Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters

Immunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines. Here we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (ID, n=25) diseases. We show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to both virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus. Hence, additional booster doses are recommended to frail patients.

mRNA-COVID19 vaccination can be considered safe and tolerable for frail patients

BackgroundFrail 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. MethodsBetween 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. ResultsThe 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. ConclusionsOur 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. ImportanceOur study reports the safety analysis of the trial VAX4FRAIL confirming that mRNA-COVID-19 vaccination is safe in frail immunocompromised patients: expected side effects were manageable and had a minimum impact on patient care path. ObjectiveTo evaluate the safety of mRNA-COVID-19 vaccination in vulnerable patients. DesignVAX4FRAIL is a national, multicentric, observational, prospective trial (start date March 3rd, 2021 - primary completion date September 2nd, 2021). SettingMulticenter prospective trial. ParticipantsFrail patients were defined per protocol as patients under treatment with solid tumors (191), immune-rheumatological diseases (86), hematological malignancies (131), and neurological diseases (158), including multiple sclerosis and generalized myasthenia. ExposureOverall, 105 received the mRNA-1273 vaccine and 461 the BNT162b2 vaccine. Main OutcomeThe occurrence of adverse events after 1st and 2nd m-RNA-COVID-19 vaccination was analyzed. Adverse events were collected through a questionnaire comprising both open and closed questions. ResultsThe 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. Patients presenting a severe symptom after the first dose 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 was required to postpone or suspend their disease-specific treatment. Finally, 2 fatal events occurred among our 566 patients, and these two events were due to disease progression and considered unrelated to the vaccine. Conclusion and RelevanceOur 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. Study RegistrationA National, Multicentric, Observational, Prospective Study to Assess Immune Response to COVID-19 Vaccine in Frail Patients (VAX4FRAIL). NCT04848493 https://clinicaltrials.gov/ct2/show/NCT04848493 Key PointsO_ST_ABSQuestionC_ST_ABSCan m-RNA-COVID19 vaccination be considered safe for frail patients? FindingsIn this national, multicentric, observational, prospective trial (NCT04848493) that included 566 frail patients, the occurrence of both local and systemic adverse events was manageable and did not negatively impact on the general treatment program. MeaningmRNA-COVID19 vaccination is safe among frail immunocompromised patients.

Humoral and T-cell immune response after three doses of mRNA SARS-CoV-2 vaccines in fragile patients: the Italian VAX4FRAIL study

BackgroundPatients with solid or hematological tumors, neurological and immune-inflammatory disorders represent potentially fragile subjects with increased risk to experience severe COVID-19 and inadequate response to SARS-CoV2 vaccination. MethodsWe designed a prospective Italian multicentric study to assess humoral and T-cell response to SARS-CoV2 vaccination in patients (n=378) with solid tumors (ST), hematological malignancies (HM), neurological (ND) and immuno-rheumatological diseases (ID). The immunogenicity of primary vaccination schedule and of the booster dose were analyzed. ResultsOverall, patient seroconversion rate after two doses was 62.1%. A significant lower rate was observed in HM (52.4%) and ID (51.9%) patients compared to ST (95.6%) and ND (70.7%); a lower median level of antibodies was detected in HM and ID versus the others (p<0.0001). A similar rate of patients with a positive SARS-CoV2 T-cell response was observed in all disease groups, with a higher level observed in the ND group. The booster dose improved humoral responses in all disease groups, although with a lower response in HM patients, while the T-cell response increased similarly in all groups. In the multivariable logistic model, the independent predictors for seroconversion were disease subgroups, type of therapies and age. Notably, the ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (p<0.0001), but had no effects on the T-cell responses. ConclusionsImmunosuppressive treatment more than disease type per se is a risk factor for low humoral response after vaccination. The booster dose can improve both humoral and T-cell response. Articles main point- Lower rate of seroconversion was observed in fragile patients as compared to healthy controls - The booster dose improves humoral and T-cell response in all fragile patient groups - Immunosuppressive treatment was associated with the worst humoral response to vaccination, but had no effects on T-cell responses.

Lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: An inverse probability of treatment weighting analysis.

PURPOSE: Data from common clinical practice were used to generate balanced cohorts of patients receiving either sorafenib or lenvatinib, for unresectable hepatocellular carcinoma, with the final aim to investigate their declared equivalence. METHODS: Clinical features of lenvatinib and sorafenib patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint and occurrence of adverse events was the secondary. RESULTS: The analysis included 385 patients who received lenvatinib, and 555 patients who received sorafenib. In the unadjusted cohort, lenvatinib did not show a survival advantage over sorafenib (HR: 0.85, 95% CI 0.70-1.02). After IPTW adjustment, lenvatinib still not returned a survival advantage over sorafenib (HR: 0.82, 95% CI: 0.62-1.07) even in presence of balanced baseline characteristics. Lenvatinib provided longer survival than sorafenib in patients previously submitted to TACE (HR: 0.69), with PS of 0 (HR: 0.73) or without extrahepatic disease (HR: 0.69). CONCLUSION: Present results confirmed randomized controlled trial in the real-life setting, but also suggests that in earlier stages some benefit can be expected.

COVID-19 SCREENING AND MONITORING OF ASYMPTOMATIC HEALTH WORKERS WITH A RAPID SEROLOGICAL TEST

BackgroundHealth workers are at high risk for SARS-CoV-2 infection and, if asymptomatic, for transmitting the virus on to fragile cancer patients. Materials and methodWe monitored health care workers (HCW) of our Cancer Institute with the rapid serological test Viva-DiagTM analyzing COVID-19 associated-IgG/IgM. Test were performed at time 0 and after 14 days; Rt-PCR and CLIA assays were also perfoRmed in positive Viva-DiagTM cases. 606 and 393 HCW had blood sample taken at time 0 and 14, respectively. ResultsOverall, 9 HCW (1.5%) resulted not-negative at Viva-DiagTM and one of them was confirmed positive for SARS-COV2 infection at RT-PCR oropharingeal swab. At time 0, all 9 cases showed some IgM expression and only one IgG; after 14 days IgM persisted in all cases while IgG became evident in 4 ones. A parallel CLIA test was performed in 23 quaratined subjetcs and in all Viva-Diag not negative cases. CLIA confirmed a positive level of IgM in 5/13 positive Viva-Diag cases; conversely, IgG was confirmed positive at CLIA in 4/5 cases positive at Viva-Diag. These results pose the question of different performances of the two tests. ConclusionsOur study suggest that Viva-Diag assay can be of help in individualizing SARS_COV2 infected people fisrt of all in cohorts of subjetcs with high prevalence. Different performances of serological colorimetric and CLIA tools remain to be ascertained.

RAPID SEROLOGICAL TESTS HAVE A ROLE IN ASYMPTOMATIC HEALTH WORKERS COVID-19 SCREENING

Health workers are at high risk for SARS-CoV-2 infection and, if asymptomatic, for transmitting the virus on to fragile cancer patients. We screened 525 health workers of our Cancer Institute with rapid serological test Viva-Diag analyzingCOVID-19 associated-IgG/IgM. Six subjects (1,1%) resulted with Viva-Diag test not-negative for IgM. All 6 cases had RT-PCR SARS-CoV-2 test negative; repeating analysis ofIgG/IgM expression by CLIA assay also, 2 cases resulted IgM positive and 1 case IgG/IgM positive. This latter subject reported a contact with an infected SARS-CoV-2 person, a month earlier.In conclusion our study seems to suggest: a) a different analytical sensitivity inIgG/IgM evaluation for Viva-Diag and CLIA assays needing to be further determined; b) the ability of Viva-Diagrapid COVID-19 test to evidence health workers positive for Immunoglobulins expression. Discordant results of rapid serological tests with respect to RT-PCR stress the different clinical meaning the two assays can have, question clearly referring to further studies to optimize the utilization of rapid serological test in asymptomatic subjects at high risk for infection.

Clinical meanings of rapid serological assay in patients tested for SARS-Co2 RT-PCR

BackgroundRT-PCR test for identification of viral nucleic acid is the current standard diagnostic method for the diagnosis of COVID-19 disease but technical reasons limit the utilization of this assay onlarge scalescreenings. MethodWe verified in a consecutive series of 191 symptomatic patients the clinical information that new rapid serological colorimetric test qualitatively analyzing IgM/IgG expression can provide with respect to standard assay and with respect to clinical outcome of patients. ResultsRapid serological test showed a sensitivity of 30% and a specificity of 89% with respect to the standard assay but, interestingly, these performances improve after 8 days of symptoms appearance. After 10 days of symptoms the predictive value of rapid serological test is higher than that of standardassay. When the behaviour of the two immunoglobulins was evaluated with respect to time length of symptoms appaerance, no significant difference in immunoglobulins behaviour was shown. ConclusionsThe rapid serological test analyzed in the present study is candidate to provide information on immunoreaction of the subject to COVID-19 exposure.