Six-Month Humoral and Cellular Immune Response to the Bnt162b2 Mrna Covid-19 Vaccine Booster in the Patients with Solid Tumors on Active Treatment: Focus on Variants of Concern (Vocs)

Background: The role and the durability of immunogenicity of the 3rd dose of vaccine against COVID-19 variants of concern (VOCs) in cancer patients remains to be elucidated. The aim of this study is to evaluate the immunogenicity of the 3rd dose of the SARS-CoV-2 BNT162b2 mRNA vaccine in triggering both the humoral and the cell-mediated immune response in the patients with solid tumors undergoing active treatment 6 months after booster Methods: We have prospectively evaluated kinetics of humoral and cellular immune response elicited by booster BNT162b2 anti-SARS-CoV-2 vaccine dose up to 6 months. Samples were collected at the enrollment (T0), 21 days after the booster (T1) and 6 months after (T2). Sera were tested for Spike trimeric IgG (cut off 33.8 BAU/mL) and SARS-CoV-2 neutralizing antibodies (NT Abs;cut off 1:10), T-cell response against Spike protein was detected by IFNgamma release assay (IGRA from Euroimmun). Result(s): One-hundred patients (36F/50M;median age 65, range 26-89) were included in the study. In 9 subjects, a COVID-19 infection was reported before the administration of the 1st dose of vaccine. Preliminary analyses were performed in a cohort of 79 previously unexposed subjects. The 3rd dose was administered at median 176 days (range 91-281) after the 1st dose. At T0 anti-S IgG response was median 170 (IQR 67.8-421.4) BAU/mL and it increased to median 2080 (IQR 2080-2080) BAU/mL at T1;a decrease of response was observed at T2 (median 1605 IQR 822-2080 BAU/mL). Overall, 11/79 (13.9%) patients were negative at baseline and 10/11 reached positive level of response at T1. Only 2 subjects were negative for serological response at T2. A similar trend was observed for SARS-CoV-2 NTAbs. In 65 patients we compared NT Abs levels reached against wild type (WT) strain, Delta and Omicron variants at T2. Median response against WT strain was 1:320 (IQR 1:40-1:640) while it decreased to 1:80 (IQR 1:20-1:320) and 1:10 (IQR <1:10-1:40) against Delta and Omicron variants (p value 0.08 and <0.001, respectively). Overall, 4/65 (6.2%) patients were negative for WT SARS-CoV-2 NT Abs while 6/65 (9.2%) and 17/65 (26.2%) were negative for Delta and Omicron SARSCoV- 2 NT Abs, respectively. Conclusion(s): Preliminary data suggest an enhanced immunogenicity elicited by booster in cancer patients, also against variant strains, even if a decrease NT Abs level was observed against Omicron. T-cellular response and multivariable analysis on demographic/clinical data will be presented at the meeting.

Six-month humoral and cellular immune response to the third dose of BNT162b2 anti-SARS-CoV-2 vaccine in patients with solid tumors: a longitudinal cohort study with a focus on the variants of concern.

BACKGROUND: The role and the durability of the immunogenicity of the third dose of vaccine against COVID-19 variants of concern in cancer patients have to be elucidated. PATIENTS AND METHODS: We have prospectively evaluated the immunogenicity of the third dose of the SARS-CoV-2 BNT162b2 messenger RNA vaccine in triggering both humoral and cell-mediated immune response in patients with solid tumors undergoing active treatment 6 months after the booster. Neutralizing antibody (NT Ab) titers and total anti-spike immunoglobulin G concentrations were measured in serum. Heparinized whole blood samples were used for the SARS-CoV-2 interferon-γ release assay (IGRA). RESULTS: Six months after the third dose only two patients (2.4%) showed negative spike-specific immunoglobulin G antibody levels (<33.8 BAU/ml). The median level of SARS-CoV-2 NT Abs decreased and only 39/83 (47%) subjects showed maximum levels of NT Abs. T-cellular positive response was observed in 38/61 (62.3%) patients; the highest median level of response was observed 21 days after the third dose (354 mIU/ml, interquartile range 83.3-846.3 mIU/ml). The lowest median level of NT Ab response was observed against the Omicron variant (1 : 10, interquartile range 1 : 10-1 : 40) with a significant reduced rate of responder subjects with respect to the wild-type strain (77.5% versus 95%; P = 0.0022) and Delta variant (77.5% versus 93.7%; P = 0.0053). During the follow-up period, seven patients (8%) had a confirmed post-vaccination infection, but none of them required hospitalization or oxygen therapy. CONCLUSIONS: Our work highlights a significant humoral and cellular immune response among patients with solid tumors 6 months after the third BNT162b2 vaccine dose, although a reduction in neutralizing activity against Omicron was observed.

Humoral and cell-mediated immune response to the third dose of BNT162b2 anti- SARS-CoV-2 vaccine in patients with cancer on active treatment: Focus on wild type, Delta and Omicron strains

Background: Although a full course of COVID-19 vaccine is effective in cancer patients, the duration of the protection and the efficacy of a booster dose against the new variants remain unknown. We prospectively evaluated the immunogenicity of the third dose of the SARS-CoV-2 BNT162b2 mRNA vaccine in cancer patients undergoing active treatment. Methods: Patients with solid cancer, vaccinated with a booster dose during active treatment, were prospectively enrolled in this study. Patients were classified in SARS-CoV-2 naïve (without previous COVID-19 infection) and SARS-CoV-2 experienced (with previous COVID-19 infection). Neutralizing antibody (NT Abs) titer and total anti-Spike IgG concentration were quantified in serum. Heparinized whole blood samples were used for SARS-CoV-2 Interferon Gamma Release Assay (IGRA). The primary endpoint was to assess the increase of IgG antibody level between baseline (T0) and 3 weeks after the booster (T1). Results: 142 consecutive patients were recruited. In SARS-CoV-2 naïve subjects, median level of IgG was 157 BAU/mL (interquartile range (IQR) 62-423) at T0 and reached median of 2080 (IQR 2080-2080) at three weeks after booster administration (T1;p < 0.0001). A median 16-fold increase of SARS-CoV-2 NT Abs titre (IQR 4-32) was observed in naïve subjects (from median 20 IQR 10-40 to median 640 IQR 160-640;p < 0.0001). Median IFN-γ level at T1 was significantly higher than that measured at T0 in SARS-CoV- 2 naïve subjects (p = 0.0049) but not in SARS-CoV-2 experienced patients. No difference was observed in terms of median response between patients treated with immunotherapy and chemotherapy (p > 0.05). A stronger correlation between SARS-CoV-2 NT Abs and total IgG level was observed at T0 (r = 0.76;p < 0.0001) compared to T1 (r = 0.27, p = 0.0081). No correlation as regards the number of days was observed from the first to the third vaccination and SARS-CoV-2 NT Abs/total IgG. The median level of SARS-CoV-2 NT Abs was 32-fold lower against Omicron compared to wild type strain (p = 0.0004) and 12-fold lower compared to Delta strain (p = 0.0110). Conclusions: The third dose is able to trigger both the humoral and the cell-mediated immune response in cancer patients on active treatment. Our preliminary data about the neutralization of the SARS-CoV-2 vaccine against variants of concern (VOCs) seem to confirm the vaccine lower activity. (Table Presented).

Immunogenicity and safety after the third dose of BNT162b2 anti-SARS-CoV-2 vaccine in patients with solid tumors on active treatment: a prospective cohort study.

BACKGROUND: Although a full course of coronavirus disease 2019 (COVID-19) vaccine is effective in cancer patients, the duration of the protection and the efficacy of a booster dose against the new variants remain unknown. We prospectively evaluated the immunogenicity of the third dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BNT162b2 messenger RNA vaccine in cancer patients undergoing active treatment. PATIENTS AND METHODS: Patients with solid cancer, vaccinated with a booster dose during active treatment, were enrolled in this study. Patients were classified into SARS-CoV-2 naïve (without previous COVID-19 infection) and SARS-CoV-2 experienced (with previous COVID-19 infection). Neutralizing antibody (NT Ab) titer and total anti-Spike immunoglobulin G (IgG) concentration were quantified in serum. Heparinized whole blood samples were used for SARS-CoV-2 Interferon Gamma Release Assay (IGRA). The primary endpoint was to assess the increase of IgG antibody level between baseline and 3 weeks after the booster. RESULTS: One hundred and forty-two consecutive patients were recruited. In SARS-CoV-2-naïve subjects, the median level of IgG was 157 BAU/ml [interquartile range (IQR) 62-423 BAU/ml] at T0 and reached a median of 2080 BAU/ml (IQR 2080-2080 BAU/ml) at 3 weeks after booster administration (T1; P < 0.0001). A median 16-fold increase of SARS-CoV-2 NT Ab titer (IQR 4-32) was observed in naïve subjects (from median 20, IQR 10-40, to median 640, IQR 160-640; P < 0.0001). Median interferon-γ level at T1 was significantly higher than that measured at T0 in SARS-CoV-2-naïve subjects (P = 0.0049) but not in SARS-CoV-2-experienced patients. The median level of SARS-CoV-2 NT Abs was 32-fold lower against Omicron compared to the wild-type strain (P = 0.0004) and 12-fold lower compared to the Delta strain (P = 0.0110). CONCLUSIONS: The third dose is able to trigger both the humoral and the cell-mediated immune response in cancer patients on active treatment. Our preliminary data about the neutralization of the SARS-CoV-2 vaccine against variants of concern seem to confirm the lower vaccine activity.

The immunogenity, efficacy and safety of BNT162b2 anti-SARSCoV- 2 vaccine in cancer patients treated with PD-1/PD-L1 inhibitors: An observational ambispective multicenter study

Background and Aim: Cancer patients are underrepresented in ongoing phase 3 clinical trials of COVID-19 vaccines. The aim of this study is to evaluate the magnitude of the T- and B-cell response in these patients treated with Immune Checkpoint Inhibitors (ICIs) and receiving the BNT162b2 vaccine. A group of vaccinated healthy subjects has been used as a validation control Methods: Consecutive cancer patients in ICIs were enrolled from the beginning of the vaccination campaign for frail patients. Samples were collected before vaccination (T0), at time of the 2nd dose (T1) and 21days after complete vaccination schedule (T2). Sera were tested for S1/S2 IgG (cut off 15 AU/mL) and SARS-CoV-2 neutralizing antibodies (NT Abs;cut off 1:10), while peripheral blood mononuclear cells (PBMC) were isolated and used for Spike specific ELISpot assay (cut off 10 net spots/million PBMC) Results: Preliminary results on 65 patients (18 females and 47 males;median age 67) were obtained. At T0,8/65 (12.3%) were positive for S1/S2 IgG since they had experienced COVID-19 disease (median 61 IQR 27.5-133.5 AU/mL). All subjects developed a sustained humoral response at T1 in terms of both S1/S2 IgG (median 2735 IQR 2220-3768 AU/mL) and SARS-CoV-2 NT Abs. 35/57 patients (61.4%) were still seronegative at T1 since they showed a S1/S2 IgG level lower than 15 AU/mL. The level of humoral response at T1 was significantly reduced compared to the level observed in healthy subjects (p=0.0187). Spike-specific T-cell response was analyzed in 26 subjects at T0 (median 5 IQR 0-16.5 net spots/million PBMC). Response increased significantly from T1 to T2 (median 22.5 IQR 5-95 and 180 IQR 92.5-380 net spots/million PBMC). The most common side-effects were pain at the injection site (6%, 4/65) and fever (5%, 3/65). One patient presented 2 immune-related sideeffects (hepatitis and colitis G3) 10 days after the 1st dose of vaccine: she received high-dose steroid therapy, with clinical remission Conclusions: BNT162b2 mRNA vaccine elicited a humoral response after the 1st dose in about 40% of the patients. Differences with healthy subjects may depend on the older age and time gap between start of ICIs and vaccine administration. Additional data, including long term analysis (+6months), T-cellular response and multivariable analysis on demographic/clinical data, will be presented at the meeting. Overall, our preliminary data suggest a reassuring safety profile of vaccination in cancer patients undergoing ICIs.

Analysis of the humoral and cellular immune response after a full course of BNT162b2 anti-SARS-CoV-2 vaccine in cancer patients treated with PD-1/PD-L1 inhibitors with or without chemotherapy: an update after 6 months of follow-up.

BACKGROUND: The durability of immunogenicity of SARS-CoV-2 vaccination in cancer patients remains to be elucidated. We prospectively evaluated the immunogenicity of the vaccine in triggering both the humoral and the cell-mediated immune response in cancer patients treated with anti-programmed cell death protein 1/programmed death-ligand 1 with or without chemotherapy 6 months after BNT162b2 vaccine. PATIENTS AND METHODS: In the previous study, 88 patients were enrolled, whereas the analyses below refer to the 60 patients still on immunotherapy at the time of the follow-up. According to previous SARS-CoV-2 exposure, patients were classified as SARS-CoV-2-naive (without previous SARS-CoV-2 exposure) and SARS-CoV-2-experienced (with previous SARS-CoV-2 infection). Neutralizing antibody (NT Ab) titer against the B.1.1 strain and total anti-spike immunoglobulin G concentration were quantified in serum samples. The enzyme-linked immunosorbent spot assay was used for quantification of anti-spike interferon-γ (IFN-γ)-producing cells/106 peripheral blood mononuclear cells. Fifty patients (83.0%) were on immunotherapy alone, whereas 10 patients (7%) were on chemo-immunotherapy. We analyzed separately patients on immunotherapy and patients on chemo-immunotherapy. RESULTS: The median T-cell response at 6 months was significantly lower than that measured at 3 weeks after vaccination [50 interquartile range (IQR) 20-118.8 versus 175 IQR 67.5-371.3 IFN-γ-producing cells/106 peripheral blood mononuclear cells; P < 0.0001]. The median reduction of immunoglobulin G concentration was 88% in SARS-CoV-2-naive subjects and 2.1% in SARS-CoV-2-experienced subjects. SARS-CoV-2 NT Ab titer was maintained in SARS-CoV-2-experienced subjects, whereas a significant decrease was observed in SARS-CoV-2-naive subjects (from median 1 : 160, IQR 1 : 40-1 : 640 to median 1 : 20, IQR 1 : 10-1 : 40; P < 0.0001). A weak correlation was observed between SARS-CoV-2 NT Ab titer and spike-specific IFN-γ-producing cells at both 6 months and 3 weeks after vaccination (r = 0.467; P = 0.0002 and r = 0.428; P = 0.0006, respectively). CONCLUSIONS: Our work highlights a reduction in the immune response in cancer patients, particularly in SARS-CoV-2-naive subjects. Our data support administering a third dose of COVID-19 vaccine to cancer patients treated with programmed cell death protein 1/programmed death-ligand 1 inhibitors.

A snapshot of the immunogenicity, efficacy and safety of a full course of BNT162b2 anti-SARS-CoV-2 vaccine in cancer patients treated with PD-1/PD-L1 inhibitors: a longitudinal cohort study.

BACKGROUND: Very few cancer patients were enrolled in coronavirus disease-2019 vaccine studies. In order to address this gap of knowledge, real-world studies are mandatory. The aim of this study was to assess both humoral and cellular response after a messenger RNA vaccination schedule. PATIENTS AND METHODS: Eighty-eight consecutive cancer patients treated with programmed cell death protein 1/programmed death-ligand 1 inhibitors were enrolled from the beginning of the vaccination campaign for frail patients. Blood samples for humoral and cell-mediated immune response evaluation were obtained before vaccination (T0), before the second administration (T1) and 21 days after the second dose (T2). The primary endpoint was the evaluation of the percentage of participants showing a significant increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells, measured by an enzyme-linked immunospot assay, after the second dose of BNT162b2 vaccine. The proportion of patients who reached the primary endpoint is computed together with its exact binomial 95% confidence interval. RESULTS: In SARS-CoV-2-naïve subjects, spike-specific T-cell response was almost undetectable at T0 [median 0.0 interferon-γ (IFN-γ) spot forming units (SFU)/million peripheral blood mononuclear cell (PBMC) interquartile range (IQR) 0-7.5] and significantly increased at T1 and T2 (median 15.0 IFN-γ SFU/million PBMC, 25th-75th 0-40 versus 90 IFN-γ SFU/million PBMC, 25th-75th 32.5-224, respectively) (P < 0.001). Focusing on naïve and experienced SARS-CoV-2 subjects, no differences were reported both in terms of CD4- and CD8-specific T-cell response, suggesting that BNT162b2 is able to elicit both adaptive responses after complete vaccination schedule, regardless of previous SARS-CoV-2 exposure. The level of SARS-CoV-2 neutralizing antibodies was low at T1 in SARS-CoV-2-naïve subjects [median 1 : 5 (IQR 1 : 5-1 : 20)] but reached a significantly higher median of 1 : 80 (25th-75th 1 : 20-1 : 160) at T2 (P < 0.0001). Moreover, no COVID-19 cases were documented throughout the period of study. CONCLUSIONS: Our data have demonstrated that the administration of a full course of BNT162b2 vaccine elicited a sustained immune response against SARS-CoV-2 regardless of the type of cancer and/or the type of immune checkpoint inhibitors.