Trends in Vaccine Development

Recent advances in nanoparticulate RNA delivery systems Nanoparticle-based RNA delivery has shown great progress in recent years with the approval of two mRNA vaccines for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and a liver-targeted siRNA therapy. Here, we discuss the preclinical and clinical advancement of new generations of RNA delivery therapies along multiple axes. Improvements in cargo design such as RNA circularization and data-driven untranslated region optimization can drive better mRNA expression. New materials discovery research has driven improved delivery to extrahepatic targets such as the lung and splenic immune cells, which could lead to pulmonary gene therapy and better cancer vaccines, respectively. Other organs and even specific cell types can be targeted for delivery via conjugation of small molecule ligands, antibodies, or peptides to RNA delivery nanoparticles. Moreover, the immune response to any RNA delivery nanoparticle plays a crucial role in determining efficacy. Targeting increased immunogenicity without induction of reactogenic side effects is crucial for vaccines, while minimization of immune response is important for gene therapies. New developments have addressed each of these priorities. Last, we discuss the range of RNA delivery clinical trials targeting diverse organs, cell types, and diseases and suggest some key advances that may play a role in the next wave of therapies. https://lnkd.in/eFcRVFbi

Nucleic acid vaccines have grown in importance over the past several years, with the development of new approaches remaining a focus. We describe a lipid nanoparticle-formulated DNA (DNA-LNP) formulation which induces robust innate and adaptive immunity with similar serological potency to mRNA-LNPs and adjuvanted protein. Using an influenza hemagglutinin (HA)-encoding construct, we show that priming with our HA DNA-LNP demonstrated stimulator of interferon genes (STING)-dependent upregulation and activation of migratory dendritic cell (DC) subpopulations. HA DNA-LNP induced superior antigen-specific CD8+ T cell responses relative to mRNA-LNPs or adjuvanted protein, with memory responses persisting beyond one year. In rabbits immunized with HA DNA-LNP, we observed immune responses comparable or superior to mRNA-LNPs at the same dose. In an additional model, a SARS-CoV-2 spike-encoding DNA-LNP elicited protective efficacy comparable to spike mRNA-LNPs. Our study identifies a platform-specific priming mechanism for DNA-LNPs divergent from mRNA-LNPs or adjuvanted protein, suggesting avenues for this approach in prophylactic and therapeutic vaccine development. Interesting study detailing the development of a nucleic acid vaccine platform using lipid nanoparticle-formulated DNA (DNA-LNP), by Nicholas Tursi and larger team at The Wistar Institute and University of Pennsylvania Perelman School of Medicine: https://lnkd.in/dCvxV4y5 Additional information on companies involved in Nucleic Acid Vaccine Development and Lipid Nanoparticle (LNP) Drug Delivery for those interested: INOVIO Pharmaceuticals, Inc. Arcturus Therapeutics Moderna BioNTech SE Tonix Pharmaceuticals Immunomic Therapeutics, Inc. PDC*line Pharma Oxford Biomedica Entos Pharmaceuticals Pfizer Enara Bio GeoVax Labs, Inc. Valo Therapeutics Ltd Acuitas Therapeutics Evonik FORMUMAX SCIENTIFIC INC. GenScript FUJIFILM Pharmaceuticals U.S.A., Inc. Prorenata Biotech Camurus Ethris

🔬 A Must-Read Review on mRNA Medicines: Recent Advances in Chemical Modifications, Design, and Engineering This comprehensive and insightful review, recently published in Nano Research by Xiaowen Hou et al., is one of the best I’ve read on mRNA medicines. It provides a clear and detailed overview of how chemical modifications, sequence optimization, and next-generation engineering are shaping the future of mRNA therapeutics. 💡 Key Takeaways: 🔹 Chemical Modifications – Enhancing Stability, Boosting Expression & Reducing Immune Response ✔ Nucleoside Modifications – Replacing uridine (U) with Ψ (pseudouridine) and other analogs (m1A, m6A, m5C, mo5C, m5U, s2U, 5moU) ✔ 5′ Cap Enhancements – Cap 1, Cap 2 structures, and anti-reverse cap analogs (ARCAs) ✔ Poly(A) Tail Engineering – Optimizing tail length and incorporating m6A modifications 🔹 Sequence Optimization – Maximizing Stability & Expression ✔ Fine-tuning UTRs & ORF Engineering – Adjusting 5’ and 3’ UTRs and using synonymous codon substitutions ✔ AI-Powered mRNA Design – Tools like LinearDesign generate ultra-stable mRNA in just 11 minutes, boosting protein expression up to 128-fold 🔹 mRNA Engineering – Expanding Therapeutic Potential ✔ Circular RNA (circRNA) & Self-Amplifying RNA (saRNA) – Offering longer stability, higher efficiency, and lower doses for therapies ✔ Multitailed mRNA – Enabling controlled protein expression for precise therapeutic applications 🚀 Beyond Vaccines – The Big Picture mRNA isn’t just for vaccines—it holds transformative potential in cancer immunotherapy, rare disease treatments, and beyond. The next big challenge? Refining stability, delivery, and expression control to bring these innovations from the lab to the clinic. ❓ What do you think is the biggest challenge for next-gen mRNA medicines? Let’s discuss! ⬇️ 📖 Find the full open-access paper in the comments below. 🔗 Follow me for insights on oligonucleotide synthesis, RNA therapeutics, and cutting-edge drug development. #mRNA #Biotech #DrugDevelopment #RNAtherapeutics #mRNAEngineering #SyntheticBiology

The immunogenicity of lipid nanoparticle (LNP) formulations is a double-edged sword: while we aim to elicit strong immune responses to the encoded effective LNP-vaccines, we also seek to minimize reactogenicity driven by the LNP itself, which can cause adverse effects. Understanding which LNP components contribute to immunogenicity and reactogenicity is key to optimizing both efficacy and safety. A recent study reveals that adjusting PEG‑lipid length/ratio as well as replacing cholesterol and phospholipids in LNPs can enhance vaccine potency while reducing adverse reactions. It's a promising step toward safer, better‑tolerated mRNA‑LNP vaccine platforms. 🔍 Key Findings: 1. PEG‑lipids: Shortening PEG chains and lowering their molar ratio boosted antigen‑specific antibody responses and CD8⁺ T cell activity. 2. Cholesterol: Replacing cholesterol with plant sterols maintained strong immune responses while reducing inflammatory cytokines and side effects like fever. 3. Phospholipids: Swapping in phospholipids with different headgroups or tail structures achieved similar benefits—strong immunity, but less reactogenicity. 4. Expression‑response link: Higher in vivo protein expression in specific organs correlated positively with both stronger immune responses and more adverse reactions. ACS Nano. 2025 Jul 23. doi: 10.1021/acsnano.5c10648.

The latest article in the "Recent Advances in Drug Delivery" special issue I am editing for The AAPS Journal is available: Gastrointestinal Delivery of an mRNA Vaccine Using Immunostimulatory Polymeric Nanoparticles. This article is authored by the Robert Langer and Giovanni Traverso research groups at Massachusetts Institute of Technology. Authors include Hyunjoon Kim, Ameya Kirtane, Nayoon Kim, Netra Unni Rajesh, Chaoyang Tang, Keiko Ishida, Alison M. Hayward, Robert Langer & Giovanni Traverso. Read the full paper here: https://lnkd.in/gAJ6xR7z Summary: mRNA vaccines can be translated into protein antigens, in vivo, to effectively induce humoral and cellular immunity against these proteins. While current mRNA vaccines have generated potent immune responses, the need for ultracold storage conditions (− 80 °C) and healthcare professionals to administer the vaccine through the parenteral route has somewhat limited their distribution in rural areas and developing countries. Overcoming these challenges stands to transform future deployment of mRNA vaccines. In this study, we developed an mRNA vaccine that can trigger a systemic immune response through administration via the gastrointestinal (GI) tract and is stable at 4 °C. A library of cationic branched poly(β-amino ester) (PBAE) polymers was synthesized and characterized, from which a polymer with high intracellular mRNA delivery efficiency and immune stimulation capacity was down-selected. mRNA vaccines made with the lead polymer-elicited cellular and humoral immunity in mice. Furthermore, lyophilization conditions of the formulation were optimized to enable storage under refrigeration. Our results suggest that PBAE nanoparticles are potent mRNA delivery platforms that can elicit B cell and T cell activation, including antigen-specific cellular and humoral responses. This system can serve as an easily administrable, potent oral mRNA vaccine.

Many #vaccines are only partially effective, have waning efficacy, or do not work well in the very young or the very old. For more than a decade, the Precision Vaccines Program at Boston Children's Hospital, have tried improving vaccines by adding compounds known as #adjuvants to boost vaccine recipients' #immuneresponses. Now they've identified a new and promising adjuvant of their own, dubbed PVP-037. "In principle, this compound can be added to any vaccine to enhance its action," says Levy, who directs the Precision Vaccines Program. "Adjuvants are like rocket fuel for the immune system. PVP-037 is one of the most active adjuvants we've discovered, and we think it induces a greater, more durable, and broader immune response to vaccines." The researchers began by screening more than 200,000 small molecules from a Harvard Medical School library in human #immunecells —specifically, in primary peripheral blood mononuclear cells, obtained from donors and cultured in their own plasma using a method developed within the Precision Vaccines Program. This yielded about 25 confirmed hits, with PVP-037 being the most active. PVP-037 belongs to a family of molecules called imidazopyrimidines, which the study found to be active immunomodulators. PVP-037 and its analogs target the #innate #immunesystem, stimulating the pattern-recognition receptors TLR7 and TLR8 on #antigen -presenting cells such as monocytes and dendritic cells. "Screening small molecules against human primary cells is messier than using a homogenous cell line, because each individual is different," says Levy. "But that's the whole point: It's more reflective of human biology. A good adjuvant needs to be able to work across diverse populations. PVP-037 would not have been discovered by screening cell culture lines." In live mice, it enhanced antibody responses against influenza and #covid19 SARS-CoV-2 vaccine proteins. On tap: Tests against flu, whooping cough, and fentanyl Boston Children's holds multiple patents on these discoveries, with Levy and Dowling as named inventors. They plan to assess PVP-037 across all age groups and test its ability to enhance immune responses to #influenza and #pertussis (whooping cough) vaccines as well as an #opioid vaccine aimed at preventing #fentanyl #overdosedeaths. World Health Organization FDA Centers for Disease Control and Prevention #nih #mrna #vaccination More information: Dheeraj Soni et al, From Hit to Vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation, Science Advances (2024). DOI: 10.1126/sciadv.adg3747. https://lnkd.in/eMRXDDBC

🟥 Exosome Vaccines for Immunotherapy Exosomes are ideal carriers for cancer and infectious disease vaccine development because they are derived from various cell types, are biocompatible, and can carry antigens, nucleic acids, and immunomodulatory molecules. Therefore, exosome-based vaccines are a breakthrough innovation in immunotherapy, characterized by the use of the natural properties of exosomes to enhance immune responses. Exosomes derived from tumor cells or modified to carry tumor-associated antigens can effectively deliver these antigens to dendritic cells (DCs). This process can stimulate the activation of cytotoxic T lymphocytes (CTLs), enhancing the body's ability to recognize and attack tumor cells. Some tumor-derived exosome vaccines have shown promise in inducing strong anti-tumor immune responses in preclinical models. Exosome vaccines can also be combined with immunostimulatory molecules such as adjuvants or cytokines to enhance immune activation. For example, exosomes loaded with IL-12 or GM-CSF can enhance the recruitment and activation of immune cells to promote a strong and sustained response. Currently, exosome vaccines carrying antigens from pathogens such as viral envelope proteins or bacterial toxins are being developed to fight infectious diseases. These vaccines can mimic pathogen structure and improve antigen presentation, providing a safer alternative to traditional vaccines. Looking ahead, exosome vaccines represent a promising direction for immunotherapy, providing innovative solutions for personalized medicine. Several ongoing studies and clinical trials are expected to realize their full potential, paving the way for safer and more effective vaccines against cancer and infectious diseases. References [1] Patrick Santos and Fausto Almeida, Frontiers in Immunology 2021 (doi: 10.3389/fimmu.2021.711565) [2] Min Deng et al., Asian Journal of Pharmaceutical Sciences 2023 (https://lnkd.in/eDiGG_q4) #Immunotherapy #ExosomeVaccines #CancerResearch #VaccineInnovation #Nanomedicine #BiomedicalInnovation #PrecisionMedicine #InfectiousDiseases #ExosomeTherapy #LifeSciences #OncologyBreakthroughs #ImmuneBoosting

JIT for weekend viewing - full Pivotal Paper panel on clinical results for an optimized srRNA vaccine:https://lnkd.in/eFnMrBne The pivotal paper series brings to a wider audience a sharp focus on important advances in the biomedical field. Troubling times for the vaccine industry currently beset by misinformation and disinformation. In our inaugural "Pivotal Paper" we hear from a panel of vaccine heavyweights which comprises Philip Dormitzer MD-PhD, Hospitalist Physician, Coastal Medical Associates, Phil Felgner , PhD, Professor, UC Irvine , Andy Geall , PhD, Co-founder and Chief Development Officer, Replicate Bioscience, Inc.  & Chairman of the board, Alliance for mRNA Medicines , and Jeffrey Ulmer PhD, President, Techimmune LLC. From the paper’s introduction we learn: Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed in the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions and demonstrate immunogenicity and safety in preclinical and clinical development. As overview comments we hear directly from the panelists: Andy Geall, PhD: “I'd say our therapeutic index stands out. It's greater than 100. Most other vaccines, whether they are first generation self-amplifying or linear mRNA are in the range of one to 10, so outstanding. The fact that we didn't reach a maximum tolerated dose means we can dose higher, and this comes into play with multivalent vaccines" Phillip Felgner, PhD: “One of the targets in vaccine science in general is for the field to develop single dose vaccine technology. The self-replicating RNA has the potential for doing just that.” Phillip Dormitzer, MD-PhD: “We've long known that at lab scale, if you focus on making a small amount of the best self-replicating RNA you can make, it outperforms everything else. The question was, could you scale it and get it to the point where you can actually manufacture with that kind of quality? And I think that's been the barrier that sort of prevented the self-replicating RNA from being the dominant RNA. But it does appear with this paper that those barriers really have been overcome.” Jeffrey Ulmer, PhD: “As you said, up to now there's been some uncertainty about the prospects. If the technology could be making high quality [drug product], could we make it potent enough? We see in humans what we've seen in the animal models, and I think what this paper clearly demonstrates is yes, it has. The technology has arrived. " BioPharm International Pharmaceutical Technology MJH Life Sciences® #vaccine #pandemic #mRNA #titer #dose #bioprocess #srRNA

Functionality and translation fidelity characterization of mRNA vaccines using platform-based mass spectrometry detection Recently published in Nature Portfolio Journal, Vaccines, researchers from Merck developed a new analytical method combining cell-free translation (CFT) and liquid chromatography - mass spectrometry to detect, characterize, and quantify antigen proteins from #mRNA constructs. This approach enabled: - Evaluation of mRNA functionality under thermal stress - Assessment of multivalent formulations with high sequence homology - Identification of +1 ribosomal frameshifting linked to N1 - methylpseudouridylation. The CFT-MS method [conducted on an #Evosep One (Evosep Biosystems) coupled to a Thermo Fisher Scientific Orbitrap Exploris 480 mass spectrometer] demonstrated high sensitivity and specificity, accurately identifying all six translated proteins from a hexavalent mRNA drug product in a dose-dependent manner. It was found that cleanup of the peptides in the #Evotip, was critical due to the viscous nature of the cell-free translation system. This platform-based approach eliminates the need for antibodies, making it a valuable analytical approach for assessing mRNA quality and functionality in vaccine development, potentially accelerating the response to rapidly mutating pathogens like SARS-CoV-2 and influenza or other emerging infectious diseases. The full manuscript can be read here: https://lnkd.in/eHeVYrCP Congratulations to the team for this impressive work: Alyssa Stiving, Ben Roose, Christopher Tubbs, Mark Haverick, Ashley Gruber, Richard Rustandi, Jesse Kuiper, Matt Schombs, Hillary Schuessler, PhD, Xuanwen Shawn Li

💡 Breakthrough in mRNA Vaccine Delivery Researchers at Cornell, led by Prof. Shaoyi Jiang, have developed a next-gen lipid nanoparticle that could significantly enhance the safety and effectiveness of mRNA vaccines — including those used against COVID-19 and cancer. The innovation? Replacing polyethylene glycol (PEG), a common ingredient known to trigger immune responses in some people, with a zwitterionic polymer called poly(carboxybetaine) (PCB). Unlike PEG, PCB blends seamlessly with the body’s water-rich environment, avoiding detection by the immune system and enabling better delivery of mRNA to cells. This "stealth" material is not only biocompatible but also ideal for higher-dose vaccines, like those needed for cancer immunotherapy. Already being explored with leading institutions, this could mark a major leap in precision medicine. 🧬 The future of vaccine delivery just got a lot more efficient — and a lot more human-friendly. 🔬 Read more in Nature Materials (May 29). https://lnkd.in/gqmkUCwn #Biotech #mRNA #VaccineInnovation #LipidNanoparticles #Immunotherapy #CancerResearch #CornellEngineering #BiomedicalEngineering #MedTech #PharmaInnovation #DrugDelivery #Zwitterion #mRNAtechnology #LifeSciences