Omicron is the evolutionarily most distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in ...BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 VOCs but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding memory B (B
) cells against epitopes shared broadly among variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted B
cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. Whereas selective amplification of B
cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.
Evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has led to the emergence of sublineages with different patterns of neutralizing antibody evasion. We ...report that Omicron BA.4/BA.5 breakthrough infection of individuals immunized with SARS-CoV-2 wild-type-strain-based mRNA vaccines results in a boost of Omicron BA.4.6, BF.7, BQ.1.1, and BA.2.75 neutralization but does not efficiently boost BA.2.75.2, XBB, or XBB.1.5 neutralization. In silico analyses showed that the Omicron spike glycoprotein lost most neutralizing B cell epitopes, especially in sublineages BA.2.75.2, XBB, and XBB.1.5. In contrast, T cell epitopes are conserved across variants including XBB.1.5. T cell responses of mRNA-vaccinated, SARS-CoV-2-naive individuals against the wild-type strain, Omicron BA.1, and BA.4/BA.5 were comparable, suggesting that T cell immunity against recent sublineages including XBB.1.5 may remain largely unaffected. While some Omicron sublineages effectively evade B cell immunity, spike-protein-specific T cell immunity, due to the nature of polymorphic cell-mediated immune responses, may continue to contribute to prevention/limitation of severe COVID-19 manifestation.
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•Omicron evades vaccine-elicited immunity by altering neutralizing B cell epitopes•XBB.1.5 even escapes neutralization by Omicron-convalescent vaccinee sera•Most T cell spike epitopes are conserved across the Omicron lineage, including XBB.1.5•T cell immunity of vaccinated individuals against Omicron remains largely intact
Muik et al. show that although recent SARS-CoV-2 Omicron sublineages exhibit an increasingly effective evasion of neutralizing B cell immunity, spike-protein-specific T cell responses remain largely unaffected. Their observations indicate that preserved T cell immunity may mitigate diminished neutralizing antibody activity in preventing or limiting severe COVID-19.
The natural killer gene complex (NKC) encodes several dozens of C-type lectin-like receptors that, in various ways, tune the reactivity of NK cells and other cytotoxic lymphocytes depending on the ...cellular environment. Among these are C-type lectin-like receptors such as NKG2D, CD94/NKG2A and the murine Ly49 receptors that bind to cell surface glycoproteins of the major histocompatibility complex (MHC) class I family and thereby facilitate detection of stressed cells or cells exhibiting aberrant MHC class I expression. In contrast, NKRP1 receptors including the prototypic NK1.1 do not engage ligands with an MHC class-I-like fold, but rather interact with the likewise C-type lectin-like CLEC2 glycoproteins. Notably, CLEC2 and NKRP1 molecules not only share the same fold, but are also genetically linked in the NKC. Recent research efforts began to systematically elucidate the expression and function of the numerous NKRP1 and CLEC2 family members in rodents and revealed previously unnoticed corresponding receptor/ligand pairs in humans. Here, we provide a snapshot of the current knowledge on receptors of the NKRP1 family and their genetically linked CLEC2 ligands in mouse and man.
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide due to high recurrence rates after curative treatment and being frequently diagnosed at an advanced ...stage. Immune-checkpoint inhibition (ICPI) has yielded impressive clinical successes in a variety of solid cancers, however results in treatment of HCC have been modest. Vaccination could be a promising treatment to synergize with ICPI and enhance response rates. Cancer testis antigens (CTAs) were recently discovered to be widely expressed in HCC and expression in macroscopically tumor-free tissues correlated with recurrence, implying the presence of micro-satellites. To determine whether CTAs are immunogenic in HCC patients, we analyzed systemic T-cell and humoral responses against seven CTAs in 38 HCC patients using a multitude of techniques; flowcytometry, ELISA and whole antigen and peptide stimulation assays. CTA-specific T-cells were detected in all (25/25) analyzed patients, of which most had a memory phenotype but did not exhibit unequivocal signs of chronic stimulation or recent antigen encounter. Proliferative CD4
+
and CD8
+
T-cell responses against these CTAs were found in 14/16 analyzed HCC patients. CTA-peptide stimulation-induced granzyme B, IL2, and TNFa in 8/8 analyzed patients, including two MAGEA1 peptides included based on in silico prediction. Finally, IgG responses were observed in 13/32 patients, albeit with low titers. The presence of CD4
+
and CD8
+
T-cells and IgG responses shows the immunogenicity of these CTAs in HCC-patients. We hypothesize that vaccines based on these tumor-specific antigens may boost preexisting CTA-specific immunity and could enhance therapeutic efficacy of ICPI in advanced HCC.
Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with ...treatment-refractory tumours
. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4
and CD8
T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.
Innate lymphocytes comprise cytotoxic natural killer (NK) cells and tissue‐resident innate lymphoid cells (ILC) that are subgrouped according to their cytokine profiles into group 1 ILC (ILC1), ILC2, ...and ILC3. However, cell surface receptors unambiguously defining or specifically activating such ILC subsets are scarcely known. Here, we report on the physiologic expression of the human activating C‐type lectin‐like receptor (CTLR) NKp65, a high‐affinity receptor for the CTLR keratinocyte‐associated C‐type lectin (KACL). Tracking rare NKp65 transcripts in human blood, we identify ILC3 to selectively express NKp65. NKp65 expression not only demarcates “bona fide” ILC3 from likewise RORγt‐expressing ILC precursors and lymphoid tissue inducer cells but also from mature NK cells which acquire the NKp65‐relative NKp80 during a Notch‐dependent differentiation from NKp65+ precursor cells. Hence, ILC3 and NK cells mutually exclusively and interdependently express the genetically coupled sibling receptors NKp65 and NKp80. Much alike NKp80, NKp65 promotes cytotoxicity by innate lymphocytes which may become relevant during pathophysiological reprogramming of ILC3. Altogether, we report the selective expression of the activating immunoreceptor NKp65 by ILC3 demarcating ILC3 from mature NK cells and endowing ILC3 with a dedicated immunosensor for the epidermal immune barrier.
T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome ...vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.
Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly ...occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.
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