CARPA

The KNOWN adverse event no one talks about

I think I have been talking about CARPA since 2021. It is HARDLY talked about in the literature, among most MFM doctors and I really do not know why. IMHO, the fact that CARPA occurs, was predicted, and was minimized is another huge red flag regarding these so called vaccines.

What is CARPA?

CARPA is a NON-IgE-mediated hypersensitivity reaction caused by rapid activation of the complement system, especially the C3a and C5a anaphylatoxins, typically in response to nanoparticles, liposomes, or PEGylated compounds. It can result in:

• flushing

• rash

• chest tightness

• hypotension

• tachycardia

• rarely, anaphylaxis-like events

So it looks like an anaphylactic reaction, but it is not because it is NOT IgE mediated. We used to call these anaphylactoid reactions. I have seen quite a few in my career, some mild and some life-threatening. CARPA is actually quite common but is under-recognized. CARPA is an innate immune response, specifically triggered by complement system activation. It occurs when nanoparticles (like LNPs in mRNA vaccines) or their components (e.g., PEG) activate complement proteins (C3, C5), leading to the release of anaphylatoxins (C3a, C5a). These mediators can cause mast cell degranulation, histamine release, and symptoms like flushing, hypotension, or anaphylaxis-like reactions.

But it is A KNOWN ADVERSE EFFECT OF ALL PEGYLATED NANOPARTICLES. Of interest, previous liposomal nanotechnology of therapeutic nucleic acids (for example a miR-34a mimic) exhibited serious infusion-related adverse events in a Phase I trial which were severe and, in some cases, fatal. It was withdrawn from the market because of CARPA. ¹

So it SHOULD have been anticipated. Was it?

CARPA Is a Hypersensitivity Reaction

Complement activation-related pseudoallergy: A stress reaction in blood triggered by nanomedicines and biologicals

I think Szebeni says it best. It is a STRESS reaction.

There is a long list of complement related diseases but CARPA is hardly studied. One reason may be is that there are NO ANIMAL MODELS. Mice and rats don’t get CARPA, neither do non-human primates. The pig model is the best we have.

Hypersensitivity reaction to drugs are also referred as drug allergy, but the terms infusion reaction, anaplylactic-,anaphylactoid-reaction, idiosyncratic or non-immune HSRs are often used for the rapid unexpected reactions, as synonyms. CARPA is more common with IV infusions, or drugs given IV or IM. Here is a schematic of what happens with CARPA by the expert in the field Janos Szebeni.

Remember this was written in 2014 so it was KNOWN.

What does complement activation do? This article be Zhou et al² is quite informative on the mRNA/LNPs and their immunological and pharmacological aspects. Because the LNPs look and act like viruses, complement activation can occur because the body thinks it is a pathogen.

The main result of the complement activation is triggering inflammation, stimulating phagocytosis, and forming a membrane attack complex that leads to the elimination of pathogens. The complement system has three pathways: the classical pathway, the alternative pathway, and the lectin pathway. All pathways form a C3 convertase that cleaves C3 into C3b and C3a. C3b may bound to the microbial surface and stimulate the phagocytosis or form the membrane attack complex (C3b-9), which disregards the cell membrane and causes cell lysis. C3a (and C5a) are anaphylatoxins that recruit phagocytes such as Neutrophils, MQs, and eosinophils and promote inflammation Anaphylatoxins in large amounts cause a systemic allergic reaction that is mediated by Th2 cells and immunoglobulin E (IgE) antibodies. It may be referred to as complement activation-related pseudoallergy (CARPA) or non-immune allergy in the nanomedical literature.

CARPA can last for more than a few hours and in rare cases, for days especially if the nanoparticles persist, sensitization is present, or downstream cytokine/coagulation pathways are engaged. Which I believe occurred, but I need to do more work on proving this. Most reactions are acute, but some patients may have prolonged or biphasic manifestations that are under-recognized.

---

Possible Mechanisms Behind Prolonged or Recurrent CARPA Symptoms

1. LNP Persistence
   Lipid nanoparticles, especially PEGylated ones, can remain in the body for days particularly in organs like the liver and spleen continuing to activate complement locally. Maybe even weeks.

2. Cytokine Amplification
   CARPA can trigger secondary cytokine cascades (e.g., IL-6, TNF-α), contributing to flu-like malaise, fever, and fatigue lasting days, similar to a mild cytokine release syndrome (CRS).

3. Endothelial and Coagulation Involvement
   Complement activation (especially C5a and SC5b-9) can stimulate endothelial cells and platelets, potentially creating low-grade inflammation that lingers. They can induce a pro-coagulant state by upregulating coagulation factors or impairing anticoagulants. If there is enough inflammation those individuals with risk factors such as prior thrombosis, antiphospholipid syndrome, or high anti-PEG antibody levels may be more prone to clotting.

4. Liver and Bone Marrow Effects
   Because the LNPs go to the liver, and lymph nodes/bone marrow, complement activation in these tissues might result in transient hepatopathy, malaise, or cytopenias, contributing to delayed systemic symptoms. We have seen this clinically.

What Drugs Cause CARPA?

Well there are a whole list of them. Szebeni lists them below, but the ones in bold I have seen with my own eyes. I would also add contrast media and vancomycin to this list as fairly common to cause CARPA.

Symptoms of CARPA, Some Can be Life-Threatening

Even though we call them anaphylactoid, and used to dismiss them as just a reaction you get and recover from completely, some CARPA reactions can be very scary indeed.

Here are some of the symptoms of CARPA. Do you notice metallic taste? Has anyone experienced these after receiving a Covid shot? I had a horrible reaction to Orencia (abatacept) with the GI, systemic and some of the neuro-psych symptoms listed below. You don’t need to experience all of them. A urticarial rash is not uncommon as well.

CARPA vs Anaphylaxis

1. Immune mechanism

   1. CARPA is Complement activation (C3a, C5a, SC5b-9)

   2. Anaphylaxis is IgE cross-linking on mast cells and basophils

2. Onset

   1. Both are rapid onset but CARPA can occur on first exposure, anaphylaxis needs prior sensitization

3. Symptoms: Both are very similar and sometimes hard to tell clinically, but CARPA usually doesn’t have airway edema or lip swelling. Both can cause a sense of impending doom. Ask me how I know.

   1. CARPA: Flushing, hypotension, tachycardia, chest/back pressure, dyspnea, nausea

   2. Anaphylaxis: Urticaria, angioedema, wheezing, hypotension, anaphylactic shock

4. Labs

   1. CARPA: elevated complement split products (C3a/C5a), typsin normal

   2. Anaphylaxis: typsin elevation, complement products normal

5. PEG skin testing

   1. CARPA: may be negative

   2. Anaphylaxis: may be positive

6. Treatment

   1. CARPA: Epinephrine, antihistamines, supportive care; complement inhibitors in research (Soliris [eculizumab])

   2. Anaphylaxis: Epinephrine, antihistamines, corticosteroids, airway support

CARPA can resolve without treatment, anaphylaxis usually not. Note that PEG lipids can cause anaphylaxis in addition to triggering complement.

Factors Triggering Complement Activation

The modRNA vaccines have all of them. Just about.

Where CP=classical complement pathway; AP=alternative complement pathway

ALL OF THESE ARE PRESENT in the LNPs of the modRNA vaccines.

And I think I am the first person to suggest that inhomogeneity and aggregates are causing immunotoxicity such as CARPA. This was especially prevalent with the purple topped Pfizer vials which had the PBS buffer.

I talk about it here³

I was told that there wasn’t enough material in the vaccine shots that CARPA would even be considered a possibility. I disagree.

What about the FDA and Medical Allergy Associations?

This is what I find most disturbing. Allergy to the vaccines was discussed often at the beginning of the rollout, but CARPA itself was never used by name. The focus was on IgE mediated anaphylaxis.

1. FDA Briefing Document on Pfizer-BioNTech EUA (Dec 2020)⁴

   1. The mechanism of anaphylaxis is not known. Possibilities include IgE-mediated and non-IgE-mediated mechanisms, including complement activation.

   2. Recognizes alternative mechanisms but CARPA is not named directly.

2. Pfizer-BioNTech EUA Fact Sheet for Healthcare Providers (2023)⁵

   1. Do not administer Pfizer-BioNTech COVID-19 Vaccine or Pfizer-BioNTech

      COVID-19 Vaccine, Bivalent to individuals with known history of a severe allergic reaction (e.g., anaphylaxis) to any component of the Pfizer-BioNTech COVID-19 Vaccine

   2. Focus on PEG, no deeper mechanistic discussion. No CARPA mentioned.

3. Morbidity and Mortality Weekly Report (MMWR), CDC, Jan 2021⁶

   1. Anaphylaxis appears to be rare. Most occurred within 15 minutes of vaccination. Skin testing to PEG and polysorbate may be useful.

   2. Locations administering COVID-19 vaccines should adhere to CDC guidance including screening recipients for contraindications and precautions, having the necessary supplies available to manage anaphylaxis,….. and immediately treating suspected cases of anaphylaxis with IM injection of epinephrine.

   3. Physician reviewers also used their clinical judgment to categorize reports that were considered not anaphylaxis as nonanaphylaxis allergic reactions or nonallergic adverse events. Nonallergic adverse events, mostly vasovagal or anxiety-related, were excluded from the analysis.

   4. CARPA not mentioned, possible hypersensitivity reactions dismissed as vasovagal or anxiety-related

4. Greenhawt et al., J Allergy Clinical Immunology. In Practice, 2021⁷

   1. convened by experts in allergy, immunology and emergency medicine

   2. Immediate reactions after mRNA vaccines may not be IgE-mediated.

   3. Tryptase is often normal. Non-IgE mechanisms including complement activation may be involved.

   4. Suggests non-IgE routes but stops short of CARPA term.

   5. Then suggests caution regarding excipients as causes for allergic reactions!! Remember the LNPs were considered excipients.

      

5. AAAAI Clinical Guidance on COVID-19 Vaccines and Allergic Reactions (Jan–Mar 2021)⁸

   1. Patients with immediate reactions to dose 1 may be evaluated with PEG and polysorbate skin testing. Second doses have been tolerated in most cases.

   2. All anaphylactic reactions should be managed immediately with epinephrine as the first line treatment.

   3. Although the specific vaccine component causing the anaphylaxis has not been identified, polyethylene glycol (PEG) is one of the ingredients in the mRNA vaccines and has been known to cause anaphylaxis (in addition to CARPA?).

   4. no CARPA mentioned

Did the FDA and physician experts in allergy downplay the risk of CARPA and its management? These guidelines mean that pharmacies and vaccine clinics managed anaphylaxis and CARPA with epinephrine only.

Regulatory Bodies’ Stance on Complement Assay Requirements

We can see that the modRNA vaccines have all the features of causing CARPA. We know patients had allergic reactions after the vaccines. But were many of these reactions misclassified? Were patients having CARPA reactions (which can be treated and managed) and dismissed as VASOVAGAL or just ANXIETY?

Major regulatory agencies including the FDA, EMA, Health Canada, and WHO did not formally require or request routine complement activation assays (e.g., C3a, C5a, SC5b-9) during the clinical development or post-marketing surveillance of mRNA vaccines. Which is usually required for liposomal drugs and pegylated nanoparticles. Although they acknowledged theoretical risks of complement activation and non-IgE hypersensitivity, no mandates or pharmacovigilance protocols included complement testing. This omission likely contributed to under-recognition of CARPA in clinical practice. Ya think????

Actually, in the leaked EMA rolling review, the scientific reviewers did ask and requested

“Complement (C) activation-related pseudoallergy (CARPA) can be a serious side effect of liposomal drugs, biologicals, and many other modern therapeutic and diagnostic agents. The Applicant is asked to discuss the absence of quantitative and targeted assays of C3c and C4 proteins.”

This recommendation to the manufacturer was not addressed in the final European Public Assessment Report (EPAR), presumably because these events were not described in the clinical trial by Polack et al as no signs indicative of such clinical manifestations were detected.

But if you are only looking for IgE mediated anaphylaxis and you excluded anyone with a PEG allergy, clinical manifestations may not have been that obvious.

Why Has CARPA Has Been Underevaluated and Underreported?

Here are some possibilities

1. Lack of clinical familiarity and training on CARPA among healthcare providers.

   1. well I can tell you most hospital pharmacists know about CARPA and it is well described in the pharmacy literature. Less so in the medical literature except perhaps for allergists and maybe emergency docs (I don’t know how many ER docs I had to educate on CARPA though).

   2. all messaging from the FDA/HC/EMA was on anaphylaxis and to be ready with epinephrine. That’s it.

2. Absence of standard diagnostic pathways including complement assays

   1. but this should have been included in the pivotal clinical trial as discussed

   2. CARPA needs a diagnostic pathway

3. Vaccines are not held to the same immunotoxicological standards as PEGylated drugs

   1. why do vaccines get away with stuff NO OTHER drug or device can?

   2. what is so special about vaccines?

   3. If RFK Jr is reading this (as if), please include CARPA as an assessment for ALL vaccines. PLEASE?

4. Public health messaging framed allergic reactions narrowly, minimizing the complex innate immune reactions associated with CARPA

5. Lack of follow-up protocols and lab testing for evaluation in VAERS for example

   1. therefore no specific identification of CARPA in vaccine vigilance. Instead we get

      1. rashes

      2. anxiety

      3. vasovagal

      4. “allergic” reactions

Scientific gatekeeping and publication bias against adverse reactions. Discussion of CARPA would fuel vaccine hesitancy of course.

But Industry is Looking at Replacing the PEG in the LNPs Because of the Risk of CARPA⁹

Why is it urgent?

Numerous studies have proven that the observance of side effects after vaccination is indeed positively correlated to the level of anti-PEG antibodies (IgM or IgG), which are enhanced by PEGylated preparations like LNP vaccine and environmental exposure. After literature research and review in the past two decades, it was found that the many clinical trial failures (BIND-014, RB006 fell in phase II) of PEG modified delivery system or PEGylated drug were related to the high expression of anti-PEG IgM and IgG. In the background of shooting multiple mRNA-LNP vaccines in billions of people around the world in the past three years, the level of anti-PEG antibodies in the population may have significantly increased, which brings potential risks for PEG-modified drug development and clinical safety.

So lots of people are now walking around with anti-PEG antibodies which means that FUTURE drugs which may need pegylation for improved efficacy will cause much more serious adverse events than even 5 years ago. Normally, these pegylated drugs are for serious diseases and require prophylactic drug treatment in some patients. But now the risk may be extended and IM pegylated drugs (like Neulasta) might need premedication. Now that would be difficult and cause real issues for clinical management.

Furthermore, if you want to treat cancer with LNPs and mRNA, then all these anti-PEG antibodies may make destroy your LNP due to the ABC phenomenon. These antibodies can bind with PEGylated drugs, potentially reducing their half-life, accelerating blood clearance (ABC) of PEGylated drugs, or causing premature drug release.

The authors provide some options.

So this is bad. Ignoring CARPA and PEG antibodies for the mRNA vaccines to avoid “vaccine hesitancy” might just knee-cap the burgeoning mRNA applications in cancer. Think about it. MWAHAHAHAH.

Holy Toledo.

Discuss.

SUMMARY

1. modRNA vaccines can cause allergic reactions that range from mild to life-threatening but are not classical IgE mediated anaphylaxis

2. This is due to antibodies to the PEG on the LNPs plus the ionizable lipid itself and other factors and sets off the complement cascade

3. This risk for CARPA was known for pegylated nanoparticles but was neither tested for or documented in any vaccine vigilance program

4. Some of the immediate adverse events after vaccination may have been due to CARPA but were unrecognized or even not reported since they were seen as just normal events post vaccination

5. The regulators should have required testing and mitigation for CARPA and launch cohort studies to identify biomarkers associated with reactions.

6. We need to add “CARPA-like reaction” as a selectable AE category and mandate reporting of all rapid-onset reactions within 30 minutes, even if resolved without epinephrine.

7. The consequences of injecting billions of people with a product that causes PEG antibodies is just starting to hit home.

PS I will do a more scientific paper on the mechanisms of CARPA and what it actually entails in another substack.

---

PS Personal Note.

My daughter was 7 months pregnant with her second child when she was mandated to take the shots. She is very allergic to PEG. Breaks out in urticaria if she uses PEG containing shampoos and the like. She asked for a medical exemption. They sent her to the allergist who did a skin test for allergy to PEG. They tested the higher molecular weight PEG (ie 2000 similar to what was in the vaccines) to the lower PEG in cosmetic products. My daughter had an immediate reaction to the shorter PEG but not the longer PEG. The allergist said she could receive the vaccine with “monitoring”. She left the office and within an hour she broke out in a urticarial rash all over her body. She called the allergist. He hemmed and hawed then asked if she could take maternity leave early but did not give her a medical exemption.

She has yet to go back to work as the mandates are still in place. She had a healthy baby. We shudder to think what would have happened otherwise. That allergist was a coward.

But as always, pray the rosary. Guess I need to pray for that allergist as well.

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC7251107/

2. https://www.mdpi.com/1999-4923/17/6/798#

3. https://mariagutschi.substack.com/publish/post/151214921

4. https://www.fda.gov/media/144246/download

5. https://labeling.pfizer.com/ShowLabeling.aspx?id=17227&format=pdf

6. https://www.cdc.gov/mmwr/volumes/70/wr/mm7002e1.htm?s_cid=mm7002e1_w

7. https://pmc.ncbi.nlm.nih.gov/articles/PMC8248554/pdf/main.pdf

8. https://acaai.org/news/acaai-updates-to-guidance-on-risk-of-allergic-reactions-to-covid-19-vaccines/

9. https://www.mdpi.com/1999-4923/17/6/798