Vaccine Development Insights

📚 Stacking multiple mRNAs in a single LNP is straightforward in formulation. It is not straightforward immunologically. In this preclinical Moderna paper, HBV trivalent vaccine (PreS1/PreS2 + Core + Polymerase), shows a clear antigen interference. Core- and Polymerase-specific T-cell responses dropped sharply compared to monovalent mRNAs, and only reappeared when total mRNA dose increased. Mechanistically, this reflects competitive antigen expression, intracellular routing, and immune hierarchy, features that remain invisible at the sequence level. For development and CMC, the implication is direct: multivalent mRNA is not an additive system. Antigen ratio, relative expression kinetics, and immune prioritization all become functional comparability parameters, not formulation footnotes. We can already see echoes of this across other therapeutic vaccine programs, where stacking more mRNAs rarely yields linear gains. Overcoming antigen interference is as important to potency as lipid chemistry itself. This HBV mRNA–LNP candidate is still at the preclinical stage. The data show that mRNA can elicit the kind of HBV-specific responses needed for a functional cure in animal models, but issues like antigen interference, dose, and combination with immune modulators would need to be resolved before a realistic first-in-human program in chronic HBV patients. Clinically, the most advanced therapeutic vaccine efforts in chronic HBV are still non-mRNA platforms, such as VTP-300 (ChAd/MVA), BRII-179 (recombinant protein/VLP, often in combination with siRNA and interferon), and TherVacB (protein prime/MVA boost), all of which are in ongoing Phase 1–2 trials. Where do you see the biggest challenge when several mRNAs share the same LNP? #RNA #LNP #DrugDelivery #Vaccines #HBV #Immunology #CMC

Quite a nice (and updated) review -RNA therapeutics and LNPs for extrahepatic delivery LNPs have become a cornerstone in delivering RNA therapeutics, successfully used in mRNA vaccines and gene therapies. Despite their success, LNPs' tendency to preferentially accumulate in the liver remains a critical limitation. This liver tropism hinders their effectiveness in treating diseases in other organs, such as the lungs, brain, and pancreas. 🔬 Recent research has made significant strides in re-engineering LNPs to deliver RNA to organs beyond the liver. One approach is to adjust the composition of LNP formulations, either by adding a cationic lipid (like DOTAP) or replacing the ionizable lipid's ester linkers with amide linkers. These modifications change the physicochemical properties of LNPs, influencing the biomolecular corona that forms post-administration, which ultimately determines organ-specific targeting. For instance, lung-targeted LNPs can transfect up to 65% of endothelial cells and 40% of epithelial cells in the lungs, demonstrating a potential breakthrough for treating pulmonary diseases like cystic fibrosis and pulmonary fibrosis. Spleen-specific delivery has been achieved by incorporating anionic lipids, enabling the targeting of immune cells like macrophages and T cells, essential for in vivo immunotherapy applications. Meanwhile, LNPs designed for bone marrow delivery are showing promise in treating hematopoietic disorders like sickle cell disease. 🧠 Still, delivering RNA to the brain remains a considerable challenge (you know, the usual BBB). However, promising strategies, like adding neurotransmitter-derived lipids to LNP formulations, are showing early success in crossing this barrier, paving the way for treating neurological diseases. 🎯 As we look to the future, designing LNPs that can target specific cell types and improve safety profiles is paramount. Advances in overcoming physiological barriers, such as the BBB and tissue-specific targeting, will revolutionize how we approach gene therapies for previously untreatable conditions. From organ-selective LNPs to fine-tuned biomolecular coronas, the future of RNA delivery is more promising than ever. Learn more here: https://lnkd.in/ecQjkNaq #Nanomedicine #LipidNanoparticles #GeneTherapy #RNA #BiotechInnovation #TargetedDelivery #DrugDelivery

What if the next vaccine was designed before the outbreak began? Last time, we saw a “vaccine in a ball you could carry in your backpack.” That was about storage and portability. Here’s part two of the story: What if vaccines could be designed in weeks, not years? The Problem Today mRNA vaccines are powerful but fragile. To protect them, we wrap RNA inside tiny fat bubbles called lipid nanoparticles (LNPs). Here’s the bottleneck: there are thousands of possible bubble recipes. Each behaves differently in the body. Testing them one by one is slow, expensive, and unpredictable. The Breakthrough MIT researchers built an AI model trained on thousands of past LNP experiments. It learned the underlying patterns: which chemical structures, charges, and sizes made RNA delivery successful. Now, instead of trial-and-error, the AI can predict which new formulations will work best even with entirely new materials. And it’s not just theory: results published in Nature Nanotechnology showed these AI-designed particles worked in both lab cells and live models. Why This Matters Speed → Vaccine design shrinks from months to weeks. Precision → Tailored therapies for specific tissues, viruses, and even chronic diseases. Scale → Less wasted effort, lower costs, more access worldwide. The Bigger Picture If part one (the backpack nanoball) solved storage, part two (AI-driven design) solves speed. Together, they point to a future where vaccines and RNA therapies aren’t just reactive, they’re proactive. Suchitaa Paatil Sanju S Anju Goel Ajay Nandgaonkar Amit Saxena Taruna Anand #AI #HealthcareInnovation #Vaccines #RNA #mRNA #Biotech #FutureOfHealth #ArtificialIntelligence #DrugDiscovery #Innovation

A simple trick to improve vaccine efficacy. Vaccine design often revolves around the design of either antigen or adjuvant. However, in our latest paper led by Morgan Janes, PhD, we show that a simple addition of a polyphenol to the vaccine formulation increases its persistence at the injection site, and it subsequently increases its exposure to the immune microenvironment, a strategy we call a TAPER vaccine. The result is a significant improvement in the antibody titers against the antigen. TAPER vaccine durably improved humoral response against the receptor-binding domain (RBD) of SARS-CoV-2 while concomitantly enhancing the antigen-specific T cell response. https://lnkd.in/eTiPpWEy Owing to simplicity and ultra-low cost, TAPER vaccine offers a potential tool to improve vaccination outcomes at a larger scale. Alex Gottlieb Charles Park Shrinivas Acharya Griff Bibbey #vaccination #immunization #infectious_disease

🧬 mRNA vaccines… that build 𝘵𝘩𝘦𝘪𝘳 𝘰𝘸𝘯 𝘯𝘢𝘯𝘰𝘱𝘢𝘳𝘵𝘪𝘤𝘭𝘦𝘴 inside your body? 𝗩𝗮𝗰𝗰𝗶𝗻𝗲𝘀 have saved 𝟭𝟱𝟰 𝗺𝗶𝗹𝗹𝗶𝗼𝗻 𝗹𝗶𝘃𝗲𝘀 in the last 50 years. The greatest healthcare invention ever! And after COVID, we all know the power of 𝗺𝗥𝗡𝗔 𝘃𝗮𝗰𝗰𝗶𝗻𝗲𝘀. But they’re not the only ones! Can we mix modalities and get better vaccines? Exactly what the authors of this paper thought! They combined mRNA vaccines and protein nanoparticle vaccines, hoping that each would bring their immunological advantages: - mRNA: Intracellular antigen expression, robust CD8 T cell activation, and rapid manufacturing. 🧬 - Protein nanoparticles: Strong B cell activation and neutralizing antibody responses. Instead of injecting a pre-made nanoparticle, the researchers designed an mRNA vaccine that encodes a 𝘀𝗲𝗹𝗳-𝗮𝘀𝘀𝗲𝗺𝗯𝗹𝗶𝗻𝗴 𝗽𝗿𝗼𝘁𝗲𝗶𝗻 𝗻𝗮𝗻𝗼𝗽𝗮𝗿𝘁𝗶𝗰𝗹𝗲. Cells take up the mRNA → produce protein subunits → and those assemble into a 𝟲𝟬-𝗺𝗲𝗿 𝗽𝗮𝗿𝘁𝗶𝗰𝗹𝗲, displaying viral antigens all over the surface. They dubbed this approach: mRNA-launched vaccines! Super cool. Here’s the build: — A computationally designed icosahedral scaffold   — Fused to a stabilized SARS-CoV-2 antigen (Rpk9, RBD variant)  — Delivered via lipid nanoparticles And the results? In mice, these mRNA-launched vaccines: — Produced 𝟰× 𝗵𝗶𝗴𝗵𝗲𝗿 𝗮𝗻𝘁𝗶𝗯𝗼𝗱𝘆 𝘁𝗶𝘁𝗲𝗿𝘀 than standard mRNA vaccines 🧫  — Reached similar protection at ~𝟮𝟱× 𝗹𝗼𝘄𝗲𝗿 𝗱𝗼𝘀𝗲𝘀  — Generated strong neutralizing antibodies across variants  — Fully protected against viral challenge (no detectable virus in lungs!) All while keeping the T-cell response. Incredible! A great example of 𝗿𝗮𝘁𝗶𝗼𝗻𝗮𝗹 𝘃𝗮𝗰𝗰𝗶𝗻𝗲 𝗱𝗲𝘀𝗶𝗴𝗻, which merges the strengths of two platforms! Of course, the authors know the limitations:  — in vivo assembly and stability  — translation to humans  — manufacturing and scalability But it’s so cool! Could it be a new age for vaccines? PS: Read the full write-up here! https://lnkd.in/esSxxNfu ------ Ciao, I'm Marco! 👋 I post about protein design, DNA nanotech, and synthetic biology. If you like my content, follow me to see more!

🚀 Exploring mRNA Vaccine Delivery with Lipid Nanoparticles (LNPs) 🧬 💊 Lipid nanoparticles (#LNPs) have revolutionized #nonviral gene #delivery, especially in COVID-19 #mRNA #vaccines. Besides #size and surface potential, the #internal lipid structure is vital for mRNA delivery and immune stimulation. 📚 Most studies suggest the "#bleb" structure, made with classic ionizable lipid formulations, as the active LNP structure. LNPs are typically characterized by particle #size, #polydispersity, and mRNA #loading efficiency. However, their internal structures, which can be highly #heterogeneous, have not been well defined. To create strong and lasting immune responses, it is crucial to understand LNP characteristics. 📄 In a recent study, Kangzeng Wu from Zhejiang University, Yuhong Xu from HighField Biopharmaceuticals, and their collaborators investigated the structure-function relationship of lipid nanoparticles having distinct internal structures: ① Emulsion-like LNPs (eLNPs) ② Membrane-rich LNPs (mLNPs) ③ Classic "bleb" structure LNPs (cLNPs) https://lnkd.in/dt_FYnMT They found : 👉 #eLNPs have a higher molar percent of ionizable lipid and a lower molar percent of DSPC and cholesterol. 👉 Different lipid organizations lead to varying mRNA #delivery activities in vitro and in vivo. 👉 eLNPs induced a rapid immune response (higher titers at week 2) and sustained it longer (higher titers at week 8) compared to cLNPs and mLNPs. 👉 The rapid onset and local antigen expression by eLNPs may enhance antigen recognition and presentation, despite lower overall mRNA expression in the liver and other organs. 📊 The data suggest that eLNPs could be a more suitable delivery system for mRNA vaccines due to their high immunogenicity and low systemic toxicity. #LNPs #mRNA #VaccineResearch #Immunology #GeneDelivery

mRNA, Lipid Nanoparticles, and a New Way Forward for Malaria Vaccines: I am pleased to share a new paper published in Nature Microbiology (Nature Portfolio), resulting from a close collaboration between my laboratory and led by John T. Harty. mRNA vaccination overcomes haemozoin-mediated impairment of whole-parasite malaria vaccines in mice Hassert et al., Nature Microbiology (2026) https://lnkd.in/g-RmNRjg The challenge Whole-parasite malaria vaccines can induce strong protection, but they are far less effective in individuals with prior malaria exposure. Our study shows why: haemozoin, a pigment that persists after infection, interferes with how immune cells take up and present vaccine antigens, weakening protective CD8+ T cell responses. The approach To overcome this barrier, we developed an mRNA vaccine delivered using lipid nanoparticles fabricated in my laboratory. These nanoparticles enable immune cells to produce malaria antigens internally, bypassing haemozoin-impaired antigen uptake. In malaria-experienced mice, this lipid nanoparticle-mRNA vaccine restored effective T cell responses and protection. When combined with a whole-parasite vaccine, it further enhanced liver-resident memory T cells and immunity. Why it matters This work highlights how mRNA vaccines and lipid nanoparticles can complement existing vaccine strategies, particularly in settings where prior infection alters immune responsiveness. It also underscores the importance of collaborative, cross-disciplinary approaches in solving long-standing challenges in global health. Grateful to John Harty and the entire team for an outstanding collaboration.

What if a tumor could teach the immune system how to destroy it? A new frontier in cancer therapy proposes just that: instead of delivering pre-made vaccines, we could deliver mRNA instructions directly into tumors, enabling them to assemble or make more 'presentable' according to a person's HLA types their own neoantigens — effectively turning the tumor into a self-generating vaccine site. The Concept: By encoding enzymes derived from viral self-assembly mechanisms or mobile genetic elements (like “jumping genes”), scientists could equip tumor cells to process fragments of their own mutated mRNA, package them into immunogenic peptides, and alert the immune system from within. What’s Already Possible: Today, personalized mRNA cancer vaccines (e.g., Moderna’s mRNA-4157 and BioNTech’s autogene cevumeran) are made by sequencing tumors, selecting neoantigens, and delivering synthesized mRNA systemically via lipid nanoparticles. These are already in human trials. What’s Emerging: Researchers are beginning to explore in situ vaccination — delivering immune-stimulating genes directly into the tumor microenvironment. Others are developing self-assembling nanoparticles that improve antigen delivery and presentation within tumors. What Comes Next: The next leap could be combining these approaches — designing nanoparticles that deliver not just antigens, but the tools to create and multiply antigens locally, inside the tumor. This would allow for real-time, patient-specific, in-tumor vaccine production, possibly overcoming resistance mechanisms and tumor heterogeneity. This concept isn’t far-fetched — it’s a logical next experiment, built on today’s tools. #CancerImmunotherapy #InSituVaccine #mRNAtechnology #NeoantigenVaccine #OncologyInnovation #FutureOfMedicine #TumorMicroenvironment #SelfAssemblingTherapies #BiotechFrontiers

🔬 𝐀𝐝𝐯𝐚𝐧𝐜𝐢𝐧𝐠 𝐦𝐑𝐍𝐀 𝐓𝐡𝐞𝐫𝐚𝐩𝐞𝐮𝐭𝐢𝐜𝐬: 𝐓𝐨𝐰𝐚𝐫𝐝 𝐒𝐮𝐬𝐭𝐚𝐢𝐧𝐞𝐝 𝐏𝐫𝐨𝐭𝐞𝐢𝐧 𝐄𝐱𝐩𝐫𝐞𝐬𝐬𝐢𝐨𝐧 💉 While the clinical success of LNP-mRNA vaccines has highlighted the immense potential of mRNA-based medicines, a key challenge remains: achieving sustained protein expression without frequent dosing. This is particularly crucial for therapeutic—not just prophylactic—applications. 🧬 This review comprehensively explores strategies to enhance the durability and translation efficiency of mRNA, focusing on two main pillars: 1️⃣ 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝐸𝑛𝑔𝑖𝑛𝑒𝑒𝑟𝑖𝑛𝑔 𝑜𝑓 𝑅𝑁𝐴 2️⃣ 𝐵𝑖𝑜𝑚𝑎𝑡𝑒𝑟𝑖𝑎𝑙-𝑎𝑢𝑔𝑚𝑒𝑛𝑡𝑒𝑑 𝐷𝑒𝑙𝑖𝑣𝑒𝑟𝑦 𝑃𝑙𝑎𝑡𝑓𝑜𝑟𝑚𝑠 💡 𝐇𝐢𝐠𝐡𝐥𝐢𝐠𝐡𝐭𝐬 𝐟𝐫𝐨𝐦 𝐑𝐍𝐀 𝐄𝐧𝐠𝐢𝐧𝐞𝐞𝐫𝐢𝐧𝐠 𝐀𝐩𝐩𝐫𝐨𝐚𝐜𝐡𝐞𝐬: • 𝐂𝐚𝐩 𝐬𝐭𝐫𝐮𝐜𝐭𝐮𝐫𝐞 𝐨𝐩𝐭𝐢𝐦𝐢𝐳𝐚𝐭𝐢𝐨𝐧 (Cap-2) for immune evasion and translation enhancement • 𝐂𝐨𝐝𝐨𝐧 𝐨𝐩𝐭𝐢𝐦𝐢𝐳𝐚𝐭𝐢𝐨𝐧 and 𝐦𝐨𝐝𝐢𝐟𝐢𝐞𝐝 𝐧𝐮𝐜𝐥𝐞𝐨𝐬𝐢𝐝𝐞𝐬 (e.g., m¹Ψ) for extended half-life • 𝐂𝐢𝐫𝐜𝐮𝐥𝐚𝐫 𝐑𝐍𝐀 (circRNA) and 𝐬𝐞𝐥𝐟-𝐚𝐦𝐩𝐥𝐢𝐟𝐲𝐢𝐧𝐠 𝐑𝐍𝐀 (saRNA) platforms for prolonged expression beyond conventional IVT mRNA 🧪 𝐈𝐧𝐧𝐨𝐯𝐚𝐭𝐢𝐨𝐧𝐬 𝐢𝐧 𝐃𝐞𝐥𝐢𝐯𝐞𝐫𝐲 𝐒𝐲𝐬𝐭𝐞𝐦𝐬: • 𝐌𝐢𝐜𝐫𝐨𝐧𝐞𝐞𝐝𝐥𝐞 𝐩𝐚𝐭𝐜𝐡𝐞𝐬 embedding LNP-mRNA enable temperature-stable, minimally invasive delivery with sustained release • 𝐇𝐲𝐝𝐫𝐨𝐠𝐞𝐥 𝐝𝐞𝐩𝐨𝐭𝐬 and 𝐬𝐜𝐚𝐟𝐟𝐨𝐥𝐝 𝐬𝐲𝐬𝐭𝐞𝐦𝐬 (e.g., GelMA, MCMs) act as local reservoirs, modulating both mRNA protection and spatiotemporal protein availability 📌 The convergence of synthetic biology and materials science is creating modular, tunable systems capable of addressing the major pharmacokinetic limitations of mRNA. This progress will be pivotal for extending mRNA’s utility beyond vaccines—into regenerative medicine, oncology, and chronic disease management. 🎯 𝐊𝐞𝐲 𝐓𝐚𝐤𝐞-𝐀𝐰𝐚𝐲𝐬: • ⚙️ mRNA stability can be enhanced through cap, codon, and tail modifications • 🔁 Self-replicating and circular RNA offer platforms for longer expression with lower doses • 🧴 Biomaterial integration (e.g., hydrogels, microneedles) enables controlled, localized, and prolonged mRNA delivery • 🧠 Tissue-specific delivery is becoming more feasible through ligand-functionalized LNPs • 🌐 The interplay between delivery kinetics and immune modulation is central to future clinical translation 🔗 𝐅𝐮𝐥𝐥 𝐫𝐞𝐯𝐢𝐞𝐰 available here (behind paywall 💰): https://lnkd.in/e_X2wjrB #RNAtherapeutics #mRNAtechnology #DrugDelivery #LipidNanoparticles #Biomaterials #TranslationalScience #PharmaceuticalInnovation #ControlledRelease Dinglingge Cao, Meng Tian, Zhengwei Liu, Kaiyuan Guo, Jonathan Peng, Anjali Ravichandra, Caroline Ferrell & Yizhou Dong

At the AAPS meeting in San Antonio, we have several papers this coming week. Here is one by Ishaan Duggal, Rohini Sreenivasan, Ridhi Patil, Brinkley Morse, Ananya Anand, Armaan Verma, Nicholas Peppas entitled "Engineering Stimuli-Responsive Hierarchical Nanogels for Programmable Pulsatile Oral Vaccine Delivery" Purpose: Pulsatile drug delivery systems are designed to release therapeutic agents in a time-controlled, discrete manner that mimics the body’s natural biological rhythms or is triggered by specific physiological stimuli. This controlled, pulsatile release approach improves therapeutic efficacy, reduces side effects, and enhances patient compliance by minimizing frequent dosing. This research focuses on the development of an advanced oral vaccine delivery system that utilizes stimuli-responsive hierarchical nanogel platform to achieve programmable pulsatile antigen release. The goal is to mimic natural immunological rhythms, thereby enabling strong immune activation with fewer doses and improved patient adherence. Methods: The delivery platform is based on hierarchical nanoparticles synthesized from Poly (acrylamide-co-itaconic acid) copolymers synthesized via inverse emulsion polymerization. Systematic variation of comonomer ratios, surfactant/co-surfactant concentrations, and crosslinker type and content enabled precise control over polymer composition, particle size, crosslinking density, and degradation kinetics. Molecular imprinting strategies were employed to assess whether selective antigen recognition by imprinted nanogels modulates the resulting immune response. Hierarchical assembly was achieved through electrostatic layer-by-layer deposition of polyethylenimine (PEI) and CpG oligodeoxynucleotides to enhance mucosal uptake and activate antigen-presenting cells. At the core, antigen-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating ovalbumin (OVA) as a model antigen are being used to achieve a delayed secondary release pulse designed to mimic booster-like kinetics. Physicochemical characterization included dynamic light scattering for pH-responsive size and polydispersity, electron microscopy for morphology, titrimetric analysis for acidic group density, microBCA assays for protein loading and release efficiency, and spectroscopic methods to confirm chemical composition. In vitro release studies under simulated gastrointestinal pH conditions validated pulsatile behavior, while cytotoxicity was assessed using MTS and LDH assays. Future work will focus on comprehensive in vivo immunogenicity studies to evaluate the platform’s efficacy. Systemic immune responses will be quantified by measuring serum IgG titers using ELISA, while mucosal immunity will be assessed via secretory IgA levels in feces, saliva, or intestinal washes. Cellular immunity will be evaluated through T-cell proliferation assays and cytokine profiling using ELISpot and flow cytometry.