The highly mutated SARS-CoV-2 Omicron (B.1.1.529) variant has been shown to evade a substantial fraction of neutralizing antibody responses elicited by current vaccines that encode the WA1/2020 spike ...protein
. Cellular immune responses, particularly CD8
T cell responses, probably contribute to protection against severe SARS-CoV-2 infection
. Here we show that cellular immunity induced by current vaccines against SARS-CoV-2 is highly conserved to the SARS-CoV-2 Omicron spike protein. Individuals who received the Ad26.COV2.S or BNT162b2 vaccines demonstrated durable spike-specific CD8
and CD4
T cell responses, which showed extensive cross-reactivity against both the Delta and the Omicron variants, including in central and effector memory cellular subpopulations. Median Omicron spike-specific CD8
T cell responses were 82-84% of the WA1/2020 spike-specific CD8
T cell responses. These data provide immunological context for the observation that current vaccines still show robust protection against severe disease with the SARS-CoV-2 Omicron variant despite the substantially reduced neutralizing antibody responses
.
B-cell and T-cell responses were measured to assess the stability and duration of vaccine-induced immunity. Responses to BNT162b2 and mRNA-1273 peaked early and declined over 6 to 8 months. The ...response to Ad26.CoV2.S reached a lower peak but continued without evidence of notable decline for 8 months. Response levels correlating with protection have not yet been defined.
BackgroundSuccessful advancement of vaccine strategies for the treatment of solid tumors has been limited due to the limitations of vaccine delivery platforms and inadequate immune responses. ELI-002 ...immunotherapy uses Amphiphile (Amph) lymph node targeting to improve the potency of vaccination. Amph-modification promotes lipid-mediated binding to albumin resulting in delivery of antigen/adjuvant to lymph nodes where uptake by antigen-presenting cells leads to effective T cell activation. Kirsten rat sarcoma (KRAS) is mutated in one-quarter of human solid tumors, including approximately 90% of pancreatic ductal adenocarcinoma (PDAC) and 50% of colorectal cancer (CRC), making it an attractive target for lymph node-targeted immunotherapy using the Amph platform. ELI-002 2P was well tolerated, and 77% of patients exhibited biomarker response including 32% who exhibited circulating tumor DNA (ctDNA) clearance.MethodsELI-002–001 is a first-in-human Phase 1 trial of ELI-002 2P immunotherapy as adjuvant treatment for subjects with high relapse-risk mutant KRAS (mKRAS) PDAC and CRC. ELI-002 2P consists of 2 Amph-modified mKRAS peptide antigens, Amph-G12D and Amph-G12R (Amph-Peptides 2P), and a Amph-modified immune-stimulatory oligonucleotide adjuvant (Amph-CpG-7909). 25 subjects were randomized to receive ELI-002 2P at 1.4 mg of Amph-Peptides 2P and Amph-CpG-7909 at 5 dose levels; 0.1, 0.5, 2.5, 5, and 10 mg. Peripheral blood was collected longitudinally to assess specificity, polyfunctionality, and phenotype of mKRAS-specific T cells.Results87% of evaluable subjects (20/23) induced mKRAS-specific T-cells post-vaccination as assessed by direct ex vivo Fluorospot and/or ICS assays with an average 56-fold increase from baseline. Further, a balanced CD4+ and CD8+ T cell response was observed in 50% of subjects and a majority were central and effector memory T cells. Evaluation of the breadth of responses to 7 different KRAS mutations revealed broad cross-reactivity to KRAS mutants including non-immunizing epitopes and low responses to WT. A high frequency of polyfunctional cells secreting IFNγ, TNFα, IL-2, and/or Granzyme B was observed. Additional phenotypic and functional analysis of mKRAS-specific T cells is ongoing.ConclusionsELI-002 induces robust and broadly reactive mKRAS-specific T cell responses in most subjects (87%) at high risk for relapse. This off-the-shelf lymph node-targeted vaccine has many advantages including high immunogenicity yielding balanced CD4+ and CD8+ T cell responses targeting vaccine antigens that are critical for tumor survival. A Phase 1/2 clinical trial investigating a new 7 peptide formulation, ELI-002 7P (G12D, R, V, A, C, S, G13D; NCT NCT05726864), is currently in progress.Trial RegistrationNCT04853017Ethics ApprovalThe study was approved by the local institutional review board at each study site and the US FDA. All patients provided written and informed consent.
Immunogenicity of BA.5 Bivalent mRNA Vaccine Boosters Collier, Ai-ris Y.; Miller, Jessica; Hachmann, Nicole P. ...
New England journal of medicine/The New England journal of medicine,
02/2023, Volume:
388, Issue:
6
Journal Article
Peer reviewed
Open access
In a small study, neutralizing antibody titers against the ancestral strain of SARS-CoV-2 were higher than titers against omicron BA.5 after both monovalent and bivalent boosting.
The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we ...show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers and undetectable Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Moreover, virologic control correlated with both antibody and T cell responses. These data suggest that both humoral and cellular immune responses contribute to vaccine protection against a highly mutated SARS-CoV-2 variant.
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•Ad26.COV2.S and BNT162b2 led to rapid virologic control following Omicron challenge•Both Omicron-specific antibodies and T cells contributed to protection•Virologic failure correlated with moderate antibodies and negligible CD8+ T cells
Heterologous as well as homologous prime-boosting with the mRNA vaccine BNT162b2 and adenovirus-vector-based Ad26.COV2.S vaccine provides robust protection against SARS-CoV-2 Omicron in cynomolgus macaques, with both humoral and cellular immune responses being critical for overall protection.
2636 Background: Diverse KRAS mutations occur in 25% of solid tumors with G12D, V and R most frequent. ELI-002 7P is an expanded spectrum vaccine comprised of lymph-node targeted Amphiphile ...(Amph)-modified G12D, V, R, C, S, A, and G13D mutant KRAS peptides with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Earlier ELI-002 2P showed high rates of T cell and tumor biomarker response (both 21/25, 84%), with median relapse-free survival not reached versus 4.01 months (HR 0.14; p=0.0167) comparing patients (pts) above versus below T cell median (12.75X). Methods: This multicenter phase IA trial assessed safety, immunogenicity and preliminary antitumor activity of ELI-002 7P in pancreatic (PDAC) and colorectal pts with minimal residual disease (MRD) following standard locoregional treatment. Pts with elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker (CA19-9/CEA), and KRAS mutation were enrolled and treated with subcutaneous fixed dose Amph-CpG-7909 and 1.4 mg or 4.9 mg of Amph-Peptides 7P (Table). Safety, T cell change, and preliminary antitumor activity including biomarker reduction/clearance are reported. Results: No dose-limiting toxicities, no treatment related SAEs or cytokine release syndrome were observed, no maximum tolerated dose was identified, and the recommended phase 2 dose (RP2D) was 10.0 mg Amph-CpG-7909 with 4.9 mg Amph-Peptides 7P. Safety: all grade 1, fatigue (29%), malaise (21%), and injection site reaction (7.1%). At data cutoff Dec 18, 2023, polyfunctional mKRAS-specific T cells were observed in 100% (n=11/11). Both CD8+ and CD4+ responses were induced in 63.6% of pts (7/11), with higher median fold-change from baseline at RP2D and durable responses post-booster immunization in 100% of pts (7/7). Biomarker reductions were observed in 2/5 (40%) at the 1.4 mg Amph-Peptides 7P dose level and in 5/7 (71%) at the RP2D 4.9 mg dose level in pts with all the common G12X (D, V, R) and G13 (D) KRAS mutations; MRD clearance was observed in 1 G12V PDAC pt at 4.9mg. Conclusions: ELI-002 7P was safe with median RP2D T cell responses exceeding the prior formulation (7P median 109.2; 2P 12.75), and early indications of antitumor activity. The randomized phase II is now open in patients with pancreas cancer. Clinical trial information: NCT05726864 . Table: see text
Pancreatic and colorectal cancers are often KRAS mutated and are incurable when tumor DNA or protein persists or recurs after curative intent therapy. Cancer vaccine ELI-002 2P enhances lymph node ...delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909). We treated 25 patients (20 pancreatic and five colorectal) who were positive for minimal residual mKRAS disease (ctDNA and/or serum tumor antigen) after locoregional treatment in a phase 1 study of fixed-dose Amph-Peptides-2P and ascending-dose Amph-CpG-7909; study enrollment is complete with patient follow-up ongoing. Primary endpoints included safety and recommended phase 2 dose (RP2D). The secondary endpoint was tumor biomarker response (longitudinal ctDNA or tumor antigen), with exploratory endpoints including immunogenicity and relapse-free survival (RFS). No dose-limiting toxicities were observed, and the RP2D was 10.0 mg of Amph-CpG-7909. Direct ex vivo mKRAS-specific T cell responses were observed in 21 of 25 patients (84%; 59% both CD4
and CD8
); tumor biomarker responses were observed in 21 of 25 patients (84%); biomarker clearance was observed in six of 25 patients (24%; three pancreatic and three colorectal); and the median RFS was 16.33 months. Efficacy correlated with T cell responses above or below the median fold increase over baseline (12.75-fold): median tumor biomarker reduction was -76.0% versus -10.2% (P < 0.0014), and the median RFS was not reached versus 4.01 months (hazard ratio = 0.14; P = 0.0167). ELI-002 2P was safe and induced considerable T cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors. ClinicalTrials.gov identifier: NCT04853017 .
Abstract Background: Colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) are the second and third leading causes of cancer death in the United States. Kirsten rat sarcoma driver ...mutations (mKRAS) are prevalent in CRC (52%) and PDAC (93%), making them attractive targets for immunotherapy where therapeutic options are otherwise limited. ELI-002 2P immunotherapy enhances lymph node delivery and immune responses using Amphiphile (Amph) modification of vaccine components. 84% of patients (21/25) induced mKRAS-specific T-cells post-vaccination as assessed by direct ex vivo Fluorospot and/or ICS assays with an average 58-fold increase from baseline. A balanced CD4+ and CD8+ T cell response was observed in 59% of patients. Reductions in ctDNA or serum tumor biomarker antigen from baseline were observed in 84% of patients (21/25) and 24% (6/25) had complete biomarker clearance. The induction of strong mKRAS T cell responses correlated with reductions in tumor biomarker response/clearance and relapse-free survival (RFS) in patients. Methods: ELI-002-001 is a first-in-human Phase 1 trial (NCT04853017) of ELI-002 2P cancer vaccine as adjuvant treatment for patients with high relapse-risk mKRAS+ PDAC and CRC. ELI-002 2P consists of 2 Amph-modified mKRAS peptide antigens, Amph-G12D and Amph-G12R (Amph-Peptides 2P), and an Amph-modified immune-stimulatory oligonucleotide adjuvant (Amph-CpG-7909). 25 patients received ELI-002 2P at 1.4 mg of Amph-Peptides 2P and Amph-CpG-7909 at 5 dose levels; 0.1, 0.5, 2.5, 5, and 10 mg. Peripheral blood and circulating tumor DNA (ctDNA) or serum tumor antigen were collected longitudinally to assess T cell immunogenicity and reductions in clinical biomarkers. Results: A majority of patients who received the booster immunizations maintained or increased mKRAS-specific T cell responses relative to baseline. A high frequency of polyfunctional cells secreting IFNγ, TNFα, IL-2, and/or Granzyme B was observed. CD4+ T regulatory cells were not induced after ELI-002 2P immunization. Assessment of the breadth of responses to 7 different KRAS mutations revealed broad cross-reactivity to KRAS mutants, including non-immunizing epitopes, and no responses to WT. Additional phenotypic and functional qualities were assessed. Conclusions: ELI-002 is an off-the-shelf vaccine targeting common KRAS tumor mutations demonstrating several key advantages: lymph node-targeted vaccine design, high immunogenicity, with balanced CD4+ and CD8+ T cell responses, HLA-agnostic activity, and targeting of vaccine antigens critical for tumor survival. A randomized Phase 2 clinical trial (NCT05726864) investigating a 7-peptide formulation (G12D, R, V, A, C, S, G13D) is underway. Citation Format: James R. Perry, Haley VanWyk, Amy M. Tavares, Thian Kheoh, Esther Welkowsky, Christopher M. Haqq, Peter C. DeMuth, Lisa K. McNeil. Durable immunogenicity of ELI-002 2P in AMPLIFY-201: Lymph node targeted mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT107.
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