key: cord-0794921-e5nbe3r0
authors: Thakkar, Astha; Gonzalez-Lugo, Jesus D.; Goradia, Niyati; Gali, Radhika; Shapiro, Lauren C.; Pradhan, Kith; Rahman, Shafia; Kim, So Yeon; Ko, Brian; Sica, R. Alejandro; Kornblum, Noah; Bachier-Rodriguez, Lizamarie; McCort, Margaret; Goel, Sanjay; Perez-Soler, Roman; Packer, Stuart; Sparano, Joseph; Gartrell, Benjamin; Makower, Della; Goldstein, Yitz D.; Wolgast, Lucia; Verma, Amit; Halmos, Balazs
title: Seroconversion rates following COVID-19 vaccination amongst patients with cancer
date: 2021-06-05
journal: Cancer Cell
DOI: 10.1016/j.ccell.2021.06.002
sha: 7d52d4f8ee6176f30b6b173f4a687ad1263f25af
doc_id: 794921
cord_uid: e5nbe3r0

As COVID-19 adversely affects patients with cancer, prophylactic strategies are critically needed. Using a validated antibody assay against SARS-CoV-2 spike protein, we determined a high seroconversion rate (94%) in 200 patients with cancer in New York City that had received full dosing with one of the FDA-approved COVID-19 vaccines. Comparing to solid tumors (98%), a significantly lower rate of seroconversion was observed in patients with hematological malignancies (85%), particularly recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%). Patients receiving immune checkpoint inhibitor therapy (97%) or hormonal therapies (100%) demonstrated high seroconversion post-vaccination. Patients with prior COVID-19 infection demonstrated higher anti-spike IgG titers post-vaccination. Relatively lower IgG titers were observed following vaccination with the adenoviral than mRNA-based vaccines. These data demonstrate generally high immunogenicity of COVID-19 vaccination in oncology patients and identify immunosuppressed cohorts that need novel vaccination or passive immunization strategies.

COVID-19 can result in increased morbidity and mortality in cancer patients (Kuderer et al., 2020 , Mehta et al., 2020 , Bakouny et al., 2020 suggesting the need for prophylactic strategies in this immunosuppressed population. In patients with cancer that were affected by COVID-19, increased age, co-morbidities, poor performance status, thoracic and hematologic malignancies have been identified as adverse prognostic indicators for reduced survival. (Grivas et al., 2021 , Robilotti et al., 2020 , Mehta et al., 2020 . Followup studies on seroconversion in cancer patients with COVID-19 demonstrated that while most will develop antibody response similar to the general population, subgroups of cancer patients with hematologic malignancies, receiving anti-CD20 antibody therapies and stem cell transplant exhibit lower rates of seroconversion (Thakkar et al., 2021 , Marra et al., 2020 . These results suggested that overall high seroconversion rates might be anticipated in patients with malignancies following COVID-19 vaccinations as well, with likely reduced immunogenicity in certain subgroups of patients manifesting from different degrees and mechanisms of immune suppression. Patients with cancer can be immunocompromised due to a multitude of factors, such as the underlying malignancy itself, bone marrow suppressive effects of cytotoxic chemotherapy, prior or ongoing treatments with high degree of immunosuppressive effects, such as J o u r n a l P r e -p r o o f corticosteroids, B cell depleting therapies (i.e. anti-CD20 antibodies), cell therapies (especially CAR-T cell), and stem cell transplantation.

It is critical to understand the immunogenicity of approved vaccines for assessing the need of ongoing social isolation and other strategies to mitigate the risk of contracting COVID-19 by immunosuppressed patients, designing and rapidly conducting clinical studies focused on passive immunization strategies and vaccine trials assessing unique schedules to enable boosting of immune response. However, trials of the currently approved COVID-19 vaccines in general excluded patients with a diagnosis of a malignancy, therefore information on the safety and efficacy of these vaccines as to the development of effective immunity currently is extremely sparse (Friese et al., 2021) .

Given the higher morbidity and mortality of patients with cancer and COVID-19, their ongoing need to be exposed to the health care system and their frequent need for immunosuppressive therapies; patients with cancer have been identified as a highpriority subgroup for COVID-19 vaccinations-an effort supported by multiple key organizations (Ribas et al., 2021 , van der Veldt et al., 2021 , Desai et al., 2021 .

While patients with cancer clearly represent a highly susceptible group with a strong and immediate need to be protected by available, effective vaccines, there remain many uncertainties. For example, following certain immunosuppressive therapies --such as an autologous or allogeneic stem cell transplant, anti-CD20 or T cell directed regimens --vaccinations have low efficacy and their best timing is unclear (Jaffe et al., 2006 , Rubin et al., 2014 . Such guidance is also lacking for patients undergoing cytotoxic chemotherapy. One randomized study did not suggest notable differences as to influenza vaccine immunogenicity efficacy dependent on whether vaccination was given on day of chemotherapy or during the neutropenic period of the treatment cycle (Keam et al., 2017) . While many agencies have suggested administering vaccines 1-2 weeks prior to a chemotherapy dose, this recommendation has not been practical with limited vaccination slot availability, variable chemotherapy (e.g. weekly) and vaccine administration schedules (e.g. 2 doses of BNT162b2 are recommended to be given 21 while mRNA-1273 are given 28 days apart) leading to liberal recommendations to allow most rapid vaccination of these immunosuppressed patients (Desai et al., 2021) .

Vaccine safety and immunogenicity information is also generally lacking in the context J o u r n a l P r e -p r o o f of therapies that stimulate the immune system, such as immune checkpoint inhibitor (ICI) therapy with a few studies suggesting general safety and possibly heightened immunity in this context (Waissengrin et al., 2021) .

To narrow this key knowledge gap, we conducted this study to comprehensively determine the immunogenicity of vaccines in a cohort of patients with a diagnosis of a malignancy in New York City via evaluation of rates of anti-spike IgG antibody positivity following vaccination with one of the three FDA-approved COVID-19 vaccines.

Two hundred and thirteen patients were enrolled in the study via informed-consent process. An additional 29 patients with cancer who underwent SARS-CoV-2 spike IgG testing were identified by retrospective chart review. Eighteen patients did not have a SARS-CoV-2 spike IgG test performed after consenting and were excluded. Another 20 patients were excluded as they had a SARS-CoV-2 spike IgG test before completion of full vaccination series according to FDA guidance (6 with negative and 14 with positive results). Two more patients were excluded who had a negative SARS-CoV-2 spike IgG and no clear documentation of dates or types of vaccine and two more patients were excluded due to duplicate medical records. Finally, 233 patients with cancer having completed the FDA recommended two doses of the mRNA vaccines [BNT162b2 (Polack et al., 2020) or mRNA-1273 (Baden et al., 2020) ] or one dose of the adenoviral vaccine [AD26.COV2.S (Sadoff et al., 2021) ] were included in the safety analysis (Fig   1) . A cohort of 200 patients underwent a SARS-CoV-2 spike IgG test and were included in the immunogenicity analysis. Serological data (positive or negative IgG test) from these 200 patients was used in association studies between cancer subtypes and treatments. We also investigated association between the quantitative titer of SARS-CoV-2 spike IgG and cancer subtypes and treatments. One hundred eighty-five of 200 patients had IgG titers available that were at least 7 days post the last dose of the vaccine ('vaccinated cohort with titers'). Twenty-six de-identified patients without a cancer diagnosis who had completed COVID-19 vaccination and received a SARS-J o u r n a l P r e -p r o o f CoV-2 IgG spike antibody test > 7 days after their most recent vaccine dose was used as a control cohort (Supp Table 1 ). This is represented in the CONSORT diagram (Fig   1) .

A total of 200 patients who completed their full vaccination schedule according to FDA guidance were included in the efficacy study. The median age of the patient population Table 1) . As patients were recruited from our outpatient hematology/oncology clinics, most patients had an active cancer diagnosis. One hundred fifty patients (75%) had an active malignancy and 135 patients (67%) were in active cancer therapy at the time of their vaccination with 112 (56%) of patients on active chemotherapy. patients were on active chemotherapy within 48 hours of at least one of the vaccine doses. Types of cancer therapies are listed in detail in Table 2 . One hundred and fifteen patients (54%) had completed vaccination with the BNT162b2, 62 (31%) with the mRNA-1273 mRNA vaccine and 20 (10%) had received the single dose Ad26.COV2.S vaccine. Three patients had received a complete mRNA vaccination series, however the information about the type (BNT162b2 vs mRNA-1273) was not available.

Anti-SARS-CoV-2 spike protein antibody test (Abbott) was performed which demonstrated a high rate of seropositivity (94%) with only 13 (6%) patients with a negative value (titer below 50 arbitrary units/milliliter [AU/ml]). Percent positivity appeared similarly between the vaccine types (BNT162b2 95%, mRNA-1273 94%, Ad26.COV2.S 85%) with a trend towards lesser positivity with the Ad26.COV2.S vaccine. We also assessed antibody titers in a sub-cohort of 185 patients with available IgG levels >7 days post final dose of vaccine (vaccinated cohort matching the definition J o u r n a l P r e -p r o o f of our non-cancer control cohort). The median time between spike antibody test and vaccine dose for this sub-cohort is 30 days (IQR 19-53 days). In solid malignancy patients, the median is 31.5 days and in patients with hematologic malignancies the median is 28.5 days.

Highest IgG titers were seen with the mRNA-1273 vaccine (Median 11963 AU/ml, standard deviation(SD)18742) followed by the BNT162b2 vaccine (Median 5173 AU/ml, SD 16699) and the single dose Ad26.COV2.S vaccine (Median 1121 AU/ml, SD 17571) (p value < 0.05, Kruskall Wallis Test, Fig 2A) . We recognize that the Ad26.COV2.S vaccine was introduced late into the market which might or might not account for the lower titers of spike antibodies, we assessed associations of antibody seropositivity and antibody titers with time from completion of vaccination. While there was no association with titer levels, we found a statistically significant positive association between the time from vaccination till IgG testing and antibody seropositivity (p = 0.03, Kruskal Wallis test). We then conducted a multivariate analysis with a generalized linear model and observed that the relationship between vaccine type and titers remained significant after accounting for the effect of time from vaccine (Supp Fig 1) .

Vaccinations appeared to be generally very safe amongst this cohort with mostly mild and moderate anticipated adverse effects reported. In the safety analysis, 139 patients 

In the cohort of patients with solid tumors, seropositivity post vaccination was high (98%), while a significantly lower seropositivity rate was seen in patients with hematological malignancies (85%, p = 0.001, Fisher's exact test). Analysis of the subcohort of 185 patients with available IgG titers >7 days post vaccination revealed J o u r n a l P r e -p r o o f significantly higher titer values in solid tumors (median 7858 AU/ml, SD 18103) than hematologic malignancies (median 2528 AU/ml, SD 12338, p = 0.013, Kruskal Wallis test). Furthermore, to ensure that the difference in titers was not confounded by different time intervals from vaccination, we conducted a multivariate analysis using time from vaccination to IgG assay testing as a confounder and determined that lower titers in hematologic malignancies than solid tumors were still significant (p = 0.0012).

Comparison of titers from non-cancer controls (Table S1) revealed no significant difference when compared to solid tumor patients but, showed a statistically significant difference when compared to patients with hematological malignancy (p = 0.01, Kruskal Wallis test) (Fig 2B) .

No significant differences in seroconversion were seen when comparing patients on active cancer therapy versus patients who were not (96% vs 93%). However, significantly lower rates of seropositivity were seen in patients on active cytotoxic chemotherapy (92%) versus others (99%, p=0.04) without notable differences in titer levels (Fig 3) . Next, we focused our analysis on patients who had received specific immunosuppressive therapies, such as stem cell transplantation, anti-CD20 therapy or CAR-T cell therapy. We observed significantly lower seroconversion rates in patients underwent these therapies: stem cell transplant (73%, p = 0.0002, Fisher's exact test), anti-CD20 therapies (70%, p = 0.0001, Fisher's exact test) and CAR-T cell treatments (all 3 patients remained seronegative after vaccination, p = 0.0002, Fisher's exact test) ( Table 3) . Of the 26 stem cell transplant patients, 23 received an autologous and 3 an allogeneic transplant (2 seropositive, 1 seronegative). Accordingly, significantly lower titer levels were also seen in patients receiving anti-CD20 therapies compared to the overall group of patients (Fig 4) . These results highlighted the continued susceptibility of patients receiving these therapies during the pandemic.

Age: Our patient population had a wide age range (27-90 years). We studied the association between age and SARS-CoV-2 IgG spike antibody seroconversion rates J o u r n a l P r e -p r o o f and observed no statistically significant association between these variables (p = 0.13, Kruskal Wallis test) Ethnicity: Given the ethnically diverse cohort in this study, we studied association between seropositivity and patient ethnicity. We observed that there was no statistically significant association between ethnicity and spike antibody seroconversion rates (p = 0.4574, Fisher's exact test) Time since immunosuppressive therapy: We also studied association between time since specific immunosuppressive therapies and immunogenicity. We divided patients into two groups: <365 days and >365 days since anti-CD20 antibody therapy or stem cell transplant and anti-SARS-CoV-2 spike IgG testing. The comparison between seropositivity and time since immunosuppressive treatment was not statistically significant (p = 1, Fisher's exact test). Treatment within 48 hours of a vaccine dose: We collected data to evaluate if patients who received active cancer therapies 48 hours before or after a vaccine dose had lesser seropositivity rates. Thirty-eight patients met the above criteria. We observed that 3 patients were seronegative, and there was no statistically significant association whether patients received cancer therapies within 48 hours of the vaccine or not (p = 0.7, Fisher's exact test). These patients were compared with the entire cohort These analyses are available in Supplementary table 2.

We observed high rates of seroconversion post vaccination in patients on hormonal therapy (100% seropositivity, p = 0.04) and ICI therapy (97%, p = 0.69, Fisher's exact test), when compared to the rest of the cohort, respectively. Interestingly, while all patients on CDK4/6 inhibitor treatment showed positive anti-spike IgG test results, notably antibody titers were very low in this small subset (n=5, median 1242 AU/ml SD 2435 versus median 6887 AU/ml, SD 17843 for overall cohort) (Fig 5) . Given the known J o u r n a l P r e -p r o o f involvement of the CDK4/6 pathway in immune activation (Chen-Kiang, 2003 , Cingöz and Goff, 2018 , Laphanuwat and Jirawatnotai, 2019 this might be biologically plausible and calls for further studies into the impact of CDK4/6 inhibitor on vaccine efficacy. We also noted trends towards lower titers amongst other subgroups, such as patients having received BCL2-or BTK-targeted therapy consistent with prior observations on their negative impact on vaccine efficacy (Pleyer et al., 2021) (Suppl figure 3) .

Previous studies have reported heightened antibody responses to vaccinations in patients with a prior COVID-19 infection (Krammer et al., 2021) . Our cohort included 22 patients with cancer who had known prior COVID-19 and a high rate of seroconversion was seen in this subset (21/22 seroconverted for a 95% seroconversion rate with one patient not seroconverting having received an autologous stem cell transplant). Antibody titers in previously infected patients were significantly higher than those who were not known to be priorly infected (prior COVID-19: median 46737AU/ml, SD 18681; others: median 5296AU/ml, SD 16193, p < 0.001, Kruskall

Wallis test) (Fig 5D) .

COVID-19 disease has had a devastating impact worldwide and especially so among patients with a cancer diagnosis. Various factor adversely affect outcomes in cancer patients affected with COVID-19 including impact of underlying disease on performance status, age/co-morbidities of affected patients, immune suppression related to disease such as in patients with hematological malignancies as well as immune suppressive effects of disease-directed therapies (Lee et al., 2020a , Lee et al., 2020b , Jee et al., 2020 , García-Suárez et al., 2020 , Mehta et al., 2020 , Westblade et al., 2020 . In addition, patients with cancer requiring active therapy face frequent exposure to the Barrière et al.) . Lower seropositivity rates have also been observed in patients with CLL and myeloma (Herishanu et al., 2021 , Terpos et al., 2021 , Bird et al., 2021 and in those undergoing therapy with BTK inhibitors or venetoclax/anti-CD20 therapy in line with our observations (Herishanu et al., 2021) . These early studies clearly highlight the need to complete full vaccination schedules for optimum seroconversion and also emphasize the need for larger cohort studies to determine the immunogenicity of Covid-19 vaccines amongst patients receiving distinct cancer therapeutics.

Several shortcomings of our study need to be listed. These include limited representation of some patient cohorts not allowing clear conclusions as to seroconversion rates amongst less common malignancy types or less frequently used treatment approaches. Our cohort also over-represented patients on active therapy as recruitment occurred over a short period in our outpatient departments. In addition, our study relies solely on the anti-spike protein IgG levels as a surrogate for immunity to COVID-19. Admittedly, the anti-spike IgG antibody used in our study, albeit specific to the receptor binding domain (RBD) of the spike protein, might still not necessarily correlate with virus neutralizing activity. Our study did not evaluate the level of SARS-CoV-2-specific T cell responses either. Further research will be needed to directly assess virus neutralization and cellular immunity (Bange et al., 2021) . Another potential limitation is under-estimation of titer values for anti-spike antibodies as evidence suggests titers may rise over time and the upper limit of detection of our assay is 50000 AU/mL (Widge et al., 2020) ; however, a cut-off of 7 days was used to match the control cohort and eliminate bias in the analysis. Lastly, some observations are based on smaller subsets and post-hoc analyses, thereby larger studies are needed for validation.

Our study along with other emerging data, strongly highlights the continued need to vaccinate patients with a cancer diagnosis urgently and broadly as vaccinations are likely to be highly effective. On the other hand, our study highlights at-risk cohorts of patients, in particular patients with hematological malignancies following receipt of immunosuppressive therapies-stem cell transplant, anti-CD20 therapies, CAR-T cell treatments. These cohorts of patients could potentially benefit from passive immunization with anti-COVID antibodies in the face of the ongoing pandemic. In fact, monoclonal anti-COVID-19 antibodies have shown therapeutic and prophylactic potential in transplant or at-risk patient cohorts (Rizk et al., 2021 , Hurt and Wheatley, 2021 , Dhand et al., 2021 . In addition, higher doses or booster doses of some vaccines or vaccinations of mixed vaccine types might offer stronger immunogenicity and need to be explored in immunosuppressed patients. Lastly, protective measures such as masking, social distancing will remain logical aspects of defensive management strategies for highly immune suppressed patients during the pandemic until safe herd immunity levels of population level vaccinations are reached.

In summary, we present a large cohort of patients with malignancy who underwent full COVID-19 vaccination according to FDA guidance. In this cohort of ethnically diverse patients with broad representation of a wide range of malignancies and therapies, very high seropositivity rates were observed in contrast to previously published smaller cohort studies focusing on unique subsets of susceptible patients or non-standard vaccination schedules. Statistically significantly lower seropositivity rates were observed in patients with hematological malignancies and patients having received immunosuppressive therapies. Our findings support broad and urgent COVID-19 vaccinations in patients with a cancer diagnosis enabling optimal cancer treatment delivery during the ongoing COVID-19 pandemic. Anti-spike protein IgG antibody titers (AU/ml) after full vaccination did not significantly differ in patients having received stem cell transplantation (SCT) (A) or anti-CD38 antibody therapy (B) when compared to respective counterparts. Patients receiving anti-CD20 antibody treatments (C) or CAR-T cell therapy (D) had a significantly lower titer after vaccination when compared to respective counterparts. Box plots are shown and differences assessed by Kruskal Wallis Test. J o u r n a l P r e -p r o o f Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Balazs Halmos, bahalmos@montefiore.org.

This study did not generate new unique reagents.

The published article includes all data generated and analyzed during this study. Data will be made available freely from the corresponding authors upon request. The utilized computer code has been deposited in GitHub (https://github.com/kithpradhan/CovidVaccineReport/blob/main/report.R). All analyses were conducted with built-in and freely available R packages.

The study was approved by the Montefiore-Einstein Institutional Review Board. This study was designed as a cross-sectional cohort study and enrolled subjects being seen in the outpatient practices of the Montefiore/Einstein Cancer Center during April 2021.

Participants were enrolled in the study after signing informed consent. Subjects underwent anti-SARS-CoV-2 spike IgG assay, completed a questionnaire focusing on details and adverse effects of COVID-19 vaccination and provided optional consent for future biobanking for research. The protocol also allowed data collection via retrospective chart review for a small number of patients who underwent anti-SARS- 

The AdviseDx SARS-CoV-2 IgG II assay was used for the assessment of anti-spike IgG antibody testing. AdviseDx is an automated, two-step chemiluminescent immunoassay performed on the Abbott i2000SR instrument. The assay is designed to detect IgG antibodies directed against the receptor binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2. The RBD is a portion of the S1 subunit of the viral spike protein and has a high affinity for the angiotensin converting enzyme 2 (ACE2) receptor on the cellular membrane (Pillay, 2020 , Yang et al., 2020 .

The procedure, in brief, is as follows. Patient serum containing IgG antibodies directed against the RBD is bound to microparticles coated with SARS-CoV-2 antigen. The mixture is then washed of unbound IgG and anti-human IgG, acridinium-labeled, secondary antibody is added and incubated. Following another wash, sodium hydroxide is added and the acridinium undergoes an oxidative reaction which releases light energy which is detected by the instrument and expressed as relative light units (RLU).

There is a direct relationship between the amount of anti-spike IgG antibody and the RLU detected by the system optics. The RLU values are fit to a logistic curve which was J o u r n a l P r e -p r o o f used to calibrate the instrument and expresses results as a concentration in AU/mL (arbitrary units/milliliter). This assay recently has shown high sensitivity (100%) and positive percent agreement with other platforms including a surrogate neutralization assay (Bradley et al., 2021{Bradley, 2021 and also demonstrated high specificity both in the post COVID-19 infection and post vaccination settings. The cutoff value for this assay is 50 AU/mL with <50 AU/ml values reported as negative and the maximum value is 50000 AU/mL.

Association between two categorical variables was tested with a Fisher exact test.

Association between one categorical and one ordinal variable was tested with a Kruskal-Wallis Rank Sum test. Pre-specified hypotheses to be tested included assessing correlation of seropositivity with solid and hematologic malignancies and between the overall cohort and highly immunosuppressive therapies. All analyses were done in R (version 3.6.2).

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