The Barbastro Report

Possible cause of the coronavirus pandemic:

Immunological interference between POLYSORBATE 80 in adjuvanted influenza vaccine and SARS-CoV-2

Juan F. Gastón Añaños (1), Ana Martínez Giménez (2), Elisa Ma Sahún García (1). (1) Pharmacy Service. (2) Preventive Medicine Service. Barbastro Hospital.

Abstract

The objective of this study is to analyze the coronavirus pandemic from the double point of view of Pharmacoepidemiology and Pharmacovigilance.

Based on an epidemiological analysis of deaths from COVID-19 in the Health Sector attended by the Hospital de Barbastro, and the study of the pharmacotherapeutic history of affected patients, it was found that the most common drug for all the deceased was Chiromas®. This led to the hypothesis that influenza vaccination for the 2019-2020 campaign could be associated with a higher risk of death from COVID-19 in people over 65 years of age, that is, with the suspicion of possible iatrogenesis, which is suspected confirmed when accessing data from another sector.

The current situation of the Pharmacovigilance of vaccines in Spain is reviewed, seeking a means of communication of the aforementioned suspicion that is agile and dynamic. There is an apparent overconfidence in the safety of vaccines, far removed from the principle of prudence.

A possible mechanism of action is proposed for the hypothesis of immunological interference with parenteral POLYSORBATE 80, and the degree of concordance of the expected data against those observed is compared, reaching the conclusion that the hypothesis could be valid, therefore that it is decided to publish it.

Key words: COVID-19, adjuvanted influenza vaccine, POLYSORBATE 80, immune interference, cytokine storm.

Introduction

The Health Sector served by the Hospital de Barbastro geographically occupies the eastern half of the province of Huesca, with a largely dispersed rural population of 100,000 inhabitants.

Pharmacovigilance is part of the daily work of the hospital pharmacist, who must be vigilant to prevent and, where appropriate, detect and resolve possible cases of iatrogenesis in the patients he cares for. Within this Pharmacovigilance work, the registration of confirmed cases of death from COVID-19 was carried out in the hospital itself on 04/30/2020, and the analysis of their previous treatments. Subsequently, on 05/05/2020, the study was extended to the entire Health Sector, in order to expand the sample, using the Electronic Medical Record (EHR) as a data source.

Results

The first relevant data found is the fact that the 20 deceased in the Sector were all over 65 years of age. Of them, 17 had registered the administration of the vaccine and its batch by Primary Care, and of the other 3 there is no record. Those vaccinated against influenza would therefore represent at least 85% of the total number of deaths.

This data was higher than expected according to the vaccination rate in the Barbastro Health Sector, which, according to the Aragón Weekly Epidemiological Bulletin (1), had been 63.1% in that age segment. According to these results, flu vaccination not only would not have improved the prognosis of the vaccinated elderly with respect to COVID-19, but it would have worsened it.

The inconsistency of the data on the effectiveness of influenza vaccination in the prevention of complications such as pneumonia, hospitalisation, and general mortality in institutionalised elderly people with comorbidities has already been highlighted by previous studies with a much higher number of cases (2).

The data found led to the hypothesis that influenza vaccination for the 2019-2020 campaign could be associated with a higher risk of death from COVID-19 in people over 65 years of age.

To test the hypothesis, we sought to compare these 20 deaths / 100,000 inhabitants with other data from the environment, in an attempt to expand the sample. The deceased in the other Sector of the province of Huesca was analysed, finding certain difficulties in accessing the vaccination registry in the HCE. The data of a nursing home that had 94 inmates as of 11/08/2019 is accessed, of which 25 have died from COVID-19, which reveals the finding that more people have died in that nursing home with 94 inmates (25 deceased) than in our health sector 100,000 (20 deceased), in a proportion 1000 times higher.

After solving the lack of registration in EHR, due to a computer problem, access to the primary care manual registration of vaccination in the residence is achieved, with the following results:

• Of the 80 vaccinated, 24 have died, 30%.
• Of the 14 not vaccinated, 13 are still alive today, and 1 has died. That is, 7% have died.

Therefore, the death rate in the vaccinated registered is four times that of the non-vaccinated, in an already significant sample of 94 individuals. Thus, confirmation of the initial suspicion is obtained, and a geographical-social-health component is observed that can be investigated in greater depth.

Discussion

As an initial step to rule out possible contamination of the vaccine itself with SARS-CoV-2, the Microbiology Service of our center was asked to carry out the PCR test on the content of a syringe left over from the campaign, from the batch administered at more deceased. The test result was negative.
Subsequently, the composition of the adjuvanted vaccine administered to those over 65 years of age was studied within the Public Health campaign in the Community of Aragon, Chiromas®, whose technical sheet (3) reports the following components:

Influenza virus surface antigens (hemagglutinin and neuraminidase) grown in embryonated chicken eggs from healthy chickens and with adjuvant MF59C.1, of the strains:

• A / Brisbane / 02/2018 (H1N1) pdm09-like strain (A / Brisbane / 02/2018, IVR-190) 15 micrograms HA (haemagglutinin).
• A / Kansas / 14/2017 (H3N2)-like strain (A / Kansas / 14/2017, NYMC X-327) 15 micrograms HA (haemagglutinin).
• Strain similar to B / Colorado / 06/2017 (B / Maryland / 15/2016, wild type) 15 micrograms HA (haemagglutinin).

Adjuvant: MF59C.1 is an exclusive adjuvant: 9.75 mg squalene; 1,175 mg of POLYSORBATE 80; 1,175 mg of sorbitol trioleate; 0.66 sodium citrate; 0.04 mg of citric acid and water for injections.

The adjuvant component is what differentiates the Chiromas® vaccine from the Chiroflu® vaccine (4), which is the one that has been administered to healthcare providers. Adjuvants (from Latin, “adjuvare”, literally “to help”) are substances used in combination with a specific antigen that produce a more robust immune response than the antigen alone (5). Squalene is a hydrophobic natural hydrocarbon originally obtained for commercial purposes from shark liver oil, but it is produced by all complex organisms, including humans, since it is a precursor to cholesterol. It is therefore not a foreign product for our body.

An initial bibliographic search was carried out for the rest of the adjuvant components, which led to the focus of the study on POLYSORBATE 80, a cosmetic ingredient also known as TWEEN-80, Polyoxyethylene 20 sorbitan monooleate, Sorbimacrogol oleate 300, and with the acronym E-433. In the INCI list (International Nomenclature of Cosmetic Ingredients) it is called POLYSORBATE-80 (6).

Chemically, POLYSORBATE 80 has a hydrophilic and a lipophilic part, which allows it to improve the solubility in water of hydrophobic molecules such as squalene, stabilizing the emulsions.

The effectiveness of POLYSORBATE 80 as a surfactant is confirmed by the importance of the drugs that include it to enable the parenteral administration of macromolecules of the size and complexity of monoclonal antibodies (adalimumab, infliximab, tocilizumab, secukinumab …), epoetin alfa, anakinra, amiodarone … in injectable solution, or triamcinolone acetonide in suspension.

POLYSORBATE 80 is very well tolerated and is not irritating to the skin and mucous membranes topically, but the Acofarma information sheet reports that “polysorbates have been associated with serious adverse effects, including death, in low birth weight neonates at that parenteral preparations with polysorbates were administered “.

Warnings regarding POLYSORBATE 80 are included in several technical data sheets: Thus, the Torisel® technical data sheet warns that polyvinyl chloride (PVC) bags and medical devices should not be used for the administration of preparations containing POLYSORBATE 80, since that POLYSORBATE 80 leaches di-(2-ethylhexyl)phthalate (DEHP) from PVC (7); The Trangorex® technical data sheet warns that cases of hepatotoxicity have been reported with amiodarone after its iv administration that could be due to the solvent (POLYSORBATE 80) that carries it, instead of the drug itself (8).

The Chiromas® technical data sheet was studied, which reports “Immune system disorders: Allergic reactions, including anaphylactic shock (rarely), anaphylaxis and angioedema”.

We searched the literature on immunological adverse effects described for other parenteral vaccines that also contain POLYSORBATE 80. The following were found:

• Pandemrix®: After the 2009-2010 influenza vaccination campaign in Sweden, an association between the use of the Pandemrix® vaccine was demonstrated with an increase in cases of narcolepsy, especially in those under 20 years of age who carry the HLA-DQB1 * 06 allele. : 02, by multiplying the risk of suffering this disorder by twelve (9).
• Gardasil®: Among the adverse effects detected for this vaccine against Human Papillomavirus in post-marketing, are “Immune system disorders (frequency not known): Hypersensitivity reactions including anaphylactic / anaphylactoid reactions” (10).
• Prevenar®: Among the adverse effects detected for this post-marketing pneumococcal vaccine are: “Immune system disorders: Rare: Hypersensitivity reaction, including facial edema, dyspnea, bronchospasm” (11).

The current state of Vaccine Pharmacovigilance in Spain was analysed, with the following relevant findings:

• Flu vaccines are drugs whose composition changes every year, but strangely they do not have an additional black triangle for monitoring.
• The flu vaccine is considered a prescription drug, but in the vaccination campaign there is neither a medical prescription, nor are individualised prescriptions issued per patient, nor are the vaccines dispensed in the pharmacy. The vaccine is administered “per protocol”.
• Vaccines are often delivered on pallets from the pharmaceutical laboratory to the administration centres, without basic pharmaceutical controls, delivery notes, or distributed batches.
• The document on the Pharmacovigilance Plan for Pandemic Vaccines of the AEMPS is dated October 14, 2009 (12), that is to say no less than prior to the date on which the association of the use of the influenza vaccine Pandemrix® was demonstrated with an increased risk of narcolepsy 4 to 9 times higher in vaccinated children and adolescents compared to non-vaccinated (13).

This seems to indicate that there is a generalised confidence in our health environment about the safety of vaccines, and specifically of the flu. Faced with this situation, it was decided to directly notify each of the aforementioned deaths that occurred within the Hospital as a suspicion of possible ALVa (adverse event linked to vaccination) to the Pharmacovigilance Centre of Aragon.

Conclusions

Although the notification of suspected possible adverse effect of a drug does not oblige the declarant to propose a mechanism of action for it, the hospital experience and the consulted documentation allow us to propose a hypothetical mechanism for the possible immunological interference, which requires the 3-element concurrency:

• Previous exposure of the subject to the administration of POLYSORBATE 80 by parenteral route, either through the adjuvanted vaccine or other parenteral drugs that contain it.
• Non-optimal immunological status of the subject: advanced age, concomitant autoimmune diseases, immunosuppressive treatments …
• Subsequent contagion with a strain of the SARS-CoV-2 coronavirus.

That is, by themselves, neither the polysorbate nor the coronavirus would be able to trigger the hypersensitivity reaction. The possible interference between acquired immunity against POLYSORBATE 80 and coronavirus infection would occur at the time of viral replication within infected cells, and in subjects with a non-100% efficient immune status.

But another variable must come into play: The contradictory results of the PCR tests obtained for patients in our centre, with alternative results (+) and (-), seem to suggest the idea that at least two strains of SARS-CoV- could coexist. 2, one would give the PCR positive and another would give it negative. During the replication process in the infected cell, a mutation could occur that would give rise to coronavirus of the other strain.
The (+) strain of the coronavirus, when replicating in a cell of the pulmonary mucosa or vascular epithelium, would cause it to express some polysorbate-like antigen on its surface, and would be responsible for immunological interference, by confusing an immune system not 100% efficient, making it use the acquired immunity against polysorbate against the cells in which that strain is replicating (+), attacking and destroying them as foreign cells.

The double strain would explain the fact that there are certain individuals with a non-100% efficient immune system and those who in November-December 2019 were administered POLYSORBATE 80 parenterally as part of the adjuvanted vaccine, who only suffer from the initial infectious syndrome mild due to SARS-CoV-2, and would be those infected by the (-) strain that would generate antibodies against it and defeat it.

On the other hand, in those others infected by the (+) strain, or in those in which the (-) strain mutates in the process of replication to the (+) strain, the described immunological interference could take place, triggering a reaction of severe hypersensitivity, the inflammatory process known as “cytokine storm” (14), which is what would ultimately cause death.

The clinical complications of this process can manifest as acute respiratory distress syndrome (ARDS), disseminated vascular coagulation, acute pancreatitis (15), depending on the cells in which the coronaviruses are replicating, which are attacked by the reaction autoimmune of the patient, with the very serious known consequences.

The hypothesis would explain facts observed in the pandemic, such as the following:

• Geographical differences in terms of COVID-19 cases worldwide, focusing on the northern hemisphere (Europe, United States, Mexico …), where influenza vaccination was carried out prior to winter, while in the southern hemisphere it was autumn (16).
• Late appearance of COVID-19 in Brazil, where the influenza vaccination campaign began on March 23, 2020 (17), and has been followed by an exponential increase in the number of affected (18).
• Geographic differences in terms of COVID-19 cases at the European level, where there are flu vaccination rates in people over 65 years of age that are very low in Eastern European countries, such as Estonia, which does not even reach 5%, compared to Spain , United Kingdom, France or Italy, with rates of 50-60% (19). There are also differences in access to vaccines. Thus, in Estonia, the flu vaccine is paid for (20).
• Geographical and social differences at the national level, with higher rates in aged residences and rural areas, where the vaccination rate is higher than in residents at home and in urban areas. Aragon would be an emblematic case of rural affectation and residences, with a greater casuistry than that which would correspond to it due to its low population density (21)(22).

We believe that given the severity of the pandemic, which has already claimed more than 400,000 lives worldwide, the publication of our study could open the door to more in-depth studies on the hypothesis of immune interference, which, if not refuted, but confirm it, could serve as a theoretical basis to radically change the strategy followed up to now by the different health administrations.

Bibliography

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