Immunogenicity of quadrivalent human papillomavirus vaccine among Alaska Native children aged 9-14 years at 5 years after vaccination.

BACKGROUND: Persistent human papillomavirus (HPV) infection can cause anogenital and oropharyngeal cancers. Many HPV infections and HPV-associated cancers are vaccine-preventable. Studies suggest long-term persistence of vaccine-induced antibodies. However, data are limited among Alaska Native people. METHODS: During 2011-2014, we enrolled Alaska Native children aged 9-14 years who received a 3-dose series of quadrivalent HPV vaccine (4vHPV). We collected sera at 1 month and 1, 2, 3, and 5 years post-vaccination to evaluate trends in type-specific immunoglobulin G antibody concentrations for the 4vHPV types (HPV 6/11/16/18). RESULTS: All participants (N = 469) had detectable antibodies against all 4vHPV types at all timepoints post-vaccination. For all 4vHPV types, antibody levels peaked by 1 month post-vaccination and gradually declined in subsequent years. At 5 years post-vaccination, antibody levels were higher among children who received 4vHPV at a younger age. CONCLUSIONS: Alaska Native children maintained antibodies against all 4vHPV types at 5 years post-vaccination.

Preclinical evaluation of two phylogenetically distant arenavirus vectors for the development of novel immunotherapeutic combination strategies for cancer treatment.

BACKGROUND: Engineered arenavirus vectors have recently been developed to leverage the body's immune system in the fight against chronic viral infections and cancer. Vectors based on Pichinde virus (artPICV) and lymphocytic choriomeningitis virus (artLCMV) encoding a non-oncogenic fusion protein of human papillomavirus (HPV)16 E6 and E7 are currently being tested in patients with HPV16+ cancer, showing a favorable safety and tolerability profile and unprecedented expansion of tumor-specific CD8+ T cells. Although the strong antigen-specific immune response elicited by artLCMV vectors has been demonstrated in several preclinical models, PICV-based vectors are much less characterized. METHODS: To advance our understanding of the immunobiology of these two vectors, we analyzed and compared their individual properties in preclinical in vivo and in vitro systems. Immunogenicity and antitumor effect of intratumoral or intravenous administration of both vectors, as well as combination with NKG2A blockade, were evaluated in naïve or TC-1 mouse tumor models. Flow cytometry, Nanostring, and histology analysis were performed to characterize the tumor microenvironment (TME) and T-cell infiltrate following treatment. RESULTS: Despite being phylogenetically distant, both vectors shared many properties, including preferential infection and activation of professional antigen-presenting cells, and induction of potent tumor-specific CD8+ T-cell responses. Systemic as well as localized treatment induced a proinflammatory shift in the TME, promoting the infiltration of inducible T cell costimulator (ICOS)+CD8+ T cells capable of mediating tumor regression and prolonging survival in a TC-1 mouse tumor model. Still, there was evidence of immunosuppression built-up over time, and increased expression of H2-T23 (ligand for NKG2A T cell inhibitory receptor) following treatment was identified as a potential contributing factor. NKG2A blockade improved the antitumor efficacy of artARENA vectors, suggesting a promising new combination approach. This demonstrates how detailed characterization of arenavirus vector-induced immune responses and TME modulation can inform novel combination therapies. CONCLUSIONS: The artARENA platform represents a strong therapeutic vaccine approach for the treatment of cancer. The induced antitumor immune response builds the backbone for novel combination therapies, which warrant further investigation.

Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C.

BACKGROUND: Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored. METHODS: We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination's efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials. RESULTS: Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+ T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+ T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included. CONCLUSION: Intratumoral injection of poly(I:C) sensitizes MHClow tumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.

Effects of antineoplastic and immunomodulating agents on postvaccination SARS-CoV-2 breakthrough infections, antibody response, and serological cytokine profile.

BACKGROUND: Despite immunization, patients on antineoplastic and immunomodulating agents have a heightened risk of COVID-19 infection. However, accurately attributing this risk to specific medications remains challenging. METHODS: An observational cohort study from December 11, 2020 to September 22, 2022, within a large healthcare system in San Diego, California, USA was designed to identify medications associated with greatest risk of postimmunization SARS-CoV-2 infection. Adults prescribed WHO Anatomical Therapeutic Chemical (ATC) classified antineoplastic and immunomodulating medications were matched (by age, sex, race, and number of immunizations) with control patients not prescribed these medications yielding a population of 26 724 patients for analysis. From this population, 218 blood samples were collected from an enrolled subset to assess serological response and cytokine profile in relation to immunization. RESULTS: Prescription of WHO ATC classified antineoplastic and immunomodulatory agents was associated with elevated postimmunization SARS-CoV-2 infection risk (HR 1.50, 95% CI 1.38 to 1.63). While multiple immunization doses demonstrated a decreased association with postimmunization SARS-CoV-2 infection risk, antineoplastic and immunomodulatory treated patients with four doses remained at heightened risk (HR 1.23, 95% CI 1.06 to 1.43). Risk variation was identified among medication subclasses, with PD-1/PD-L1 inhibiting monoclonal antibodies, calcineurin inhibitors, and CD20 monoclonal antibody inhibitors identified to associate with increased risk of postimmunization SARS-CoV-2 infection. Antineoplastic and immunomodulatory treated patients also displayed a reduced IgG antibody response to SARS-CoV-2 epitopes alongside a unique serum cytokine profile. CONCLUSIONS: Antineoplastic and immunomodulating medications associate with an elevated risk of postimmunization SARS-CoV-2 infection in a drug-specific manner. This comprehensive, unbiased analysis of all WHO ATC classified antineoplastic and immunomodulating medications identifies medications associated with greatest risk. These findings are crucial in guiding and refining vaccination strategies for patients prescribed these treatments, ensuring optimized protection for this susceptible population in future COVID-19 variant surges and potentially for other RNA immunization targets.

Identification of pan-cancer/testis genes and validation of therapeutic targeting in triple-negative breast cancer: Lin28a-based and Siglece-based vaccination induces antitumor immunity and inhibits metastasis.

BACKGROUND: Cancer-testis (CT) genes are targets for tumor antigen-specific immunotherapy given that their expression is normally restricted to the immune-privileged testis in healthy individuals with aberrant expression in tumor tissues. While they represent targetable germ tissue antigens and play important functional roles in tumorigenesis, there is currently no standardized approach for identifying clinically relevant CT genes. Optimized algorithms and validated methods for accurate prediction of reliable CT antigens (CTAs) with high immunogenicity are also lacking. METHODS: Sequencing data from the Genotype-Tissue Expression (GTEx) and The Genomic Data Commons (GDC) databases was used for the development of a bioinformatic pipeline to identify CT exclusive genes. A CT germness score was calculated based on the number of CT genes expressed within a tumor type and their degree of expression. The impact of tumor germness on clinical outcome was evaluated using healthy GTEx and GDC tumor samples. We then used a triple-negative breast cancer mouse model to develop and test an algorithm that predicts epitope immunogenicity based on the identification of germline sequences with strong major histocompatibility complex class I (MHCI) and MHCII binding affinities. Germline sequences for CT genes were synthesized as long synthetic peptide vaccines and tested in the 4T1 triple-negative model of invasive breast cancer with Poly(I:C) adjuvant. Vaccine immunogenicity was determined by flow cytometric analysis of in vitro and in vivo T-cell responses. Primary tumor growth and lung metastasis was evaluated by histopathology, flow cytometry and colony formation assay. RESULTS: We developed a new bioinformatic pipeline to reliably identify CT exclusive genes as immunogenic targets for immunotherapy. We identified CT genes that are exclusively expressed within the testis, lack detectable thymic expression, and are significantly expressed in multiple tumor types. High tumor germness correlated with tumor progression but not with tumor mutation burden, supporting CTAs as appealing targets in low mutation burden tumors. Importantly, tumor germness also correlated with markers of antitumor immunity. Vaccination of 4T1 tumor-bearing mice with Siglece and Lin28a antigens resulted in increased T-cell antitumor immunity and reduced primary tumor growth and lung metastases. CONCLUSION: Our results present a novel strategy for the identification of highly immunogenic CTAs for the development of targeted vaccines that induce antitumor immunity and inhibit metastasis.

[Adverse effect incidence of Pfizer/BioNTech COVID-19 vaccine: Retrospective cohort study]. / Incidencia de efectos adversos de la vacuna contra COVID-19 Pfizer/BioNTech: estudio de cohorte retrospectivo.

Background: Coronavirus SARS-CoV-2 has been the cause of multiple hospitalizations due to respiratory distress, pneumonia, multi-organic failure and death in all the world. The BioNTech/Pfizer lab was the first to get the approval from the Food and Drug Administration (FDA) for vaccine application, beginning with health workers. However, there are a few studies about adverse effects after applying the COVID-19 vaccine. Objective: To assess the presence and time of onset of adverse effects produced by the COVID-19 vaccine. Material and methods: A retrospective cohort study was carried out, including medical residents from the Hospital de Especialidades No. 1 (Specialties Hospital No. 1) from the Bajío National Medical Center, who received two doses of Pfizer-BioNTech vaccine and decided to participate voluntarily. We obtained the information by a self-assessment tool sent via email. All adverse effects were collected emphasizing those described in the literature. Results: A total of 101 medical residents were included. It was observed that 55.54% presented adverse effects after the first dose, which appeared in the first 24 hours after the vaccine was administered. After the second dose, 54.5% presented symptomatology, 41.6% during first 24 hours after the vaccine was administered. Conclusions: It was observed symptomatology after applying the complete series (two doses) of BioNTech/Pfizer; however, there were mild and of short duration.

Introducción: el coronavirus SARS-CoV-2 ha sido causa de múltiples hospitalizaciones por distrés respiratorio, neumonía, falla multiorgánica y fallecimientos en todo el mundo. El laboratorio de BioNTech/Pfizer fue el primero en conseguir aprobación por la Food and Drug Administration (FDA) para la aplicación a gran escala de su prototipo de vacuna, comenzando la aplicación en el sector salud. Sin embargo, existen pocos estudios sobre los efectos adversos tras la aplicación de dicha vacuna. Objetivo: evaluar la presencia y el tiempo de inicio de efectos adversos producidos por la vacuna contra COVID-19. Material y métodos: se realizó un estudio de cohorte retrospectivo, se incluyeron médicos residentes adscritos al Hospital de Especialidades No. 1 del Centro Médico Nacional del Bajío, quienes recibieron dos dosis de la vacuna BioNTech/Pfizer y que decidieron participar voluntariamente. Se recabó la información mediante un instrumento de evaluación autoaplicable vía electrónica. Se recolectaron todos los eventos adversos y se hizo énfasis en los descritos en la literatura. Resultados: se incluyeron un total de 101 médicos residentes. Se observó que el 55.4% presentó efectos secundarios después de la primera dosis, mismos que aparecieron en las primeras 24 horas tras la aplicación. Posterior a la aplicación de la segunda dosis, el 54.5% presentó sintomatología, el 41.6% en las primeras 24 horas posterior a la aplicación. Conclusiones: se observó la aparición de sintomatología posterior a la aplicación del esquema de vacunación con BioNTech/Pfizer; sin embargo, se trató de síntomas leves de corta duración.

Vaccination with post-translational modified, homocitrullinated peptides induces CD8 T-cell responses that mediate antitumor immunity.

BACKGROUND: Post-translational modification of proteins has the potential to alter the ability of T cells to recognize major histocompatibility complex (MHC) class -I and class-II restricted antigens, thereby resulting in altered immune responses. One such modification is carbamylation (homocitrullination) that results in the formation of homocitrulline (Hcit) residues in a non-enzymatic reaction of cyanate with the lysine residues in the polypeptide chain. Homocitrullination occurs in the tumor microenvironment and CD4-mediated immune responses to Hcit epitopes can target stressed tumor cells and provide a potent antitumor response in mouse models. METHODS: Homocitrullinated peptides were identified and assessed in vitro for HLA-A2 binding and in vivo in human leukocyte antigen (HLA) transgenic mouse models for immunogenicity. CD8 responses were assessed in vitro for cytotoxicity and in vivo tumor therapy. Human tumor samples were analyzed by targeted mass spectrometry for presence of homocitrullinated peptides. RESULTS: Homocitrullinated peptides from aldolase and cytokeratin were identified, that stimulated CD8-mediated responses in vivo. Modified peptides showed enhanced binding to HLA-A2 compared with the native sequences and immunization of HLA-A2 transgenic mice generated high avidity modification specific CD8 responses that killed peptide expressing target cells. Importantly, in vivo the homocitrullinated aldolase specific response was associated with efficient CD8 dependent antitumor therapy of the aggressive murine B16 tumor model indicating that this epitope is naturally presented in the tumor. In addition, the homocitrullinated aldolase epitope was also detected in human tumor samples. CONCLUSION: This is the first evidence that homocitrullinated peptides can be processed and presented via MHC-I and targeted for tumor therapy. Thus, Hcit-specific CD8 T-cell responses have potential in the development of future anticancer therapy.

Responses of patients with cancer to mRNA vaccines depend on the time interval between vaccination and last treatment.

BACKGROUND: Personalized mRNA vaccines are promising new therapeutic options for patients with cancer. Because mRNA vaccines are not yet approved for first-line therapy, the vaccines are presently applied to individuals that received prior therapies that can have immunocompromising effects. There is a need to address how prior treatments impact mRNA vaccine outcomes. METHOD: Therefore, we analyzed the response to BioNTech/Pfizer's anti-SARS-CoV-2 mRNA vaccine in 237 oncology outpatients, which cover a broad spectrum of hematologic malignancies and solid tumors and a variety of treatments. Patients were stratified by the time interval between the last treatment and first vaccination and by the presence or absence of florid tumors and IgG titers and T cell responses were analyzed 14 days after the second vaccination. RESULTS: Regardless of the last treatment time point, our data indicate that vaccination responses in patients with checkpoint inhibition were comparable to healthy controls. In contrast, patients after chemotherapy or cortisone therapy did not develop an immune response until 6 months after the last systemic therapy and patients after Cht-immune checkpoint inhibitor and tyrosine kinase inhibitor therapy only after 12 months. CONCLUSION: Accordingly, our data support that timing of mRNA-based therapy is critical and we suggest that at least a 6-months or 12-months waiting interval should be observed before mRNA vaccination in systemically treated patients.

Prospective, randomized, double-blind phase 2B trial of the TLPO and TLPLDC vaccines to prevent recurrence of resected stage III/IV melanoma: a prespecified 36-month analysis.

BACKGROUND: The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients. METHODS: Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS). RESULTS: After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002). CONCLUSIONS: The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial. TRIAL REGISTRATION NUMBER: NCT02301611.

Personalized neoantigen viro-immunotherapy platform for triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) corresponds to approximately 20% of all breast tumors, with a high propensity for metastasis and a poor prognosis. Because TNBC displays a high mutational load compared with other breast cancer types, a neoantigen-based immunotherapy strategy could be effective. One major bottleneck in the development of a neoantigen-based vaccine for TNBC is the selection of the best targets, that is, tumor-specific neoantigens which are presented at the surface of tumor cells and capable of eliciting robust immune responses. In this study, we aimed to set up a platform for identification and delivery of immunogenic neoantigens in a vaccine regimen for TNBC using oncolytic vaccinia virus (VV). METHODS: We used bioinformatic tools and cell-based assays to identify immunogenic neoantigens in TNBC patients' samples, human and murine cell lines. Immunogenicity of the neoantigens was tested in vitro (human) and ex vivo (murine) in T-cell assays. To assess the efficacy of our regimen, we used a preclinical model of TNBC where we treated tumor-bearing mice with neoantigens together with oncolytic VV and evaluated the effect on induction of neoantigen-specific CD8+T cells, tumor growth and survival. RESULTS: We successfully identified immunogenic neoantigens and generated neoantigen-specific CD8+T cells capable of recognizing a human TNBC cell line expressing the mutated gene. Using a preclinical model of TNBC, we showed that our tumor-specific oncolytic VV was able to change the tumor microenvironment, attracting and maintaining mature cross-presenting CD8α+dendritic cells and effector T-cells. Moreover, when delivered in a prime/boost regimen together with oncolytic VV, long peptides encompassing neoantigens were able to induce neoantigen-specific CD8+T cells, slow tumor growth and increase survival. CONCLUSIONS: Our study provides a promising approach for the development of neoantigen-based immunotherapies for TNBC. By identifying immunogenic neoantigens and developing a delivery system through tumor-specific oncolytic VV, we have demonstrated that neoantigen-based vaccines could be effective in inducing neoantigen-specific CD8+T cells response with significant impact on tumor growth. Further studies are needed to determine the safety and efficacy of this approach in clinical trials.

A biologic-device combination product delivering tumor-derived antigens elicits immunogenic cell death-associated immune responses against glioblastoma.

BACKGROUND: IGV-001 is a personalized, autologous cancer cell-based immunotherapy conceived to deliver a tumor-derived antigenic payload in the context of immunostimulatory signals to patients with glioblastoma (GBM). IGV-001 consists of patient-derived GBM cells treated with an antisense oligodeoxynucleotide against insulin-like growth factor 1 receptor (IGF1R) and placed in proprietary biodiffusion chambers (BDCs). The BDCs are then exposed to 5-6 Gy radiation and implanted at abdominal sites for ~48 hours. IGV-001 has previously been shown to be generally safe with promising clinical activity in newly diagnosed GBM patients. METHODS: Mouse (m) or human (h) variants of IGV-001 were prepared using GL261 mouse GBM cells or human GBM cells, respectively. BDCs containing vehicle or mIGV-001 were implanted in the flanks of C57BL/6 albino female mice in preventative and therapeutic experiments, optionally in combination with a programmed cell death 1 (PD-1) blocker. Bioactivity of the general approach was also measured against hepatocellular carcinoma Hepa 1-6 cells. Mice were followed for the growth of subsequently implanted or pre-existing tumors and survival. Draining lymph nodes from mice receiving mIGV-001 were immunophenotyped. mIGV-001 and hIGV-001 were analyzed for extracellular ATP and high mobility group box 1 (HMGB1) as indicators of immunogenic cell death (ICD), along with flow cytometric analysis of viability, surface calreticulin, and reactive oxygen species. Stress and cell death-related pathways were analyzed by immunoblotting. RESULTS: IGV-001 causes oxidative and endoplasmic reticulum stress in GL261 cells, resulting in a cytotoxic response that enables the release of antigenic material and immunostimulatory, ICD-associated molecules including ATP and HMGB1 from BDCs. Immunophenotyping confirmed that IGV-001 increases the percentage of dendritic cells, as well as effector, and effector memory T cells in BDC-draining lymph nodes. Consistent with these observations, preventative IGV-001 limited tumor progression and extended overall survival in mice intracranially challenged with GL261 cells, a benefit that was associated with an increase in tumor-specific T cells with effector features. Similar findings were obtained in the Hepa 1-6 model. Moreover, therapeutically administered IGV-001 combined with PD-1 delayed progression in GBM-bearing mice. CONCLUSIONS: These results support treatment with IGV-001 to induce clinically relevant ICD-driven anticancer immune responses in patients with GBM.

Id-neoantigen vaccine induces therapeutic CD8+ T cells against multiple myeloma: H chain-loss escapees cause FLC MM.

BACKGROUND: Multiple myeloma (MM) cancers originate from plasma cells that have passed through the germinal center reaction where somatic hypermutation of Ig V regions takes place. Myeloma protein V regions often express many mutations and are thus a rich source of neoantigens (traditionally called idiotopes (Id)). Therefore, these are highly tumor-specific and excellent targets for immunotherapy. METHODS: We have developed a DNA Id vaccine which as translated protein targets conventional dendritic cells (cDC) for CCL3-mediated delivery of myeloma protein V regions in a single-chain fragment variable (scFv) format. Vaccine efficacy was studied in the mouse MM model, mineral oil-induced plasmacytoma 315.BM. RESULTS: The Id vaccine protected mice against a challenge with MM cells. Moreover, the vaccine had a therapeutic effect. However, in some of the vaccinated mice, MM cells not producing H chains escaped rejection, resulting in free light chain (FLC) MM. Depletion of CD8+ T cells abrogated vaccine efficacy, and protection was observed to be dependent on cDC1s, using Batf3-/- mice. Modifications of scFv in the vaccine demonstrated that CD8+ T cells were specific for two mutated VH sequences. CONCLUSIONS: VH neoantigen-specific CD8+ T cells elicited by CCL3-containing Id vaccines had a therapeutic effect against MM in a mouse model. MM cells could escape rejection by losing expression of the H chain, thus giving rise to FLC MM.

Eficacia y seguridad de vacunas contra SARS-CoV-2 en pacientes con enfermedades reumatológicas autoinmunes / Efficacy and safety of SARS-CoV-2 vaccines in patients with autoimmune rheumatologic diseases / Eficácia e segurança das vacinas SARS-CoV-2 em pacientes com doenças reumatológicas autoimunes

Los pacientes con enfermedades reumatológicas autoinmunes tienen mayor riesgo de infección por SARS-CoV-2 por factores propios de la enfermedad, así como los derivados por el tratamiento, con el desarrollo de vacunas se ha priorizado la inmunización en este grupo de pacientes, no obstante, la eficacia y seguridad de vacunas contra SARS-CoV-2 no se ha estudiado en esta población por su exclusión en los ensayos clínicos de fase II-III. Objetivo. analizar la eficacia y seguridad de vacunas contra SARS-CoV-2 en pacientes con enfermedades reumatológicas autoinmunes. Metodología. Se realizó una revisión sistemática, usando la declaración PRISMA, como criterios de búsqueda fueron considerados publicaciones portugués, inglés y español, relacionada con la eficacia y seguridad de vacunas contra SARS-CoV-2 durante los últimos 6 años. La búsqueda de artículos se desarrolló en las bases de datos como PubMed, Scopus y ScienceDirect publicados en idiomas inglés, portugués y español publicados durante los últimos 6 años hasta la actualidad. Resultados. Se encontraron 79 artículos, 27 en PubMed, en Google Scholar 52; la cantidad se redujo a 60, eliminando 19 por duplicidad, 27 por resumen de artículo, luego de un análisis exhaustivo del contenido de la información para así obtener un total de 8 artículos para el análisis del estudio. Conclusión. La eficacia de vacunas contra SARS-CoV-2 en pacientes con enfermedades reumatológicas se encuentra reducida, atribuida al uso de glucocorticoides y de terapias inmunosupresoras en las que se destaca rituximab, micofenolato de mofetilo y metotrexato, mientras que la seguridad basada en los efectos adversos es similar a los encontrados en la población general.

Patients with autoimmune rheumatologic diseases have a higher risk of infection by SARS-CoV-2 due to factors inherent to the disease, as well as those derived from treatment. With the development of vaccines, immunization has been prioritized in this group of patients; however, the efficacy and safety of vaccines against SARS-CoV-2 has not been studied in this population due to their exclusion in phase II-III clinical trials. Objective. to analyze the efficacy and safety of vaccines against SARS-CoV-2 in patients with autoimmune rheumatologic diseases. Methodology. A systematic review was performed, using the PRISMA statement, as search criteria were considered Portuguese, English and Spanish publications, related to the efficacy and safety of vaccines against SARS-CoV-2 during the last 6 years. The search for articles was developed in databases such as PubMed, Scopus and ScienceDirect published in English, Portuguese and Spanish published during the last 6 years to date. Results. A total of 79 articles were found, 27 in PubMed, 52 in Google Scholar; the number was reduced to 60, eliminating 19 for duplicity, 27 for article ABSTRACT, after an exhaustive analysis of the content of the information to obtain a total of 8 articles for the analysis of the study. Conclusion. The efficacy of vaccines against SARS-CoV-2 in patients with rheumatologic diseases is reduced, attributed to the use of glucocorticoids and immunosuppressive therapies in which rituximab, mycophenolate mofetil and methotrexate stand out, while safety based on adverse effects is similar to those found in the general population.

Pacientes com doenças reumatológicas autoimunes têm maior risco de infecção pelo SARS-CoV-2 devido a fatores inerentes à doença, bem como àqueles derivados do tratamento. Com o desenvolvimento de vacinas, a imunização tem sido priorizada nesse grupo de pacientes; no entanto, a eficácia e a segurança das vacinas contra o SARS-CoV-2 não foram estudadas nessa população devido à sua exclusão dos ensaios clínicos de fase II-III. Objetivo. Analisar a eficácia e a segurança das vacinas contra o SARS-CoV-2 em pacientes com doenças reumatológicas autoimunes. Metodologia. Foi realizada uma revisão sistemática utilizando a declaração PRISMA, tendo como critério de busca publicações em português, inglês e espanhol relacionadas à eficácia e à segurança de vacinas contra o SARS-CoV-2 nos últimos 6 anos. A busca de artigos foi desenvolvida em bancos de dados como PubMed, Scopus e ScienceDirect, publicados em inglês, português e espanhol, publicados nos últimos 6 anos até o presente. Resultados. Foram encontrados 79 artigos, 27 no PubMed, 52 no Google Scholar; o número foi reduzido para 60, eliminando 19 por duplicidade, 27 por resumo do artigo, após uma análise exaustiva do conteúdo das informações para obter um total de 8 artigos para a análise do estudo. Conclusões. A eficácia das vacinas SARS-CoV-2 em pacientes com doenças reumatológicas é reduzida, atribuída ao uso de glicocorticoides e terapias imunossupressoras, incluindo rituximabe, micofenolato mofetil e metotrexato, enquanto a segurança baseada em efeitos adversos é semelhante à encontrada na população em geral.

Immunogenicity, effectiveness and safety of COVID-19 vaccine in older adults living in nursing homes: A real-life study / Inmunogenicidad, efectividad y seguridad de la vacuna COVID-19 en adultos mayores que viven en hogares geriátricos: un estudio de la vida real

Introduction: BNT162b2 (BioNTech and Pfizer) is a nucleoside-modified mRNA vaccine that provides protection against SARS-CoV-2 infection and is generally well tolerated. However, data about its efficacy, immunogenicity and safety in people of old age or with underlying chronic conditions are scarce. Purpose: To describe BNT162b2 (BioNTech and Pfizer) COVID-19 vaccine immunogenicity, effectiveness and reactogenicity after complete vaccination (two doses), and immunogenicity and reactogenicity after one booster, in elders residing in nursing homes (NH) and healthy NH workers in real-life conditions. Methods: Observational, ambispective, multicenter study. Older adults and health workers were recruited from three nursing homes of a private hospital corporation located in three Spanish cities. The primary vaccination was carried out between January and March 2021. The follow-up was 13 months. Humoral immunity, adverse events, SARS-CoV-2 infections, hospitalizations and deaths were evaluated. Cellular immunity was assessed in a participant subset. Results: A total of 181 residents (mean age 84.1 years; 89.9% females, Charlson index ≥2: 45%) and 148 members of staff (mean age 45.2 years; 70.2% females) were surveyed (n:329). After primary vaccination of 327 participants, vaccine response in both groups was similar; ≈70% of participants, regardless of the group, had an antibody titer above the cut-off considered currently protective (260BAU/ml). This proportion increased significantly to ≈ 98% after the booster (p<0.0001 in both groups). Immunogenicity was largely determined by a prior history of COVID-19 infection. Twenty residents and 3 workers were tested for cellular immunity. There was evidence of cellular immunity after primary vaccination and after booster. (AU)

Introducción: La vacuna BNT162b2 (BioNTech y Pfizer) es una vacuna de ARNm modificado con nucleósidos que proporcionó protección contra la infección por el SARS-CoV-2 y generalmente fue bien tolerada. Sin embargo, los datos sobre su efectividad y seguridad en personas de edad avanzada o con enfermedades crónicas subyacentes son escasos. Objetivo: Describir la inmunogenicidad, efectividad y seguridad de esta vacuna tras la vacunación completa (dos dosis), y la inmunogenicidad y reactogenicidad tras un refuerzo, en ancianos residentes en hogares geriátricos y trabajadores sanos de estos lugares en condiciones reales. Métodos: Estudio observacional, ambispectivo y multicéntrico. Se reclutaron ancianos y trabajadores sanitarios de tres hogares geriátricos de ancianos de un grupo hospitalario de entidad privada situados en tres ciudades españolas. La vacunación primaria se realizó entre enero y marzo de 2021. El seguimiento fue de 13 meses. Se evaluó la inmunidad humoral, los eventos adversos, las infecciones por SARS-CoV-2, las hospitalizaciones y las muertes. Se evaluó la inmunidad celular en un subconjunto de participantes. Resultados: Se registraron datos de 181 residentes (edad promedio 84,1 años; 89,9% mujeres, índice de Charlson ≥2: 45%) y 148 trabajadores (edad promedio 45,2 años; 70,2% mujeres) (n:329). Tras la primera dosis a 327 de los participantes, la respuesta a la vacuna en ambos grupos fue similar; ≈70% de los participantes, independientemente del grupo, tuvieron un título de anticuerpos por encima del corte considerado actualmente como protector (260 BAU/ml). Esta proporción aumentó significativamente a ≈ 98% después del refuerzo (p<0,0001 en ambos grupos). La inmunogenicidad se determinó en gran medida por los antecedentes de infección por COVID-19. Se analizó la inmunidad celular de 20 residentes y 3 trabajadores. Hubo evidencia de inmunidad celular después de la vacunación primaria y después del refuerzo. (AU)

Immunogenicity, effectiveness and safety of COVID-19 vaccine in older adults living in nursing homes: A real-life study.

INTRODUCTION: BNT162b2 (BioNTech and Pfizer) is a nucleoside-modified mRNA vaccine that provides protection against SARS-CoV-2 infection and is generally well tolerated. However, data about its efficacy, immunogenicity and safety in people of old age or with underlying chronic conditions are scarce. PURPOSE: To describe BNT162b2 (BioNTech and Pfizer) COVID-19 vaccine immunogenicity, effectiveness and reactogenicity after complete vaccination (two doses), and immunogenicity and reactogenicity after one booster, in elders residing in nursing homes (NH) and healthy NH workers in real-life conditions. METHODS: Observational, ambispective, multicenter study. Older adults and health workers were recruited from three nursing homes of a private hospital corporation located in three Spanish cities. The primary vaccination was carried out between January and March 2021. The follow-up was 13 months. Humoral immunity, adverse events, SARS-CoV-2 infections, hospitalizations and deaths were evaluated. Cellular immunity was assessed in a participant subset. RESULTS: A total of 181 residents (mean age 84.1 years; 89.9% females, Charlson index ≥2: 45%) and 148 members of staff (mean age 45.2 years; 70.2% females) were surveyed (n:329). After primary vaccination of 327 participants, vaccine response in both groups was similar; ≈70% of participants, regardless of the group, had an antibody titer above the cut-off considered currently protective (260BAU/ml). This proportion increased significantly to ≈ 98% after the booster (p<0.0001 in both groups). Immunogenicity was largely determined by a prior history of COVID-19 infection. Twenty residents and 3 workers were tested for cellular immunity. There was evidence of cellular immunity after primary vaccination and after booster. During the study, one resident was hospitalized for SARS-CoV-2. No SARS-CoV-2-related deaths were reported and most adverse events were mild. CONCLUSIONS: Our results suggest that the BNT162b2 mRNA COVID-19 vaccine is immunogenic, effective and safe in elderly NH residents with underlying chronic conditions.

Dominant neoantigen verification in hepatocellular carcinoma by a single-plasmid system coexpressing patient HLA and antigen.

BACKGROUND: Previous studies confirmed that most neoantigens predicted by algorithms do not work in clinical practice, and experimental validations remain indispensable for confirming immunogenic neoantigens. In this study, we identified the potential neoantigens with tetramer staining, and established the Co-HA system, a single-plasmid system coexpressing patient human leukocyte antigen (HLA) and antigen, to detect the immunogenicity of neoantigens and verify new dominant hepatocellular carcinoma (HCC) neoantigens. METHODS: First, we enrolled 14 patients with HCC for next-generation sequencing for variation calling and predicting potential neoantigens. Then, the Co-HA system was established. To test the feasibility of the system, we constructed target cells coexpressing HLA-A*11:01 and the reported KRAS G12D neoantigen as well as specific T-cell receptor (TCR)-T cells. The specific cytotoxicity generated by this neoantigen was shown using the Co-HA system. Moreover, potential HCC-dominant neoantigens were screened out by tetramer staining and validated by the Co-HA system using methods including flow cytometry, enzyme-linked immunospot assay and ELISA. Finally, antitumor test in mouse mode and TCR sequencing were performed to further evaluate the dominant neoantigen. RESULTS: First, 2875 somatic mutations in 14 patients with HCC were identified. The main base substitutions were C>T/G>A transitions, and the main mutational signatures were 4, 1 and 16. The high-frequency mutated genes included HMCN1, TTN and TP53. Then, 541 potential neoantigens were predicted. Importantly, 19 of the 23 potential neoantigens in tumor tissues also existed in portal vein tumor thrombi. Moreover, 37 predicted neoantigens restricted by HLA-A*11:01, HLA-A*24:02 or HLA-A*02:01 were performed by tetramer staining to screen out potential HCC-dominant neoantigens. HLA-A*24:02-restricted epitope 5'-FYAFSCYYDL-3' and HLA-A*02:01-restricted epitope 5'-WVWCMSPTI-3' demonstrated strong immunogenicity in HCC, as verified by the Co-HA system. Finally, the antitumor efficacy of 5'-FYAFSCYYDL-3'-specific T cells was verified in the B-NDG-B2mtm1Fcrntm1(mB2m) mouse and their specific TCRs were successfully identified. CONCLUSION: We found the dominant neoantigens with high immunogenicity in HCC, which were verified with the Co-HA system.

Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils.

BACKGROUND: Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy. METHODS: The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans. RESULTS: Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy. CONCLUSION: Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

First-in-human, phase 1 study of PF-06753512, a vaccine-based immunotherapy regimen (VBIR), in non-metastatic hormone-sensitive biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR). METHODS: For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety. RESULTS: Ninety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2-45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9-4.2) and 10.1 (6.9-28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA. CONCLUSIONS: PrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT. TRIAL REGISTRATION NUMBER: NCT02616185.

Prevalence, Risk Factors and Vaccine Response against Hepatitis B in People Aged 50 Years or Older.

Universal immunization against hepatitis B has contributed to reducing incidence of the disease, but older individuals remain susceptible to acquiring the hepatitis B virus worldwide. Thus, this study aimed to investigate the epidemiology of HBV infection in individuals aged 50 years and over in central Brazil and to evaluate the immunogenicity of the monovalent vaccine against hepatitis B in this age group using two vaccine regimens. METHOD: Initially, a cross-sectional and analytical study was carried out to investigate the epidemiology of hepatitis B. Then, individuals without proof of vaccination for hepatitis B were recruited for a phase IV randomized and controlled clinical trial using two vaccine regimens: Intervention Regimen (IR) (three doses of 40 µg at months 0, 1 and 6) vs. Comparison Regimen (CR) (three doses of 20 µg at months 0, 1 and 6). RESULTS: The overall prevalence of exposure to HBV was 16.6% (95% CI: 14.0%-9.5%). In the clinical trial, statistical differences in protective titers were observed (p = 0.007; IR 96% vs. CR 86%) and the geometric mean of anti-HBs titers was higher in individuals who received the IR (518.2 mIU/mL vs. 260.2 mIU/mL). In addition, the proportion of high responders was higher among those who received the IR (65.3%). CONCLUSION: reinforced doses should be used in individuals aged 50 years or older to overcome the lower efficacy of the vaccine against hepatitis B.

COVID-19 vaccination in patients with cancer receiving immune checkpoint inhibitors: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICI) can cause off-target inflammatory and immune-related adverse events (irAE). Conceivably, COVID-19 vaccination could trigger an inflammatory and immune response that could induce or aggravate irAE. METHODS: The objective of this systematic review is to appraise the efficacy and safety of COVID-19 vaccination in patients with cancer treated with ICI. The literature search was performed in PubMed and Embase in English from December 2019 to February 2022. The review included clinical trials, observational cohort studies, case series, and case reports reporting on the clinical efficacy and safety of COVID-19 vaccines on patients with cancer treated with ICI. Outcomes of interest included seroconversion, SARS-CoV-2 infection rate, severe COVID-19, COVID-19 mortality rate. Incidence of ICI irAEs was also ascertained as well as vaccine adverse events. A meta-analysis was conducted to estimate the pooled effect sizes of the outcomes when possible, using random effects models. RESULTS: Overall, 19 studies were included for the analysis (n=10 865 with 2477 receiving ICI). We analyzed 15 cohort studies, 1 cross-sectional study, and 3 case reports. There were no statistically significant differences in seroconversion rates after the second dose of the vaccine when comparing patients with cancer receiving ICI with patients without cancer (risk ratio, RR 0.97, 95% CI 0.92 to 1.03) or with patients with cancer without active treatment (RR 1.00, 95% CI 0.96 to 1.04). There was a higher probability of seroconversion in patients with cancer treated with ICI compared with patients with cancer treated with chemotherapy (RR 1.09, 95% CI 1.00 to 1.18). In a single study in patients receiving ICI, no differences were observed in risk of irAE between those receiving inactivated vaccine and those unvaccinated (pneumonitis RR 0.88, 95% CI 0.33 to 2.3; rash RR 1.03, 95% CI 0.66 to 1.62; arthralgia RR 0.94, 95% CI 0.51 to 1.75). There were no studies for other types of vaccines comparing vaccinated vs not vaccinated in patients treated with ICI. The most common vaccine-related adverse events were local pain or fatigue. Overall, the quality of evidence was rated as very low. CONCLUSION: COVID-19 vaccination appears to be effective and safe in patients with cancer receiving ICI.