SARS-CoV-2 mRNA vaccines decouple anti-viral immunity from humoral autoimmunity.

mRNA-based vaccines dramatically reduce the occurrence and severity of COVID-19, but are associated with rare vaccine-related adverse effects. These toxicities, coupled with observations that SARS-CoV-2 infection is associated with autoantibody development, raise questions whether COVID-19 vaccines may also promote the development of autoantibodies, particularly in autoimmune patients. Here we used Rapid Extracellular Antigen Profiling to characterize self- and viral-directed humoral responses after SARS-CoV-2 mRNA vaccination in 145 healthy individuals, 38 patients with autoimmune diseases, and 8 patients with mRNA vaccine-associated myocarditis. We confirm that most individuals generated robust virus-specific antibody responses post vaccination, but that the quality of this response is impaired in autoimmune patients on certain modes of immunosuppression. Autoantibody dynamics are remarkably stable in all vaccinated patients compared to COVID-19 patients that exhibit an increased prevalence of new autoantibody reactivities. Patients with vaccine-associated myocarditis do not have increased autoantibody reactivities relative to controls. In summary, our findings indicate that mRNA vaccines decouple SARS-CoV-2 immunity from autoantibody responses observed during acute COVID-19.

Coincidental Onset of Ocular Myasthenia Gravis Following ChAdOx1 n-CoV-19 Vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

BACKGROUND: The Oxford-AstraZeneca vaccine ChAdOx1 (AZD1222, Vaxzevria) is playing a crucial role in counteracting the coronavirus disease-2019 (COVID-19) pandemic [1]. Since March 2021, reports of unexpected thrombotic events associated with thrombocytopenia and vaccination have been published [2]. To the best of our knowledge there is only one report about vaccination-associated myasthenia gravis (MG) occurring after a second dose of BNT162b2 (Pfizer-BioNTech).

Neurological Immune-Related Adverse Events After COVID-19 Vaccination: A Systematic Review.

The coronavirus disease 2019 (COVID-19) pandemic has affected millions of individuals worldwide. The global scientific effort to design an effective vaccine against this virus has led to the development of several vaccine candidates. The expedited rollout of these vaccines has created some public distrust regarding the safety of these new vaccines. This review compiles clinical data from reports of diagnosed immune-related neurological events that have occurred after COVID-19 vaccine administration with the exception of those secondary to hematological abnormalities. A systematic literature search was performed, using several databases, to identify reports of postvaccination adverse neurological events. The search resulted in 18 studies that met our criteria. These studies included 61 patients who had received COVID-19 vaccines and experienced at least 1 neurological adverse effect. The most common neurological event was facial nerve palsy (50% of all events). Other less frequently reported events included the reactivation of herpes zoster, Guillain-Barre syndrome, other demyelinating diseases, and neuropathy. The underlying mechanism was hypothesized to be related to vaccine-induced type 1 interferon production leading to decreased tolerance of the myelin sheath antigens. Other hypotheses include vaccine-induced transient lymphopenia and immune dysregulation. Most of the reported events were time limited and resolved spontaneously. Given the rarity of reported neurological events compared to the total number of vaccines administered, and the similarity in the incidence of events between COVID-19 vaccines and other more common vaccines, there is little evidence to support a causal relationship between COVID-19 vaccines and adverse neurological events.

Antibody or Anybody? Considering the Role of MRGPRX2 in Acute Drug-Induced Anaphylaxis and as a Therapeutic Target.

Acute anaphylaxis to small molecule drugs is largely considered to be antibody-mediated with immunogloblin E (IgE) and mast cell activation being key. More recently, a role for drug-reactive immunoglobulin G (IgG) with neutrophil activation has also been suggested, at least in reactions to neuromuscular blocking agents (NMBAs). However, the mast cell receptor MRGPRX2 has also been highlighted as a possible triggering mechanism in acute anaphylaxis to many clinically used drugs. Significantly, MRGPRX2 activation is not dependent upon the presence of drug-recognising antibody. Given the reasonable assumption that MRGPRX2 is expressed in all individuals, the corollary of this is that in theory, anybody could respond detrimentally to triggering drugs (recently suggested to be around 20% of a drug-like compound library). But this clearly is not the case, as the incidence of acute drug-induced anaphylaxis is very low. In this mini-review we consider antibody-dependent and -independent mechanisms of mast cell activation by small molecule drugs with a focus on the MRGPRX2 pathway. Moreover, as a juxtaposition to these adverse drug actions, we consider how increased understanding of the role of MRGPRX2 in anaphylaxis is important for future drug development and can complement exploration of this receptor as a drug target in broader clinical settings.

Impact of Patient Age on Clinical Efficacy and Toxicity of Checkpoint Inhibitor Therapy.

The addition of immune checkpoint inhibitors (ICIs) to the therapeutic armamentarium for solid malignancies has resulted in unprecedented improvements in patient outcomes in many cancers. The landscape of ICIs continues to evolve with novel approaches such as dual immune checkpoint blockade and combination therapies with other anticancer agents including cytotoxic chemotherapies and/or antiangiogenics. However, there is significant heterogeneity seen in antitumor responses, with certain patients deriving durable benefit, others experiencing initial benefit followed by acquired resistance necessitating change in therapy, and still others who are primarily refractory to ICIs. While generally better tolerated than traditional cytotoxic chemotherapy, ICIs are associated with unique toxicities, termed immune-related adverse events (irAEs), which can be severe or even lethal. As a disease of aging, older individuals make up a large proportion of patients diagnosed with cancer, yet this population is often underrepresented in clinical trials. Because ICIs indirectly target malignant cells through T cell activation, it has been hypothesized that age-related changes to the immune system may impact the efficacy and toxicity of these drugs. In this review, we discuss differences in the clinical efficacy and toxicity of ICIs in patients at the extremes of age.

Innate Immunity Modulating Impurities and the Immunotoxicity of Nanobiotechnology-Based Drug Products.

Innate immunity can be triggered by the presence of microbial antigens and other contaminants inadvertently introduced during the manufacture and purification of bionanopharmaceutical products. Activation of these innate immune responses, including cytokine secretion, complement, and immune cell activation, can result in unexpected and undesirable host immune responses. These innate modulators can also potentially stimulate the activation of adaptive immune responses, including the formation of anti-drug antibodies which can impact drug effectiveness. To prevent induction of these adverse responses, it is important to detect and quantify levels of these innate immunity modulating impurities (IIMIs) that may be present in drug products. However, while it is universally agreed that removal of IIMIs from drug products is crucial for patient safety and to prevent long-term immunogenicity, there is no single assay capable of directly detecting all potential IIMIs or indirectly quantifying downstream biomarkers. Additionally, there is a lack of agreement as to which of the many analytical assays currently employed should be standardized for general IIMI screening. Herein, we review the available literature to highlight cellular and molecular mechanisms underlying IIMI-mediated inflammation and its relevance to the safety and efficacy of pharmaceutical products. We further discuss methodologies used for direct and indirect IIMI identification and quantification.

Safety and Efficacy of the Rechallenge of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer: A Systemic Review and Meta-Analysis.

Introduction: Little evidence exists on the safety and efficacy of the rechallenge of immune checkpoint inhibitors (ICIs) after immune-related adverse events (irAEs) in patients with cancer. Methods: We searched PubMed, Web of Science, Embase, and Cochrane for articles on ICI rechallenge after irAEs for systemic review and meta-analysis. The outcomes included the incidence and associated factors for safety and objective response rate (ORR) and disease control rate (DCR) for efficacy. Results: A total of 789 ICI rechallenge cases from 18 cohort studies, 5 case series studies, and 54 case reports were included. The pooled incidence of all-grade and high-grade irAEs after rechallenge in patients with cancer was 34.2% and 11.7%, respectively. Compared with initial ICI treatment, rechallenge showed a higher incidence for all-grade irAEs (OR, 3.81; 95% CI, 2.15-6.74; p < 0.0001), but similar incidence for high-grade irAEs (p > 0.05). Types of initial irAEs (pneumonitis and global irAEs) and cancer (non-small cell lung cancer and multiple cancer) recapitulated these findings. Gastrointestinal irAEs and time interval between initial irAEs and ICI rechallenge were associated with higher recurrence of high-grade irAEs (p < 0.05), whereas initial anti-PD-1/PD-L1 antibodies were associated with a lower recurrence (p < 0.05). Anti-PD-1/PD-L1 antibodies rechallenge was associated with a lower all-grade irAE recurrence (p < 0.05). The pooled ORR and DCR after rechallenge were 43.1% and 71.9%, respectively, showing no significant difference compared with initial ICI treatment (p > 0.05). Conclusions: ICI rechallenge after irAEs showed lower safety and similar efficacy outcomes compared with initial ICI treatment. Systematic Review Registration: PROSPERO, identifier CRD42020191405.

Metabolic disease and adverse events from immune checkpoint inhibitors.

OBJECTIVE: Obese and overweight body mass index (BMI) categories have been associated with increased immune-related adverse events (irAEs) in patients with cancer receiving immune checkpoint inhibitors (ICIs); however, the impact of being overweight in conjunction with related metabolic syndrome-associated factors on irAEs have not been investigated. We aimed to evaluate the impact of overweight and obese BMI according to metabolic disease burden on the development of irAEs. DESIGN AND METHODS: We conducted a retrospective observational study of patients receiving ICIs at a cancer center. Our main study outcome was development of ≥grade 2 (moderate) irAEs. Our main predictor was weight/metabolic disease risk category: (1) normal weight (BMI 18.5-24.9 kg/m2)/low metabolic risk (<2 metabolic diseases [diabetes, dyslipidemia, hypertension]), (2) normal weight/high metabolic risk (≥2 metabolic diseases), (3) overweight (BMI ≥25 kg/m2)/low metabolic risk, and (4) overweight/high metabolic risk. RESULTS: Of 411 patients in our cohort, 374 were eligible for analysis. Overall, 111 (30%) patients developed ≥grade 2 irAEs. In Cox analysis, overweight/low metabolic risk was significantly associated with ≥grade 2 irAEs (hazard ratio [HR]: 2.0, 95% confidence interval [95% CI]: 1.2-3.4) when compared to normal weight/low metabolic risk, while overweight/high metabolic risk (HR: 1.3, 95% CI: 0.7-2.2) and normal weight/high metabolic risk (HR: 1.5, 95% CI: 0.7-3.0) were not. CONCLUSIONS: Overweight patients with fewer metabolic comorbidities were at increased risk for irAEs. This study provides an important insight that BMI should be evaluated in the context of associated metabolic comorbidities in assessing risk of irAE development and ICI immune response.

Bilateral Immune-Mediated Keratolysis After Immunization With SARS-CoV-2 Recombinant Viral Vector Vaccine.

PURPOSE: The purpose of this study was to report an unusual case of bilateral immune-mediated corneal melting and necrosis after ChAdOx1 nCoV-19 (Covishield) vaccination. METHODS: This is a case report and literature review. RESULTS: A 48-year-old man presented to the ophthalmic emergency department with progressive bilateral corneal melting 5 weeks after receiving the first dose of ChAdOx1 nCoV-19 (Covishield) vaccine. Systemic complaints of fever, diarrhea, and vomiting were noted in the first 2 weeks, which subsided before the onset of ocular symptoms at day 21 of vaccine administration. The patient could only perceive light bilaterally and demonstrated features of bilateral keratolysis with choroidal detachment on ultrasonography. The microbiological scraping specimen did not reveal growth of any microorganism. Tectonic penetrating keratoplasty was performed, and the host corneal tissue was sent for histopathology, bacterial culture, fungal culture, polymerase chain reaction for herpes simplex virus, varicella zoster virus, cytomegalovirus, adenovirus, and SARS-CoV-2. Microbial culture was sterile, and viral polymerase chain reaction reports were negative. Histopathological examination revealed dense inflammatory cell infiltration. Detailed systemic workup revealed no underlying systemic or autoimmune pathology. CONCLUSIONS: Immune-mediated keratolysis after ChAdOx1 nCoV-19 (Covishield) vaccination is a rare entity, and we believe that this is the first report of a temporal association between a serious ocular adverse event after a single dose of any SARS-CoV-19 vaccine. It may be included as a possible adverse event associated with this vaccine.

A potential mechanism of the onset of immune-related pneumonitis triggered by anti-PD-1 treatment in a patient with advanced adenocarcinoma lung cancer: case report.

BACKGROUND: In recent years, the application of immunotherapy combined with chemotherapy in the first-line lung cancer has showed significant benefit in improving long-term survival. Immunotherapy also has risks of immune-related pneumonitis (IRP) after long-term treatment. Despite the treatment strategy of the IRP has been very clear. However, the mechanism is unclear. CASE PRESENTATION: A 73-year-old male patient was diagnosed with left lung adenocarcinoma IVa, EGFR, ALK, ROS1 negative. The patient received anti-PD1 antibody combined with pemetrexed and cisplatin. After 5 cycles of treatment, partial response was obtained. Subsequently, the patient continued the treatment of anti-PD1 antibody combined with pemetrexed. Before the 7th cycle, the CT found a new lesion in the basal segment of the right lower lobe. It was diagnosed with IRP and pneumocystis jirovecii. The patient did not give trimethoprim-sulphamethoxazole (TMP-SMX) and corticosteroids, symptoms and radiological lesions had improved. We describe the report of immune-related pneumonitis trigged by anti PD-1 and monitored the dynamic changes of CD4+, CD8+ T lymphocytes, MDSC and Treg cells in the bilateral bronchoalveolar alveolar lavage fluid. From the point of view of immune cells, the mechanism of immune reconstitution inflammatory syndrome is confirmed. Based on the current case report and literature, this study proposes a potential mechanism of the onset. CONCLUSION: Immune reconstitution inflammatory syndrome may be potential mechanism of IRP. This study may improve our understanding of the pathogenesis underlying IRP. We believe the detection and dynamic monitoring CD4+, CD8+ T lymphocytes, MDSC and Treg cells can provide more accurate procedures.

Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory immune-related adverse events (irAEs). We sought to determine the activity of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in treatment or prevention of auto-immune irAE in ICI-treated patients. METHODS: Institutional databases from 2 melanoma centers were reviewed for patients treated with ICIs and tocilizumab. Longitudinal assessment of C-reactive protein (CRP) and assessment of clinical improvement or prevention of flare of pre-existing auto-immune conditions were utilised to evaluate the benefit of tocilizumab. RESULTS: Twenty-two patients were identified. Two were treated prophylactically. Twenty were treated for management of irAEs. Median time to irAE onset from ICI start was 48 days (range 8-786) and from irAE onset to tocilizumab 32 days (range 1-192). Median time to irAE resolution from tocilizumab was 6.5 days (range 1-93). Clinical improvement/benefit was demonstrated in 21/22 patients. Median CRP prior to ICI administration was 32 mg/l (range 0.3-99), at the onset of irAE 49.5 mg/L (range 0.3-251, P = 0.047) and after tocilizumab 18 mg/L (range 0.3-18, P = 0.0011). Tocilizumab was well tolerated with self-limiting and transient toxicities in 11 (50%) patients. From start of ICI, median progression-free survival was 6 months (range 3.9-18.8) and median overall survival was not reached. CONCLUSIONS: Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of flare of pre-existing auto-immune disorders. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.

Patient-reported outcomes for monitoring symptomatic toxicities in cancer patients treated with immune-checkpoint inhibitors: A Delphi study.

BACKGROUND: Immune-related adverse events (IrAEs) associated with the use of immune checkpoint inhibitors (ICIs) may not be fully covered by existing measures like the PRO-CTCAE™. Selecting PRO-CTCAE™ items for monitoring symptomatic adverse events is hindered by the heterogeneity and complexity of IrAEs, and no standardised selection process exists. We aimed to reach expert consensus on the PRO-CTCAE™ symptom terms relevant for cancer patients receiving ICIs and to gather preliminary expert opinions about additional symptom terms reflecting ICI symptomatic toxicities. Additionally, we gathered expert consensus about a core set of priority symptom terms for prospective surveillance and monitoring. DESIGN: This Delphi study involved an international panel of experts (n = 6 physicians; n = 3 nurses, n = 1 psychiatrist and n = 1 patient advocates). Experts prioritised the relevance and importance of symptom terms to monitor in patients treated with ICIs. RESULTS: Experts reached a consensus on the relevance of all (n = 80) PRO-CTCAE™ Symptom Terms. Consensus on the importance of these symptom terms for prospective monitoring in patients receiving ICIs was reached for 81% (n = 65) of these terms. Additional symptoms terms (n = 56) were identified, with a consensus that 84% (47/56) of these additional symptom terms should also be considered when monitoring symptomatic IrAEs. CONCLUSION: This study identified a prioritised list of symptom terms for prospective surveillance for symptomatic IrAEs in patients receiving ICI treatment. Our results indicate the need to strengthen the validity of PRO measures used to monitor patients receiving ICIs. While these results provided some support for the content validity of the PRO CTCAE™ and resulted in a preliminary set of salient symptomatic adverse events related to the use of ICIs, broader international agreement and patient involvement are needed to further validate our initial findings.

Real world data of cemiplimab in locally advanced and metastatic cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) has an overall favourable outcome, except for patients with an advanced stage disease. The programmed death protein-1 (PD-1) inhibitor cemiplimab has been approved for use in advanced cSCC. We report clinical outcomes from the named patient programme-compassionate use of cemiplimab for patients with advanced cSCC in Italy. METHODS: This is a retrospective, observational, multicentre study. We analysed medical records of patients with advanced cSCC treated with cemiplimab between May 2019 and February 2020 in 17 referral Italian centres. We assessed the safety profile according to the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v 5.0), the clinical activity in terms of response rate, clinical benefit and duration of response and baseline clinical-pathologic characteristics associated with response. RESULTS: 131 patients were included, with a median age of 79 years. Of them, 9.2% had a concurrent chronic lymphoproliferative disease and 8.5% a concomitant autoimmune disease. Some 42.7% of the total patients had at least one treatment-related adverse events (AEs); out of above, 9.2% had grade 3-4 adverse events, and there were two fatal adverse events. The overall response rate (ORR) was 58%, and the disease control rate (DCR) was 71.7%. Cutaneous squamous cell carcinomas (cSCCs) arising on the head and neck area (p = 0.007) and haemoglobin values in normal range (p = 0.034) were significantly associated with a better response, while cSCCs on the genitalia (p = 0.041), treatment with any systemic antibiotic within 1 month of cemiplimab initiation (p = 0.012), performance status ≥1 (p = 0.012), chronic corticosteroids therapy (p = 0.038), previous radiation therapy to lymph nodes (p = 0.052) and previous chemotherapy (p = 0.0020) were significantly associated with a worse response. CONCLUSIONS: Our real-world study showed safety and effectiveness results comparable to those obtained in clinical trials. We identified some clinical and biochemical factors potentially associated with response to cemiplimab.

[Importance of HLA in Determining Individual Differences in the Onset of Adverse Drug Reactions].

Individuals vary in their susceptibility to adverse reactions to medications, some of which can be potentially life-threatening. Idiosyncratic drug toxicity (IDT) has been shown to be strongly associated to specific polymorphisms in genes encoding human leukocyte antigens (HLAs) by recent genome-wide association studies. However, the pathogenic mechanisms governing such reactions remain unclarified, at least in part because of a lack of suitable experimental animal models to assess IDT. This review describes our work on the specific allele/drug combination of HLA-B*57:01 and abacavir, an antiretroviral drug targeting the human immunodeficiency virus. As abacavir is known to trigger an HLA-dependent immune response, we engineered a transgenic mouse model-HLA-Tg-by partially substituting the mouse HLA sequence for the corresponding human sequence. Local abacavir exposure was found to trigger a significant immune response in an HLA-dependent manner, and oral administration induced liver injury partially via concurrent activation of the innate immune system. Additionally, we developed a technique for evaluating structural alterations in HLA complexes resulting from drug exposure based on phage display to ensure specificity. Further scrutiny of the mechanism(s) underlying drug-induced immune reactions using the HLA-Tg model, as well as enhanced methods for predicting adverse event incidence, are anticipated to help resolve issues surrounding HLA-associated drug hypersensitivity.

An Integrated Analysis of Dostarlimab Immunogenicity.

Monoclonal antibodies that block the interaction between programmed cell death 1 (PD-1) and its ligand (PD-L1) have revolutionized cancer immunotherapy. However, immunogenic responses to these new therapies-such as the development of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)-may represent a significant challenge to both efficacy and safety in some patients. Dostarlimab (TSR-042) is an approved, humanized, anti-PD-1 monoclonal antibody that has shown efficacy in multiple solid tumor types. Here, we report the results of an immunogenicity analysis of dostarlimab monotherapy in patients enrolled in the GARNET trial, a multicenter, open-label, single-arm phase 1 study. Overall, 477 of 478 patients (99.8%) were included in the analysis of dostarlimab antibody prevalence, and 349 out of 478 enrolled patients (73.0%) were evaluable for treatment-emergent antibodies to dostarlimab. The incidence of treatment-emergent ADAs was 2.5% at the recommended therapeutic dose (500 mg Q3W for the first 4 doses, 1000 mg Q6W until discontinuation), which is comparable to other anti-PD-(L)1 drugs. NAbs were detected in only 1.3% of patients. In the small percentage of patients who developed ADAs, there was no evidence of altered efficacy or safety of dostarlimab at the recommended dosing regimen. These findings demonstrated that treatment with dostarlimab was associated with a low risk of eliciting clinically meaningful ADAs over the course of this study, and dostarlimab is already approved by health authorities.

HLA-associated adverse drug reactions - scoping review.

Alleles of the human leukocyte antigen (HLA) system have been associated with the occurrence of idiosyncratic adverse drug reactions (ADRs). Accordingly, it is assumed that pre-emptive testing for the presence of certain HLA alleles (HLA-typing) could prevent these ADRs in carriers. In order to perceive the current evidence for HLA-associated ADRs, we conducted a scoping review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The literature search on PubMed and on Embase was carried out on the July 8 and 9, 2020, respectively. To be included in the scoping review, the studies had to investigate an association of any HLA-associated ADR with any small molecule approved and available on the Swiss market. We considered English and German primary literature published since 2002. A total of 149 studies were included, whereof most were retrospective, whereas one was a prospective randomized controlled trial. The majority of the studies (n = 33) described the association of HLA-B*15:02 with carbamazepine. It was not possible to directly compare the studies, as they were too heterogeneous in terms of the ADR definition, the HLA alleles, the number of participants, and the study types. Therefore, we summarized the results in a descriptive manner. Even if an interpretation of the outcomes remains open, the descriptive overview revealed the prevailing complexity and uncertainty in the field. For the future, consistent definitions on the different phenotypes need to be established and applied and the reporting of association studies should follow a harmonized structure.

Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19.

Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being deployed, but the global need greatly exceeds the supply, and different formulations might be required for specific populations. Here we report Day 42 interim safety and immunogenicity data from an observer-blinded, dose escalation, randomized controlled study of a virus-like particle vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein (CoVLP: NCT04450004 ). The co-primary outcomes were the short-term tolerability/safety and immunogenicity of CoVLP formulations assessed by neutralizing antibody (NAb) and cellular responses. Secondary outcomes in this ongoing study include safety and immunogenicity assessments up to 12 months after vaccination. Adults (18-55 years, n = 180) were randomized at two sites in Quebec, Canada, to receive two intramuscular doses of CoVLP (3.75 µg, 7.5 µg, and 15 µg) 21 d apart, alone or adjuvanted with AS03 or CpG1018. All formulations were well tolerated, and adverse events after vaccination were generally mild to moderate, transient and highest in the adjuvanted groups. There was no CoVLP dose effect on serum NAbs, but titers increased significantly with both adjuvants. After the second dose, NAbs in the CoVLP + AS03 groups were more than tenfold higher than titers in Coronavirus 2019 convalescent sera. Both spike protein-specific interferon-γ and interleukin-4 cellular responses were also induced. This pre-specified interim analysis supports further evaluation of the CoVLP vaccine candidate.

Association between immune-related dermatologic adverse events and efficacy of pembrolizumab in non-small cell lung cancer patients.

We retrospectively evaluated the incidence of skin immune-related adverse effects (irAEs) in patients treated with pembrolizumab (PMB) and explored and the relationship between skin irAEs and PMB efficacy. Thirty-two patients with non-small cell lung cancer treated with PMB between April 2017 and May 2018 were enrolled. The patients were separated into two groups, namely, skin irAEs and no-skin irAEs group. We investigated the ratio and degree of express skin irAEs, period of skin irAEs and treatment, and the PFS between the two groups. Additionally, we evaluated the PFS between the irAE and no-irAEs groups. The median patient age was 76.5 (range 56-92) years. The European Cooperative Oncology Group Performance Status (ECOG PS) score of 26, 5, and 1 was 0-1, 2, and 3, respectively. The male/female ratio was 23/9. In terms of clinical stages, 6, 21, and 5 patients were in stages III and IV, and postoperative relapse, respectively. Skin irAEs were observed in 10 patients (31%). The progression-free survival of patients with skin irAEs (median, 390 days) was longer than that of patients without skin irAEs (median, 128.5 days). Overall, we suggested a significant association between skin irAEs and the efficacy of PMB in treating non-small cell lung cancer. As skin irAEs can be an indicator of treatment efficacy, it is important for medical staff, including pharmacists, to closely observe these adverse events.

Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis.

BACKGROUND: The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood. PATIENTS AND METHODS: E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034). RESULTS: Occurrence of grades 1-2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1-2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1-2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1-2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1-2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3-4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3-4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1-2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found. CONCLUSIONS: Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3-4 irAEs.

Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study.

BACKGROUND: The Pfizer-BioNTech (BNT162b2) and the Oxford-AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccines have shown excellent safety and efficacy in phase 3 trials. We aimed to investigate the safety and effectiveness of these vaccines in a UK community setting. METHODS: In this prospective observational study, we examined the proportion and probability of self-reported systemic and local side-effects within 8 days of vaccination in individuals using the COVID Symptom Study app who received one or two doses of the BNT162b2 vaccine or one dose of the ChAdOx1 nCoV-19 vaccine. We also compared infection rates in a subset of vaccinated individuals subsequently tested for SARS-CoV-2 with PCR or lateral flow tests with infection rates in unvaccinated controls. All analyses were adjusted by age (≤55 years vs >55 years), sex, health-care worker status (binary variable), obesity (BMI <30 kg/m2vs ≥30 kg/m2), and comorbidities (binary variable, with or without comorbidities). FINDINGS: Between Dec 8, and March 10, 2021, 627 383 individuals reported being vaccinated with 655 590 doses: 282 103 received one dose of BNT162b2, of whom 28 207 received a second dose, and 345 280 received one dose of ChAdOx1 nCoV-19. Systemic side-effects were reported by 13·5% (38 155 of 282 103) of individuals after the first dose of BNT162b2, by 22·0% (6216 of 28 207) after the second dose of BNT162b2, and by 33·7% (116 473 of 345 280) after the first dose of ChAdOx1 nCoV-19. Local side-effects were reported by 71·9% (150 023 of 208 767) of individuals after the first dose of BNT162b2, by 68·5% (9025 of 13 179) after the second dose of BNT162b2, and by 58·7% (104 282 of 177 655) after the first dose of ChAdOx1 nCoV-19. Systemic side-effects were more common (1·6 times after the first dose of ChAdOx1 nCoV-19 and 2·9 times after the first dose of BNT162b2) among individuals with previous SARS-CoV-2 infection than among those without known past infection. Local effects were similarly higher in individuals previously infected than in those without known past infection (1·4 times after the first dose of ChAdOx1 nCoV-19 and 1·2 times after the first dose of BNT162b2). 3106 of 103 622 vaccinated individuals and 50 340 of 464 356 unvaccinated controls tested positive for SARS-CoV-2 infection. Significant reductions in infection risk were seen starting at 12 days after the first dose, reaching 60% (95% CI 49-68) for ChAdOx1 nCoV-19 and 69% (66-72) for BNT162b2 at 21-44 days and 72% (63-79) for BNT162b2 after 45-59 days. INTERPRETATION: Systemic and local side-effects after BNT162b2 and ChAdOx1 nCoV-19 vaccination occur at frequencies lower than reported in phase 3 trials. Both vaccines decrease the risk of SARS-CoV-2 infection after 12 days. FUNDING: ZOE Global, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, UK Medical Research Council, Wellcome Trust, UK Research and Innovation, American Gastroenterological Association.