High‐titer post‐vaccine COVID‐19 convalescent plasma for immunocompromised patients during the first omicron surge

Transplant and hematologic malignancy patients have high Coronavirus disease 2019 (COVID‐19) mortality and impaired vaccination responses. Omicron variant evades several monoclonal antibodies previously used in immunocompromised patients. Polyclonal COVID‐19 convalescent plasma (CCP) may provide broader neutralizing capacity against new variants at high titers. Vaccination increases severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) titer in convalescent donors.

low or absent anti-SARS-CoV-2 antibody titers after immunization. [4][5][6] Therapeutic antibody studies in hospitalized immunocompetent COVID-19 patients with both COVID-19 convalescent plasma (CCP) and SARS-CoV-2 monoclonal antibodies (mAb) have largely been disappointing, whereas outpatient studies have revealed benefits against hospitalization and severe disease. [7][8][9] As the omicron variants rendered several SARS-CoV-2-specific mAb ineffective, pre-omicron post-vaccine CCP has retained in vitro neutralization activity against omicron virus. 10 High-titer post-vaccine CCP is derived from donors who have recovered from a COVID-19 infection in the past 6 months and have also received an authorized COVID-19 vaccine. Post-vaccine CCP more potently neutralizes viruses compared with CCP collected from non-vaccinated donors. It has been referred to as "hybrid CCP" and "Vax-CCP." 11 CCP is hypothesized to bolster immunocompromised patients by targeting multiple viral epitopes to enhance antiviral immune activity. 12 Currently, we have limited therapeutic approaches to decrease severity of established COVID-19 infection in hospitalized immunocompromised patients, and there is a need for antibody-based therapies to pace with new variants. Large randomized controlled trials looking at the benefit of remdesivir, 13 dexamethasone, 14 tocilizumab, 15 and mAb 8 did not include significant numbers of patients with immunocompromising conditions. We conducted a retrospective chart review to describe our institution's experience with giving high-titer primarily post-vaccine CCP to hospitalized immunocompromised patients with COVID-19 infection during the first omicron wave.

Convalescent plasma donors, units, and transfusion
All CCP units included in this study were collected at the Stanford Blood Center (Palo Alto, CA, USA) between February and April 2021 from individuals who had recovered from a symptomatic confirmed COVID-19 infection and met the FDA criteria for CCP donors. 18 Transfused units were collected from donors within 6 months following their symptom resolution (mean of 90 days). CCP units were collected by apheresis, and a single unit could be transfused to multiple patients (∼200 mL/dose). SARS-CoV-2 immunoglobulin G (IgG) antibodies were quantified with the Abbott AdviseDx SARS-CoV-2 IgG (Architect and Alinity i) assay (Abbott, Chicago, IL, USA). All units met the FDA requirement for high titer at ≥1280 AU/mL. 16 After the FDA EUA update in December 2021, all immunocompromised patients admitted to our hospital with COVID-19 were eligible for CCP administration, regardless of the time from symptom onset or coadministration of remdesivir. With the increase in omicron incidence, CCP rose in our inpatient treatment algorithm to replace monoclonal antibody use. The decision to administer CCP was made by each patient's attending physician, often in consultation with the Infectious Diseases service. Immunocompromised patients who did not receive CCP had contraindications to blood transfusions, declined transfusion, or were not offered CCP by primary attending physician.

Statistical analysis
We used univariate Cox proportional hazard models to make comparisons between patient subgroups for our two primary outcomes of time to death and time to discharge from the hospital.

Patient characteristics
Between January and March 2022, 45

Hospitalization and treatments
The average time from symptom onset to admission was 9.7 days (0-39) and to CCP was 11.5 days (0-39   Table 2).
Most patients also received remdesivir. Other COVID-19 therapies given are listed in Table 1.

Clinical outcomes and mortality
Our cohort had an overall 30-day all-cause mortality of 4.5% (2/44) after CCP; both had hematologic malignancies. The cause of death was septic shock with multiorgan failure in one and brain herniation following a large stroke in another.  Figure 2).

Subgroup analyses
With two deaths out of five patients, hematologic malignancy patients had the highest 30-day mortality (40%). No patients with SOT, HCT, or autoimmune disease expired within 30 days of CCP administration. In the extended 100-day follow-up period, five additional patients expired, including 3/26 SOT (11.5%) and 2/10 HCT recipients (20%).
Compared to SOT patients, patients with hematologic malignancy and HCT did not have significantly different risks of mortality or time to discharge from the hospital (Figure 3). Patients with hematologic malignancy had the highest WHO scores throughout the study period, although the differences were not statistically significant compared to SOT, HCT, or autoimmune disease patients ( Figure 4B).  higher IS than lower IS patients (p = .03; Figure 4C). Patients with higher IS had significantly longer hospital stays compared to those with lower IS, with a hazard ratio of 2.1 (p = .04; Figure 3). There was no corresponding statistically significant difference in mortality between higher and lower immunosuppression groups at 30-or 100day post-CCP ( Figure 3 and data not shown). Of the 12 patients with positive pre-CCP serology, 10 had lower IS when SARS-CoV-2 IgG was measured, and 8 had lower IS at CCP administration.
When grouped by time from symptom onset to CCP, patients who received CCP between 6 and 10 days or after 10 days did not have a significant difference in mortality or time to discharge compared to patients who received CCP within 5 days of symptom onset (Figure 3).
Moreover, there was no significant difference in mean WHO scores at any time point by interval from symptom onset and CCP administration ( Figure 4D).

DISCUSSION
Our study is one of the largest retrospective studies to describe  The omicron variant may cause less severe COVID-19 in immunocompromised patients. Mortality rates ranging from 3.6% to 23% in hospitalized immunocompromised patients have been reported. [38][39][40] Whether the high vaccination rate of our cohort (71%) reduced mortality is debatable, as only 47.8% of patients who received at least two doses of mRNA vaccines had detectable SARS-CoV-2 antibodies after vaccination. This is lower than that reported in a meta-analysis that showed 62.3% seropositivity in hematologic malignancy and 89% in SOT recipients after two doses of COVID-19 vaccine, which may reflect the high degree of immunosuppression in our cohort. 41 The immune response to SARS-CoV-2 infection and COVID-19 vaccination should be affected by immunosuppression level. 5 The optimal timing of CCP may vary by patient population.

LIMITATIONS
Limitations include a small sample size and the retrospective chart review design. We cannot draw conclusions about whether CCP reduces mortality. We did not have an appropriate comparator group of omicron-infected patients at our institution who did not receive mAbs. Contemporaneously hospitalized patients who did not receive CCP likely differed from our cohort in severity of illness and underlying conditions.
The generalizability of our results might be limited to post-vaccine CCP with titers much higher than the FDA requirement. With the abundance of vaccinated donors, high-titer post-vaccine CCP could become more available.
The half-life of IgG antibodies is 21-28 days, 52 but we have nevertheless included 100-day outcomes because of the interest in long-term outcomes after COVID-19 therapies.

CONCLUSION
High-titer post-vaccine CCP was shown to be safe for immunocompromised patients admitted to the hospital for COVID-19 in the era of omicron. Thirty-day mortality was low. Randomized controlled trials of post-vaccine CCP in immunocompromised patients as early and late treatment, pre-exposure prophylaxis, and postexposure prophylaxis are warranted. The global availability of CCP and its potential to treat and mitigate the emergence of new variants should make such studies a public health priority.

AUTHOR CONTRIBUTIONS
Anne Y. Liu, Ralph Tayyar, and Lisa Kanata Wong designed the study.
Suchitra Pandey provided the data for the study. Ralph Tayyar collected the data of the study. Alex Dahlen, Elaine Shu, and Ralph Tayyar analyzed the data for the study. All authors participated in writing and reviewing the paper and approved the final version of this manuscript.

ACKNOWLEDGMENTS
We thank Benjamin Pinsky and the Stanford Virology Laboratory for providing data on variants sequenced at our institution during the study period. We also thank the Stanford REDCap platform (http:// redcap.stanford.edu).