgG4-related lymphadenopathy is often asymptomatic and may not require immediate treatment but our patient was very young and had significant lung disease with severe systemic repercussion and failure to thrive.
Benign/reactive lymph nodes are more common in children but are less frequently excised compared to adults. Differential diagnostic is broad and although the findings have some distinctive features, in many circumstances, they may not be sufficiently distinctive as to exclude a diagnosis of IgG4-related lymphadenopathy.
Multiorgan disease may be evident at diagnosis but also can evolve metachronously over months to years. Spontaneous improvement is reported in a minority of cases but not in intrathoracic IgG4-RD [1, 5, 9].
No randomized treatment trials have been conducted, particularly in children. Glucocorticoids are the first line of therapy and most IgG4-RD patients respond favourably to this treatment. Most centers start with prednisolone at a dose of 0.6 mg per kilogram of body weight or 40 mg for 2 to 4 weeks and taper the dose over a period of 3 to 6 months, although some authors suggest to continue at a dose between 2.5 and 5 mg per day for up to 3 years [1, 5, 6, 9, 15].
Our patient had a good clinical response to glucocorticoids but durability of treatment response is unclear after prednisolone tapering and relapse is frequent. A major determinant of treatment responsiveness is the degree of fibrosis, which was absent in this case [1, 5]. Serial measurements of IgG4 concentrations have been proposed as indicator of disease activity but although IgG4 concentrations become lower with glucocorticoid treatment, they remain above normal value in most patients [1, 3, 5].
The natural history of IgG4-RD has not been well defined, particularly in paediatric patients. Long-term follow-up is necessary to closely monitor relapses and additional organ involvement. Other courses of steroid therapy may be needed and eventually immunosuppressive therapy.
Our second paper is a systematic review from 2016 by Karim et al.:“IgG4-related disease: a systematic review of this unrecognized disease in pediatrics”11
Background
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition with an unclear pathophysiological mechanism affecting different parts of the body. If untreated, the disease can lead to fibrosis and irreversible organ damage. IgG4-RD mostly has been described in adults, hence it is generally unknown among pediatricians. This systematic search of the literature provides an overview of all reports published on IgG4-RD in children in order to create awareness of IgG4-RD in pediatrics and to emphasize the broad clinical presentation of this disease.
Methods
A systematic literature search of Embase, Medline, Web-of-Science, PubMed publisher, Cochrane and Google Scholar was performed for case reports on IgG4-RD in children.
Results
Of total 740 articles identified by the search, 22 case reports including 25 cases of IgG4-RD in children were found. The median age of the children was 13 years, of which 64 % were girls. IgG4-related orbital disease (44 %) and autoimmune pancreatitis type 1/IgG4-related pancreatitis (12 %) predominantly occurred. Less frequently, other manifestations as pulmonary manifestation, cholangitis and lymphadenopathy were also found. Almost all cases were histologically proven. Prednisone was the first choice of treatment leading to favorable clinical response in 83 % of the cases. Maintenance therapy with steroid sparing agents was required in 43 % of the cases needing therapy. Rituximab was successful in all 4 cases, whereas, the disease modifying rheumatic drugs (DMARDs) mycophenolate mofetil, azathioprine and methotrexate were effective in almost 50 % of the cases.
Conclusion
IgG4-RD in children is a generally unknown disease among pediatricians, but several pediatric cases have been described. Prednisone is the first choice of treatment leading to disease remission in the majority of the cases. DMARDs and rituximab are alternative effective steroid sparing agents with more positive evidence for the latter.
Fig. 3. Histology of the orbital tissue of an adult patient from our hospital with IgG4-related orbital disease. a HE-staining demonstrating multiple lymphoid infiltrates and fibrosis. b Immunohistochemical staining for IgG showing diffuse scattered IgG (brown color). c Immunohistochemical staining for IgG4 revealing widely scattered IgG4 positive plasma cells (dark brown) with an average of 339 per HPF out of 2 HPF with a ratio of 0.67 to total IgG plasma cells in the tissue. HE = Hematoxylin and Eosin, HPF = High-power field
Treatment
When untreated, IgG4-RD can cause irreversible organ damage hence early and aggressive treatment is indicated [36]. Glucocorticoids are the first choice of the treatment for the adults, mostly effective at a prednisone dosage of 0.5 -1 mg/kg/day, adjusted according to aggressive disease [37]. In the presented study prednisone appeared first choice therapy for pediatric IgG4-RD. There is no consensus on prednisone dosage in pediatrics, but in general prednisone 1 to 2 mg/kg/day should be appropriate. Prednisone can thereafter be tapered according to individual response. Treatment with prednisone is often rapidly effective, but this treatment should be maintained for 2 to 4 weeks after initiation. In the presented study prednisone was generally effective first line therapy in 83 % of the cases. However, only in 43 % of the cases prednisone single therapy sufficed.The rest of the cases required maintenance (immunosuppressive) therapy. According to previous studies, especially on adults, about 25 % of patients show relapse of the disease despite prednisone maintenance therapy making steroid sparing agents necessary [37]. MMF, azathioprine and methotrexate were effective in about 50 % of the cases in this study. The role of DMARDs in the treatment of IgG4-RD is not yet clear and management of this disease with these agents has not been outlined [37]. Recently, increasing evidence for the efficacy of rituximab treatment of IgG4-RD has been demonstrated [38]. In this review four patients were treated with rituximab leading to significant clinical outcomes in all cases. We recommend rituximab as a strong alternative when a patient is refractory to therapy. Intravenous or subcutaneous immunoglobulin treatment has been successfully used in other inflammatory or immune mediated diseases, but this therapy has not yet been applied in IgG-RD [39].
Conclusion
In conclusion, IgG4-RD is a relatively new disease and generally unknown to pediatricians. The results of this study suggest that the average age of patients is lower than suggested in the literature.Early recognition and therapy are important to prevent serious and irreversible organ damage. Treatment with prednisone is the first choice for this disease, but maintenance therapy with DMARDs is often required. Rituximab may be a good alternative in therapy refractory disease. Further (epidemiological) studies should confirm these preliminary conclusions. Moreover, serological and histological studies and studies on treatment of children with IgG4-RD are needed in order to confirm the same results in children compared with previous studies performed in adults.
Sobering conclusions. I will be on alert for case reports, going forward.
Our final paper reports 2 cases of swollen lymph nodes in children: “Report of Two Cases of Pediatric IgG4-Related Lymphadenopathy (IgG4-LAD): IgG4-Related Disease (IgG4-RD) or a Distinct Clinical Pathological Entity?“12 (2022) by Meli et al.
Abstract
IgG4-related disease (IgG4-RD) is a recently discovered immune-mediated fibroinflammatory condition, uncommon in the pediatric population, that could involve multiple organs and induce cancer-like lesions and organ damage. Its main features are multiple injuries in different sites, a dense lymphoplasmacytic infiltrate rich in IgG4 plasma cells, storiform fibrosis, and often high serological concentrations of IgG4. Autoimmune pancreatitis is the most common manifestation, mainly in adults. Two cases of IgG4-RD in children with lymph node localization of disease are reported. Localized or systemic lymph node involvement is common, but lymph node enlargement as the first and only manifestation of IgG4-RD is unusual, and therefore, hard to differentiate from other diseases. IgG4-related lymphadenopathy (IgG4-LAD) is most likely a distinct disease, described as isolated lymphadenopathy, related to the presence of elevated numbers of IgG4-positive plasma cells. Both disorders are likely to be misdiagnosed in children because they are characterized by rare and polymorphic features. IgG4-RD and IgG4-LAD should be considered in the differential diagnosis of disorders characterized by lymphadenopathy of uncertain etiology.
Two cases of children with lymphadenopathy associated with high levels of IgG4 plasma cells in the histological exam are reported. Both patients were admitted to the Pediatric Hemato-Oncologic Unit of the University of Catania.
The first case is about a 14-year-old Caucasian male with related parents. He complained about a 5-month left submandibular lymphadenopathy. Lymph node ultrasound results showed oval morphology, hypoechoic structure, thickened capsule, and evident central stria with a 3 cm diameter. Laboratory results showed a normal blood cell count, C-reactive protein (CRP) test, and erythrosedimentation rate (ESR); the anti-cytomegalovirus, Epstein-Barr virus, Rubeola virus, Herpes simplex virus 1 and 2, toxoplasmosis, and Bartonella IgM were absent. Head and neck computed tomography (CT) scans detected multiple enlarged lymph nodes with hypervascularity and normal central hyperechoic stria.
Not knowing it was an IgG4-RD they administered antibiotics without success.
Two courses with amoxicillin-clavulanic acid and ampicillin sulbactam, respectively, were given, with no benefit. Furthermore, a tuberculosis and thyroid function test were administered and the results were negative. Immunoglobulins had normal values compared with age, but a high level of IgG4 was present: 1.85 g/L (normal: 0.08–1.4). Therefore, the patient underwent a total body CT scan, which showed bilateral lymphadenopathy in the neck with a maximum diameter of 3 cm, whereas no pathological evidence was detected in the chest or abdomen. Excisional biopsy of the neck lymph nodes revealed preserved lymph node architecture with reactive follicular hyperplasia, and immunohistochemical studies showed normal distribution of B cells (CD20-positive) and T cells (CD3-positive).
BCL-2 expression is a prognostic marker for B-cell lymphoma, and tested negative:
No immunoreactivity for BCL-2 in germinal centers of lymphatic follicles was observed. Instead, there was marked intrafollicular but also interfollicular plasmacytosis, with an elevated number of polyclonal plasma cells. This was detected and confirmed by immunohistochemistry for kappa and lambda light chains, especially for IgG4 heavy chains (absolute number of IgG4 + cells 40–50/HPF; percentage of cells IgG4+/IgG+ about 40% in germinal centers) (Figure 1). Castleman disease was ruled out due to negative search for HHV.
What we don’t know is what child vaccines they received, and when?
Based on these clinical, serological, morphological, and immunohistochemical features, a diagnosis of type II (reactive follicular hyperplasia-like) IgG4-related lymphadenopathy was reached. No treatment was administered. Clinical and ultrasound follow-up was performed for 8 years, with normalization of serum IgG4 level and no relapse and/or new organ involvement.
Figure 1. Case 1: histological examination shows follicular hyperplasia (A); with thickened mantle zones and lymphocytes arranged in layers—an onion skin appearance (B); there are numerous plasma cells in interfollicular area (C) stained with CD138 (D). Immunoreactivity for IgG4 shows positivity in about 40 plasma cells/HPF (E).
“Castleman disease is a rare disorder that involves an overgrowth of cells in your body's lymph nodes. The most common form of the disorder affects a single lymph node, usually in the chest or abdomen. This form is called unicentric Castleman disease.
Multicentric Castleman disease, or MCD, affects multiple lymph nodes throughout the body.”
The second case concerns a 16-year-old boy with negative family history and a psychomotor delay. He presented in the emergency room because of two episodes of loss of consciousness and muscle tone with spontaneous resolution. His brain CT was negative. Laboratory results showed high acute-phase reactants (ESR 110 mm/h, CRP 176.4 mg/dL, normal range 0–5 mg/dL) and anemia (Hb 8.9 g/dL). The abdominal ultrasound highlighted hepato-splenomegaly and detected some hypervascularized lymph nodes that were increased in volume (maximum diameter 5 cm) in the mesentery and mesogastric regions. Upon admission to our unit, the patient was in good general condition and reported no weight loss, sweating, or other noteworthy symptoms.
“A classic form of ALPS-related autoimmunity occurs when antibodies are formed that attack red blood cells (haemolytic anaemia) and platelets (thrombocytopenia), leading to tiredness and pallor, easy bruising and bleeding.”
Normocytic anemia was confirmed whereas hepatic and renal function blood tests, viral tests, celiac disease screening, fecal occult blood, and fecal calprotectin tests were negative, and ALPS was excluded.
It appears they diagnosed IgG4-RD coincidentally with admission for an epileptic fit, rather than being due to the lymphadenopathies:
Electroencephalogram (EEG) showed a pathological pattern, with generalized tip/wave discharges; although the brain MRI was unremarkable, anti-epileptic therapy with Levetiracetam was administered. A neck-chest-abdomen CT scan confirmed multiple lymphadenopathies in the abdomen. A tru-cut biopsy revealed nonspecific hyperplastic lymphadenitis; subsequently, the patient underwent excisional biopsy of the biggest lymph node (Figure 2A,F). Histology results showed remarkable and diffuse follicular hyperplasia, sometimes with atretic germinal centers traversed by penetrating vessels—lollipop follicles—and thickened mantle zones with lymphocytes arranged in layers—onion skin appearance—simulating Castleman disease. Rare progressively transformed germinal centers, focal intranodal fibrous septa, and aspects of capsular venulitis were observed. Interfollicular zones were expanded by numerous polyclonal plasma cells (Figure 2H,I). Immunohistochemical studies revealed normal distribution of B cells (CD20-positive) and T cells (CD3-positive). No immunoreactivity for BCL-2 in the germinal centers of lymphatic follicles was detected. A significant number of interfollicular plasma cells (CD138-positive; (Figure 2D,G) (>40/HPF) was also positive for IgG4 (Figure 2L). Two diagnostic hypotheses were considered, namely a multicentric plasma cell variant of Castleman disease (clinical presentation: hepatosplenomegaly; morphological features of Castleman-like disease) or IgG4-related lymphadenopathy. IgG4 levels turned out to be elevated (1.98 g/L, normal: 0.08–1.4), whereas immunohistochemical analyses for HHV8 (specific for Castleman disease) was negative, thus leading to the final diagnosis of IgG4-related lymphadenopathy. The patient was discharged and put on a “wait and see” follow-up with ultrasound surveillance; no therapy was prescribed. The patient is currently healthy after four years follow-up.
IgG4-RD in children, like many autoimmune disorders, concerns me more than cancer in some ways. Some cases may resolve without relapse, but a lot don’t.
Although some cancers may quickly become end-stage there is usually just one mutating cell line to treat. Ignoring risks from burning, cutting and poisoning, unless the tumour is inoperable its 100% removal theoretically shouldn’t endanger the patient: aegrescit medendo (the cure is worse than the disease).
Whereas with IgG4-RD if the antigen is from your own organs you can hardly be cured by eliminating all these cells, for obvious reasons. Immunosuppressants help, but these bring with them their own risks to health, and 100% elimination of all the leukocytes that express Abs isn’t a viable option either.
And finally, with IgG4-RD it is a double-whammy, as benign tumour formation is common, together with an almost 3-fold increased risk of overall cancer; a 4-fold increased risk of pancreatic cancer; and a huge 69-fold increased risk of lymphoma13, keeping in mind the frequent lymph node involvement.
Prevention is much better than cure with IgG4-RD. In other words, these dangerous engineered mRNA products need to be placed under an immediate moratorium.
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Kobbe R, Rau C, Schulze-Sturm U, et al. Delayed Induction of Noninflammatory SARS-CoV-2 Spike-Specific IgG4 Antibodies Detected 1 Year After BNT162b2 Vaccination in Children.The Pediatric Infectious Disease Journal.:10.1097/INF.0000000000004488. doi:10.1097/INF.0000000000004488
Kucia M, Ratajczak J, Bujko K, et al. An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner.Leukemia. 2021;35(10):3026-3029. doi:10.1038/s41375-021-01332-z
Zhang Y, Clarke A, Regan KH, et al. Isolated IgG2 deficiency is an independent risk factor for exacerbations in bronchiectasis.QJM. 2021;115(5):292-297. doi:10.1093/qjmed/hcab129
Raszek M, Cowley D, Redwan EM, Uversky VN, Rubio-Casillas A. Exploring the possible link between the spike protein immunoglobulin G4 antibodies and cancer progression. Explor Immunol. 2024;4(2):267-284. doi:10.37349/ei.2024.00140
Rathore U, Saha P, Kesavardhana S, et al. Glycosylation of the core of the HIV-1 envelope subunit protein gp120 is not required for native trimer formation or viral infectivity.J Biol Chem. 2017;292(24):10197-10219. doi:10.1074/jbc.M117.788919
Joshi D, Nyhoff LE, Zarnitsyna VI, et al. Infants and young children generate more durable antibody responses to SARS-CoV-2 infection than adults.iScience. 2023;26(10). doi:10.1016/j.isci.2023.107967
Nziza N, Deng Y, Wood L, et al. Humoral profiles of toddlers and young children following SARS-CoV-2 mRNA vaccination.Res Sq. Published online April 6, 2023:rs.3.rs-2748734. doi:10.21203/rs.3.rs-2748734/v1
Karim F, Loeffen J, Bramer W, et al. IgG4-related disease: a systematic review of this unrecognized disease in pediatrics.Pediatr Rheumatol Online J. 2016;14:18. doi:10.1186/s12969-016-0079-3
Meli M, Arrabito M, Salvatorelli L, et al. Report of Two Cases of Pediatric IgG4-Related Lymphadenopathy (IgG4-LAD): IgG4-Related Disease (IgG4-RD) or a Distinct Clinical Pathological Entity?Children. 2022;9(10):1472. doi:10.3390/children9101472
1. Yu T, Wu Y, Liu J, Zhuang Y, Jin X, Wang L. The risk of malignancy in patients with IgG4-related disease: a systematic review and meta-analysis. Arthritis Research & Therapy. 2022;24(1):14. doi:10.1186/s13075-021-02652-2
The targeting of children with the mRNA concoction reminded me of a conversation I had with a young mother in 2021. She talked about the pressure she was experiencing to give permission for her 13 yr old daughter to be injected with the Covid “vaccination”. She was made to feel she was being a bad mother for refusing, I remember reassuring her she was being the very best mother in protecting her child from this experimental injection, thankfully she stuck to her guns and never allowed the vaccinators near her child. Reading your informative article I am very thankful this mother stayed strong and resisted the pathological gaslighting, it is utterly horrific that even one child was injected by this experimental substance.
Gram-negative Endotoxin is clearly implicated in IgG4 disease.
Septic Pancreatitis and Hypergammaglobulinaemia with disruption of IgG4 have been linked to E coli Endotoxin
Moriarty written here about Galectin as an antigen associated with IgG4 Disease that drives expansion of circulating plasmablasts and CD4+ cytotoxic T cells.
The targeting of children with the mRNA concoction reminded me of a conversation I had with a young mother in 2021. She talked about the pressure she was experiencing to give permission for her 13 yr old daughter to be injected with the Covid “vaccination”. She was made to feel she was being a bad mother for refusing, I remember reassuring her she was being the very best mother in protecting her child from this experimental injection, thankfully she stuck to her guns and never allowed the vaccinators near her child. Reading your informative article I am very thankful this mother stayed strong and resisted the pathological gaslighting, it is utterly horrific that even one child was injected by this experimental substance.
Gram-negative Endotoxin is clearly implicated in IgG4 disease.
Septic Pancreatitis and Hypergammaglobulinaemia with disruption of IgG4 have been linked to E coli Endotoxin
Moriarty written here about Galectin as an antigen associated with IgG4 Disease that drives expansion of circulating plasmablasts and CD4+ cytotoxic T cells.
https://geoffpain.substack.com/p/igg4-affected-by-endotoxin-in-mrna