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Cardoso, M.; Ragan, I.; Hartson, L.; Goodrich, R.P. Riboflavin + UV Light Pathogen Reduction Technology. Encyclopedia. Available online: (accessed on 23 June 2024).
Cardoso M, Ragan I, Hartson L, Goodrich RP. Riboflavin + UV Light Pathogen Reduction Technology. Encyclopedia. Available at: Accessed June 23, 2024.
Cardoso, Marcia, Izabela Ragan, Lindsay Hartson, Raymond P. Goodrich. "Riboflavin + UV Light Pathogen Reduction Technology" Encyclopedia, (accessed June 23, 2024).
Cardoso, M., Ragan, I., Hartson, L., & Goodrich, R.P. (2023, December 28). Riboflavin + UV Light Pathogen Reduction Technology. In Encyclopedia.
Cardoso, Marcia, et al. "Riboflavin + UV Light Pathogen Reduction Technology." Encyclopedia. Web. 28 December, 2023.
Riboflavin + UV Light Pathogen Reduction Technology

Blood transfusions are essential in treating patients with anemia, blood loss, and other medical conditions. However, these lifesaving procedures can contribute to infectious disease transmission, particularly to vulnerable populations. New methods have been implemented on a global basis for the prevention of transfusion transmissions via plasma, platelets, and whole blood products. Implementing proactive pathogen reduction methods may reduce the likelihood of disease transmission via blood transfusions, even for newly emerging agents.

transfusion blood pathogen reduction

1. Introduction

Historically, diseases were spread under the conditions of war, trade, and travel. Today, in the age of globalization, the mobility of goods and people is extremely high [1]. Moreover, human population growth has led to an increased urbanization of wild habitats and the over-exploitation of water and fossil fuels, which are culminating in a remarkable increase in land and ocean temperatures since 1981 [2][3][4]. The effects of these changes are seen in the increased number of floods and intense storms, as well as the thawing of permafrost and melting of sea ice, which will continue to push people and animals into more restricted geographical areas [5]. We now see an increased proximity of humans to wild animals, including primates, as well as the presence of insect vectors in temperate regions previously only found in the tropics [3]. All of these propagate the impact of the disease triangle comprising the environment, pathogens, and society [6].
Over the past 40 years, we have seen an increasing emergence and re-emergence of infectious diseases. HIV was identified as the agent of a pivotal species cross-over infection leading to the global AIDS epidemic. Its spread was facilitated by modern human practices and social behaviors, e.g., sexual activity, blood transfusions, and intravenous drug abuse [7][8]. Outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) in Southeast Asia, Ebola virus disease in Africa, Middle East respiratory syndrome coronavirus (MERS-CoV) in the Middle East, and Zika virus disease, chikungunya, yellow fever, and dengue in the Americas followed in the ensuing two decades [9][10]. Finally, in 2020, the WHO declared the COVID-19 outbreak caused by SARS-CoV-2 a pandemic, which was responsible for over 6.8 million human deaths globally [11].
Emerging and re-emerging pathogens pose an important risk to transfusion medicine. Along with the classic bloodborne pathogens, HIV, HBV, and HCV, arbovirus transmission through blood transfusion has been increasingly reported in the past 20 years [12][13]. While there have been numerous reports of transfusion-transmitted infectious by West Nile and Dengue viruses, there are other arboviruses tentatively implicated in disease transmissions, such as Zika virus, yellow fever virus, tick-borne encephalitis virus, Japanese encephalitis virus, Powassan virus, St. Louis encephalitis virus, Ross River virus, and Colorado tick fever virus [14].
In the past 40 years, blood transfusion safety measures have been developed and implemented as a reaction to the identification of new infectious threats. Initially, the detection of infections was based on immunological assays. Currently, HBV/HCV/HIV nucleic-acid-based tests or NATs are part of the blood screening algorithm in many parts of the world. These tests are able to detect pathogens at an earlier phase of infections [12]. In accordance with local epidemiology, WNV-NATs have also been integrated in the blood donation screening strategies of some countries, and most recently, NATs to detect Babesia sp. and Zika virus infections have been implemented in the USA, the latter of which was eventually discontinued [12][15][16][17][18]. Testing strategies have been very effective in reducing risks once identified [19]. Yet, the climate/social developments of the past several years make the emergence of novel pathogens unpredictable and highlight the inadequacy of reactive prevention strategies in quickly addressing emergent needs in a timely way.
Pathogen reduction (PR) is a proactive strategy to mitigate the risk of transfusion-transmitted infections (TTI). Available PR methods involve the physicochemical disruption of pathogen structural elements or the photochemical modification of nucleic acids to prevent replication [20][21][22]. The plasma fractionation industry has the longest and most successful experience with PR, starting 30 years ago with the systematic application of methods of pathogen inactivation/removal in the manufacturing process to increase the safety of plasma-derived medicine products to the high levels seen today [23].
As for labile blood components, methods of PR have been gradually implemented in Europe in the last 10 years and lately in the USA, mostly for the treatment of platelet concentrates and plasma for transfusions [16][24]. Commercially available systems utilize different wavelengths of UV light or visible light with or without different photochemical or photodynamic compounds [21]. The Theraflex MB System (MacoPharma) was developed for the treatment of individual plasma for transfusions [22]. It combined methylene blue as the photoreactive compound and visible light and was the first commercialized system. It was followed by the Intercept system (Cerus Corp) for the treatment of platelets and plasma using the chemical substance amotosalen hydrochloric acid (S-59), a synthetic psoralen, and UV-A. The Mirasol PRT System for plasma, platelets, and whole blood utilizes riboflavin or vitamin B2 as the photosensitizer and UV light. Recently, the Theraflex UV Platelet system was developed by MacoPharma and relies only on illumination with UV-C light.
In 2016, the results of an AIMS randomized clinical trial which investigated the effectiveness and feasibility of a riboflavin + UV light treatment of whole blood for transfusions in a highly malaria-endemic country were published. It showed for the first time the effectiveness of the PRT System in reducing the incidence of transfusion-transmitted disease, in this case, malaria [25][26]. Moreover, the componentization of whole blood treated with riboflavin and UV light and the transfusion of processed red cell concentrates have shown promising results in relation to safety and therapeutic effectiveness in a cohort of pediatric patients [27]. Treatments to inactivate pathogens in red cell concentrates are still under development [22][28].
Doubtless, worldwide adoption of such proactive technology will depend on the availability of a technology for treatment of all blood derived components universally and at acceptable cost. Yet, component treatment has proven that the concept of a universal pathogen-inactivated transfusion is possible, as demonstrated by the recent report of patients receiving all blood components treated with riboflavin plus UV technology [24].

2. Riboflavin + UV Light Pathogen Reduction Technology

The effectiveness of the Mirasol PRT System against a broad range of pathogens has been previously described for multiple blood product types [29]. Designed to be a pathogen-agnostic system, the technology has a demonstrated ability to reduce the infectious pathogen load of viruses, bacteria, and parasites in plasma, platelets, and whole blood products, including against emerging diseases for which the development of diagnostic tests may lag behind the emergence of the pathogen. Of importance, the Mirasol PRT System has been demonstrated to be effective against mpox, SARS-CoV-2, Ebola, and HEV (Table 1).
Table 1. Blood product types used to evaluate PRT inactivation of viruses of interest.
Viral Pathogen Platelets Plasma Whole Blood Reference
Hepatitis E Not tested [30]
Ebola Not tested [31]
SARS-CoV-2 [32][33][34]
Mpox Not tested [35]
✓ indicates blood product type has been tested.

2.1. Mpox

To evaluate the effectiveness of the Mirasol PRT System against the mpox virus that emerged in 2022, plasma and whole blood products (n = three of each) were inoculated with the mpox virus (USA_2003), with pre-treatment titers of 3.50 and 3.08 log10 pfu/mL, respectively [35]. These pre-treatment viral titers were clinically relevant based on the amount of the virus detected in the patients infected with the mpox virus. All products were treated with the Mirasol System as per the manufacturer’s instructions for each product type, and for all products, the post-treatment titer was below the limit of detection.

2.2. SARS-CoV-2

Before it was known whether SARS-CoV-2 could be transmitted via blood, several studies were performed to assess the ability of the Mirasol PRT System to reduce the viral load in blood products. In one study, plasma and whole blood products were inoculated with 3–4 log10 pfu/mL of SARS-CoV-2 virus (USA-WA1/2020) [32]. The rate of viral inactivation was evaluated in the plasma products with energy doses of 30, 60, and 100% of the target dose delivered, and the post-treatment titers were measured. The whole blood products were treated as per the manufacturer’s instructions with 100% of the target UV dose. The viral titers reached the limit of detection at 60% of the target energy dose in the plasma products, while the treatment of the whole blood products yielded an average viral reduction of 3.30 log10, demonstrating that Mirasol is efficacious in inactivating SARS-CoV-2 in plasma and whole blood products.
These data were further bolstered in a second study that reported the results from a Mirasol treatment of both plasma and platelet products in plasma [33]. The pre-treatment titers for all the products were greater than 4.3 log10 pfu/mL, and, as in the first study, the treatment resulted in no detectable virus plaques, meaning that the remaining infectious titers were below the limit of detection of the standard plaque assay.
Because convalescent plasma collected from patients who had recovered from SARS-CoV-2 infection was utilized in the early days of the pandemic to treat patients with active disease, a third study was performed to evaluate whether the neutralizing antibodies present in SARS-CoV-2 convalescent plasma products would be preserved following Mirasol PRT treatment [36]. Plasma products collected from known SARS-CoV-2 convalescent donors were collected, and pre-treatment neutralizing antibody titers were determined by both a plaque reduction neutralization test against the live SARS-CoV-2 virus, as well as a pseudovirus reporter viral particle neutralization (RVPN) assay. Spike protein receptor-binding domain (RBD) and subunits S1 and S2 were also evaluated using an enzyme-linked immunosorbent assay (ELISA). Minimal effects to the measured antibodies were demonstrated in all the assays, suggesting that the Mirasol System is effective in reducing the viral burden in blood products while simultaneously conserving the therapeutic benefits of convalescent plasma components.

2.3. Ebola

The Ebola epidemic that originated in Guinea, West Africa in 2013 lasted for over two years and claimed over 10,000 lives, spreading not only within Africa but to other continents as well, as health care workers working on the front lines traveled back to their home countries and then tested positive for infection. At the time, there was no approved vaccine for EBOV, and the use of convalescent plasma was implemented to combat the disease.
Cap et al. (2016) evaluated the effectiveness of a Mirasol PRT treatment of plasma and whole blood for the inactivation of Ebola virus. The investigators reported that the UV+ riboflavin treatment reduced the EBOV titers to non-detectable levels in both nonhuman primate serum (≥2.8- to ≥3.2-log reduction) and human whole blood (≥3.0-log reduction) without decreasing the protective antibody titers in human plasma [31].

2.4. Hepatitis E

Initially believed to only be transmitted orally [37][38], HEV is now understood to be also transmitted by blood transfusion [39] and can cause severe hepatitis. HEV is classified into four genotypes (G1–G4), with G3 being the most widely distributed globally. In order to evaluate the ability of the Mirasol System to be used as a tool to prevent transfusion transmissions of HEV, Owada et al. (2014) reported that they used plasma and serum specimens collected and cultured from HEV-RNA-positive patients to produce the JRC-HE3 strain for G3 and a UA1 strain for G4 [30]. These authors further observed that the Mirasol PRT system achieved a >3 log inactivation for the JRC-HE3 strain and a >2 log inactivation for the UA1 strain of HEV. They concluded that the Mirasol PRT system “inactivated greater than 2 to 3 logs of live HEV in PLTs and can potentially be used to lower the possibility of bloodborne HEV transmission”.


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