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The emergence of vaccinomics and system vaccinology represents a transformative shift in immunization strategies, advocating for personalized vaccines tailored to individual genetic and immunological profiles. Integrating insights from genomics, transcriptomics, proteomics, and immunology, personalized vaccines offer the promise of enhanced efficacy and safety, revolutionizing the field of vaccinology. However, the development of personalized vaccines presents multifaceted challenges, including technical, ethical, economic, and regulatory considerations. Addressing these challenges is essential to ensure equitable access and safety of personalized vaccination strategies. Despite these hurdles, the potential of personalized vaccines to optimize responses and mitigate disease burden underscores the significance of ongoing research and collaboration in advancing precision medicine in immunization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Montin, Santilli, Beni, Costagliola, Martire, Mastrototaro, Ottaviano, Rizzo, Sgrulletti, Miraglia Del Giudice and Moschese.)

Competing Interests: FM-T reports his institution received trial fees from the GSK group of companies, Ablynx, Abott, Jansen, Medimmune, MSD Merck, Novartis, Novavax, Pfizer, Regeneron, Roche, Sanofi Pasteur and Seqirus for activities outside the presented work. FM-T also reports his institution received research grants from AstraZeneca, Jansen, MSD Merck and Pfizer for activities outside the presented work. FM-T also reports having received personal fees / honorarium from Biofabri, Novavax, Sanofi Pasteur, Seqirus, GSK group of companies, MSD Merck and Pfizer for activities outside the presented work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Mass SARS-Cov-2 vaccination campaign represents the only strategy to defeat the global pandemic we are facing. Immunocompromised patients represent a vulnerable population at high risk of developing severe COVID-19 and thus should be prioritized in the vaccination programs and in the study of the vaccine efficacy. Nevertheless, most data on efficacy and safety of the available vaccines derive from trials conducted on healthy individuals; hence, studies on immunogenicity of SARS-CoV2 vaccines in such populations are deeply needed. Here, we perform an observational longitudinal study analyzing the humoral and cellular response following the BNT162b2 mRNA COVID-19 vaccine in a cohort of patients affected by inborn errors of immunity (IEI) compared to healthy controls (HC). We show that both IEI and HC groups experienced a significant increase in anti-SARS-CoV-2 Abs 1 week after the second scheduled dose as well as an overall statistically significant expansion of the Ag-specific CD4+CD40L+ T cells in both HC and IEI. Five IEI patients did not develop any specific CD4+CD40L+ T cellular response, with one of these patients unable to also mount any humoral response. These data raise immunologic concerns about using Ab response as a sole metric of protective immunity following vaccination for SARS-CoV-2. Taken together, these findings suggest that evaluation of vaccine-induced immunity in this subpopulation should also include quantification of Ag-specific T cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Amodio, Ruggiero, Sgrulletti, Pighi, Cotugno, Medri, Morrocchi, Colagrossi, Russo, Zaffina, Di Matteo, Cifaldi, Di Cesare, Rivalta, Pacillo, Santilli, Giancotta, Manno, Ciofi Degli Atti, Raponi, Rossi, Finocchi, Cancrini, Perno, Moschese and Palma.)

Background: Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic immune disorders. While some PIDs can manifest with more than one phenotype, signs, and symptoms of various PIDs overlap considerably. Recently, novel defects in immune-related genes and additional variants in previously reported genes responsible for PIDs have been successfully identified by Next Generation Sequencing (NGS), allowing the recognition of a broad spectrum of disorders. Objective: To evaluate the strength and weakness of targeted NGS sequencing using custom-made Ion Torrent and Haloplex (Agilent) panels for diagnostics and research purposes. Methods: Five different panels including known and candidate genes were used to screen 105 patients with distinct PID features divided in three main PID categories: T cell defects, Humoral defects and Other PIDs . The Ion Torrent sequencing platform was used in 73 patients. Among these, 18 selected patients without a molecular diagnosis and 32 additional patients were analyzed by Haloplex enrichment technology. Results: The complementary use of the two custom-made targeted sequencing approaches allowed the identification of causative variants in 28.6% ( n = 30) of patients. Twenty-two out of 73 (34.6%) patients were diagnosed by Ion Torrent. In this group 20 were included in the SCID/CID category. Eight out of 50 (16%) patients were diagnosed by Haloplex workflow. Ion Torrent method was highly successful for those cases with well-defined phenotypes for immunological and clinical presentation. The Haloplex approach was able to diagnose 4 SCID/CID patients and 4 additional patients with complex and extended phenotypes, embracing all three PID categories in which this approach was more efficient. Both technologies showed good gene coverage. Conclusions: NGS technology represents a powerful approach in the complex field of rare disorders but its different application should be weighted. A relatively small NGS target panel can be successfully applied for a robust diagnostic suspicion, while when the spectrum of clinical phenotypes overlaps more than one PID an in-depth NGS analysis is required, including also whole exome/genome sequencing to identify the causative gene.