Blood donor SARS-CoV-2 infection or vaccination and adverse outcomes in plasma and platelet transfusion recipients

Abstract

BACKGROUND:

Despite data supporting the safety of SARS-CoV-2 vaccination, concerns regarding receipt of blood products from donors previously infected or vaccinated against SARS-CoV-2 persist. We assessed whether transfusions of plasma or platelet products from donors with prior SARS-CoV-2 infection or vaccination were associated with adverse outcomes in patients without COVID-19.

METHODS:

We linked donor SARS-CoV-2 spike and nucleocapsid antibody data and vaccination history to blood products transfused between 6/1/2020 and 3/31/2022. We used logistic regression, adjusting for demographics and comorbidities, to calculate odds ratios and 95% confidence intervals (CI) for post-transfusion thrombosis, increased respiratory requirement, and hospital mortality. Outcomes were assessed per transfused unit from previously infected or vaccinated donors compared to units from uninfected or unvaccinated donors.

RESULTS:

Among 8,715 hospitalizations of 7,773 transfusion recipients linked to donor SARS-CoV-2 antibody data, there were 251 thromboses, 700 hospitalizations with increased respiratory requirement, and 1,443 deaths. Among 15,167 transfused plasma units, 4,993 and 1,106 were from vaccinated donors and previously infected donors, respectively. Among 19,295 transfused platelet units, 8,530 and 1,368 were from vaccinated and previously infected donors, respectively. There were no associations between the transfusion of blood products from vaccinated or previously infected donors and thrombosis, increased respiratory requirement, or hospital mortality (all CI including 1). Nor were there associations between the receipt of blood products from recently infected or vaccinated donors or high SARS-CoV-2 antibody titers and adverse outcomes.

DISCUSSION:

Donor SARS-Cov-2 infection and vaccination do not influence adverse patient outcomes and do not need to be considered in blood allocation.

INTRODUCTION

The COVID-19 pandemic brought unprecedented challenges to healthcare systems worldwide, including the management of blood donations and transfusions.¹ As the pandemic progressed, the development and widespread administration of vaccines became a critical tool in combating the pandemic.² Although uncommon, adverse thrombotic events were reported in recipients of adenoviral-based vaccines and were hypothesized to be related to the development of autoantibodies.³ However, these adverse events also led to concerns among patients requiring blood transfusions regarding the safety and implications of receiving blood from vaccinated donors.⁴

These vaccine-related events, compounded by misinformation and a lack of understanding about how RNA vaccines work, led to the fear that components of the vaccine, such as mRNA or viral vectors, could be transferred through blood products and cause adverse effects.⁴ In parallel to patients purposely treated with COVID-19 convalescent plasma (CCP), passive transfer of donor SARS-CoV-2 antibodies is recognized to occur in transfusion recipients without COVID-19, including recipients of platelet products.^5,6 It is recognized that dramatic boosting of SARS-CoV-2 antibody levels occurs in donors with previous SARS-CoV-2 infections who are vaccinated and following infection of vaccinated donors compared to those who were infected but not vaccinated.^7,8 Even in 2024, patient advocacy groups and even lawmakers continue to raise concerns without specific evidence regarding the presence of vaccine-induced antibodies in blood products and their potential impact in recipients.^4,9

These concerns are not without historical basis, as the introduction of any new medical intervention naturally raises questions about its safety and efficacy.¹⁰ For decades, the scientific community has been actively researching and addressing similar concerns to ensure the immunological safety of blood transfusions (e.g., transfusion-related acute lung injury or TRALI.¹¹ Thromboses and systemic inflammatory events have separately been associated with severe COVID-19, COVID-19 vaccines, and blood transfusion.^11,12 In this observational study, we assessed whether the transfusion of plasma or plasma-rich platelet products from blood donors with prior SARS-CoV-2 infection and/or vaccination were associated with increased risks of thrombotic events, respiratory requirements, or hospital mortality in transfusion recipients without COVID-19.

METHODS:

Design Overview:

We conducted a retrospective cohort study using electronic health record (EHR) data from Kaiser Permanente Northern California (KPNC), which serves a population of 4.6 million members. We included all hospitalized adult, non-obstetric KPNC patients who were transfused plasma or platelet products in 21 hospitals from June 1, 2020 through March 31, 2022. Transfused patients were grouped as recipients of plasma or platelet components and were allowed to contribute multiple hospital episodes if they were transfused plasma or platelet units during more than one hospitalization. Beginning in March 2020, all patients who were hospitalized at a KPNC facility were tested for SARS-CoV-2 by nasal swab polymerase chain reaction at the time of hospital admission, and we excluded subjects with a positive result within 90 days prior to hospitalizations in which they were transfused to avoid adverse events attributable to COVID-19 in recipients and recipients of CCP.

SARS-CoV-2 serologic testing and vaccinations of blood donors:

Information on blood donors, donations and processing was obtained from databases of Vitalant and the American Red Cross which supply blood components to all 21 KPNC hospital facilities. Both blood collection organizations participated in universal SARS-CoV-2 screening of all blood donations from June 2020-June 2021 and subsequently as part of the CDC-funded Nationwide Blood Donor Serosurveillance (NBDS) study.^13–15 Blood donor samples were tested for antibodies against the S1 portion of the spike (S) protein using the VITROS chemiluminescent S1 total Ig assay (Ortho Clinical Diagnostics). Specimens with S antibodies were tested for nucleocapsid (N) antibodies using the chemiluminescent Roche Elecsys Total Ig Assay (Roche Diagnostics).

From July through December 2020, only specimens with borderline positive SARS-CoV-2 spike antibody results (ie, signal-to-cutoff ratio, 1–10) were tested for nucleocapsid antibodies, based on previous results that demonstrated that all specimens collected during 2020 with SARS-CoV-2 spike antibody signal-to-cutoff ratios greater than 10 had nucleocapsid antibodies.^16,17 Beginning in January 2021, after COVID-19 vaccine administration began, all specimens with spike antibodies were tested for nucleocapsid antibodies to differentiate infection- and vaccination-induced seropositivity.¹⁶ In addition, beginning in January 2021, both blood collection organizations surveyed blood donors regarding the receipt and timing of COVID-19 vaccine prior to each donation.

We defined SARS-CoV-2 infection and vaccination status based on serologic assays for SARS-CoV-2 antibodies and self-reported vaccination history, respectively. SARS-CoV-2 infection was defined as seropositivity for nucleocapsid antibodies or, in the absence of a history of vaccination, seropositivity for spike antibodies. Hybrid immunity was defined as evidence of prior SARS-CoV-2 infection and history of COVID-19 vaccination. The timing of donation from the date of the first (index) donation with spike or nucleocapsid antibody was calculated, quantifying the number of plasma or platelet donations occurring within 60 or 180 days of index donation documented seroconversion. In addition, we examined tertiles of positive spike or nucleocapsid antibody signal-to-cutoff ratios, quantifying the number of plasma or platelet units from the highest tertiles of each as an exposure.

Exposures:

The primary exposure of interest was the number of transfused plasma or platelet units from previously vaccinated and/or previously infected blood donors. Secondary exposures include the number of transfused plasma or platelet units from donors with the highest strata of spike or nucleocapsid antibody or donations within 60 or 180 days of index donation seroconversion.

Outcomes:

Post-transfusion arterial or venous thrombosis, maximal level of respiratory support, hospital mortality

The incidence of arterial and venous thromboses after plasma or platelet transfusion was defined using the combination of diagnosis codes and timing of new anticoagulant administration following transfusion.^18–20 We categorized the maximal level of respiratory support using mutually exclusive, hierarchical categories (room air, nasal cannula, high flow oxygen, noninvasive ventilation, invasive ventilation). Maximal level of respiratory support was assessed prior to index transfusion and daily thereafter. We defined increased level of respiratory support as the need for greater oxygen than delivered by nasal cannula 24 to 48 hours following index plasma or platelet transfusion.

Patients with a history of thrombosis or were receiving anticoagulation prior to transfusion, or those who already required increased levels of respiratory support (i.e., more than the use of a nasal cannula) prior to transfusion were excluded from analysis of thrombosis and respiratory outcomes, respectively. All participating sites received institutional review board approval prior to performing the study.

Covariates:

We considered individual-level factors, including sex, age, body mass index, comorbidities and severity of illness at the time of hospitalization. We classified patients as having emergency or elective admission based on whether they were admitted through the emergency department. We classified hospitalizations as surgical admissions based upon the occurrence of surgical procedural codes during hospitalization.²¹ We quantified comorbid disease burden using the COPS2 (Comorbidity Points Score, version 2), which is based upon patients’ medical diagnoses within the 12 months preceding hospitalization.^21–23 We quantified severity of illness at admission with the LAPS2 (Laboratory Acute Physiology Score, version 2), which is based on laboratory test results, vital signs, and neurologic status within 72 hours prior to hospital entry.²² Concomitant transfusion of red blood cell components was analyzed as a covariate in models.

Statistical Analysis:

Descriptive analyses are presented as counts and percentages, medians, and interquartile ranges (IQRs), or proportions. Accordingly, we used chi-square tests for equal proportion or Wilcoxon rank sum tests to test differences. Transfusion of plasma and platelet units from previously infected or vaccinated donors were quantified as per unit exposures. Adjusting for covariates including the total number of plasma or platelet units transfused, we assessed outcomes per transfused unit from previously infected or vaccinated donors compared to units from uninfected or unvaccinated donors. In parallel, transfusion of plasma and platelet units from recently infected or vaccinated donors (within 60 or 180 days of index donation seroconversion) or from donors with the highest strata of antibody signal-to-cutoff ratios were quantified as per unit exposures.

Using the above covariates, we constructed multivariable regression models with thrombosis, increased respiratory support, and hospital mortality as dependent variables. As a sensitivity analysis, we excluded patients with a history of thrombosis or those receiving anticoagulation as well as those with increased levels of respiratory support prior to transfusion in the analysis of our three outcomes. We used logistic regression via generalized estimating equation (GEE) with exchangeable working correlation structure to account for repeated within-individual observations. We reported results for dichotomous outcomes as adjusted odds ratios (OR’s) with corresponding 95% confidence intervals (CI). Statistical significance was indicated by the 95% CI not containing the null or two-sided p-values less than 0.05. Statistical analyses were performed using Stata Version 14.2 and SAS version 9.4.

Role of the funding source

The study sponsor collaborated on the study design and had no role in data collection, data analysis, data interpretation, or preparation of the manuscript. The REDS-IV-P publications committee reviewed the manuscript and approved its submission for publication.

RESULTS:

Patient characteristics and outcomes

From 6/1/2020 through 3/31/2022 there were 8,715 hospitalizations of 7,773 patients in which plasma or platelet products were transfused. Baseline recipient characteristics are presented in Table 1. The mean recipient age at the time of hospitalization was 65 years (standard deviation [SD], 16 years), and 42.2% of recipients (n=3,682) were female. The median number of hospitalizations per patient was 1 (IQR 1–1) with 742 patients having greater than one hospitalization with plasma or platelet transfusion. Of the 8,715 hospitalizations 79.6% (n=6,939) were emergency admissions and 36.9% (n=3,215) were surgical.

Table 1:

Hospitalization characteristics

	n=8,715
Agea	65 ± 16
Female (%)	3,682 (42.2)
Body mass indexb (IQR)	27 (23–31)
Comorbidity Point Score 2 (COPS2)b,c	60 (27–97)
Laboratory Acute Physiology Score 2 (LAPS2)b,d	79 (40–122)
Emergency admission (%)	6,939 (79.6)
Surgical admission (%)	3,215 (36.9)
Intensive care admission (%)	4,584 (52.6)
Trnsfused plasma (%)	4,271 (49.0)
Transfused platelets (%)	6,068 (69.6)
Transfused red blood cells (%)	5,495 (63.1)
Pre-TX anticoagulation (%)	1,262 (14.5)
Pre-TX history of thrombosis (%)	1,318 (15.1)
Increased pre-TX respiratory requirement (%)e	1,825 (20.9)
Post-TX thrombosis (n=6,180)	251 (4.1)
Increased post-TX respiratory requirement (n=6,612)	700 (10.6)
Hospital mortality (%)	1,443 (16.6)

Abbreviation: IQR, interquartile range; ICU, intensive care unit; TX, transfusion

^aMean ± standard deviation

^bMedian (interquartile range)

^cLongitudinal, diagnosis-based score. Association with hospital mortality rates for scores < 50 are less than 2%, while scores above 100 are associated with mortality rates of 5% or more.

^dIncreasing degrees of physiologic derangement are reflected in a higher LAPS2. The univariate association between LAPS2 and mortality is such that mortality rates for scores < 50 are less than 1.5% while scores above 125 are associated with mortality rates of 10–15% or more.

^eDefined as greater than the use of oxygen delivery by nasal cannula prior to transfusion

Among the 8,715 hospitalizations, 2,535 had a history of thrombosis or were already on anticoagulation prior to transfusion (Figure 1). Excluding these hospitalizations, 251 arterial and venous thromboses occurred in 6,180 hospitalizations (4.1%). Among the 8,715 hospitalizations, 20.9% (n=1,825) of patients had increased respiratory requirements prior to transfusion (Table 1). Excluding these hospitalizations, respiratory requirements were increased in 700 (10.6%) hospitalizations during the 24-to-48-hour period following transfusion. Hospital mortality occurred in 1,443 of the 8,715 (16.6%) hospitalizations.

Figure 1: Flow Diagram for the number of hospitalizations by outcome.

Number of hospitalizations by outcome (thrombosis, oxygen requirement, hospital mortality)

713 hospitalizations had both increased pre-transfusion respiratory requirements and a history of thrombosis or anticoagulation.

Donor SARS-CoV-2 Infection and Vaccination Characteristics

Over the study period, a total of 19,295 platelet units and 15,167 plasma units were transfused into eligible patients (Table 2). Among recipients of each component type, the median number of transfused units per hospitalization was 2 (IQR 1–3) for both plasma and platelet transfusion. Among plasma donations, 4,993 were from vaccinated donors and 1,106 had evidence of prior infection based on SARS-CoV-2 spike and nucleocapsid seropositivity. Among these 1,106 donations, 472 units were from donors with hybrid immunity (history of vaccination and prior infection). 24.3% (1213/4993) and 50.1% (2503/4993) of plasma donations from previously vaccinated donors occurred with 60 and 180 days of index donation seropositivity, respectively (Table 3). Among plasma donations from previously infected donors, 32.7% (362/1,106) of units were donated within 60 days of index nucleocapsid antibody seropositivity. 33.3% (1,706/5123) of SARS-CoV-2 spike antibody positive units and 32.7% (362/1,106) of SARS-CoV-2 nucleocapsid antibody positive units were from the highest titer tertile.

Table 2:

Donor SARS-CoV-2 infection and vaccination characteristics

	Donations
Plasma Donor Characteristics	N=15,167 units
SARS-CoV-2 Vaccinationa	4,993
Vaccination within 60 days	1213
Vaccination within 180 days	2503
Vaccinated / Uninfectedb	4,521
SARS-CoV-2 Spike seropositive	5,123
Donation within 60 days of index seroconversion	974
Donation within 180 days of index seroconversion	2122
Lowest tertile positive S-Ab	1685
Middle tertile positive S-Ab	1732
Highest tertile positive S-Ab	1706
SARS-CoV-2 Nucleocapsid seropositive	835
Lowest tertile positive N-Ab	360
Middle tertile positive N-Ab	364
Highest tertile positive N-Ab	382
SARS-CoV-2 Infectionb	1,106
Donation within 60 days of initial seroconversion	362
Vaccinated / Infectedc	472
Unvaccinated / Infected	634
Platelet Donor Characteristics	N=19,295 units
SARS-CoV-2 Vaccinationa	8,530
Vaccination within 60 days of donation	2,499
Vaccination within 180 days of donation	4,757
Vaccinated / Uninfectedb	7,695
SARS-CoV-2 Spike seropositive	8,277
Donation within 60 days of index seroconversion	1,886
Donation within 180 days of index seroconversion	3,742
Lowest tertile S-Ab	2,807
Middle tertile S-Ab	2,757
Highest tertile S-Ab	2,713
SARS-CoV-2 Nucleocapsid seropositive	1,249
Lowest tertile positive N-Ab	424
Middle tertile positive N-Ab	412
Highest tertile positive of N-Ab	413
SARS-CoV-2 Infectionb	1,386
Donation within 0–60 days of index seroconversion	532
Vaccinated / Infectedc	835
Unvaccinated / Infected	551

^aVaccination status based upon self-reported vaccination history

^bSARS-CoV-2 infection was defined as seropositivity for nucleocapsid antibodies or, in the absence of a history of vaccination, seropositivity for spike antibodies

^cHybrid immunity was defined as evidence of SARS-CoV-2 nucleocapsid seropositivity and history of COVID-19 vaccination

Table 3:

Donor exposures and recipient outcomes of thrombosis, oxygen requirements, and mortality

N (episodes)	Thrombosis N=6,180	Increased O2 requirement N=6,612	Hospital mortality N=8,715
Plasma Donor Characteristics	aOR (95% CI)a	aOR (95% CI)	aOR (95% CI)
SARS-CoV-2 Vaccinationa	0.96 [0.90–1.02]	1.00 [0.98–1.04]	1.02 [0.99–1.05]
Vaccination within 60 days	1.00 [0.87–1.15]	0.94 [0.85–1.05]	1.04 [0.99–1.09]
Vaccination within 180 days	0.95 [0.89–1.02]	0.97 [0.91–1.03]	1.01 [0.99–1.03]
Vaccinated / Uninfectedb	1.02 [0.98–1.06]	1.01 [0.98–1.05]	1.02 [0.99–1.06]
SARS-CoV-2 Spike seropositive	0.96 [0 .91–1.02]	1.00 [0.97–1.04]	1.01 [0.98–1.04]
Donation within 60 days of index seroconversion	1.04 [0.90–1.20]	0.94 [0.85–1.04]	1.06 [0.98–1.07]
Donation within 180 days of index seroconversion	0.99 [0.91–1.07]	0.97 [0.91–1.03]	1.03 [0.85–1.51]
Lowest tertile positive S-Ab	0.94 [0.80–1.10]	0.98 [0.90–1.06]	0.99 [0.92–1.06]
Middle tertile positive S-Ab	1.00 [0.87–1.15]	0.97 [0.88–1.06]	1.00 [0.93–1.08]
Highest tertile positive S-Ab	1.00 [0.87–1.14]	1.05 [0.97–1.13]	0.97 [0.92–1.01]
SARS-CoV-2 Nucleocapsid seropositive	0.93 [0.74–1.16]	0.94 [0.81–1.10]	1.01 [0.99–1.02]
Lowest tertile positive N-Ab	0.73 [0.40–1.34]	0.85 [0.55–1.31]	0.94 [0.68–1.30]
Middle tertile positive N-Ab	0.91 [0.46–1.80]	0.95 [0.63–1.42]	0.78 [0.56–1.10]
Highest tertile positive N-Ab	1.18 [0.72–1.94]	0.96 [0.62–1.48]	1.00 [0.99–1.02]
SARS-CoV-2 Infectionc	1.00 [0.84–1.18]	0.97 [0.88–1.08]	1.02 [0.97–1.08]
Donation within 60 days of initial seroconversion	1.02 [0.73–1.45]	1.03 [0.80–1.33]	1.01 [0.87–1.16]
Vaccinated / Infectedd	0.91 [0.66–1.25]	0.89 [0.70–1.14]	1.04 [0.90–1.20]
Unvaccinated / Infected	1.03 [0.87–1.24]	0.98 [0.87–1.10]	1.02 [0.96–1.08]
Platelet Donor Characteristic	aOR (95% CI)a	aOR (95% CI)	aOR (95% CI)
SARS-CoV-2 Vaccinationa	1.00 [0.96–1.04]	0.99 [0.96–1.02]	1.01 [0.99–1.04]
Vaccination within 60 days	1.03 [0.93–1.14]	0.98 [0.89–1.07]	0.99 [0.98–1.00]
Vaccination within 180 days	1.00 [0.93–1.08]	0.98 [0.93–1.04]	0.99 [0.98–1.00]
Vaccinated / Uninfectedb	1.00 [0.96–1.05]	0.99 [0.95–1.03]	0.98 [0.97–1.00]
SARS-CoV-2 Spike seropositive	1.00 [0.96–1.05]	0.99 [0.95–1.04]	1.01 [0.98–1.03]
Donation within 60 days of index seroconversion	0.99 [0.91–1.08]	1.00 [0.93–1.07]	0.96 [0.90–1.02]
Donation within 180 days of index seroconversion	1.00 [0.94–1.06]	0.99 [0.95–1.04]	0.99 [0.95–1.03]
Lowest tertile positive S-Ab	0.94 [0.80–1.10]	1.02 [0.93–1.11]	1.00 [0.90–1.12]
Middle tertile positive S-Ab	1.00 [0.87–1.15]	0.95 [0.87–1.05]	1.00 [0.90–1.10]
Highest tertile positive S-Ab	1.03 [0.96–1.10]	1.00 [0.94–1.06]	1.00 [0.97–1.04]
SARS-CoV-2 Nucleocapsid seropositive	1.03 [0.83–1.26]	1.03 [0.88–1.21]	0.99 [0.98–1.01]
Lowest tertile positive N-Ab	1.16 [0.74–1.81]	1.01 [0.72–1.42]	1.00 [0.75–1.33]
Middle tertile positive N-Ab	0.96 [0.63–1.46]	1.08 [0.76–1.52]	0.96 [0.63–1.46]
Highest tertile positive N-Ab	0.90 [0.55–1.46]	1.00 [0.70–1.43]	0.99 [0.80–1.22]
SARS-CoV-2 Infectionc	1.04 [0.85–1.28]	1.05 [0.90–1.24]	0.97 [0.88–1.08]
Donation within 60 days of initial seroconversion	1.06 [0.78–1.44]	1.10 [0.86–1.41]	0.87 [0.74–1.02]
Vaccinated / Infectedd	0.89 [0.67–1.20]	1.13 [0.93–1.38]	1.00 [0.89–1.13]
Unvaccinated / Infected	1.24 [0.94–1.62]	0.92 [0.71–1.20]	0.93 [0.80–1.09]

^aAdjusted odds ratios (aOR) with 95% confidence intervals (CI) for outcomes of thrombosis, increased respiratory requirement, or hospital mortality per plasma or platelet unit transfused with the donor characteristic (relative to an equal number of transfused units without this donor exposure)

^bVaccination status based upon self-reported vaccination history

^cSARS-CoV-2 infection was defined as seropositivity for nucleocapsid antibodies or, in the absence of a history of vaccination, seropositivity for spike antibodies

^dHybrid immunity was defined as evidence of SARS-CoV-2 nucleocapsid seropositivity and history of COVID-19 vaccination

Among platelet donations, 8,530 were from vaccinated donors and 1,386 had evidence of prior infection based on SARS-CoV-2 spike and nucleocapsid seropositivity. Among these 1,386 donations, 835 units were from donors with hybrid immunity. 28.8% (2,381/8,277) and 57.5% (4,757/8,277) of platelet donations from previously vaccinated donors occurred with 60 and 180 days of index seropositivity, respectively (Appendix Table 1). In parallel, 38.4% (532/1,386) of platelet donations from previously infected donors occurred within 60 days of index seropositivity. 32.8% (2,713/8,277) of SARS-CoV-2 spike antibody positive units and 29.8% (413/1,386) of SARS-CoV-2 nucleocapsid antibody positive units were from the highest titer strata.

Association of SARS-CoV-2 vaccination and/or infection on thrombosis, respiratory requirements, and hospital mortality in transfusion recipients

Controlling for the total number of transfused units as part of multivariable analysis, we found no associations between the number of platelet transfusions from SARS-CoV-2 vaccinated blood donors and outcomes of thrombosis (OR 1.00 [95% CI 0.96, 1.04]), increased respiratory requirement (OR 0.99 [95% CI 0.96, 1.02]), or hospital mortality (OR 1.01 [95%CI 0.99–1.04]) in recipients (Table 3). In parallel, there were no associations between the number of plasma transfusions from SARS-CoV-2 vaccinated blood donors with thromboses (OR 0.96 [95% CI 0.90–1.02), respiratory requirements (OR 1.00 [95% CI 0.98, 1.04]), or hospital mortality (OR 1.02 [95% CI 0.99–1.05]). There were also no significant associations between the receipt of plasma and platelet units from SARS-CoV-2 uninfected vaccinated donors and donors with hybrid immunity. In our sensitivity analysis excluding patients with a history of thrombosis or anticoagulation and those with increased pre-transfusion levels of respiratory support, we found no associations for the above donor exposures and our three outcomes in plasma and platelet transfusion recipients. We found no associations with our three outcomes in recipients of plasma or platelet donors with new evidence of spike antibody seropositivity or history of vaccination within 60 and 180 days of donation (Table 3). Furthermore, we found no evidence of adverse outcomes in recipients of plasma or platelet units within 60 days of initial nucleocapsid antibody seroconversion, indicating recent infection. Lastly, we found no association of adverse outcomes with receipt of plasma or platelet units with the highest titers of SARS-CoV-2 spike or nucleocapsid antibodies.

DISCUSSION:

In our cohort of transfused patients without evidence of active COVID-19, we found no association of thromboses, levels of respiratory support, or hospital mortality with the receipt of plasma and platelet products from previously SARS-CoV-2 vaccinated and/or infected blood donors. In addition, we found no association between the receipt of blood products from recently infected or vaccinated donors and the adverse outcomes we evaluated. Lastly, the receipt of plasma or platelet units with the highest titers of SARS-CoV-2 spike and nucleocapsid antibodies were not associated with adverse events. In sum, the transfusion of plasma and platelet components from previously vaccinated and/or infected blood donors was not associated with acute thrombosis, increased respiratory requirements, or mortality in SARS-CoV-2 negative transfusion recipients.

Several studies have shown that the components of COVID-19 vaccines do not remain in the bloodstream for prolonged periods after vaccination and thus would be unlikely to be present in donated blood unless donation occurred soon after vaccination.^24,25 Furthermore, the antibodies produced in response to vaccination are similar or more robust than those generated by natural infection, and there is no evidence of harm when transfused.^20,26 Our findings are also consistent with laboratory-based studies that did not find evidence of an impact of convalescent plasma transfusion on the adaptive immune response of recipients.²⁷ Despite these reassurances, patient anxiety persists, highlighting the need for evidence-based information to support clear communication and address patient misconceptions. Our results support the notion that blood transfusions from vaccinated or previously infected blood donors are safe.

Recognizing that there are specific concerns regarding the presence of vaccine mRNA or autoantibodies in blood products from recently vaccinated donors, we examined multiple subgroups of transfusion events based on the strata of antibody titers or timing of donation after vaccination and found no worsening of outcomes. Antibody levels in blood donors are known to increase by several logs following repeated exposure to novel SARS-CoV-2 variants or vaccine doses.^28,29 While we did examine outcomes related to exposure to high antibody titer plasma or platelet units, we were not able to evaluate repeated infection or vaccination in our donor cohort. However, in our prior work, we examined outcomes during the during serial time periods including the period of SARS-CoV-2 Omicron variant predominance.²⁰ We found no differences in recipient outcomes during this period where large numbers of vaccinated blood donors had substantial boosting of antibody levels due to SARS-CoV-2 reinfection or vaccine boosting. In sum, these findings do not indicate that donor SARS-CoV-2 infection and vaccination status need to be considered when allocating blood products for transfusion. Our hope is that these results will help alleviate blood safety concerns regarding the timing of blood donation after SARS-CoV-2 infection or vaccination.

Despite the comprehensive nature of this study, several limitations should be acknowledged. First, the observational design of the study limits the ability to establish causality between donor characteristics and patient outcomes. Second, we attempted to control for other factors that might be related to patient survival (e.g., admission severity of illness, comorbidity indices and concomitant RBC transfusions); however, residual confounding may persist. While minimal plasma volumes (and associated antibodies) are present in RBC units stored in additive solutions, we did not examine donor SARS-CoV-2 antibody status for RBC transfusions in our analyses. Third, our patient population reflects the regional community practice of transfused adults at 21 medical centers in Northern California, it may not reflect outcomes of pediatric age groups, or specific populations (e.g., immunocompromised and obstetric patients). Fourth, the study focused on short-term hospital events, and long-term outcomes and the potential for delayed adverse effects were not assessed. Finally, the study did not explore the potential impact of different SARS-CoV-2 variants on donor characteristics and patient outcomes. As new variants continue to emerge, their influence on transfusion safety should be investigated.

In conclusion, this study provides reassuring insights into the safety of blood transfusions from donors with varying SARS-CoV-2 exposure histories. These results provide some reassurance in the context of the national prevalence of blood donor SARS-CoV-2 prior infection and vaccination. Nationally, the combined infection- and vaccination-induced SARS-CoV-2 donor seroprevalence was estimated to be 96% by September 2022.^13,15 The findings support the continued use of blood products from vaccinated and previously infected donors, addressing patient concerns about potential risks.

Appendix Table 1: Sensitivity analysis of donor exposures & recipient outcomes of thrombosis, oxygen requirements, and mortality^a

N (episodes)	Thrombosis N=5,296	Increased O2 requirement N=5,296	Hospital mortality N=5,296
Plasma Donor Characteristics
SARS-CoV-2 Vaccinationb	0.95 [0.88–1.02]	1.00 [0.96–1.06]	1.02 [0.98–1.06]
Vaccinated / Uninfectedc	0.93 [0.86–1.02]	1.00 [0.96–1.05]	1.02 [0.98–1.06]
SARS-CoV-2 Spike seropositive	0.99 [0.93–1.05]	0.99 [0.95–1.03]	0.98 [0.94–1.02]
SARS-CoV-2 Nucleocapsid seropositive	0.99 [0.76–1.29]	0.86 [0.67–1.09]	0.81 [0.65–1.02]
SARS-CoV-2 Infectionc	1.02 [0.88–1.18]	0.95 [0.85–1.08]	0.96 [0.85–1.09]
Vaccinated / Infectedd	0.93 [0.64–1.36]	0.82 [0.61–1.10]	1.07 [0.80–1.43]
Unvaccinated / Infected	1.02 [0.87–1.20]	0.96 [0.84–1.10]	0.91 [0.74–1.12]
Platelet Donor Characteristic
SARS-CoV-2 Vaccinationb	1.01 [0.96–1.05]	0.99 [0.95–1.03]	1.01 [0.97–1.05]
Vaccinated / Uninfectedc	1.01 [0.96–1.06]	0.99 [0.95–1.03]	1.01 [0.97–1.05]
SARS-CoV-2 Spike seropositive	1.01 [0.97–1.05]	1.00 [0.96–1.04]	1.01 [0.97–1.05]
SARS-CoV-2 Nucleocapsid seropositive	0.99 [0.79–1.25]	0.97 [0.80–1.17]	0.96 [0.80–1.15]
SARS-CoV-2 Infectionc	1.05 [0.84–1.30]	0.96 [0.83–1.19]	1.01 [0.85–1.20]
Vaccinated / Infectedd	0.91 [0.67–1.25]	1.06 [0.85–1.34]	1.02 [0.81–1.29]
Unvaccinated / Infected	1.23 [0.91–1.65]	0.90 [0.65–1.22]	1.02 [0.79–1.33]

^aSensitivity analysis excluding patients with a history of thrombosis or those receiving anticoagulation and those with increased levels of respiratory support prior to transfusion outcomes.

^bVaccination status based upon self-reported vaccination history

^cSARS-CoV-2 infection was defined as seropositivity for nucleocapsid antibodies or, in the absence of a history of vaccination, seropositivity for spike antibodies

^dHybrid immunity was defined as evidence of SARS-CoV-2 nucleocapsid seropositivity and history of COVID-19 vaccination