key: cord-0936116-f37ezj1h authors: Ligumsky, Hagai; Safadi, Esraa; Etan, Tal; Vaknin, Noam; Waller, Manuel; Croll, Assaf; Nikolaevski-Berlin, Alla; Greenberg, Inbal; Halperin, Tami; Wasserman, Asaf; Galazan, Lior; Arber, Nadir; Wolf, Ido title: Immunogenicity and Safety of the BNT162b2 mRNA COVID-19 Vaccine Among Actively Treated Cancer Patients date: 2021-08-28 journal: J Natl Cancer Inst DOI: 10.1093/jnci/djab174 sha: 3d15d4595a6abbf24d6bea6c4efc01287f131826 doc_id: 936116 cord_uid: f37ezj1h BACKGROUND: Activity and safety of the SARS-CoV2 BNT162b2 vaccine in actively treated patients with solid tumors is currently unknown. METHODS: We conducted a retrospective study of 326 patients with solid tumors treated with anti-cancer medications to determine the proportion of cancer patients with immunogenicity against SARS-CoV2, following two doses of the BNT162b2 vaccine. Control group was comprised of 164 vaccinated healthy adults. Anti-SARS-CoV-2 S IgG (Immunoglobulin G) antibodies (Abs) were measured, using level>50 AU/ml as cutoff for seropositivity. Adverse effects were collected using a questionnaire. All statistical tests were 2-sided. RESULTS: Most patients (205, 62.9%) were treated with chemotherapy, either alone or with additional therapy, 55 (16.9%) were treated with immune checkpoint inhibitors (ICI) and 38 (11.7%) with targeted therapy alone, 28 (8.6%) received other combinations. The vaccine was well tolerated and no severe side effects were reported. Among patients with cancer 39 (11.9%) were seronegative, compared to 5 (3.0%) of the control group (P=0.001). Median IgG titers were statistically significant lower among patients with cancer compared to control (931 AU/ml vs. 2817 AU/ml, P=0.003). Seronegativity proportions were higher in the chemotherapy treated group (19, 18.8%) compared to the ICI-treated patients (5, 9.1%) and to those treated with targeted therapy (1, 2.6%) (P=0.02. Titers were also statistically significant different among treatment types (P=0.002). CONCLUSION: The BNT162b2 vaccine is safe and effective in actively treated patients with cancer. The relatively lower antibody titers and lower proportion of seropositive patients, especially among chemotherapy treated patients, call for continuing the use of personal protective measures in these patients, even following vaccination. Patients with cancer are at increased risk for morbidity and mortality from coronavirus disease 2019 (COVID- 19) 1 , and active treatment may further increase these risks 2 . Yet, patients with cancer were excluded from the pivotal trials of the COVID-19 vaccines [3] [4] [5] Accumulating data indicate that the BNT162b2 vaccine is indeed safe in activelytreated cancer patients. We have recently reported on the short-term safety of two doses of the BNT162b2 vaccine in 134 patients with a variety of solid cancers treated with immune checkpoint inhibitors (ICI) 8 , and Monin et al reported on the safety of the vaccine in a cohort of 151 patients, of whom 95 had solid cancers and 25 received two doses 9 . No unexpected or severe side effects were noted in both studies. Similarly, the vaccine was also found to be safe among patients with chronic lymphocytic leukemia (CLL) 10 . While data regarding safety are accumulating and reassuring, data regarding activity of the BNT162b2 vaccine are lacking. Direct assessment of the ability BNT162b2 vaccine to reduce morbidity and mortality among patients with cancer is limited due to the small number of cancer patients relatively to the general population and also due to the presence of major confounding factors, including social distancing and the low prevalence of SARS-CoV-2 infection in the general population following mass vaccination. Indeed, a cohort of nearly 600,000 individuals was required in order to determine the efficacy of the BNT162b2 vaccine at the national level 11 . In order to overcome this obstacle, several surrogate markers for the activity of the vaccine are being used, with the most common is a direct measurement of anti-SARS-Cov-2 spike (S) antibody titers in the serum. Recent studies used this test and reported on antigenicity and seroconversion in patients with malignant diseases. A recent study from our institution noted an antibody response in only 40% of 167 CLL patients receiving two doses of the BNT162b2 vaccine 10 and low responses were also noted in a cohort of 29 multiple myeloma patients 12 . Response to this vaccine in patients with solid cancers was evaluated in two small cohorts 9, 13 . While both reported on ~95% immunogenicity following second vaccine dose, no association with either tumor or treatment type could be determined in either of these studies due to small number of patients. We describe here safety and antibody response following administration of the 2 nd dose of BNT162b2 vaccine, in a cohort of 326 actively-treated patients with solid tumors. This was a retrospective cohort study, designed to evaluate the safety and efficacy of the of the BNT162b2 vaccine in actively-treated patients with solid cancers. The study was conducted at the Oncology Division of Tel Aviv Sourasky Medical Center (TASMC), a tertiary referral center with over 4,000 new cancer patients a year. The study was approved by the institutional review board. The national vaccination campaign was initiated on 20 December 2020 and administration of the 2 nd dose started on January 10 th 2021. The antibody response to the BNT162b and mRNA-1273 vaccine shows a steep rise up to ~40 days following full vaccination, followed by a steady state afterwards 14, 15 . In order to avoid a bias associated with this period of antibody response upregulation, we aimed to evaluate the efficacy of the vaccine two months following the 2 nd dose. Thus, blood collection was initiated on March 15, 2021 and last patient recruited by April 30, 2021. During this period, all patients with solid tumors, actively-treated at the day-care center of the oncology division at this time, were approached and offered to participate in the study. Active treatment was defined as any IV anti-cancer medication, administered during a period starting at two weeks before the 1 st vaccine dose, and ending two weeks after the 2 nd vaccine dose. The control group consisted of fully vaccinated healthy adults with no personal history of cancer or active immune suppressive medications, who were either health care workers at the oncology division of TASMC offered to be tested for anti-SARS-CoV-2S IgG antibodies or individuals opted to test immunogenicity at the Integrated Cancer Prevention Center at TASMC. The control group was recruited at the same period of time for the purpose of this study. Following signing an informed consent form, participants filled a detailed questionnaire regarding side effects of the vaccines and blood was captured for immunogenicity analysis. Clinical data was retrieved from the hospital electronic medical records. The primary endpoint was proportion of cancer patients with immunogenicity against SARS-CoV-2, defined as antibody titer level>50AU/mL, following two doses of the BNT162b2 vaccine, compared to the healthy individuals. The secondary endpoints were antibody titer levels in cancer patients compared to the control group, association between seropositivity and cancer treatment and safety. All variables were characterized by appropriate descriptive measures. Clinical characteristics, A multivariable logistic regression model was used to evaluate the association between being a cancer patient and anti-SARS-CoV-2S IgG antibodies adjusted for age and gender, and to evaluate the effect of age, metastatic disease, time from 2 nd vaccination to IgG test, treatment type (chemotherapy Vs. no chemotherapy), and cancer type on seronegativity/positivity. All statistical tests were two-sided, and a P value less than 0.05 was considered statistically significant. Statistical analysis was done by the SPSS software. Transforming data to logs and plots formation were performed using GraphPad Prism version 9.0.1 for windows. Between March 15 and April 30, 2021, 326 out of 1383 (23.6%) actively-treated patients with cancer agreed to participate in the study. Their characteristics are presented in Table 1 . Adverse effects were collected using a detailed questionnaire. The vaccine was well tolerated with local pain (n = 64, 19.6%), weakness (n = 57, 17.5%), myalgia (n = 41, 12.6%) and headache (n = 21, 6.4%) being the most prevalent ( Figure 1 ). Importantly, no severe side effects, either life threatening or requiring hospitalization, were reported. Immunogenicity was assessed by measuring anti-SARS-CoV-2S IgG antibodies titer. According to the manufacturer's instructions 16 and based on previous reports, a titer of >50 AU/ml was considered as seropositive 17, 18 . Using this cut point, 39 (11.9%) cancer patients compared to 5 (3.0%) of the control group were found to be seronegative ( Table 2 , P=0.001). Moreover, median IgG titers were statistically significant lower the patients group compared to the healthy controls (931 AU/ml vs 2817 AU/ml, P =0.003; Table 2 ) with an odds ratio of 4.33 (95% CI = 1.66 to 11.23). The distribution of antibody titers is presented in Figure 2 . A multivariable logistic regression model indicated no statistically significant interaction between either age (P = 0.15) or gender (P = 0.11) and antibody titer levels. In order to identify additional factors contributing for reduced response to the BNT162b2 vaccine, we also compared characteristics of the 39 patients with negative antibody titer (<50 AU/ml) to the 287 patients with positive antibody titers ( Table 3) . While no statistically significant differences were found between the two groups in age, gender, metastatic disease status, time to IgG test or treatment type (chemotherapy vs no chemotherapy based treatment), the analysis is considered exploratory due to the relatively small number of patients who remained seronegative. Moreover, there was no statistically significant association between cancer type and immunogenicity status (P =0.21, Table 3 ). However, statistically significant differences were found in the distribution of antibody titers among the different cancer type (P =0.02). Multicomparisons analysis between specific cancer types revealed statistically significant difference between gynecological cancers and GI cancers (P =0.02), as for gynecological cancer the distribution of the number of antibodies tends to be higher than for GI cancer. All other comparisons were not statistically significant ( Figure 3) . Similarly, multivariable logistic regression models (generated separately for men and women as they differ by distinct cancer diagnosis) did not show any statistically significant association between seropositivity in patients with cancer and age, sex or cancer type variables (data not shown). Finally, we analyzed the association between either antibody titers or immunogenicity and treatment administered ( Table 4 ). Due to the heterogeneity of chemotherapy-based combinations the analysis was restricted to patients receiving only single type of systemic therapy: chemotherapy alone (n=101), ICI alone (n=55) or targeted therapy alone (n=38). Seronegativity proportions were higher in the chemotherapy treated group (18.8%) compared to 9.1% in the ICI-treated patients and 2.6% in those treated with targeted therapy (P =0.02 for the comparison between the groups; Table 4 ) Antibody titers differ statistically significant between treatments (P=0.002), and further examination of the differences between each pair of treatments revealed a statistically significant difference between chemotherapy and targeted therapy (P =0.001, Figure 4) As expected from routine clinical practice, the distribution of tumor types, and therefore also sex and age, were different according to treatment type. For example, no women with breast cancer were treated with ICI, while 20 (36.4%) of the ICI-treated group had non-small cell lung cancer ( Table 4 ). None of the study participant, either patients with cancer or the healthy individuals reported on contracting COVID-19 following the 2 nd vaccine dose. We report here on the safety and efficacy of the COVID-19 vaccine BNT162b2 in a large unselected population of patients with solid tumors at the time of active anti-cancer treatment. Importantly, all patients received two doses of the vaccine at the recommended schedule of days 1 and 21. Moreover, immunogenicity was examined six weeks following the 2 nd dose, a time expected to represent the steady state of protective antibodies levels. Our data indicate the vaccine to be highly effective in this population, with 88% having protective levels of anti-SARS-CoV-2S antibodies, compared to 97% in healthy controls. However, chemotherapy-treated patients had lower proportion of patients with protective antibody levels, 81%. Similarly, lower response rates were also noted in cancer patients following influenza vaccine 19 . Two small studies reported on 95% seropositivity in 18 9 Indeed, differences between patients with cancer and the healthy controls in antibody titers were highly statistically significant, with median titer of nearly 3-fold higher in the control group ( Table 2) . It is remain to be elucidated whether these differences will translate to higher chances of SARS-CoV-2 infection. The immune response may also be evaluated by testing T-cell response following As expected from previous reports 9, 13, 10 , no severe side effects were noted. Importantly, despite the relatively longer period from the 2 nd vaccine dose, no new safety signals were observed, regardless of treatment type. This finding strengthen the current recommendations to vaccinate all patients with cancer regardless of treatment type. In conclusion, our study indicates the BNT162b2 mRNA vaccine as safe and effective in actively treated patients with cancer. However, the relatively lower antibody titers and lower proportion of patients with seropositive response, especially among chemotherapy treated patients, call for continuing the use of personal protective measures in these patients, even following vaccination. Not applicable Role of the funder: Not applicable. The data underlying this article cannot be shared publicly due to ethical guidelines, aiming to protect the privacy of individuals that participated in the study. The data may be shared on reasonable request to the corresponding author, after permission from the institutional review board. 50-100 100-1000 1000-5000 5000-10000 <10000 a P values derived from the non-parametric Mann-Whitney U test, two-sided. Comparison of median IgG Ab between cancer patients and control group was adjusted for age and sex using a logistic regression model including these variables. Ab = antibody. 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