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Biosafety assays for the diagnosis and prediction of drug-related complement pathology

Periodic Reporting for period 1 - Biosafety (Biosafety assays for the diagnosis and prediction of drug-related complement pathology)

Okres sprawozdawczy: 2020-09-01 do 2021-11-30

The safety issue addressed by our consortium refers is the frequest occurrence of allergic reactions, also known as infusion-, or hypersensitivity reactions (HSRs), to nanomedicines and most recently, COVID vaccines. These are complex, immune-mediated adverse effects that can occur upon intravenous infusion of pharmaceuticals, leading to severe and sometimes life-threatening conditions in patients.These reactions are not traditional allergies, since there is no sensitization before they arise, and for this reason, the traditional allergy (skin prick) tests do not predict them. Twenty-two years ago a theory was proposed that these reactiuons are due to activation of the complement (C) system, and, hence, they represent C activation-related pseudoallergy (CARPA).
Anaphylaxis is a very rare complication of vaccinations, occurring in about 1.4 case out of a million vaccinations worldwide. The USA Center for Disease Control (CDC)’ most recent estimate is 2.5-4.7 anaphylaxis per million vaccinations with mRNA COVID vaccines, which small (2-3-fold) increased risk for this severe adverse effect still means very rare prevalence. Considering the 1% mortality rate of anaphylaxis, the clinical significance of the phenomenon seems small, yet it obtains intense regulatory, scientific and public attention.
Signs of unceasing concern about allergic reactions include the multiple questions on allergies on the COVID-19 vaccination consent forms with exclusion of people with severe allergies to any of the vaccine components, history of anaphylaxis, autoimmune diseases, Guillain-Barré syndrome, Bell’s palsy, and cosmetic dermal filler recipients; the mandated 30-minute post-vaccination monitoring for everyone getting the vaccine; the directives that vaccination centers must be prepared for emergency treatment of anaphylaxis or other forms of HSRs; and guidance on how to prevent and treat vaccine-induced anaphylaxis.
Due to all these measures, the phenomenon’s rate tends to decrease, but case reports continue to emerge in the Vaccine Adverse Effect Reporting System (VAERS) whose latest analysis (Aug 31, 2011) showed 15.41 and 14.21 cases per million vaccinations with the Pfizer/Biontech and Moderna vaccines after 193 and 139 million recipients of these vaccines, respectively. Further, more dedicated analyses claimed even greater risks, e.g. 1 reaction in ~4,000 vaccinations in health workers, and ~1 in 1,768 vaccinations administered at a large regional health center.
Since the mechanism of these reactions have been suggested to be CARPA, our sicentific studies and consortial efforts is going to increasingly focus on COVID-19 vaccine reactions.
The EU funded BIOSAFETY project aims to intensify the collaborations with SEMMELW, a “Break-through strategy” based on expertise and direct collaboration with the consortium members. The consortium reflects to the following main gaps at SEMMELW that need to be overcome in order to succeed: 1) low presence on international conferences, low international attractiveness, 2) acquisition of international grants, 3) lack of know how to translate research results relevant for industry into products 4) preparedness of SEMMELW for cooperation with the business sector.
In the first period of the project (September 1, 2020 – November 30, 2021), BIOSAFETY built a strong cooperation between SEMMELW Nanomedicine Group and the consortium partners. This cooperation lead to several successful event, as the Biosafety Summer School, the thematic workshops.
The achievements of BIOSAFETY during the first period are resumed below:
• 1 international summer school was organized;
• 1 experts visit to SEMMELW realized ;
• 2 BIOSAFETY events (kick-off meeting and 1st year reporting meeting) organized;
• 4 lectures given by BIOSAFETY partners;
• Several communication activities performed through the website, social media, logo, meetings with industry and research groups, among others;
• 5 Open Access publications were published
The project will strengthen cross-disciplinary collaborations through:
“Nanomaterial for Therapeutics”: products triggering severe adverse events can include both traditional small molecules but also biologics such as therapeutic antibodies (Abs), fusion proteins, etc. and novel formulations using liposomes or nanotechnology (KET 2–5);
“Advanced Materials, Nanotechnology and Nanomaterials”: as it is known and published that certain drugs, especially anticancer nanomedicines, therapeutic monoclonal antibodies, cause C activation during administration to the patient4 (KET 1–5).

The consortium partners will initiate joint research, innovation and educational activities, sharing best practices in policies, internationalization and research management processes. The partnership within the consortium is reviving traditional scientific, economic and societal links, utilising the close geographical and cultural proximity, and further strengthening the Budapest region, Hungary and Europe.
The scientific goals of BIOSAFETY project are: a) Purification of pig serum C proteins, b) Generation of specific polyclonal and monoclonal Abs, c) Assay development, technical assay validation and production of a test kits and d) Biological validation in pigs wherein HSRs are induced with known C activators.