Retrospective Study of COVID-19 Vaccines in Patients Undergoing Immunotherapy for Cancer.

Study Overview
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Brief Summary
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The investigators wish to set up a pharmaco-epidemiological cohort within the Hospital Territorial Groups of the Cévennes-Gard Camargue, East-Hérault and Haute-Garonne and West Tarn on a specific population, patients undergoing immunotherapy for cancer, as currently there is no data available under real life conditions following anti-COVID vaccination19. The hypothesis is that patients undergoing immunotherapy will not develop more vaccine-related adverse events than those observed in the efficacy and safety validation studies of the BNT162b2 mRNA Covid-19, mRNA-1273 SARS CoV-2, Oxford/AstraZeneca and Ad26COV2.S, JMJ Vaccine or J & J COVID-19 Vaccine.

Detailed Description
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The recent outbreak of Coronavirus 2019 (COVID-19) caused by a new zoonotic coronavirus SARS-Cov-2 poses a major public health threat, with at least 100,000,000 people infected worldwide by the end of January 2021 and over 2 million deaths. Given the scale of the pandemic, it has become imperative to quickly develop a vaccine and over 30 vaccine candidates have entered clinical evaluation. The first vaccine to receive marketing authorization in Europe and France was an mRNA vaccine, Comirnaty® (Bnt162b2; Pfizer/BioNtech). In a Phase III study of 43,448 participants, after a median follow-up of 2 months, the number of cases of COVID-19 was 8 in the vaccine arm vs. versus 162 in the placebo arm, respectively, with 1 versus 9 serious cases (Polack et al. 2020). Adverse events occurred in more than 50% of vaccinated participants and included local reactions as well as frequent systemic reactogenicity such as fatigue and headache. Fever occurred in about 15% of the participants who received the vaccine. The second vaccine to be licensed was also an mRNA vaccine: the Moderna COVID-19 mRNA (nucleoside modified) vaccine (mRNA-1273, Moderna). A Phase III trial involving 30,420 volunteers reported efficacy and safety comparable to the Pfizer/BioNtech vaccine. A severe form of COVID-19 occurred in 30 subjects, with one death; all 30 cases were in the placebo group. Moderate and transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare and the incidence was similar in both groups. Within the vaccination strategy implemented on a national level, the Comirnaty® vaccine (Pfizer/BioNtech) and the Moderna COVID-19 mRNA vaccine (nucleoside modified) may be used interchangeably, depending on logistical constraints. For several weeks now, the Oxford-AstraZeneca chimpanzee adenovirus vector vaccine ChAdOx1 nCoV-19 (AZD1222) has been available in France and its efficacy and safety of use have been evaluated. Also the non-replicating viral vector (adenovirus) vaccine for CVD 19 from Janssen Laboratories (a subsidiary of Johnson & Johnson; other names: Ad26COV2.S; JMJ Vaccine or J & J COVID-19 Vaccine) was launched in France a few weeks ago. Its efficacy and safety have been validated in a phase III trial. A number of other candidate vaccines using various techniques such as mRNA, protein subunit, viral vector or inactivated vaccines are currently under investigation and will be available soon. Cancer patients are particularly at risk of developing a severe form of COVID-19. Patients with solid tumors appear to be at a greater risk, particularly in the first year after diagnosis. Severity and mortality rates in the COVID-19 and Cancer Consortium (CCC19) registry and other cohorts range from 5% to 61% (a meta-analysis showed 26%), which is well above the general population. Although data on vaccination in cancer patients are limited, there is sufficient evidence to support anti-infective vaccination in general, even in cancer patients on immunosuppressive therapy. In its notice dated January 25th, 2021, the National Cancer Institute defined its recommendations for prioritizing cancer patients for vaccination against SARS-CoV-2. This report stresses that the data acquired from science is limited in quantity and quality concerning the emerging field of vaccination against SARS-CoV-2 and even more so in sub-populations including cancer patients. It reminds us that the challenge remains to vaccinate the entire population of patients who have or have had cancer, i.e. approximately 3.8 million people. The level of efficacy can be expected to be generally reduced in certain cancer patient populations with intense immunosuppression, such as haematopoietic stem cell transplant recipients. However, based on extrapolation of data from other vaccines and the mechanism of action of COVID-19 (non-live) vaccines, it is conceivable that the efficacy and safety of COVID-19 vaccination could be estimated to be similar to that of non-cancer patients, although data from clinical trials are lacking. The efficacy and duration of immunity in cancer patients is still unknown and unexplored. It is therefore legitimate to propose surveillance through dedicated registries and clinical trials. Furthermore, close monitoring and follow-up of cancer patients is required after COVID-19 vaccination to assess potential adverse events and measure clinical outcomes, e.g. infection, severity and mortality from COVID-19, cancer complications etc… The investigators wish to set up a pharmaco-epidemiological cohort within the Hospital Territorial Groups of the Cévennes-Gard Camargue, East-Hérault and Haute-Garonne and West Tarn on a specific population, patients undergoing immunotherapy for cancer, as currently there is no data available under real life conditions following anti-COVID vaccination19. Our hypothesis is that patients undergoing immunotherapy will not develop more vaccine-related adverse events than those observed in the efficacy and safety validation studies of the BNT162b2 mRNA Covid-19, mRNA-1273 SARS CoV-2, Oxford/AstraZeneca and Ad26COV2.S, JMJ Vaccine or J & J COVID-19 Vaccine.

Official Title
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Pharmaco-epidemiological Study of COVID 19 Vaccines in Patients Undergoing Immunotherapy for Cancer. A Retrospective Open Cohort Study.

Conditions
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Cancer, Immunotherapy

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient having been vaccinated or eligible for inoculation with one of the available anti-COVID19 vaccines (except live attenuated virus) while they were or are undergoing immunotherapy with anti-PD1, anti-PDL1 or anti-CTLA4 immunotherapy whatever the tumor (solid, liquid) managed within the medical oncology services of the Occitanie region. Patients affiliated to or beneficiaries of a health insurance scheme. Patients who have received written and oral information about the study and who have no objection to participation. Adult patients (≥ 18 years). Exclusion Criteria: Patients who have been vaccinated with a live attenuated vaccine. Patients with a contraindication to inclusion (including hypersensitivity to the active substance or to one of the excipients, COVID+ PCR test in the last 3 months). Minor patients, pregnant women, parturients, nursing mothers, persons in nursing mothers, persons in emergency situations, persons unable to persons unable to express their consent and persons under persons under court protection, subguardianship or subguardianship may not be included in this research. Patients in an exclusion period determined by another study. Patients for whom it is impossible to give clear information. Patients who have expressed an objection to participating in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients treated for cancer, vaccinated or eligible for anti-COVID vaccination.<br>Patients undergoing treatment with anti-PD immunotherapy, anti-PDL1 or anti-CTLA4 immunotherapy for any tumour (solid, liquid) treated in the medical oncology departments of the Occitanie area. who have been vaccinated or who are eligible for inoculation with one of the available anti-COVID19 vaccines. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance of immunotherapy following anti-COVID-19 vaccination | All local adverse events (pain, rashes, bruising, lymphadenopathy) and systemic adverse events (fever, headaches, fatigue, myalgia, arthralgia, nausea, shivering, diarrhoea, allergic reaction) will be recorded. | 24 hours after the vaccination | 
| Tolerance of immunotherapy following anti-COVID-19 vaccination | All local adverse events (pain, rashes, bruising, lymphadenopathy) and systemic adverse events (fever, headaches, fatigue, myalgia, arthralgia, nausea, shivering, diarrhoea, allergic reaction) will be recorded. | 48 hours after the vaccination | 
| Tolerance of immunotherapy following anti-COVID-19 vaccination | All local adverse events (pain, rashes, bruising, lymphadenopathy) and systemic adverse events (fever, headaches, fatigue, myalgia, arthralgia, nausea, shivering, diarrhoea, allergic reaction) will be recorded. | 8 days after the vaccination | 
| Tolerance of immunotherapy following anti-COVID-19 vaccination | All local adverse events (pain, rashes, bruising, lymphadenopathy) and systemic adverse events (fever, headaches, fatigue, myalgia, arthralgia, nausea, shivering, diarrhoea, allergic reaction) will be recorded. | 24 hours after the following vaccination | 
| Tolerance of immunotherapy following anti-COVID-19 vaccination | All local adverse events (pain, rashes, bruising, lymphadenopathy) and systemic adverse events (fever, headaches, fatigue, myalgia, arthralgia, nausea, shivering, diarrhoea, allergic reaction) will be recorded. | 48 hours after the following vaccination | 
| Tolerance of immunotherapy following anti-COVID-19 vaccination | All local adverse events (pain, rashes, bruising, lymphadenopathy) and systemic adverse events (fever, headaches, fatigue, myalgia, arthralgia, nausea, shivering, diarrhoea, allergic reaction) will be recorded. | 8 days after the following vaccination | 
| Tolerance of immunotherapy following anti-COVID-19 vaccination | All local adverse events (pain, rashes, bruising, lymphadenopathy) and systemic adverse events (fever, headaches, fatigue, myalgia, arthralgia, nausea, shivering, diarrhoea, allergic reaction) will be recorded. | 1 month after the following vaccination | 
| Tolerance of immunotherapy following anti-COVID-19 vaccination | All local adverse events (pain, rashes, bruising, lymphadenopathy) and systemic adverse events (fever, headaches, fatigue, myalgia, arthralgia, nausea, shivering, diarrhoea, allergic reaction) will be recorded. | 3 months after the following vaccination | 
| Tolerance of immunotherapy following anti-COVID-19 vaccination | All local adverse events (pain, rashes, bruising, lymphadenopathy) and systemic adverse events (fever, headaches, fatigue, myalgia, arthralgia, nausea, shivering, diarrhoea, allergic reaction) will be recorded. | 6 months after the following vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A. Tolerance of immunotherapy after anti-COVID-19 vaccination | Any adverse events related to the immunotherapy qualified as Grade ≥3 according to the Common Terminology Criteria for Adverse Events classification (NCI CTCAE V5.0) will be recorded. | 24 hours after the vaccination | 
| A. Tolerance of immunotherapy after anti-COVID-19 vaccination | Any adverse events related to the immunotherapy qualified as Grade ≥3 according to the Common Terminology Criteria for Adverse Events classification (NCI CTCAE V5.0) will be recorded. | 48 hours after the vaccination | 
| A. Tolerance of immunotherapy after anti-COVID-19 vaccination | Any adverse events related to the immunotherapy qualified as Grade ≥3 according to the Common Terminology Criteria for Adverse Events classification (NCI CTCAE V5.0) will be recorded. | 8 days after the vaccination | 
| A. Tolerance of immunotherapy after anti-COVID-19 vaccination | Any adverse events related to the immunotherapy qualified as Grade ≥3 according to the Common Terminology Criteria for Adverse Events classification (NCI CTCAE V5.0) will be recorded. | 24 hours after the following vaccination | 
| A. Tolerance of immunotherapy after anti-COVID-19 vaccination | Any adverse events related to the immunotherapy qualified as Grade ≥3 according to the Common Terminology Criteria for Adverse Events classification (NCI CTCAE V5.0) will be recorded. | 48 hours after the following vaccination | 
| A. Tolerance of immunotherapy after anti-COVID-19 vaccination | Any adverse events related to the immunotherapy qualified as Grade ≥3 according to the Common Terminology Criteria for Adverse Events classification (NCI CTCAE V5.0) will be recorded. | 1 month after the following vaccination | 
| A. Tolerance of immunotherapy after anti-COVID-19 vaccination | Any adverse events related to the immunotherapy qualified as Grade ≥3 according to the Common Terminology Criteria for Adverse Events classification (NCI CTCAE V5.0) will be recorded. | 3 months after the following vaccination | 
| A. Tolerance of immunotherapy after anti-COVID-19 vaccination | Any adverse events related to the immunotherapy qualified as Grade ≥3 according to the Common Terminology Criteria for Adverse Events classification (NCI CTCAE V5.0) will be recorded. | 6 months after the following vaccination | 
| B.Response to vaccine: dosage of anti-Spike antibodies (ELISA) | Quantification of anti-Spike IgG by ELISA. | Day 0 | 
| B.Response to vaccine: dosage of anti-RBD antibodies (ELISA) | Quantification of anti-RBD IgG by ELISA. | Day 0 | 
| B. Response to vaccine: Lymphocyte count by Quantiferon | Lymphocytes will be measured in µg/ml | Day 0 | 
| B. Response to vaccine: dosage of anti-Spike antibodies (ELISA) | Quantification of anti-Spike IgG by ELISA. | 1 month after the injection | 
| B. Response to vaccine: dosage of anti-RBD antibodies (ELISA) | Quantification of anti-RBD IgG by ELISA. | 1 month after the injection | 
| B. Response to vaccine: Lymphocyte count by Quantiferon | Lymphocytes will be measured in µg/ml | 1 month after the injection | 
| B. Response to vaccine: dosage of anti-spike antibodies (ELISA) | Quantification of anti-Spike IgG by ELISA. | 1 month after the following injection | 
| B. Response to vaccine: dosage of anti-RBD antibodies (ELISA) | Quantification of anti-RBD IgG by ELISA. | 1 month after the following injection | 
| B. Response to vaccine: Lymphocyte count by Quantiferon | Lymphocytes will be measured in µg/ml | 1 month after the following injection | 
| B. Response to vaccine: dosage of anti-spike antibodies (ELISA) | Quantification of anti-Spike IgG by ELISA. | 3 months after the following injection | 
| B. Response to vaccine: dosage of anti-RBD antibodies (ELISA) | Quantification of anti-RBD IgG by ELISA. | 3 months after the following injection | 
| B. Response to vaccine: Lymphocyte count by Quantiferon | Lymphocytes will be measured in µg/ml | 3 months after the following injection | 
| B. Response to vaccine: dosage of anti-spike antibodies (ELISA) | Quantification of anti-Spike IgG by ELISA . | 6 months after the following injection | 
| B. Response to vaccine: dosage of anti-RBD antibodies (ELISA) | Quantification of anti-RBD IgG by ELISA . | 6 months after the following injection | 
| B. Response to vaccine: Lymphocyte count by Quantiferon | Lymphocytes will be measured in µg/ml | 6 months after the following injection | 
| C. Efficacy of vaccination against the incidence of COVID-19 | The efficacy of vaccination against the incidence of COVID-19 will be evaluated based on the main clinical symptoms noted and a PCR test. Qualitative: YES/NO | 1 month after vaccination | 
| C. Efficacy of vaccination against the incidence of COVID-19 | The efficacy of vaccination against the incidence of COVID-19 will be evaluated based on the main clinical symptoms noted and a PCR test. Qualitative: YES/NO | 3 months after vaccination | 
| C. Efficacy of vaccination against the incidence of COVID-19 | The efficacy of vaccination against the incidence of COVID-19 will be evaluated based on the main clinical symptoms noted and a PCR test. Qualitative: YES/NO | 6 months after vaccination | 
| D. Constitution of a biobank | Unused sample aliquots (tube bottoms) at the end of the tests will be kept; constitution of a serum library and an immune bank. Samples will be stored at -80°C (plasma) and -196°C (Peripheral Blood Mononuclear Cells) at the Biological Resource Centre at Nîmes University Hospital. | Up to 6 months after vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Covid-19, Vaccination, Immunotherapy