Project description:To date, few data are available regarding Adverse events (AEs) in cancer patients who are vaccinated for coronavirus disease 2019 (COVID-19) while being actively treated with Immune-checkpoint inhibitors (ICIs). We aimed to assess the safety of COVID-19 vaccines approved in Germany. Specifically, we investigated the frequency of general side effects and immune-related AEs of COVID-19 vaccination. A triage survey was used to collect the following information for patients with metastatic skin cancer: vaccine type, date of receipt of each dose of vaccine, and self-reported side effects. Clinical data were retrieved from the patients' medical records. Of 130 patients with metastatic skin cancer, 89 patients were on immunotherapy and received COVID-19 vaccination. Of these 89 patients (median age: 64 years; 57 [64%] men), 89% had melanoma, and 71% received ICI therapy with a PD-1 antibody. Eighty-eight percent received an mRNA-based COVID-19 vaccination. The median follow-up time was 125 days after the first vaccination, and 84 days after the second. The most common observed side effects were mild to moderate pain at the injection site (40%), followed by fatigue (24%). Grade 3 irAEs were reported in eight patients, seven of whom were on nivolumab plus ipilimumab combination treatment. Of the 19 patients vaccinated within 72 h before/after ICI, five developed irAEs within 17 days (1-17 days). This small cohort study suggests that approved COVID-19 vaccinations are safe for use in cancer patients receiving ICIs. However, some precautions should be taken, especially regarding the timing of vaccination and ICI treatment.
Project description:The monoclonal antibody rituximab improves clinical outcome in the treatment of CD20-positive lymphomatous neoplasms, and it is an established drug for treatment of these cancers. Successful mRNA COVID-19 (SARS-CoV-2) vaccination is extremely important for lymphoma patients because they tend to be elderly with comorbidities which leaves them at increased risk of poor outcomes once infected by Coronavirus. Anti-CD20 therapies such as rituximab, deplete B-cell populations and can affect vaccine efficacy. Therefore, a knowledge of the effect of COVID-19 vaccination in this group is critical. We followed a cohort of 28 patients with CD20-positive lymphomatous malignancies treated with rituximab that started prior to their course of COVID-19 vaccination, including boosters. We assayed for vaccine "take" in the humoral (IgG and IgA) and cellular compartment. Here, we show that short-term and long-term development of IgG and IgA antibodies directed toward COVID-19 spike protein are reduced in these patients compared to healthy controls. Conversely, the robustness and breath of underlying T-cell response is equal to healthy controls. This response is not limited to specific parts of the spike protein but spans the spike region, including response to the conserved Receptor Binding Domain (RBD). Our data informs on rational vaccine design and bodes well for future vaccination strategies that require strong induction of T-cell responses in these patients.
Project description:Immunocompromised individuals, including multiple sclerosis (MS) patients on certain immunotherapy treatments, are considered susceptible to complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and specific vaccination regimens have been recommended for suitable protection. MS patients receiving anti-CD20 therapy (aCD20-MS) are considered especially vulnerable due to acquired B-cell depletion and impaired antibody production in response to virus infection and COVID-19 vaccination. Here, the humoral and cellular responses are analyzed in a group of aCD20-MS patients (n=43) compared to a healthy control cohort (n=34) during the first 6 months after a 2-dose cycle mRNA-based COVID-19 vaccination. Both IgG antibodies recognizing receptor binding domain (RBD) from CoV-2 spike protein and their blocking activity against RBD-hACE2 binding were significantly reduced in aCD20-MS patients, with a seroconversion rate of only 23.8%. Interestingly, even under conditions of severe B-cell depletion and failed seroconversion, a significantly higher polyfunctional IFNγ+ and IL-2+ T-cell response and strong T-cell proliferation capacity were detected compared to controls. Moreover, no difference in T-cell response was observed between forms of disease (relapsing remitting- vs progressive-MS), anti-CD20 therapy (Rituximab vs Ocrelizumab) and type of mRNA-based vaccine received (mRNA-1273 vs BNT162b2). These results suggest the generation of a partial adaptive immune response to COVID-19 vaccination in B-cell depleted MS individuals driven by a functionally competent T-cell arm. Investigation into the role of the cellular immune response is important to identifying the level of protection against SARS-CoV-2 in aCD20-MS patients and could have potential implications for future vaccine design and application.
Project description:Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2 displacement and live viral neutralization activities one month following the first and second COVID-19 vaccine doses in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm 3 . Nadir CD4+ T-cell counts ranged as low as <10 (median 280; IQR 120-490) cells/mm 3 . After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log 10 lower anti-RBD antibody concentrations (p=0.03) and ∼11% lower ACE2 displacement activity (p=0.02), but not lower viral neutralization (p=0.1) after one vaccine dose. Following two doses however, HIV was no longer significantly associated with the magnitude of any response measured. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (versus a heterologous or dual mRNA vaccine regimen) were independently associated with lower responses. After two vaccine doses, no significant correlation was observed between the most recent or nadir CD4+ T-cell counts and vaccine responses in PLWH. These results suggest that PLWH with well-controlled viral loads on antiretroviral therapy and CD4+ T-cell counts in a healthy range will generally not require a third COVID-19 vaccine dose as part of their initial immunization series, though other factors such as older age, co-morbidities, vaccine regimen type, and durability of vaccine responses will influence when this group may benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment and/or who have low CD4+ T-cell counts are needed.
Project description:Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely characterized. We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain (RBD), ACE2 displacement and viral neutralization activities one month following the first and second COVID-19 vaccine doses, and again 3 months following the second dose, in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3, though nadir CD4+ T-cell counts ranged as low as <10 cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was associated with lower anti-RBD antibody concentrations and ACE2 displacement activity after one vaccine dose. Following two doses however, HIV was not significantly associated with the magnitude of any humoral response after multivariable adjustment. Rather, older age, a higher burden of chronic health conditions, and dual ChAdOx1 vaccination were associated with lower responses after two vaccine doses. No significant correlation was observed between recent or nadir CD4+ T-cell counts and responses to two vaccine doses in PLWH. These results indicate that PLWH with well-controlled viral loads and CD4+ T-cell counts in a healthy range generally mount strong initial humoral responses to dual COVID-19 vaccination. Factors including age, co-morbidities, vaccine brand, response durability and the rise of new SARS-CoV-2 variants will influence when PLWH will benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment or who have low CD4+ T-cell counts are needed, as are longer-term assessments of response durability.
Project description:The incidence of severe immune-related adverse events (irAEs) in cancer subjects receiving immune checkpoint inhibitors (ICIs) following COVID-19 vaccination and the relationship between the incidence of severe irAE and the interval between COVID-19 vaccination and ICI dose have not been established. We performed a retrospective study evaluating the incidence of irAEs in solid tumor subjects receiving ICI therapy who received any COVID-19 vaccinations since FDA authorization. irAEs were defined as severe with one or more grade 3 or above events (CTCAE v5.0), multiple organ involvement, or requiring hospitalization for management. Two hundred and eighty-four subjects who received COVID vaccinations from December 2020 and February 2022 were included in this analysis [median age at vaccination 67 years (IQR 59.0-75.0); 67.3% male]. Twenty-nine subjects (10.2%) developed severe irAEs, of which 12 subjects (41.4%) received ICI monotherapy, 10 subjects (34.5%) received combination ICI therapy with nivolumab and ipilimumab, and 7 subjects (24.1%) received ICI plus VEGFR-TKI therapy. Hospitalization occurred in 62% of subjects with severe irAEs, with a median duration of 3 days (IQR: 3.0-7.5 days). Immunosuppressive therapy was required in 79.3%, with a median duration of 103 days (IQR: 42.0-179.0). ICI therapy was discontinued in 51.7% of subjects with severe irAE; dosing was held or interrupted in 34.5%. Among severe irAEs, the median interval between vaccination and ICI treatment closest to the occurrence of severe irAE was 15.5 days (IQR: 10.0-23.0). In solid tumor cancer subjects receiving ICIs, COVID-19 vaccination is not associated with an increased incidence of severe irAEs compared to historical data and may be safely administered during ICI cancer therapy in subjects who lack contraindications.
Project description:Patients receiving dialysis may mount impaired responses to COVID19 vaccination. We report antibody response to vaccination from 1140 patients without, and 493 patients with pre-vaccination SARS-CoV-2 RBD antibody. We used commercially available assays (Siemens) to test remainder plasma monthly in association with vaccination date and type, and assess prevalence of absent total receptor binding antibody, and absent or attenuated (index value < 10) semiquantitative receptor binding domain IgG index values. We used Poisson regression to evaluate risk factors for absent or attenuated response to vaccination. Among patients who were seronegative versus seropositive before vaccination, 62% and 56% were ≥65 years old, 20% and 24% were Hispanic, and 22% and 23% were Black. Median IgG index values rose steadily over time, and were higher among the seropositive than in the seronegative patients after completing vaccination (150 [25 th , 75 th percentile 23.2, 150.0] versus 41.6 [11.3, 150.0]). Among 610 patients who completed vaccination (assessed ≥14 days later, median 29 days later), the prevalence of absent total RBD response, and absent and attenuated semiquantitative IgG response was 4.4% (95% CI 3.1, 6.4%), 3.4% (2.4, 5.2%), and 14.3% (11.7, 17.3%) respectively. Risk factors for absent or attenuated response included longer vintage of end-stage kidney disease, and lower pre-vaccination serum albumin. More than one in five patients receiving dialysis had evidence of an attenuated immune response to COVID19 vaccination. Patients receiving dialysis face high likelihood of severe COVID19; at the same time, vaccination may be less efficacious, as prior data indicate impaired immune responses to influenza and Hepatitis B vaccination. We found that 22% of patients receiving dialysis had suboptimal responses to vaccination, irrespective of whether or not they had evidence of prior SARS-CoV-2 infection. Poorer health status and longer duration of end-stage kidney disease increased likelihood of suboptimal response. Ongoing vigilance for COVID19 in dialysis facilities and studies of modified vaccination dosing schedules will be critical to protecting patients receiving dialysis.
Project description:At this stage in the COVID-19 pandemic, most infections are 'breakthrough' infections that occur in individuals with prior immunity to SARS-CoV-2 through infection or vaccination. Understanding both innate and adaptive immune induction in the setting of breakthrough infection is critical to refining vaccine strategies to ensure long-term efficacy against emerging variants, yet existing studies have primarily focused on adaptive immune responses. Here, we performed single-cell transcriptomic, proteomic, and functional profiling of innate and adaptive immunity during primary and breakthrough COVID-19 infections by comparing immune responses between unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a significantly less activated transcriptomic profile in CD56dim NK cells and monocytes, with induction of pathways limiting NK cell proliferation and monocyte migratory potential. Furthermore, we observed a female-specific trend of increased transcriptomic activation of CD16+ monocytes and type-2 conventional dendritic cells (cDC2s) during breakthrough infections. Despite these differences, antibody-dependent cellular cytotoxicity responses were similar between breakthrough and primary infection groups. These insights suggest that prior vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.