Plasma in the fight against COVID-19
Alongside the Italian National Health Service and hospitals for plasma therapy
Industrial viral inactivation as an additional option
Contract Manufacturing in Italy
Plasma in the fight against COVID-19
To cope with the serious health emergency caused by the SARS-Cov-2 pandemic, companies that produce plasma derivatives worldwide are engaged in research projects on the use of plasma1 the protein component of the blood (which contains proteins, as well as nutrients, metabolic products, hormones and inorganic electrolytes), as a potential treatment for COVID-19 patients.
Kedrion is one of these companies. On the strength of the expertise and experience it has gained in the industry, Kedrion immediately committed its Research and Development team to identifying potential plasma therapies in the shortest possible time.
A conclusive answer on the therapeutic potential of plasma and plasma-derived drugs in the fight against COVID-19 will come from the clinical trials which are currently underway. However, as already suggested by an analysis published in the renowned international scientific journal Nature (“Convalescent serum lines up as first-choice treatment for coronavirus,” May 7, 2020) commenting on the initial studies, “Antibodies from blood donated by people who recovered from the illness and hyper-immune immunoglobulins are becoming treatments of choice for COVID-19.”
Alongside the Italian National Health Service and hospitals for plasma therapy
From the early stages of the emergency, Kedrion has made its services available to national and regional institutions and health authorities, first and foremost the Italian National Blood Center.
It was a natural choice for us, as we have been working with the Italian National Health System for many years – a system which many countries consider to be a benchmark because of the way in which it has responded to the emergency.
Specifically, between the end of February and the beginning of March, Kedrion responded to requests from the transfusion centers of the hospitals of Padua, Mantua and Pisa, which had embarked on the road to testing the use of convalescent plasma, by providing free viral inactivation2 equipment (viral inactivation guarantees the neutralization of pathogens, such as HBV and HIV) and the quantity of kits needed to start testing as quickly as possible.
Albeit provided free of charge, these supplies were managed in accordance with the codified administrative procedures for the purchase of capital goods and in compliance with precise indications of the Italian National Blood Center (www.centronazionalesangue.it), in order to ensure that the plasma used in these tests had been subjected previously to a viral inactivation process before being administered to patients.
Kedrion has no official role, but is ideally supporting all the experiments on hyperimmune plasma3, a plasma rich in antibodies for COVID-19 (anti-SARS-Cov-2), beginning with the first, at San Matteo Hospital in Pavia and Poma Hospital in Mantua, up to the one promoted by the Italian National Institute of Health and the Italian Medicines Agency (AIFA), which involves 56 centers, located in 12 Regions, and the University Hospital of Pisa and the Policlinico San Matteo in Pavia acting as principal investigators.
Although not supported conclusively by publications and scientific evidence as yet, the results of these experiments are also promising, judging by what the researchers themselves have already anticipated. In fact, some Regions are launching campaigns to recruit donors who have recovered from COVID-19 in order to build up stocks of hyperimmune plasma, in collaboration with donor associations, and in particular, with the Association of Voluntary Italian Blood Donors (AVIS).
Industrial viral inactivation as an additional option
In accordance with the Contract Manufacturing agreements codified within the Italian National Self-Sufficiency Program, Kedrion already processes plasma collected by its partner-Regions to produce an actual drug, namely, pharmaceutical grade plasma which has been virus-inactivated using the solvent/detergent (SD) technique. SD plasma is then returned to the Regions for transfusion use.
As we have already reported, in order to cope with the COVID-19 emergency, the Regions are collecting COVID-19 convalescent plasma with known anti-SARS-Cov-24 antibody titer in order to treat patients affected by the disease.
Since this plasma comes from convalescent donors, the guidelines of the Italian National Blood Center require that it should undergo the following treatments before being infused into patients:
- 1. Tests for the following three viruses: Hepatitis A, E and parvovirus B19 (HAV, HEV, PVB196), in addition to testing for HBV, HCV, HIV5 (as is already normally the case with regular donors);
- 2. Viral inactivation procedure to eliminate any pathogens;
- 3. Determination of the anti-SARS-Cov-2 antibody titer.
Consequently, the preparation in hospitals of hyperimmune plasma from convalescent patients is quite expensive, both from an organizational and economic point of view, whereas steps 1 and 2 (further testing of HAV, HEV and PVB19, and viral inactivation) are already planned and consolidated within the industrial process applied by Kedrion.
For these reasons, the Italian Regions, beginning with Lombardy, are considering starting the industrial processing of convalescent plasma from Italian donors in with the frame of the Contract Manufacturing agreements, as already occurs with standard plasma. In this way, the Regions would receive pharmaceutical grade SD plasma with all the advantages offered by industrial processing, in terms of standardization of the production process, protein content and titration of the finished product; a product which would remain the property of the Regions themselves and have a four-year shelf life, which is longer than the shelf life of fresh frozen plasma.
We believe that our production plant in Sant’Antimo in the province of Naples, which is the only plant in Italy capable of transforming fresh frozen plasma into pharmaceutical grade inactivated plasma, may represent another key element in the fight against the epidemic.
Finally, it must be stressed that pharmaceutical grade plasma is not a synthetic product: it is human plasma which undergoes industrial viral inactivation processing by means of standardized procedures.
To date, no administrative procedure has been announced for awarding contracts to manufacturers to provide industrial hyperimmune plasma inactivation services.
Hyperimmune Immunoglobulins
Convalescent plasma is proving effective in the treatment of COVID-19 patients because it contains specific antibodies against the virus. The ideal therefore would be to isolate these antibodies, particularly those that neutralize the virus, by developing a concentrate of hyperimmune Immunoglobulins7 (anti-SARS-Cov-2 antibodies) to be used for the passive immunization of patients (i.e. with specific antibodies administered externally, without stimulating an “active” response in the patient’s immune system), thus providing a new therapeutic tool for the most critical cases and a possible preventive treatment for people who have been exposed to the virus and who are at risk of infection (e.g. healthcare personnel).
To achieve this, Kedrion has decided to start a partnership with Kamada, a leading Israeli biotechnology company with a proven and agile technology for developing and rapidly producing anti-SARS-Cov-2 Immunoglobulins. An encouraging choice in view of the fact that Kamada, as recently announced, is already working on the first batches and estimates that by the end of June the product will be available for clinical trials to be conducted on COVID-19 patients in Israel, in order to test the effectiveness, safety and tolerability of the product.
The drug which Kedrion and Kamada are developing together will be produced from hyperimmune plasma collected mainly in the United States, and will be destined for international markets. As far as Italy is concerned, we hope that the hyperimmune plasma collected in our Country can be used exclusively by our National Health System under the Contract Manufacturing program for the production of anti-SARS-Cov-2 Immunoglobulins.
Contract Manufacturing in Italy
The reference model in the field of third-party plasma contract manufacturing is the Italian one, for which Kedrion was the undisputed pioneer. Started in 1984, formally established in 1990, Italian Contract Manufacturing is based on the strategic collaboration between the Italian Healthcare System, industry and donor associations, and in our country, this has led to an almost seventeen-fold increase in the availability of domestic plasma-derived drugs over the last few decades.
Kedrion has always collaborated with all the stakeholders of the Italian National Blood System, especially when it became necessary for the Italian Transfusion System to reorganize itself in order to meet the organizational and technical quality standards required by the EU.
The company supports and enhances the Italian National Self-sufficiency Program in blood components and plasma-derived drugs, a program which scientific literature has confirmed is both sustainable and advantageous compared with resorting to the free market.
For this reason, foreseeing that the demand for whole blood (from which 75% of the plasma used to produce plasma-derived drugs is derived) would decrease, Kedrion has worked alongside donor associations and has supported their initiatives in order to raise their awareness of the importance of plasma donation for producing life-saving drugs to treat patients.
In the same way, Kedrion has contributed to the debate on finding solutions that would allow the Italian National Transfusion System to continue to organize itself more efficiently.
Today, also in the case of hyperimmune plasma, the Italian National Health System will have to set up administrative procedures for entrusting both the convalescent plasma industrial inactivation service aimed at obtaining stocks to be used in event of a resurgence of the pandemic, and Contract Manufacturing activities with convalescent plasma aimed at producing specific anti-SARS-Cov-2 Immunoglobulins for the Italian System.
In both cases, it will be a matter of transforming publicly owned raw material and giving back a finished product to the Italian National Health System.
Today, even more so than before, Kedrion reaffirms its willingness to collaborate with the Italian National Health System by guaranteeing its support and by making available its services.
(1) Plasma is the liquid component of the blood (i.e. without the cellular component, composed of red blood cells, platelets and white blood cells), yellow in color and made up of about 92% water, in which salts and plasma proteins are dissolved: albumin, fibrinogen and coagulation factors produced by the liver, immunoglobulins (or antibodies for defense) produced by lymphocytes. Plasma also carries hormones and enzymes and brings nutrients, such as glucose, lipids, mineral salts, etc., to the body’s cells. At the same time, plasma removes waste products, such as carbon dioxide, lactic acid and others. Plasma helps to maintain blood pressure and also the acid-base balance, the pH of the blood. (2) The viral inactivation process helps make the blood product safer. Inactivation is performed by a machine called an “inactivator” or “illuminator.” The substance that is activated by ultraviolet rays and binds to the nucleic acids of the pathogens present in the plasma is put into the bag. In this way, it inactivates the pathogen, bacterium or virus, then destroys them, thus making them non-replicable. Other photosensitizing substances that act photodynamically under the action of light, for example methylene blue, can also be used. Inactivation may also be based on the use of other physical means, e.g. heat by pasteurization using dry heat or moist heat in the form of steam. Another technique is the neutralization of viral agents by means of corresponding monoclonal antibodies or the use of chemical or biochemical substances, including ethanol, enzymes (pepsin) together with pH changes, mixtures of solvent and detergent substances and substances capable of interacting with virus nucleic acids. (3) Hyperimmune plasma is plasma from patients who have recovered from SARS-CoV-2 infection. It is so named because of the antibodies which are developed during the period of virus infection. Only those who have a high “antibody titer,” i.e. a high level of the specific antibodies useful for eradicating the Coronavirus, are able to donate this type of plasma. (4) Anti-SARS-CoV-2 antibodies are antibodies specific to the proteins of the COVID-19 virus envelope that can neutralize it. (5) These are tests, carried out on each individual blood donation or blood component, aimed at detecting the presence of hepatitis B virus infection, hepatitis C virus and acquired immune deficiency syndrome. (6) Tests for the presence of hepatitis A, hepatitis E and ParvoVirus-B19 infection or to determine a person’s immune status. (7) Hyperimmune immunoglobulins are immunoglobulins extracted from the blood of a selected group of donors that have a high content of antibodies directed specifically against the antigens of a particular virus, bacterium or toxin produced by a bacterium. These are patients recovering from natural infections or from vaccinated donors. The most commonly used hyperimmune immunoglobulins are the anti-Rh immunoglobulins administered to Rh-negative mothers a few hours after delivery to prevent the passage of Rh-positive red blood cells from the fetus to the mother and thereby preventing hemolytic disease of the newborn in subsequent pregnancies; immunoglobulins for the hepatitis B virus, which are injected into newborns of virus-carrying mothers immediately after childbirth in order to prevent infection of the newborn; immunoglobulins against the rabies virus; immunoglobulins for botulinum toxin; and immunoglobulins for tetanus toxin
