Introduction: Patients suffering from primary or secondary immunodeficiency face times of increased insecurity and discomfort in the light of the raging Covid-19 pandemic, not knowing if and to what extend their comorbidities impact a potential Covid-19 course of disease. Furthermore, recently available vaccination options might not be amenable or effective for all patients of this heterogeneous population. Therefore, these patients often rely on passive immunization with plasma-derived, intravenous or subcutaneous immunoglobulin (IVIG/SCIG). Whether the ongoing Covid-19 pandemic and/or the progress in vaccination programs lead to increased and potentially protective titers in plasma-derived immunoglobulins (Ig) indicated e.g. for humoral immunodeficiency remains a pressing question for this patient population. Purpose: Here we investigated SARS-CoV-2 reactivity of US plasma-derived IVIG/SCIG products from the end of 2020 until 06/2021 as well as in convalescent plasma (CP) from 05/2020 to 08/2020. Methods: Final containers of IVIG/SCIG and CP donations were analyzed by commercial ELISA for SARS-CoV-2 S1-RBD IgG as well as microneutralization assay using a patient-derived SARS-CoV-2 (D614G) isolate. Neutralization capacities of 313 plasma single donations and 119 plasma-derived IVIG/SCIG lots were determined. Results obtained from both analytical methods were normalized against the international WHO standard. Finally, based on dense pharmacokinetic profiles of an IVIG preparation from previously published investigations, possible steady-state plasma levels of SARS-CoV-2 neutralization capacities were approximated based on currently measured anti-SARS-CoV-2 potencies in IVIG/SCIG preparations. Results: CP donations presented with a high variability with regards to anti-SARS-reactivity in ELISA as well as in neutralization testing. While approximately 50% of convalescent donations were none/low neutralizing, approximately 10% were at or above 1000 IU/ml. IVIG/SCIG lots derived from pre-pandemic plasma donations did not show neutralizing capacities of SARS-CoV-2. Lots produced between 12/2020 and 06/2021, entailing plasma donations after emergence of SARS-CoV-2 showed a rapid and constant increase in anti-SARS-CoV-2 reactivity and neutralization capacity over time. Neutralization capacity increased from a mean of 20 IU/ml in 12/2020 to 505 IU/ml in 06/2021, while lot-to-lot variability was substantial. Pharmacokinetic (PK) extrapolations based on non-compartmental superposition principles using steady-state reference profiles from previously published PK investigations on IVIG in PID, yielded potential steady-state trough plasma levels of 16 IU/ml based on the average final container concentration from 05/2021 with 216 IU/ml. Maximum extrapolated trough levels could reach 64 IU/ml based on the latest maximal final container potency tested in 06/2021. Conclusions: SARS-CoV-2 reactivity and neutralization capacity in IVIG/SCIG produced from US plasma rapidly and in part exponentially increased in the first half of 2021. The observed increase of final container potencies is likely trailing the serological status of the US donor population in terms of Covid-19 convalescence and vaccination by at least 5 months due to production lead times and should in principle continue at least until fall 2021. In summary, the data support rapidly increasing levels of SARS-COV-2 antibodies in IVIG/SCIG products implicating that a certain level of protection could be possible against COVID-19 for regularly substituted PID/SID patients. Nevertheless, more research to confirm, which plasma levels are needed for protection against SARS-CoV-2 infection of immune-compromised patients is still needed.
BACKGROUND: Since 2015 Zika virus (ZIKV) has spread within the Americas and even before in other regions. In 2016, the World Health Organisation (WHO) declared the ZIKV as a "Public Health Emergency of International Concern" (PHEIC). Therefore, it is very important to confirm the pathogen safety of blood plasma products. These products generally demand an effective donor selection as well as robust pathogen elimination/reduction steps within the manufacturing processes. Here, we provide experimental evidence that both solvent/detergent (S/D) treatment and pasteurization effectively inactivate ZIKV. STUDY DESIGN AND METHODS: The ZIKV inactivation capacity of the pasteurization step and the S/D treatment for different products and process conditions were investigated. Therefore, in-process material from commercial batches was collected and spiked with ZIKV in a ratio of approximately 1:10. Viral loads were determined prior to the safety steps and at pre-defined intervals during the individual processes to investigate the inactivation kinetics. Each process was investigated in duplicate runs. RESULTS: Sixty minutes after S/D treatment the viral titer was below detection limit during manufacturing of human plasma resulting in mean ZIKV reduction factor (LRF) of ≥ 6.78 log10. For immunoglobulin (IgG) after 240 min of S/D treatment the LRF was determined to be ≥ 7.00 log10. ZIKV was inactivated ≥ 6.18 log10 after 480 min by S/D treatment during the manufacture of factor VIII. During pasteurization of human albumin ZIKV infectivity was already below the detection limit after the heat-up phase. This finding was confirmed by subsequent test samples up to 2 hours. A LRF of ≥ 7.48 log10 was demonstrated. CONCLUSION: We showed that different S/D treatment procedures inactivate the ZIKV to below the detection limit. This effect was seen independently of various product matrices or the choice of S/D reagent at various concentrations and temperatures, while taking product-specific treatment times into consideration. We also showed that pasteurization is a very efficient inactivation step for the ZIKV. These results demonstrate the effectiveness of S/D treatment against even newly emerging lipid-enveloped viruses like ZIKV in the manufacturing of human plasma and derivatives thereof, such as IgG or factor VIII. Disclosures Schmidt: Octapharma: Employment. Kuehnel:Octapharma: Employment. Mueller:Octapharma: Employment. Pichotta:Octapharma: Employment. Radomski:Octapharma: Employment. Volk:Octapharma: Employment. Knaub:Octapharma: Employment.
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