key: cord-0918036-zqz1wl1r
authors: DeVoe, Catherine; Pandey, Shraddha; Shariff, Dayana; Arora, Shagun; Henrich, Timothy J.; Yokoe, Deborah S.; Langelier, Charles R.; Servellita, Venice; Chiu, Charles; Miller, Steve; Babik, Jennifer M.; Chin‐Hong, Peter; Fung, Monica
title: COVID‐19 in Vaccinated Versus Unvaccinated Hematologic Malignancy Patients
date: 2022-04-15
journal: Transpl Infect Dis
DOI: 10.1111/tid.13835
sha: dd45567f262c97a43f434d672fe2be5100dfbf1a
doc_id: 918036
cord_uid: zqz1wl1r

The effect of vaccination on severity of subsequent COVID‐19 in patients with hematologic malignancies (HM) is unknown. In this single‐center retrospective cohort study, we found no difference in severity of COVID‐19 disease in vaccinated (n = 16) versus unvaccinated (n = 54) HM patients using an adjusted multiple logistic regression model. Recent anti‐B‐cell therapy was associated with more severe illness. This article is protected by copyright. All rights reserved

Patients with hematologic malignancy (HM) and SARS-CoV-2 infection experience poor outcomes, with increased rates of severe disease and reported mortality ranging from 15-39% 1-6 . For immunocompetent patients, a primary vaccine series, consisting of two mRNA vaccine doses or one Johnson & Johnson vaccine dose, results in markedly attenuated disease severity compared to those who have not been vaccinated 7 . Given the increased risk of severe illness in HM patients, professional society guidelines have recommended that they be prioritized for vaccination 8 . However, prior studies have found that HM patients mount a decreased humoral response to COVID-19 vaccination [9] [10] [11] , and their degree of protection from clinical disease after vaccination is not well understood. The available literature suggests that HM patients who have been vaccinated can still experience severe disease 12 , including death 10, 13 . However, few studies published to date have systematically examined clinical outcomes in vaccinated HM patients who develop COVID-19, and the effect of vaccination on COVID-19 severity in this population is unknown.

We performed a retrospective multiple cohort study comparing previously vaccinated to unvaccinated HM patients with COVID-19. All adult HM patients (age≥18 years) who received inpatient or outpatient care at the University of California, San Francisco (UCSF), and who were diagnosed with COVID-19 by SARS-CoV-2 RT-PCR between December 1, 2020 and August 15, 2021, were included in the study. Subjects were identified via standard reporting to UCSF HM and Infection Control programs; these programs maintain a running list of all COVID-19 positive HM patients, both inpatients and outpatients, including those who were tested at other facilities. Vaccinated patients were defined as those who had received at least one dose of COVID-19 vaccine prior to diagnosis; "fully vaccinated" patients had first positive COVID-19 test at least two weeks after their second mRNA vaccine dose or their only adenovirus vector (Johnson & Johnson) vaccine dose. The HM program's vaccination guidance during the study period was that all patients should be vaccinated, with the exception of patients who were within the period from four weeks before to three months after hematopoietic stem cell transplant (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy.

Data extracted from the electronic medical record included demographics (age, gender, race, Latinx ethnicity), comorbidities known to be risk factors for COVID-19 disease severity (diabetes, hypertension, obesity), HM disease and treatments (subtype, whether in remission, whether receiving active chemotherapy, history of allogeneic or autologous HSCT, receipt of anti-B-cell therapy within the last 18 months), SARS-CoV-2 vaccine dates and characteristics, and COVID-19 disease characteristics and treatments. "Active chemotherapy" was defined as receipt of chemotherapy within three months prior to first positive SARS-CoV-2 test. SARS-CoV-2 variant status, as determined by whole-genome sequencing as previously described 14 were calculated using univariate logistic regression. Multiple logistic regression was then performed to control for baseline differences between the groups and likely confounders;

covariates included in the model were age, diabetes mellitus, history of chimeric antigen receptor T-cell (CAR-T) therapy, active chemotherapy, anti-B-cell therapy within the prior 18 months, and high-risk neutropenia (defined as absolute neutrophil count <500 cells/m 3 for >7 consecutive days in the prior three months). Monoclonal antibody receipt was not included as a predictor variable in the main logistic regression analyses because eligibility for monoclonal antibodies was partly dependent on the outcomes (patients who did not become symptomatic would not qualify, nor would patients who were ill enough to require hospitalization at symptom onset). All statistical analysis was conducted using Stata (15.1, StataCorp LLC, College Station, TX). The study was approved by the UCSF institutional review board. Of the 70 included subjects, 16 were classified as having breakthrough COVID-19 ( Table 1) .

All received mRNA vaccine; 15 were fully vaccinated, and one was partially vaccinated.

They developed breakthrough infection at a median of 96 days (IQR: 74.5, 126.5) after their last vaccine dose. Of note, because the study period preceded the recommendation that immunocompromised patients receive a three-dose primary series, no patient received a third dose. Vaccinated HM patients were significantly younger, but otherwise without significant differences in demographics, comorbidities, or HM disease characteristics and treatments (Table 1) . Vaccinated patients were more likely to develop COVID-19 after the delta variant became predominant in June 2021 16 (Figure 1) , and more likely to receive monoclonal antibody therapy ( Table 1) . Among the vaccinated patients, COVID-19 antispike IgG antibodies were available for five either prior to or within three days of initial positive test; 40% were positive. Samples from 11 patients underwent whole-genome sequencing for SARS-CoV-2 virus variant status, and two of three vaccinated patients and one of eight unvaccinated patients had the delta variant.

On univariate logistic regression, diabetes, high-risk neutropenia, receipt of CAR T-cell therapy, and receipt of anti-B-cell therapy were associated with increased odds of COVID-19 admission and increased COVID-19 severity, whereas receipt of active chemotherapy was associated with decreased odds of these outcomes (Table S1 ). On multiple logistic regression analyses adjusting for age and above variables, there was no significant difference between the vaccinated and unvaccinated HM patients with regards to COVID-19 outcomes: adjusted OR for hospitalization for COVID-19 was 0.85 (95% confidence interval, 0.14-5.14, p=0.86), and for COVID-19 severity by ordinal scale, 1.01 (0.28-3.73, p=0.98).

However, receipt of anti-B-cell therapy in the 18 months prior to COVID-19 diagnosis was associated with increased odds of admission for COVID-19 within the cohort as a whole (OR 

In this single-center cohort, prior vaccination did not appear to be associated with need for hospital admission or with severity of disease in HM patients with COVID-19. This was true despite a significantly higher rate of monoclonal antibody treatment in the vaccinated group, which might have been expected to bias the results toward better outcomes among vaccinated patients. Although multiple prior studies have raised the concern that HM patients mount a decreased humoral response to vaccination [9] [10] [11] [12] This result is concordant with a recently-published retrospective study that found that vaccination against COVID-19 did not protect again hospitalization or 30-day mortality among patients with cancer, including a small number of HM patients 17 . Of note, since the study period, vaccine guidance in the United States has been updated to include the recommendation that immunocompromised patients receive a three-dose primary vaccine series. No patients in the study received a third dose, and it is unknown whether patients who develop breakthrough infection after a three-dose series might have less severe disease. Further study in this area is urgently needed.

We did find that prior B-cell depleting therapy was a risk factor for COVID-19 admission and for increased severity of disease. Previous reports have suggested that anti-CD20 therapy is a risk factor for prolonged SARS-CoV-2 viral replication and lack of serologic response to infection 18 , as well as a risk factor for severe COVID-19 outcomes. In a multicenter study of 111 patients with lymphoma who required admission for COVID-19, receipt of anti-CD20 therapy was associated with a significant increase in length of stay and mortality 19 . Poor humoral response to COVID-19 vaccines after B-cell-depleting therapy has also been reported 12 . For example, in a study of 96 patients who had received B-cell-depleting therapy for a variety of indications, 49% had detectable anti-spike IgG after vaccination, compared with 100% of immunocompetent controls 20 ; in a cohort of 1303 HM patients, anti-CD20 therapy was associated with a significant decrease in quantitative anti-spike IgG levels, with a median level of 17 AU/mL, below the threshold for positivity 10 . While poor humoral response to vaccine might be expected to correspond to more severe infections after vaccination, this has not yet been shown. In our study, none of the vaccinated patients who had received B-cell depleting therapy had anti-spike IgG checked prior to infection onset.

Immune response, including presence of neutralizing antibiotics among vaccinated HM patients who develop COVID-19, is an area for future study.

Of note, the outcomes in our cohort overall were significantly better than those reported in the literature for patients with hematologic malignancy; 26% required hospitalization for COVID-19, and the rate of both mechanical ventilation and COVID-19-related mortality was just 3%. This may be a result of the study setting in a center that was adequately resourced throughout the pandemic, or could be because our case sampling included both inpatients and outpatients. The largest studies on this topic have included predominantly hospitalized patients 2,3 ; for example, in Vijenthira and colleagues' pooled analysis of outcomes in 3377 HM patients, which reported a 34% overall mortality rate, 77% of patients were hospitalized 1 .

Regardless, the small number of severe outcomes likely decreased the study's power to detect effect of vaccination, and larger studies would be needed in order to conclude that vaccination does not attenuate disease severity in this population.

Besides its small size, the study has several limitations. First, variant status as determined by whole-genome sequencing was available for only 16% of the cohort. However, 75% of the infections in vaccinated patients occurred after mid-June 2021, compared with only 6% of infections in unvaccinated patients, so it is highly likely that the vaccinated group contained a higher proportion of infections with the delta variant. As the delta variant has been associated with worse outcomes 21 , this may have decreased the apparent effect of vaccination. Second, as few serologies were available prior to infection onset, we were unable to evaluate the effect of humoral response to vaccine. Third, there may have been unmeasured differences between the vaccinated and unvaccinated patients; for example, vaccinated patients may have had greater proximity or access to care (and we hypothesize that this is the reason for the higher rate of monoclonal antibody treatment in the vaccinated group). While we attempted to ameliorate this issue by including patients going back to December 2020, prior to widespread vaccine availability, it is possible that differences remained, and this could have affected the results. Fourth, as previously mentioned, no patients in the cohort received a third vaccine dose, and conclusions cannot be drawn about severity of breakthrough infections in patients who have received a three-dose series.

Finally, most patients in the cohort were tested because of symptoms, and therefore any effect of vaccine in preventing development of symptoms or in preventing infection entirely would not have been detected by the study.

In sum, we found no association between prior vaccination and COVID-19 disease severity in our patients with hematologic malignancies, and only receipt of recent anti-B-cell therapy was significantly associated with increased severity of disease in a multivariate regression model. Additional investigation is needed to better understand the immunologic and behavioral basis for these findings. Even among unvaccinated patients, we found a lower rate of severe outcomes, including need for mechanical ventilation and mortality, than has previously been reported for this population. Further study is urgently needed to better 

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