Background: Persistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, conceived in 2020, that evoke protective spike antibody responses are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy. Methods: Using a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 × 10⁸ TCID₅₀ units of SARS-CoV-2, followed by assessment of clinical symptoms and viral load, chest radiographs, and sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream analysis. Results: Vaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature associated with enhanced development of adaptive immune responses relative to control macaques. Conclusions: We demonstrate that a room temperature stable peptide vaccine based on known immunogenic HLA class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in nonhuman primates.

A triple negative breast cancer model using the murine 4T1 tumor cell line was used to explore the efficacy of an adjuvanted survivin peptide microparticle vaccine using tumor growth as the outcome metric. We first performed tumor cell dose titration studies to determine a tumor cell dose that resulted in sufficient tumor takes but allowed multiple serial measurements of tumor volumes, yet with minimal morbidity/mortality within the study period. Later, in a second cohort of mice, the survivin peptide microparticle vaccine was administered via intraperitoneal injection at the study start with a second dose given 14 days later. An orthotopic injection of 4T1 cells into the mammary tissue was performed on the same day as the administration of the second vaccine dose. The mice were followed for up to 41 days with subcutaneous measurements of tumor volume made every 3–4 days. Vaccination with survivin peptides was associated with a peptide antigen-specific gamma interferon enzyme-linked immunosorbent spot response in the murine splenocyte population but was absent from the control microparticle group. At the end of the study, we found that vaccination with adjuvanted survivin peptide microparticles resulted in statistically significant slower primary tumor growth rates in BALB/c mice challenged with 4T1 cells relative to the control peptideless vaccination group. These studies suggest that T cell immunotherapy specifically targeting survivin might be an applicable neoadjuvant immunotherapy therapy for triple negative breast cancer. More preclinical studies and clinical trials are needed to explore this concept further.

A mutation analysis of SARS-CoV-2 genomes collected around the world sorted by sequence, date, geographic location, and species has revealed a large number of variants from the initial reference sequence in Wuhan. This analysis also reveals that humans infected with SARS-CoV-2 have infected mink populations in the Netherlands, Denmark, United States, and Canada. In these animals, a small set of mutations in the spike protein receptor binding domain (RBD), often occurring in specific combinations, has transferred back into humans. The viral genomic mutations in minks observed in the Netherlands and Denmark show the potential for new mutations on the SARS-CoV-2 spike protein RBD to be introduced into humans by zoonotic transfer. Our data suggests that close attention to viral transfer from humans to farm animals and pets will be required to prevent build-up of a viral reservoir for potential future zoonotic transfer.

Survivin (BIRC5) is a tumor-associated antigen (TAA) overexpressed in various tumors but present at low to undetectable levels in normal tissue. Survivin is known to have a high expression in breast cancer (e.g., Ductal Carcinoma in situ (DCIS) and triple negative breast cancer). Previous studies have not compared survivin expression levels in DCIS tumor samples to levels in adjacent, normal breast tissue from the same patient. To ensure the effective use of survivin as a target for T cell immunotherapy of breast cancer, it is essential to ascertain the varying levels of survivin expression between DCIS tumor tissue samples and the adjacent normal breast tissue taken from the same patient simultaneously. Next-generation sequencing of RNA (RNA-seq) in normal breast tissue and tumor breast tissue from five women presenting with DCIS for lumpectomy was used to identify sequence variation and expression levels of survivin. The identity of both tumor and adjacent normal tissue samples were corroborated by histopathology. Survivin was overexpressed in human breast tissue tumor samples relative to the corresponding adjacent human normal breast tissue. Wild-type survivin transcripts were the predominant species identified in all tumor tissue sequenced. This study demonstrates upregulated expression of wild type survivin in DCIS tumor tissue versus normal breast tissue taken from the same patient at the same time, and provides evidence that developing selective cytotoxic T lymphocyte (CTL) immunotherapy for DCIS targeting survivin warrants further study.

Background Triple negative breast cancer (TNBC) cells are, by definition, estrogen and progesterone receptor negative and do not produce high levels of the HER2 protein. Checkpoint inhibitor immunotherapy has been approved for patients with TNBC, but the prognosis for these patients is poor compared with patients presenting with other common forms of breast cancer. Survivin (BIRC5) is a tumor-associated antigen (TAA) previously described to be overexpressed in triple negative breast cancer, but not expressed, or expressed at very low levels, in normal tissue, representing targets for cytotoxic T lymphocyte (CTL) immunotherapy. Study Design A BALB/c TNBC mouse model using the 4T1 cell line was used to explore the effect of an adjuvanted microsphere synthetic vaccine containing survivin peptides on tumor growth rate. The vaccine was administered via intraperitoneal injection at study start with a second dose given 14 days later. An orthotopic injection of 4T1 cells into mammary tissue was performed on the same day as the administration of the second vaccine dose. The mice were followed for up to 41 days with subcutaneous measurements of tumor volume made every three days (Figure 1). Results Vaccination with survivin peptide antigens resulted in a statistically significant diminution of tumor-takes and a deceleration of primary tumor growth volume in BALB/c mice challenged with 4T1 cells versus control. This effect was seen in both the 250 4T1 cell and the 500 4T1 cell challenge groups. The mice produced an ELISpot immune response to one of the survivin peptide antigens used in the vaccine and this response was only seen after the adjuvanted microsphere vaccine was administered. Conclusion The synthetic, adjuvanted microsphere peptide vaccine given 14 days before challenge, and on the day of challenge, was able to diminish tumor-takes and decelerate tumor growth in BALB/c mice challenged with 250 or 500 4T1 cells injected into mammary tissue. This model suggests that T-cell immunotherapy specifically targeting survivin might be an applicable neoadjuvant immunotherapy therapy for triple negative breast cancer. More pre-clinical studies and clinical trials will be needed to explore this concept further.

Purpose of the review: The objective of this review is to provide an analysis of early-phase clinical trials investigating vaccine therapies for triple-negative breast cancer (TNBC). Specifically, the focus is on ongoing trials that are actively recruiting or in progress, while excluding vaccines that target neoantigens or those that have already completed trials. Recent findings: Over the past decade, notable transformations have occurred in the strategy of breast cancer vaccine design. Traditional approaches to identifying tumor antigens, such as SEREX, have been replaced with modern techniques, such as RNA sequencing, HLA typing, and immunoinformatics. These new methods enable the identification and characterization of tumor antigens. Notably, current clinical investigations into tumor targets extend beyond mutated self-proteins or proteins that are overexpressed following neoplastic transformation. Clinical researchers are currently examining protein targets associated with cancer stem cells or non-malignant immune regulatory cell types within the tumor microenvironment. However, the application of up-to-date antigen delivery methods for certain types of breast cancer vaccine therapies still lags behind. Another significant transformation in comparison to previous breast cancer vaccine therapies is the emphasis on stimulating robust T-cell responses against breast cancer cells, independent of any B-cell response directed at the tumor. Summary: In conclusion, we critically assessed the tumor antigens targeted by vaccine immunotherapies in these new clinical trials, the delivery methods used for these antigens, and conclude by discussing potential future directions for the development of new TNBC vaccine therapies.