Vox Sanguinis (2015) 109, 44–51 © 2015 International Society of Blood Transfusion DOI: 10.1111/vox.12247

ORIGINAL PAPER

Tolerance of platelet concentrates treated with UVC-light only for pathogen reduction – a phase I clinical trial T. Thiele,1 P. Pohler,2 T. Kohlmann,3 A. S€ umnig,1 K. Aurich,1 K. Selleng,1 A. Westphal,1 T. Bakchoul,1 A. Petersmann,4 2 1 T. H. M€ uller, A. Greinacher & A. Seltsam2 1

Institut f€ur Immunologie und Transfusionsmedizin, Universit€ atsmedizin Greifswald, Greifswald, Germany DRK Blutspendedienst NSTOB, Institut Springe, Springe, Germany 3 Institut f€ur Community Medicine, Universit€atsmedizin Greifswald, Greifswald, Germany 4 Institut f€ur Klinische Chemie und Labormedizin, Universit€ atsmedizin Greifswald, Greifswald, Germany 2

Background The THERAFLEX UV-Platelets pathogen reduction system for platelet concentrates (PCs) operates with ultraviolet C light (UVC; 254 nm) only without addition of photosensitizers. This phase I study evaluated safety and tolerability of autologous UVC-irradiated PCs in healthy volunteers. Methods Eleven volunteers underwent two single (series 1 and 2) and one double apheresis (series 3). PCs were treated with UVC, stored for 48 h and retransfused in a dose-escalation scheme: 12
5, 25% and 50% of a PC (series 1); one complete PC (series 2); two PCs (series 3). Platelet counts, fibrinogen, activated partial thromboplastin time, prothrombin time, D-dimer, standard haematology, temperature, heart rate, blood pressure and clinical chemistry parameters were measured. One- and 24-h corrected count increments were determined in series 2 and 3. Platelet-specific antibodies were assessed before and at the end of the study. Results Neither adverse reactions related to transfusions nor antibodies against UVC-treated platelets were observed. Corrected count increments did not differ between series 2 and 3. Received: 22 October 2014, revised 15 December 2014, accepted 15 December 2014, published online 6 March 2015

Conclusions Repeated transfusions of autologous UVC-treated PCs were well tolerated and did not induce antibody responses in all volunteers studied. EudraCT No. 2010-023404-26. Key words: pathogen reduction, phase I clinical trial, platelet concentrates, UVC.

Introduction Pathogen reduction technologies (PRTs) are increasingly applied to reduce the risk of pathogen transmission by transfusion of platelet concentrates (PCs). Current PRTs for PCs rely on photochemical pathogen inactivation using photo additives in the presence of ultraviolet (UV) light [1]. Recently, we developed a PRT solely based on the microbiocidal and virucidal properties of short-wave UVC-light (wavelength range, 200–280 nm) [2]. This Correspondence: Thomas Thiele, Institut f€ur Immunologie und Transfusionsmedizin, Universit€atsmedizin Greifswald, Sauerbruchstraße, 17489 Greifswald, Germany E-mail: [email protected]

44

technology, designed for the inactivation of pathogens in human platelet (PLTs), red blood cell and plasma concentrates, works by combining UVC-irradiation of a specific wavelength (254 nm) with vigorous agitation. The UVC-based PRT (THERAFLEX UV-Platelets) effectively reduces bacteria, viruses and parasites by direct interaction of UVC-light with nucleic acids [2–5]. This predominantly results in the formation of nucleotide dimers, which block the elongation of nucleic acid transcripts [6, 7]. The UVC-based PRT also effectively inactivates residual leucocytes which makes this method an alternative to gamma-irradiation, the current standard of care for prevention of transfusion-associated graft-versus-host-disease in patients at risk [8]. The UVC-irradiation procedure that uses a specific wavelength of 254 nm should mainly affect the nucleic acids of contaminating

Phase I clinical trial on UVC-treated platelets 45

pathogens and leucocytes while leaving the proteins in plasma and on cells largely intact. The storage conditions of PLT units (at room temperature, continuous agitation) favour the growth of certain bacteria allowing contaminating bacteria to grow up to high titres during storage. It is therefore critical for effective pathogen reduction to apply treatment before bacterial titres exceed the maximum capacity of the procedure. The simple and rapid procedure of the UVC-system (total processing time < 10 min) can be performed and finished very early after preparation of buffy coat and apheresis PCs. Therefore, this method can easily be integrated in any routine production process and also ensures that the ‘bacterial load’ at the time of pathogen reduction treatment is low. The UVC-based PRT does not require photoactive additives and does not create new impurities. Therefore, conventional approaches to toxicity testing such as those used for pharmaceuticals are not appropriate for UVCirradiated blood units. The wavelength of 254 nm is outside the absorption maximum of proteins. Some studies applying higher doses of UVC have shown that UV-treatment can cause damage to proteins by disulphide photolysis and oxygen radical formation [9, 10]. In vitro studies have shown only a slightly higher metabolic activity and moderate activation of UVC-treated PLTs [2, 11], which is comparable with the quality reported for other pathogeninactivated products [12–15]. Modification of macromolecules in plasma or on cells could create new antigens (neoantigens) recognized by the recipient’s immune system as foreign, which could elicit immune responses to the pathogen-reduced products, resulting in clinical symptoms of intolerance and refractoriness. A preclinical study investigating the tolerability and immunogenicity of UVC-irradiated PCs in a dog model showed that repeated transfusions of autologous UVC-treated PCs were well tolerated in all dogs studied and UVC-irradiation did not cause plasma or PLT protein modifications capable of inducing specific antibody responses in the dogs [16]. A radiolabeling study in healthy donors suggests sufficient recovery and survival of autologous UVC-treated PLTs,

Corrected count increment ¼

and clinical chemistry parameters as well as antiplatelet antibodies after repeated transfusion of UVC-treated PCs and determined corrected platelet count increments (CCIs) to check for accelerated removal of transfused PLTs as potential consequence of an immune response to UVCinduced alterations of PLT antigens.

Methods Design, participants and ethics This single centre, open label, prospective study was conducted with healthy male volunteers eligible for PLT apheresis according to the German Haemotherapy Guidelines at an age of 18–40 years and with PLT counts ≥ 250 9 10E9/l, including negative tests (serum antibodies and nucleic acid testing) for hepatitis B virus (HBV), hepatitis C virus (HCV), human immune deficiency virus (HIV) and Lues (serum antibodies). Participants gave informed consent; the study was conducted in accordance to the Helsinki Declaration and approved by the ethical committee of the University of Greifswald and the PaulEhrlich-Institute (EudraCT No. 2010-023404-26). Participants underwent two single PLT apheresis (series 1 and 2) and one double apheresis (series 3) to produce autologous PCs, which were UVC-treated and retransfused 48 h later. A washout period of 12–21 days separated the transfusion procedures (Fig. 1). In series 1, UVC-treated PCs were transfused in three partial doses (12
5%, 25%, 50%) with an interval of 30 min between transfusions. The remaining PC-volume was used for platelet antibody studies. In series 2, one full UVC-treated PLT unit was transfused. In series 3, two full UVC-treated PCs were administered with 1 h between transfusions. Primary end-points were changes in PLT count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and D-dimer levels 1 h after each transfusion compared to the values before transfusion. Secondary end-points were CCIs one and 24 h after transfusion in series 2 and 3 and calculated by the formula:

posttransfusion platelet count - pretransfusion platelet count  body surface area platelet dose transfused

which is similar to what has been reported for INTERCEPT and MIRASOL PLTs [17]. As a next step, we investigated safety and tolerance of UVC-treated PCs in a phase I clinical trial transfusing autologous UVC-treated apheresis PCs in a dose-escalation manner. We assessed vital, coagulation, haematology

© 2015 International Society of Blood Transfusion Vox Sanguinis (2015) 109, 44–51

Further safety variables were blood pressure, temperature, heart rate, and complete blood cell counts before and after transfusion and occurrence of any clinical symptoms of intolerability. The clinical chemistry parameters sodium, potassium, calcium, alanine aminotransferase, gamma-glutamyl transferase, bilirubin, creatinine,

46 T. Thiele et al.

Fig. 1 Study design.

lactate dehydrogenase and C-reactive protein were determined after transfusion. These variables were also screened within 7 days prior to the first apheresis and again at least 21 days after the last transfusion. Serum IgE was assessed at screening and 24 h after transfusion of the last PC.

Preparation of UVC-treated platelet concentrates PLTs were collected in 180 or 360 ml (for double apheresis) plasma and acid-citrate-dextrose Formula A (ACD-A) using Com.Tec cell separators (Fresenius Hemocare, Schweinfurt, Germany) [18]. Additive solution (SSP+, Macopharma, Tourcoing, France) was added to yield 3 9 10E11 PLTs in about 350 ml containing approximately 35% plasma. UVC-treatment was done within 1 h after collection with a dose of 0
2 J/cm² using a Macotronic device (Macopharma) [5]. PCs were stored under blood bank conditions. Sterility was tested after 48 h of storage with validated standard procedures after sterile collection of ~20 ml of each PC.

Vital signs and standard laboratory measurements Blood pressure was determined by Riva Rocci‘s method, temperature was assessed using an infrared ear thermometer (Braun, Kronberg, Germany). Heart rate was determined by palpation of the radialis pulse. Blood counts were measured on an Advia 2120 haematology analyzer (Siemens, Eschborn, Germany). Coagulation and clinical chemistry parameters were determined on a BEP III analyzer (Siemens). Antibodies against HIV, HBV (Anti-HBc), HCV and Lues as well as the HBs-antigen were determined using the Enzygnost test kits on a BEP III analyzer (Siemens). Nucleic acid testing of HIV-1 and 2 and HCV was performed with a Cobas TaqScreen Multiplex test system (Roche Diagnostics, Mannheim, Germany).

Antibody assays PLT-reactive antibodies were determined before the first apheresis and at least 21 days after the last transfusion. Free serum antibodies were measured with the PLT immunofluorescence test for flow cytometry [19–21], an in-house platelet ELISA [22], and the monoclonal antibody-specific immobilization of platelet antigens (MAIPA; GPIIbIIIa; GPIbIX; GPIaIIa) assay using test PLTs of four different donors and the UVC-treated autologous platelets obtained in series 1 [23, 24]. Antibodies bound on autologous PLT glycoproteins (GPIIbIIIa, GPIbIX, GPIaIIa) were screened by direct MAIPA.

Statistics All participants, who received PCs during the trial, were included in the evaluation of safety and tolerance. Statistics was performed using the statistical software package SPSS (version 20; IBM, Armonk, NY, USA). Diagrams were drawn using commercially available software (Prism 6; GraphPad Software, version 6
02, Inc., La Jolla, CA, USA). Primary and secondary safety end-points were analysed using inferential statistics on the basis of 95% confidence intervals. A P < 0
05 was considered as significant. End-points with confidence intervals not covering the null value were considered clinically relevant only if the value after the autologous transfusion is outside of the reference range.

Results Study cohort Eleven male Caucasian volunteers with a mean age of 25
2 (range: 22–35) years were included into the trial. One subject was excluded from the clinical trial after © 2015 International Society of Blood Transfusion Vox Sanguinis (2015) 109, 44–51

Phase I clinical trial on UVC-treated platelets 47

series 2 due to an apheresis-related serious adverse event. This volunteer reported progressive dizziness and nausea 1 day after platelet apheresis (and before retransfusion of the PC), which led to detailed clinical assessment including 24 h in hospital observation. No pathologic conditions were found and symptoms resolved spontaneously and completely. Due to the short precautious hospital stay, the adverse event was classified as serious and the volunteer was excluded from further study. Hence, 11 data sets were available for series 1 and 2; and 10 for series 3.

Characteristics of UVC-treated platelet concentrates The mean PLT count in UVC-treated PCs was 3
27 (range: 2
78–4
06) 9 10E11 in a mean volume of 352 (range: 334–371) ml. PCs were validated to have a residual white blood cell count of < 1 9 10E6/unit, a red blood cell count of < 3 9 10E9/unit and a pH-value between 6
4 and 7
8. All 42 transfused PCs were tested sterile 48 h after apheresis.

Coagulation parameters and platelet counts PT, aPTT, fibrinogen and D-dimers did not show significant changes comparing the values obtained before and 1 h after transfusion in all three series (P > 0
05) (Table 1). PLT counts rose significantly after transfusion of the UVC-treated PCs. During series 1 (about 88% of a full PC in three partial doses), the mean PLT count increase was 22
2 9 10E9/l (245
3 9 10E9/l vs. 267
5 9 10E9/l; P < 0
001); during series 2 (full dose), the mean increase was 29
1 9 10E9/l (256
2 9 10 E9/l vs. 285
3 9 10 E9/l; P < 0
001); and during series 3 (double dose), 52
1 9 10E9/l (198
2 9 10E9/l vs. 250
3 9 10E9/l; P < 0
001). PLT count increases nicely reflected the dose-escalation scheme as the lowest increase was observed after a partial dose and the highest after transfusion of two UVC-treated PCs.

Corrected count increments One hour corrected count increments were determined in series 2 and 3 after transfusion of each PC as secondary end-point. The mean 1 h-CCI was 18
92 (95% confidence interval (CI) 10
3–27
5) in series 2; in series 3, it was 16
5 (95% CI 8
3–24
8) after transfusion of the first PC and 13
65 (95% CI 5
2–22
1) after transfusion of the second PC. The comparison of 1 h-CCIs revealed no significant difference between series 2 and 3 after transfusion of the first and the second PC (P > 0
05 for each comparison), respectively (Fig. 2). © 2015 International Society of Blood Transfusion Vox Sanguinis (2015) 109, 44–51

Mean 24 h-CCIs in series 2 were 29
7 (95% CI 15
1– 44
3) and 17
7 (95% CI 13
4–22
0) in series 3. The 24 hCCI of series 3 did not differ significantly from the CCI of series 2 (P > 0
05; Fig. 2).

Adverse reactions, vital signs, haematology, clinical chemistry No adverse reactions known to be associated with PLT transfusions such as chills, fever, allergy, or thromboembolic complications did occur. Changes in heart rate, body temperature, white and red cell counts before and after transfusion as well as clinical chemistry parameters after transfusion were all minor and considered as clinically irrelevant and/or not related to transfusion of UVC-treated PCs (Table 1). Serum IgE-levels at screening and 24 h after transfusion of the last PC in series 3 did not change (P > 0
05).

Platelet antibody testing No free or PLT-bound antibodies reacting with native or UVC-treated PLTs were observed at screening visit before and at final assessment at least 21 days after repeated transfusions of UVC-treated PCs, as assessed by flow cytometry, ELISA and MAIPA.

Discussion This phase I study in healthy volunteers showed very good tolerability of intravenous transfusions of autologous single-donor PCs treated with the THERAFLEX UV PLTs pathogen reduction system. In addition, no prothrombotic or immunogenic reactions were observed after transfusion of up to two UVC-treated PCs, reflecting clinical transfusion practice volumes. Full therapeutic doses of UVC-treated PCs were repeatedly transfused into immunocompetent volunteers with a follow-up period of at least 3 weeks after the last transfusion covering at least 9 weeks after the first transfusion of UVC-treated PLTs. A PC-storage time of 2 days was used as in current clinical practice issue of PC units is not equally distributed over the whole shelf life and largest numbers of PC units are issued for transfusion to patients on day 2 [25, 26]. In addition, the short storage time was a precaution to avoid the very unlikely adverse effects in healthy volunteers related to bacterial contamination. As primary end-point, this study evaluated the tolerability of intravenous transfusions of UVC-treated PCs. Physical examinations and laboratory tests did not reveal any signs of local or systemic intolerance, even after multiple transfusions. In vitro studies have revealed signs of minor to moderate PLT platelet activation in vitro [2, 11],

PT [Quick %] aPTT [sec] Fibrinogen [g/l] D-Dimer [mg/l] Platelets [910E9/l] Heart rate [beats/min] Systolic blood pressure [mmHg] Diastolic blood pressure [mmHg] Body temperature [°C] Leucocytes [910E9/l] Haemoglobin [mmol/l] Sodium [mmol/l] Potassium [mmol/l] Calcium [mmol/l] Creatinine [mmol/l] ALAT [lkatal/l] GGT [lkatal/l] Bilirubin [lmol/l] LDH [lkatal/l] CRP [mg/l]

>0
05 >0
05 >0
05 >0
05 0
05 >0
05 >0
05 0
026 0
014 >0
05 >0
05 >0
05 >0
05 >0
05 >0
05 0
036 >0
05 >0
05 >0
05

-3
6 to -9
6 -0
7 to 0
5 -0
02 to 0
17 -0
02 to 0
07 14
6 to 29
8 -12
1 to 1
16 -12
0 to 3
8 -9
2 to 5
6 0
04 to 0
54 0
12 to 0
84 -0
18 to 0
13 -0
7 to 1
3 -0
19 to 0
19 -0
08 to 0
04 -13
8 to 7
3 -0
027 to 0
032 -0
052 to -0
002 -2
95 to 0
71 -0
21 to 0
32 -3
76 to 9
89

3
0 -0
1 0
07 0
03 22
2 -5
5 -4
1 -1
8 0
29 0
48 -0
03 0
3 0
00 -0
02 -3
2 0
003 -0
027 -1
12 0
06 3
06

0
45 0
45 -0
09 0
3 0
22 0
01 -3
6 0
074 -0
001 -0
86 -0
03 0

-2
7

-0
2 -0
1 0
05 0
02 29
1 -6
6 0
5

0
13 to 0
76 0
13 to 0
77 -0
023 to 0
05 -1
0 to 1
6 0
11 to 0
33 -0
05 to 0
07 -10
6 to 3
3 0
006 to 0
141 -0
052 to 0
048 -4
43 to 2
7 -0
18 to 0
12 n.a.

-8
0 to 2
6

-2
0 to 1
6 -0
6 to 0
5 -0
07 to 0
18 -0
01 to-0
05 17
3 to 40
9 -12
6 to -0
4 -5
1 to 4
2

95% confidence interval of the difference

Mean difference

P-value

95% confidence interval of the difference

Mean difference

0
01 0
011 >0
05 >0
05 0
001 >0
05 >0
05 0
035 >0
05 >0
05 >0
05 n.a.

>0
05

>0
05 >0
05 >0
05 >0
05 0
05

P-value

0
19 1
08 0
04 0
5 -0
01 -0
02 -0
3 0
07 0
01 0
18 0
01 0

2
5

5
0 -0
4 0
08 0
02 52
1 -4
7 1
2

Mean difference

>0
05 >0
05 0
05 >0
05 >0
05 >0
05 >0
05 >0
05 >0
05 >0
05 >0
05 n.a.

-0
13 to 0
51 0
58 to 1
57 -0
1 to 0
18 -0
9 to 1
9 -0
41 to 0
39 -0
1 to 0
07 -13
1 to 12
5 -0
02 to 0
16 -0
06 to 0
07 -1
87 to 2
23 -0
18 to 0
19 n.a.

>0
05 >0
05 >0
05 >0
05 0
05

P-value

-2
6 to 7
6

-0
4 to 10
4 -0
9 to 0
1 -0
05 to 0
21 -0
01 to 0
05 37
4 to 66
8 -9
0 to -0
4 -3
8 to 6
2

95% confidence interval of the difference

Series 3 (two full transfusions)

ALAT, alanine amino transferase; GGT, gamma- glutamyl transferase; LDH, lactate dehydrogenase; CRP, C-reactive protein; n.a., not applicable because all CRP values determined were below 3
1 mg/l, no confidence interval could be determined. Differences of primary end-points (platelet counts and coagulation parameters), blood pressure, heart rate and temperature were calculated from values before and 1 h after transfusion. Differences of all other values were calculated from values obtained at screening visit and 1 h after transfusion. A P-value < 0
05 was considered significant. All significant changes (except PLT counts) were minor and considered clinically not relevant because mean values after the autologous transfusion were not outside of the reference range.

Safety measures

Primary end-points

Parameter

Series 2 (one full transfusion)

Series 1 (partial transfusion)

Table 1 Primary end-points and safety measures

48 T. Thiele et al.

© 2015 International Society of Blood Transfusion Vox Sanguinis (2015) 109, 44–51

Phase I clinical trial on UVC-treated platelets 49

P > 0·05 P > 0·05

50

Corrected count increments

P > 0·05

40

30

20

10

I

rie Se

rie s Se

s

2; 24

3; 24

hC

hC

C

C

I

Tx I2 nd

hC 3; s rie

Se

Se

rie

s

Se

3;

1

1

rie s

hC

C

C

2; 1

hC

C

I

I1 st Tx

0

Fig. 2 Corrected count increments (CCIs) in series 2 and 3 (columns with mean +95% confidence interval) 1 and 24 h after transfusion.

comparable to the PLT activation reported for other PRT systems [12–15]. No significant changes were observed in global coagulation markers after transfusion of 42 UVCtreated PCs in eleven individuals with normal PLT counts. Hence, it is unlikely that transfusion of UVC-treated PCs will lead to a severe activation of the coagulation cascade in patients with low PLT counts. After allogeneic PC-transfusions, chills, fever and circulatory impairment mediated by cytokines released from PLTs during PC-storage can occur [27–29]. Theoretically, this release of bioactive molecules into the PC-storage media might have been enhanced after UVC-treatment. However, even large doses of UVC-treated PCs were well tolerated. Changes in vital signs and laboratory parameters were all minor and considered as clinically non-relevant and/or not related to transfusion of UVC-treated PCs, indicating that UVC-treatment of PCs does not cause a major release in cytokines or induction of other inflammatory processes after transfusion. Previous in vitro studies have shown low levels of white blood cell-associated cytokines and only mild increase in the levels of different PLT-derived cytokines in UVC-treated PCs during storage, which is in line with the good tolerability of UVC-irradiated PCs in volunteers observed in the present study [30]. Theoretically, the administration of UVC-treated PCs may induce neoantigens on proteins triggering the formation of PLT antibodies, potentially even cross-reacting with the patient’s own PLTs. For example, antibody formation was observed in other clinical studies of © 2015 International Society of Blood Transfusion Vox Sanguinis (2015) 109, 44–51

pathogen-reduced red blood cell concentrates, which were pretreated with chemical compounds [31–33]. Despite an ‘ideal’ immunization scheme of repetitive application of three doses of UVC-treated PLTs within intervals of 2–3 weeks in our study, no antiplatelet antibodies and no increase in IgE-levels were detected in the immunocompetent healthy volunteers within 9 weeks after the first transfusion. The absence of an antibody response is further underscored by the lack of allergic reactions and the consistent CCIs in transfusion series 2 and 3. The results of this phase I study and the fact that a previous animal study also did not show evidence of the generation of antibodies against UVC-induced neoantigens, even after repeated transfusions of UVC-treated PCs, suggests that any potential alterations in UVC-treated PCs are not highly immunogenic [16]. In this study, CIs and CCIs were primarily used to detect early removal of the transfused UVC-treated PLTs potentially mediated by PLT activation or by a PLT-specific immune response of the recipients. In fact, CCIs are widely accepted parameters to evaluate the success of PC-transfusions in patients with hypoproliferative thrombocytopenia [34, 35]. In our study, the mean CCIs calculated 1 and 24 h after transfusion of UVC-treated PCs generally exceeded the margins that usually define a successful PLT transfusion in thrombocytopenic patients. Although these data may promise very good viability of transfused UVC-treated PLTs, they do not allow any definite conclusion about the transfusion success because CCIs have never been validated in healthy volunteers, and the present study did not include a control group receiving untreated PCs for comparison. In addition, comprehensive analysis of PLT viability requires data from a sufficient number of PCs administered to patients with different diseases and clinical conditions at different days of the storage period. Hence, for further clinical approval of UVC-treated PLTs, CCIs as established parameters for evaluation of transfusion success need to be studied in adequately powered and controlled patient trials. In conclusion, UVC-treated PCs demonstrated safety and tolerance in healthy volunteers. It is the natural limitation of a phase I study with healthy volunteers that the number of recipients and exposures to UVC-treated PLTs were limited in our study. In addition, an autologous transfusion design does not reflect the clinical situation and an allogeneic setting as it occurs when patients are transfused. Future clinical studies displaying a broad spectrum of haemato-oncologic diagnoses, the genetic diversity of PLT donors and transfusion recipients as well as clinical transfusion regimens are required to assess the clinical efficacy and safety of UVC-treated PCs in human subjects.

50 T. Thiele et al.

analysed results; TT, ASe and AG wrote the manuscript. All authors read and accepted the final manuscript.

Acknowledgements We thank the staff of the PLT laboratory for technical assistance. The work of the nurses of the blood donation centre is appreciated. F. Tolksdorf and S. Reichenberg are acknowledged for providing the Macotronic UVC-irradiator. Thomas Thiele is a fellow of the foundation ‘Deutsche Stiftung f€ ur H€amotherapieforschung’ since March 2014.

Author contributions AG, TT, TM designed the study; AS€ u, KS, KA, PP, TT, ASe, TM, AG administered the study; AW, TK performed statistics; TT and TB analysed the antibody study; AP consulted standard laboratory analyses; TT, PP, AG, ASe

Conflicts of interest TM, PP and ASe received project grants from the ‘Forschungsgemeinschaft der DRK-Blutspendedienste e.V.’ and from Macopharma for the development of the UVC-based pathogen reduction technology for platelets. AG and TT received research support from Macopharma and from DRK Blutspendedienst NSTOB to perform the Phase 1 clinical trial. AG worked as a consultant for Macopharma. All other authors have no conflict of interest to declare.

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