key: cord-0303800-q0gx2dr5 authors: Teresa Lupo Stanghellini, M.; Di Cosimo, S.; Costantini, M.; Monti, S.; Mantegazza, R.; Mantovani, A.; Salvarani, C.; Luigi Zinzani, P.; Inglese, M.; Ciceri, F.; Apolone, G.; Ciliberto, G.; Baldanti, F.; Morrone, A.; Sinno, V.; Locatelli, F.; Notari, S.; Turola, E.; Giannarelli, D.; Silvestris, N. title: mRNA-COVID19 vaccination can be considered safe and tolerable for frail patients date: 2022-01-21 journal: nan DOI: 10.1101/2022.01.18.22269351 sha: 0ddcd798d7c30e29e41860759bb29e439b737205 doc_id: 303800 cord_uid: q0gx2dr5 Background Frail patients are considered at relevant risk of complications due to COVID-19 infection and, for this reason, are prioritized candidates for vaccination. As these patients were originally not included in the registration trials, fear related to vaccine side-effects and disease worsening was one of the reasons for vaccine hesitancy. Herein we report the safety profile of the prospective, multicenter, national VAX4FRAIL study (NCT04848493) to evaluate vaccines in a large trans-disease cohort of patients with solid or hematological malignancies, neurological and rheumatological diseases. Methods Between March 3rd and September 2nd, 2021, 566 patients were evaluable for safety endpoint: 105 received the mRNA-1273 vaccine and 461 the BNT162b2 vaccine. Frail patients were defined per protocol as patients under treatment with hematological malignancies (131), solid tumors (191), immune-rheumatological diseases (86), and neurological diseases (158), including multiple sclerosis and generalized myasthenia. The impact of the vaccination on the health status of patients was assessed through a questionnaire focused on the first week after each vaccine dose. Results The most frequently reported moderate-severe adverse events were pain at the injection site (60.3% after the first dose, 55.4% after the second), fatigue (30.1% - 41.7%), bone pain (27.4% - 27.2%) and headache (11.8% - 18.9%). Risk factors associated with the occurrence of severe symptoms after vaccine administration were identified through a multivariate logistic regression analysis: age was associated with severe fever presentation (younger patients vs. middle-aged vs. older ones), females presented a higher probability of severe pain at the injection site, fatigue, headache, and bone pain; the mRNA-1237 vaccine was associated with a higher probability of severe pain at the injection site and fever. After the first dose, patients presenting a severe symptom were at a relevant risk of recurrence of the same severe symptom after the second one. Overall, 11 patients (1.9%) after the first dose and 7 (1.2%) after the second one required to postpone or suspend the disease-specific treatment. Finally, 2 fatal events occurred among our 566 patients. These two events were considered unrelated to the vaccine. Conclusions Our study reports that mRNA-COVID-19 vaccination is safe also in frail patients as expected side effects were manageable and had a minimum impact on patient care path. Background Frail patients are considered at relevant risk of complications due to COVID-19 infection and, for this reason, are prioritized candidates for vaccination. As these patients were originally not included in the registration trials, fear related to vaccine side-effects and disease worsening was one of the reasons for vaccine hesitancy. Herein we report the safety profile of the prospective, multicenter, national VAX4FRAIL study (NCT04848493) to evaluate vaccines in a large trans-disease cohort of patients with solid or hematological malignancies, neurological and rheumatological diseases. The impact of the vaccination on the health status of patients was assessed through a questionnaire focused on the first week after each vaccine dose. The most frequently reported moderate-severe adverse events were pain at the injection site (60.3% after the first dose, 55.4% after the second), fatigue (30.1% -41.7%), bone pain (27.4% -27.2%) and headache (11.8% -18.9%). Risk factors associated with the occurrence of severe symptoms after vaccine administration were identified through a multivariate logistic regression analysis: age was associated with severe fever presentation (younger patients vs. middle-aged vs. older ones), females presented a higher probability of severe pain at the injection site, fatigue, headache, and bone pain; the mRNA-1237 vaccine was associated with a higher probability of severe pain at the injection site and fever. After the first dose, patients presenting a severe symptom were at a relevant risk of recurrence of the same severe symptom after the second one. Overall, 11 patients (1.9%) after the first dose and 7 (1.2%) after the second one required to postpone or suspend the disease-specific treatment. Finally, 2 fatal events occurred among our 566 patients. These two events were considered unrelated to the vaccine. The currently authorized mRNA-COVID-19 vaccines -m-RNA-1237 Moderna (1) and BNT-162b2 Pfizer BioNTech (2) -have been evaluated in clinical trials that excluded in accordance with the current regulations, immunocompromised subjects, and restricted participation to healthy volunteers. Fragile patients were not considered in such pivotal studies despite being the subjects at greatest risk of COVID-19 complications and with the potential greatest advantage. Patients diagnosed with solid or hematological malignancy or under immunosuppressive treatment due to rheumatological or neurological diseases are considered at high risk of complications and categorized as fragile (3) (4) (5) (6) (7) . The intended acceptance of the COVID-19 vaccine in fragile patients confirms the positive attitudes towards vaccination, but questions arise around the safety of these vaccines in the setting of immune alterations engendered by their diseases and/or therapies (8) (9) (10) (11) (12) (13) (14) . One of the most typical reasons for vaccine hesitancy has been fear related to vaccine side-effects and underlying disease worsening. An additional effort through public education campaigns specific to fragile patients to clarify vaccine's safety, long-term effects, and potential health implications are still needed. Over the past eight months, several groups have tried to answer questions about the efficacy and safety of COVID vaccination in different cohorts of fragile subjects. No safety concerns emerged, confirming the profile described in the series of healthy subjects (14-43) and pointing out an acceptable safety profile. VAX4FRAIL (44) study aimed at assessing immune responses to vaccination in a large trans-disease cohort of patients with hematological malignancies, solid tumors, neurological and rheumatological diseases. The study main objective is to assess prospectively the immunologic response to the COVID-19 vaccination in these specific subgroups, characterizing the kinetics of the immune response to the vaccination and its persistence over time. Longitudinal, prospective evaluation of the safety profile was part of this trans-disease study. Herein we report safety profile results as outlined in VAX4FRAIL trial. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Safety analysis was performed among patients enrolled in the VAX4FRAIL trial between t0 and t2 according to the protocol, being t0 "time point 0" at first dose of vaccine and t2 "time point 2" the blood sampling 2-4 weeks after the second dose of vaccine (44). This is a national, multicentric observational prospective study conducted in Italy with the primary aim of assessing the immune response of COVID-19 vaccination in frail, immunocompromised patients. Patients were considered for the current safety analysis if they met the general inclusion criteria: being ≥ 18 years of age, having received COVID-19 vaccination with mRNA vaccines (BNT-162b2 Pfizer-BioNTech or m-RNA-1237 Moderna vaccine), and having completed the health status assessment questionnaire after one of the two vaccine doses. Frail patients under evaluation were diagnosed with hematological malignancies, solid tumors, immune-rheumatological disease, and neurological disease. Detailed inclusion and exclusion criteria were previously reported (44) and disease stratification according to diagnosis and treatment of the primary disease. The impact of the vaccination on the health status of patients was assessed through a questionnaire focused on the first week after each vaccine dose. The questionnaire was administered to the patients after the second vaccine dose (3-4 weeks after the first dose) and at the subsequent timing according to VAX4FRAIL protocol (2-4 weeks after the second dose). The questionnaire assessed how much the patient was troubled by eight symptoms (pain or swelling at the injection site, fatigue, headache, bone pain, fever, enlarged lymph nodes, skin rash, insomnia, diarrhea, and nausea or vomiting). (See supplementary; Appendix 1) The answers were graded according to a 5-level scale (not at all, slightly, moderately, severely, and overwhelmingly). The patient was also asked to report and grade other symptoms possibly occurring after each vaccine dose and if he/she had to postpone or suspend therapies due to symptoms related to vaccination. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. For this analysis, we grouped answers to the questionnaire in three levels of troubles: not at all, moderate (slightly or moderately), and severe (severely or overwhelmingly). We estimated the probability of the occurrence of a severe symptom after the second dose of the vaccine according to the occurrence of a severe symptom after the first dose using Positive and Negative Predictive Values (PPV and NPV, respectively). The probability of occurrence of a severe symptom after one of the two doses of the vaccine according to age, sex, main diagnosis, and type of vaccine was estimated in a multivariate logistic regression analysis adjusting for all variables. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Between March 3 rd and September 2 nd , 2021, 566 patients were enrolled in the study VAX4FRAIL and were eligible for this analysis. Among 566 patients who received the first dose of the mRNA vaccine, 105 received the mRNA-1273 and 461 the BNT162b2. Among the 566 patients who received the first dose, they also received the second dose (Figure 1) . Overall, 488 patients after the 1 st dose and 489 patients after the 2 nd dose were evaluable for safety evaluation having complete clinical evaluation and questionnaires. Sixty-eight patients after the 1 st dose and 57 after the 2 nd dose did not fill the questionnaires. Consent withdrawn occurred in 8 cases after the 1 st dose and 10 cases after the 2 nd one. Patient characteristics are reported in Table 2 Overall, 438 (77.3%) patients reported any grade adverse events after the first dose (62, 11.0% reported as severe), and 373 (65.9%) after the second dose (87, 15.4% reported as severe). Detailed analysis of adverse events and severity is reported in Table 3 . After the first dose (both mRNA-1273 and BNT162b2) 53.9% of patients reported moderate pain at the injection site and 6.4% severe pain: this was the most frequently reported complaint after vaccine administration. Interestingly, after the second dose -t2 -50.3% and 5,1% reported this adverse event as moderate and severe, respectively. At t1 25.6% of patients reported fatigue as a moderate event, 4.5% as a severe one. We observed a slight increase at t2, with 35% of patients reporting fatigue as a moderate event and 6.7% as a severe one. Bone pain and headache were reported as moderate by 13.7% and 9.8% of patients at t1, while 2.7% and 2.0% respectively reported the symptoms as severe. After the second dose bone pain was All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Of note, the absence of severe symptoms after the first dose strongly predicts the high probability of the absence of the same severe symptoms after the second dose ( Table 3) . Patients reporting severe fever after the first dose were more prone to develop the same severe symptom after the second one. A multivariate logistic regression -adjusted by age, sex, diagnosis, and vaccine -was performed to identify risk factors associated with the occurrence of severe symptoms after vaccine administration ( Table 4) . Age was associated with severe fever presentation: younger patients (age 18-50 years) had a higher probability of occurrence of severe fever than middle-aged patients (age 51-70 -odd ratio 0.3, 95% confidence interval [CI] 0.1-0.7) or older ones (>/=71 -odd ratio 0.1, 95% CI 0.1-0.7) -p 0.003. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 21, 2022. ; https://doi.org/10.1101/2022.01.18.22269351 doi: medRxiv preprint Female patients presented higher probability of severe pain at the injection site (odd ratio 2.9, 95% CI 1.4-6.2, p 0.005), severe fatigue (odd ratio 2.3, 95% CI 1.2-4.5, p 0.016), severe headache (odd ratio 7.6, 95% 1.7-33.6, p 0.007), and severe bone pain (odd ratio 2.7, 95% CI 1.1-6.5, p 0.028). Diagnosis (hematological diseases, solid tumors, neurological diseases, rheumatological diseases) has no impact on the occurrence of severe fatigue, or headache, or bone pain or fever, but was associated with severe pain at the injection site: patients with a diagnosis of solid tumors reported severe pain less frequently than patients with hematological diseases (odds ratio 0.3, 95% CI 0.1-1.0), patients with a diagnosis of neurological or rheumatological diseases have a higher probability of occurrence of severe pain at the injection site in comparison with patients with the hematological disease (odd ration for neurological diseases 4, 95% CI 1.4-11; the odds ratio for rheumatological diseases 2.8, 95% CI 1.1-7.5) -p <0.001. Finally, the conditional contribution made by the vaccine (mRNA-1237 versus BNT162b2) clearly showed that mRNA-1237 was associated with a higher probability of severe pain at the injection site (odds ratio 0.3, 95% CI 0.1-0.6 -p 0.001) and a higher probability of severe fever (odds ratio 0.3, 95% CI 0.1-0.7 -p 0.004). Overall, 11 patients (1.9%) after the first dose and 7 (1.2%) after the second dose, required to postpone or suspend the disease-specific treatment due to the occurrence of symptoms associated with the vaccine. Among the 11 patients who required delays after the first dose, 7 were diagnosed with hematological disease and 4 with a solid tumor. Among the 7 patients who required delays after the second dose, 3 were diagnosed with the hematological disease and 4 with a solid tumor. No patients from the neurological diseases' cohort or the rheumatological diseases' cohort required treatment delay. Fatal events, long-term sequelae, or hospitalization related to the vaccine were not registered. Two patients died from disease progression; the events were clearly reported by the investigator as not related to the vaccine administration. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 21, 2022. ; https://doi.org/10.1101/2022.01.18.22269351 doi: medRxiv preprint Questionnaires based upon open and /or closed questions administered through the web-based app, phone interview, self-reporting forms, and face-to-face visits were all utilized to collect adverse events after COVID-19 vaccinations in the effort to clarify the safety of vaccines better. Absence of a univocal method to grade and collect this information make it almost impossible to directly compare the different experiences, but, of note, all the studies -both retrospective and prospective -are concordant in underlying the general perception of the absence of safety issue among distinct cohorts of frail patients ( Table 1) Among patients with multiple sclerosis, Lotan and colleagues (23) outlined how 15% of the participants reported new or worsening neurological symptoms following the vaccination, the most frequent being sensory disturbances (58.3%). Most symptoms occurred within the first 24 h after vaccination and resolved within 3 days. A total of 28 participants (77.8%) did not require any medication to treat their symptoms. Of note, no increased risk of relapse activity was noted across patients with multiple sclerosis (23-24) or autoimmune inflammatory rheumatic diseases (26-28): Boekel and coworkers clearly showed how multivariable logistic regression analyses showed similar odds for any adverse event, systemic adverse events, or moderate or severe adverse events All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 21, 2022. ; https://doi.org/10.1101/2022.01.18.22269351 doi: medRxiv preprint between patients and controls, which was consistent when patients with rheumatoid arthritis or multiple sclerosis were compared with healthy controls (33) . In our experience, cohort composition was clearly defined at enrolment of patients, identifying a subset of high-risk subjects for severe COVID-19. The monitoring strategy was defined per protocol and homogeneous across the 4 categories of diseases (hematological disease, solid tumors, neurological conditions, and rheumatological diseases). Overall, our study confirms the positive safety profile reported by other authors in both prospective and retrospective analysis ( Table 1) . Incidence of severe adverse events after vaccine administration was generally low and <3%. Most frequent complaints were pain at the injection site (severe 6.3%) and fatigue (severe 4.5%) after the first dose; pain at the injection site (severe 5.1%), fatigue (severe 6.8%), bone pain (severe 3.9%) and fever (severe 6%) after the second dose. Patients experiencing a severe symptom after the first dose were more likely to report the same after the second one. Similarly, the absence of a severe symptom after the first dose was significantly associated with an absence of the same symptoms also after the second dose. This observation should be taken in consideration during the counseling of patients: patients should be reassured about the possibility of adopting a preventive strategy to reduce the burden of symptoms and on the not-unexpected onset of the symptom itself. Moreover, the definition of predisposing factors to an increased possibility of presenting specific adverse events (e.g., younger patients are more likely to experience fever) can help both in the implementation of preventive measures (e.g., pre-emptive administration of painkiller drugs or antifever), in the optimization of counseling (e.g., if a patient experienced adverse events after the first shot he should be advised that the recurrence of the same after the second is very likely and that this is not unexpected, moreover strategies to counterbalance this inconvenience can be applied), and in the planning of therapies and/or vaccination itself. Of note, less than 2% of patients required a delay or a suspension of the ongoing or planned treatment of the underlying diseases due to vaccination. This pointed out the positive safety profile of the vaccine strategy and -furthermore -this aspect should be discussed with patients to confirm the absence of impact on the whole therapy program. Whatever the underlying disease (a hematological cancer, a solid tumor, a rheumatological disease or a neurological disease) the mRNA-COVID-19 vaccine should be considered a crucial step to allow a safe program of treatment All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 21, 2022. ; 1 5 more than a possible obstacle or danger to pursue the control of the disease, being the safety profile reassuring. Fatal events or hospitalization related to the vaccine were not registered in our cohort of high-risk frail patients. Despite the absence of safety concerns emerging from our study, we believe it is mandatory to maintain constant and careful surveillance concerning post-vaccination adverse events. This can only contribute to the reliability that the vaccination strategy pursues and represents a cornerstone of general medical practice. As outlined by several authors (3-9), one of the most common reasons for vaccine hesitancy was fear related to vaccine side-effects and disease worsening: we can confirm that vaccine-side effects were both manageable and in line with previously reported in the general population, without the occurrence of unexpected events and no concern related to worsening of the underlying disease or the need to delay treatment. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 21, 2022. ; https://doi.org/10.1101/2022.01.18.22269351 doi: medRxiv preprint Frail patients' candidates to mRNA-COVID-19 vaccination should be reassured about the safety profile of vaccine strategy: adverse events were in line with the report from the healthy cohort of subjects and national observatories, no evidence of worsening of the underlying disease was reported and no concern on the adherence to the treatment program of the disease itself emerged from our prospective multicenter national study. Pursuing careful and timely monitoring of expected and unexpected adverse events represents a gold standard of modern medicine and can only support evidence-based medicine. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 21, 2022. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 21, 2022. ; https://doi.org/10.1101/2022.01.18.22269351 doi: medRxiv preprint 7 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 15 Systemic events more frequent after the 2nd dose, while local effects were less common. 40 No thrombosis, hypersensitivity adverse events or vaccine-related anaphylaxis were signaled. One patient has reported two immune-related side-effects (hepatitis G3 and colitis G3) 10 days after the first dose of vaccine. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 21, 2022. 3 0 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 21, 2022. ; https://doi.org/10.1101/2022.01.18.22269351 doi: medRxiv preprint 3 2 PPV (positive predictive value) probability of occurrence of a severe symptom after the second dose according to the occurrence of the same symptom after the first dose. NPV (negative predictive value) probability of absence of a severe symptom after the second dose according to the not occurrence of the same after the first dose. NE not evaluable "Moderate" and "Severe" include patients who have been troubled slightly or moderately (moderate) and severely or overwhelmingly (severe), respectively. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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