COVID-19: Polyethylene glycol – Allergenic components of mRNA vaccine

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On 18th December 2020 emergency use authorization (EUA) provided by the US Food and Drug Administration (FDA) authorized the immediate use of the vaccine mRNA- 1273 developed by Moderna Therapeutics for the prevention of coronavirus disease 2019 (COVID-19).

TheEUA allows the immediate distribution and use of mRNA-1273 COVID-19 vaccine in the United States in subjects 18 years of age and older [1]. It is the second vaccine to be granted an EUA by US regulators after the authorization received by Pfizer-BioNTech on 11th December 2020 for the use of the vaccine BNT162b2 [2].

The authorization of mRNA-1273 was based on early phase trials [3, 4] and the revision of the results of an ongoing phase III trial that involves 33,000 adult subjects that were randomized 1:1 to receive the mRNA-1273 vaccine in a two-dose regimen or placebo. The assessment performed by the FDA demonstrated that the vaccine was 94.1% effective for the prevention of COVID-19 as determined 14 days after the administration of the second dose [1]. 196 cases were evaluated for the efficacy analysis of which 185 cases of COVID-19 were observed in the placebo group versus

11 cases observed in the mRNA-1273 group. The secondary endpoint involvd assessment of severe cases of COVID-19 and included 30 individuls. All of thesevere cases occurred in the placebo group and none of them in the mRNA-1273 vaccinated group [5].

The FDA stated that the potential benefits of mRNA-1273 outweigh the potential risks [1].

Serious allergic reactions to the active components of the vaccine itself or other components are one of the potential risks of every vaccination product. According to the New York Times [6] on the 25th December, soon after vaccination started in the US a physician in Boston developed an anaphylactic reaction to mRNA-1273. He used his own adrenaline autoinjector that he carried for his shellfish allergy and recovered well. Anaphylactic reactions to BNT162b2 were also reported in the United Kingdom (UK), Canada and the US [7, 8].

Allergic reactions to vaccines including severe anaphylaxis may be IgE-mediated but canalso be IgG and complement-mediated. They usually occur within the first 30 minutes after vaccination. The symptoms include urticarial rashes, generalized pruritus, erythema, wheezing, coughing, dyspnea, throat, tongue or eye swelling (angioedema), hypotension, dizziness, and vomiting, and these reactions may even be fatal. Severe anaphylactic reactions to vaccines are rare and the rate has been estimated to be 1.31 (95% CI, 0.90-1.84) per million vaccine doses [9].

The frequency of allergic side reactions to BNT162b2 was nearly the same in the verum and in the placebo group (0,6% versus 0,5%) [10].

Allergic reactions to the mRNA 1273 vaccine have not been reported in detail. During the phase I trial of the mRNA-1273 vaccine, one case of transient urticaria in the verum group treated with a vaccine dose of 25µg was reported after the first injection. The total number of participants in this phase I trial was 45 patients [34].

Both, BioNTech/Pfizer and Moderna excluded individuals with a history of allergic reaction to vaccines or components thereof their vaccines from the phase 3 pivotal trials. The exclusion criteria for mRNA-1273 state: “History of anaphylaxis, urticaria, or other significant adverse reaction requiring medical intervention after receipt of a vaccine” [11]. Individuals with previous allergic reactions to food or medications were not excluded but may have been underrepresented.

The anaphylactic reactions during the routine vaccination prompted authorities such as the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK or the FDA to issue an alert stating that individuals with a history of severe allergic reactions to vaccines, medicines, food, or any component of these particular vaccines should be advised against their administration and that a second dose should not be given to anyone who has experienced anaphylaxis following administration of the first dose of this vaccine [9].

Although the culprit trigger has yet to be determined, initial reports pointed at the excipient polyethylene glycol 2000 (PEG-2000), contained in the vaccine as a PEG- micellar carrier system, to be the potential cause of the anaphylactic reactions [7]. PEG- ylated microsomes used as the carrier of the vaccine can cause anaphylactic reactions in individuals with pre-existing PEG allergies as it has been previously observed for PEG- ylated drugs used in the cancer therapy and treatment of chronic diseases [7] [35] [12].

PEGs are also used as excipients in everyday products, such as toothpaste, cosmetics, shampoos, and some biologicals.

Lipid nanoparticles are similar to liposomes, which have been in use pharmaceutically for many years as carriers for drugs. Some of the approved liposome/LNP-containing drugs also contain a PEG-ylated lipid (e.g. in Caelyx pegylated liposomal® or Onpattro®). The PEG chains on the surface form a hydrate shell around the liposome/LNP. This increases stability and prevents opsonization, i.e. the mechanism by which the surface of foreign cells (e.g. bacteria, viruses) that have invaded the body is covered with antibodies and factors of the complement system. In addition, the stability and half-life of the lipid particles are increased.

Pathophysiology

Allergic reactions to such PEG-ylated lipids may be IgE-mediated, however non-IgE- mediated reactions have to be considered as well [13].

IgE activates mast cells and basophilic granulocytes via cross-links of high-affinity IgE receptors, which is indirectly measurable in an increased expression of surface markers (CD63, CD203c) on basophils [8, 14].

The symptoms of anaphylactic reactions are particularly caused by mediators released mainly from mast cells and basophilic granulocytes such as histamine, prostaglandins, leukotrienes (LTB4, LTC4, and LTD4), tryptase, platelet-activating factor (PAF), heparin, proteases, serotonin, and cytokines [8, 14].

Besides IgE, other antibody classes may trigger similar symptomatology or amplify an IgE-mediated reaction [8, 14]. Possible non-IgE-mediated reactions include complement activation-related pseudoallergy (CARPA) and have been described in the context of liposomes [15-17].

Updating the Gell and Coombs’ scheme of Type I–IV hypersensitivity reactions (HSRs) [18], CARPA may be regarded as an independent category within Type I reactions, representing “receptor-mediated” mast cell activations [17].

CARPA is partly attributed to the binding of pre-existing anti-PEG IgM to the liposomes with subsequent complement activation. Clinical symptoms of this non-IgE- mediated hypersensitivity have been described as hypo- and hypertension, airway obstruction with dyspnea and other anaphylaxis symptoms shortly after intravenous administration of liposome-containing drugs.

I ndependent of PEG-ylation, liposomes have the potential to activate complement non-specifically depending on their different surface structures and charge) [15]. Complement products C3a, C4a, and C5a (anaphylatoxins) are considered to be particularly important mediators and, in addition to basophils, neutrophils and macrophages are also considered to be relevant effector cells that can be activated via immune complex receptors (CD16, CD32, and CD64, respectively) [8, 14]. Anaphylatoxins are liberated uncontrolled in blood during complement  activation  and  function  as  efficient   small   molecular   weight regulators of cardiovascular and autonomic organ functions [17, 19].

Possible sensitization to PEG by previous use of cosmetics or drugs containing PEG is conceivable. Little is known about the prevalence of anti-PEG antibodies in the population. Some report that as much as 72% of the population have at least some IgG or IgM antibodies against PEGs [20], while others report high levels in certain groups of individuals [16].

Evidence for a possible role of IgE in triggering PEG-induced hypersensitivity is also discussed [21]. Allergic reactions following the use of PEG as an excipient in a variety of products have been described; it is also referred to as a “hidden” allergen [21, 22].

Similar to BNT162b2, the mRNA-1273 COVID-19 vaccine is a messenger ribonucleic acid (mRNA) vaccine encoding the viral spike (S) glycoprotein of SARS-CoV-2. The list of excipients of both vaccines share certain components but also differs in others. Interestingly, PEG-2000 can also be found as an excipient in the mRNA-1273 COVID- 19 vaccine (Figure 1).

It has to be noted, that PEG-2000 has never before been used in any vaccine and both Pfizer-BioNTech and Moderna are the first ones to apply this substance. PEGs are hydrophilic polyether compounds that are used as additives in medical products, cosmetics, and food.

It is branded under different names, e.g. macrogol. The molecular weight of different PEGs varies from 300 g/mol to 10,000 g/mol and hypersensitivity reactions may occur to PEGs of all molecular weights with a higher rate of reactions to molecular weights from 3350-6000 g/mol [21]. However, it has been suggested that the molecular weight threshold for PEG immediate reactions is still undetermined[23, 24].

Cross-reactivity between PEGs and its derivatives, i.e., structurally related polymers such as polysorbates, exist due to shared moieties (=CH2CH2 and =CH2CH2OH) [21]. Severe allergic reactions to PEG, although rare, have been described after administration of medications that contain this excipient. PEG has even been described as the high-risk hidden allergen, since it is difficult to detect as a possible cause of allergic reactions [21, 23-26].

PEGs are ingredients of laxatives or liquid preparations for parenteral use, gels, tablet coatings, wound dressings, ointment bases, lotions, toothpaste, oral hygiene products, food additives and even some of the biologicals that are used in clinical studies and more [21] [7].

PEG-ylation is successfully used for drug delivery to protect the drug from any damage by the immune system and deliver it to the targeted location. In addition, PEGs are additives in cosmetics and shampoos. Both, a primary cutaneous sensitization pathway and sensitization after systemic administration are possible [24].

The U.S. National Institute of Allergy and Infectious Diseases (NIAID) is initiating a study in collaboration with the FDA to analyze the response to the vaccine in people who have high levels of anti-PEG antibodies or have experienced severe allergic responses to drugs or vaccines before [25].

Additionally, and contrasting to the Pfizer-BioNTech vaccine, mRNA-1273 contains tromethamine, also named trometamol (molecular formula: C4H11NO3), an organic amine that is widely used in several medications for topical, enteral, or parenteral administration. Tromethamine/trometamol is also used in cosmetic products as an emulsifier, and contact sensitization and allergy to this compound have been described [27].

Recently, the first case of anaphylaxis to trometamol as an excipient in a gadolinium-based contrast agent (GBCA) has been reported [28]. The reaction occurred immediately after GBCA injection in a 23-year-old woman and IgE-mediated trometamol allergy could be detected in this patient [28]. Trometamol can also be found in other contrast agents such as in iodinated contrast medium (IOM).

Diagnostic options

A thorough history taking is an important prerequisite to avoid severe anaphylaxis. Reactions to PEGs in e.g. laxatives, gels, wound dressings, lotions, toothpaste, mouthwash, cosmetics and shampoos may be indicative. The use of beta-adrenoreceptor antagonists, angiotensin-converting enzyme (ACE) inhibitors and non-steroidal anti- inflammatory drugs (NSAIDs) may lead to an increase in anaphylactic symptoms [14, 29].

In patients with elevated basal serum tryptase and/or mastocytosis, anaphylaxis may be particularly severe [8, 14, 29-31].

Allergy testing should be performed in specialized allergy centres. Skin prick tests should be performed very carefully with initial dilutions from 0.001% up to 10% with 30 minutes observation after every dose step. Since it is speculated that the individual threshold for positive reactions to PEG of different molecular weights varies [23], testing should be performed with PEGs of 2000g/mol molecular weight that are used in both vaccines; published algorithms should be followed [23].

Skin tests should be performed either before but not earlier than 2-4 weeks after the hypersensitivity reaction occurred. In addition, basophil activation test (BAT) and screening for specific IgE to PEG in blood serum may be performed in patients with suspected allergy to excipients of the vaccine.

If PEG allergy can be confirmed, an emergency kit should be prescribed, and PEG-allergy information sheet provided. If not, intradermal testing with PEG of different molecular weights at a dilution of 0.01% can be carefully considered, but not in high-risk patients since systemic reactions can occur [23]. In some settings, oral provocation test can be performed if needed [21].

Trometamol as a contact sensitizer is usually tested epicutaneously for allergic reactions of the delayed-type. Testing for suspected type 1 reactions can be done by skin prick testing (concentration 1:1) followed by intradermal testing with dilutions of trometamol from 1:1000-1:10 [28, 32].

Although allergic reactions to mRNA-1273 components such as PEG and trometamol have not been frequently reported, the fact that the vaccines for COVID-19 will be extensively administrated worldwide to a high proportion of the population should caution health care providers of the potential allergic reactions that may occur in individuals previously sensitized to the components of the vaccines, especially to PEG and PEG analogs as well as trometamol in the case of mRNA-1273 [33].

Therapeutic options

This allergy is of particular interest since some of the drugs used to treat anaphylactic reactions, such as antihistamines or injectable corticosteroids contain PEGs or polysorbates. Substances cross-reactive to PEG, i.e., polysorbates, are widely distributed and commonly used in bread, pastry, chewing gums, ice cream, and so on, but also in a high number of vaccines, biologics, and mediations to treat rheumatologic, cardiovascular, haematologic, gastrointestinal, or oncologic diseases, and during diagnostic procedures. It is very likely that hypersensitivity reactions to such agents have been underestimated in the past.

Further on, two doses of the vaccine have to be administered to achieve an effect so that sensitizations might even occur during the administration of the first dose or individuals may develop allergic reactions to the second dose. Whether the new route of delivery of PEG via intramuscular injections might play a role in its allergenicity has to be determined.

Since both mRNA-1273 and BNT162b2 contain PEG-2000, PEG allergic patients or patients allergic to components cross-reactive to PEG do not have a current alternative for preventive vaccination against COVID-19 and should not be vaccinated with those substances. Further on, physicians should be aware of this potential risk and carefully interrogate for previous allergic reactions to PEG, PEG analogues, or tromethamine, and should be trained to respond to potential anaphylactic reactions during vaccination. In these patients, administration of emergency medications

containing PEG such as cetirizine, levocetirizine, fexofenadine, desloratadine, methylprednisolone acetate and triamcinolone acetonide should be avoided.. Alternatives should be considered, for example, clemastine solution for intravenous injection, cetirizine syrup for oral intake, soluble prednisolone or methylprednisolone for oral intake or injection, and of course as recommended for all patients with severe anaphylaxis most importantly adrenaline [23].


RNA vaccines
Lunar-COV19 (Acturus Therapeutics, U.S.; Duke-NUS, Singapore) is delivered by a lipid-enabled and unlocked nucleomoner agent modified RNA lipid mediated delivery system (Lunar) (Table 6), which has previously evidenced successful and efficient mRNA delivery in animal models [289,290]. Preclinical results demonstrated that a single prime vaccination in mice induced high NAb titers, which continually increased up to day 60, in addition to enhancement of CD8+ and CD4+ T-cell responses. The intermediate and high doses effectively protected SARS-CoV-2 challenged human ACE2 transgenic mice [291].

A Phase I trial for the vaccine candidate, LNP-nCoVsaRNA (Imperial College London, UK), which encodes a prefusion stabilized SARS-CoV-2 S protein, is currently ongoing (Table 6). Preclinical results were promising as the vaccine demonstrated effective viral neutralization which was directly related to the induction of SARS-CoV-2 specific IgG production.

High levels of cell-mediated responses were also observed [292]. Recruitment for Phase I clinical trials for the CVnCoV (CureVac, Germany) and ARCoV (People’s Liberation Army Academy of Military Sciences, China; Walvax Biotech, China) is currently undergoing (Table 6).

The RNA vaccine candidate, mRNA-1273 (Moderna Therapeutics, NIAID, U.S.) (Table 6), encodes the S protein which contains the S1-S2 cleavage site, essential for S-driven viral entry into lung cells [293,294,295]. The S protein is perfusion stabilized via proline substitutions, which has been shown to increase recombinant expression of viral fusion GPs [296,297].

The vaccine is encapsulated within LNPs [293], which as mentioned earlier, provides adequate protection of the mRNA molecule [89]. Vaccination in non-human primates demonstrated that a two-dose vaccination schedule with mRNA-1273 elicited robust NAb and T-cell responses and was protective against SARS-CoV-2 infection in the upper and lower airways [294].

Results of the Phase I trial conducted in adults (18–55) and older adults (≥ 56) showed that mRNA-1273 was safe and well tolerated. High NAb responses were elicited in a dose-dependent fashion in the absence of SAEs after the first vaccination. The importance of the second vaccination was indicated as the first vaccination only induced low levels of pseudovirus neutralization activity.

The 100 μg dose elicited higher binding and NAb titers in all participants, supporting the use of this dose during the Phase III trial [293,295]. Interim data from the ongoing Phase III study involving 30,000 participants, indicated that mRNA-1273 is 94.5% effective in preventing COVID-19. From 95 confirmed infections, 90 were in the placebo group and only 8 were in the vaccinated group [298]. 11 confirmed severe cases were all in the placebo group. These results are extremely promising, especially for such novel untested technology.

Several RNA vaccine candidates have been developed by BioNTech, Germany in collaboration with Fosun Pharma, China and Pfizer, U.S.: BNT162a1, b1, b2, and c2. Two encode the RBD of the SARS-CoV-2 S protein, and two encode the larger S protein (Table 6). Altered forms of conventional RNA-based vaccine platforms, including saRNA and modified mRNA, may improve efficacy.

Specifically, saRNA vaccines confer higher expression levels of the antigenic target [84], while modified mRNA incorporating pseudouridines can suppress adaptive immune response stimulation, circumventing RNA degradation and increasing efficacy [299]. BNT162b1, is a modified mRNA vaccine encoding the SARS-CoV-2 S RBD.

In Phase I/II trials, the vaccine increased RBD-specific IgG and SARS-CoV-2 NAb levels after two doses, although participants did develop dose-dependent mild to moderate local and systemic AEs [300]. BNT162b2 encodes the full S protein stabilized in the prefusion conformation. In a Phase I trial comparing the two, both BNT162b1 and BNT162b2 were able to elicit dose-dependent NAb responses, but BNT162b2 produced fewer and less severe AEs [301].

In addition to Ab responses, a Phase I/II trial administering BNT162b1 demonstrated enhanced cell-mediated responses, evidenced by increased CD4+ and CD8+ T-cell expansion which augmented IFN-γ production [302]. The safe and effective stimulation of both cell-mediated and humoral immune responses confirmed in the aforementioned trials greatly supported the progression into Phase III trials.

Interim data from Phase III trials indicated that BNT162b2 was approximately 95% effective in preventing COVID-19 [10,303]. From 170 confirmed infections, 162 were in the placebo group and 8 in the vaccinated group [10]. 9 out of 10 confirmed severe cases were in the placebo group [10,303].

Early December, the mRNA vaccine candidate, BNT162b2, was approved in the UK, making it the first RNA-based vaccine to ever be approved [10]. Shortly after, the U.S. FDA approved BNT162b2 for emergency use authorization [11]. Just a week after, mRNA-1237 was also approved by the U.S. FDA for emergency use authorization [12].

The impact of formulation design on stability is best exemplified in a comparison of the two currently leading RNA-based COVID-19 vaccine candidates: mRNA-1273 and BNT162b1. BNT162b1 must be kept frozen to prevent degradation and requires ultra-cold storage (−70 °C +/− 10 °C) and cold-chain transport. After thawing, BNT162b1 may be stored at 2–8 °C for up to 5 days [302,304]. In contrast, mRNA-1273 has been reported to remain stable at −20 °C for up to six months, at 2–8 °C for 30 days or at room temperature for up to 12 hours [305].

Nucleic acid vaccines
Nucleic acid vaccines represent a completely novel approach to imparting protective immunity, but DNA and RNA vectors are emerging as highly promising strategies. As non-viral vectors, these vaccines are thought to confer greater safety than their viral counterparts [60]. Although considered high-risk untested technologies [9,12], nucleic acid-based vaccines can have shorter development cycles, enabling quick deployment during pandemics.

The use of recombinant DNA vaccines requires successful transfer of the DNA vector into cell nuclei, transcription into messenger RNA (mRNA), and finally translation into the antigen of interest [75]. “Naked” or purified plasmid DNA is a highly attractive vehicle for antigen presentation as it is very simple to manipulate and inexpensive to generate [76].

A plasmid DNA vector typically consists of fundamental genetic components including a transcriptional promoter, RNA processing elements (polyadenylation (poly A) tail), and the gene encoding the antigen [77]. Plasmid DNA is an attractive biopharmaceutical as it can be amplified in large quantities in inexpensive prokaryotic hosts, although it must be purified [78,79]. The predominant challenge of utilizing DNA vaccines is that they generally impart low immunogenic responses in humans and larger animals compared to small animal systems [80,81].

An RNA vaccine already consists of an mRNA molecule which encodes the selected antigen, removing the need for transcription [82]. Upon delivery into a human cell, the immunogen sequence only requires translation to produce the antigen of interest. An RNA vaccine includes the mRNA transcript encoding the gene of interest surrounded by 5′ and 3′ untranslated regions and a polyA tail [83]. Some RNA vaccines can be self-amplifying (saRNA); the RNA molecule can direct its own replication and translation within the host upon delivery. As a result, more immunogen can be expressed [84].

However, there are concerns regarding the instability of delivering naked RNA, in addition to the size of the delivered molecules [83,85]. The instability of mRNA is prominently due to the ubiquitous presence of ribonucleases that actively degrade RNA [85,86]. The addition of a 5′ cap (7-methylguanosine cap) and 3′ polyA tail are essential in maintaining the stability and translation of mRNA within the cytosol [82,87].

Additionally, to protect from degradation, polymer and lipid formulations have been used [88]. Lipid nanoparticles (LNPs) are composed of ionizable cationic lipids, phospholipids, cholesterol and PEG that enable the assembly and formation of a stable lipid bilayer around the mRNA molecule [86]. Previous studies have shown sufficient protection of mRNA by effectively encapsulating it [89,90,91].

Lipo- or polyplexed DNA and RNA uptake is thought to occur primarily by endocytosis [92]. Uptake through other mechanisms such as pinocytosis and phagocytosis are more restricted [93]. LNPs enter cells through one of many endocytic pathways after interaction between the cell surface and the particle. Addition of targeting ligands to nanoparticles may therefore improve uptake through receptor-mediated endocytosis.

Endocytosed DNA nanoparticles have been confirmed within the endosomal compartment through electron microscopy [94,92] and confocal microscopy [92]. Additionally siRNA delivered via LNPs have also been confirmed within the endosomal compartment through confocal microscopy [95,96]. Escape from the endosomal compartment into the cytosol is of paramount importance for subsequent gene expression [97].

Many nanoparticles have exhibited endosomal escape [98], although the mechanisms by which they do so remain unknown. A common hypothesis is the proton sponge effect [99], whereby the polymer buffers the low pH within an endosome. This leads to excessive pumping of ions into the endosome to compensate. Eventually, the endosome lyses from buildup of osmotic pressure, releasing its captive nanoparticles into the cytosol [99].

Methods to enhance vaccine uptake and expression have been more thoroughly investigated for DNA vaccines compared to RNA, as DNA needs to bypass two cellular membranes to arrive at the nucleus, while RNA only needs to bypass one to enter the cytoplasm [9]. DNA transfection is more effective in actively dividing cells, where the nuclear membrane has broken down, compared to quiescent cells [100]. The inclusion of a nuclear localization signal [101] can facilitate active transport across the nuclear membrane, enabling gene expression in quiescent cells.

As opposed to protein pharmaceuticals, tertiary structure is not generally important for DNA or RNA function, simplifying their storage requirements. When storing nucleic acids, the key is maintenance of the molecule’s chemical integrity [69,71,102,103].

DNA itself appears to be robustly stable. Over a seven year period, supercoiled plasmid DNA was found to be stably maintained and demonstrated no difference to freshly prepared DNA when stored in 0.9% sodium chloride at −20 °C [104]. While short-term storage is possible in a refrigerator (2–8 °C) or room temperature (20–30 °C), DNA will eventually deteriorate within months (2–8 °C) or days (≥20 °C) [102,105,106].

Low temperature and pH are vital to preservation of DNA integrity in the long-term. In contrast, RNA products are very sensitive to temperature and should always be kept at extremely cold temperatures (−70 °C) during storage and distribution. The presence of ribonucleases can destroy the RNA vaccine product; therefore synthesis, purification, and storage of the product must be done in absence of enzymes to elongate its shelf-life [71]. Inexpensive excipients like PEG, trehalose, and sucrose have shown promising results in protecting RNA vaccines and increasing their stability and half-life from hours to days at ambient temperatures [69,71].

Additionally, DNA and RNA vaccines are likely formulated with cationic lipids or polymers and, as such, will have different storage conditions depending on the polymer. In general, lipoplexed DNA formulations appear to be stable at 4 °C for up to 3 months [107], which is still insufficient for widespread vaccine distribution.

However, certain lipoplexed nucleic acid formulations have shown better stability, such as up to a year when frozen [108]. Lyophilization can also be employed for long-term stability [103] and disaccharide excipients may improve stabilization of lipoplexed nucleic acids [109,110]. Lyophilized polyplexed RNA particles were even stable at 40 °C with sugar excipients [110]. Clearly, choice of excipient and the formulation of the cationic carrier will greatly affect stability.

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789827/


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