VITAL was selected under Reimagining Available Vaccines and Envisioning Novelty, or RAVEN, a Joint Science and Technology Office program dedicated to advancing multivalent prophylactic biological countermeasures. RAVEN’s remit is deliberately broad: it seeks both incremental improvements to existing vaccine technologies and entirely new preventive platforms capable of addressing multiple biological threats simultaneously. That orientation marks a departure from the traditional one-pathogen, one-vaccine model that has dominated prophylactic development for decades. The Mount Sinai proposal was chosen because it promises a framework in which the delivery, presentation, and timing of antigen exposure can be systematically engineered rather than treated as fixed parameters of a given vaccine design.

The initial proof of concept will center on H5N1, a highly pathogenic avian influenza A virus that remains a persistent pandemic concern. The team will develop an unmodified mRNA-based vaccine prototype designed for intranasal delivery, with a distinctive twist: the construct is engineered to restrict expression of the immunogen primarily to macrophages, immune cells resident in the respiratory tract that participate in antigen presentation during natural infection. By confining antigen expression to these professional immune cells, the design seeks to avoid adverse events that can arise when vaccine-derived antigen is produced in other cell types that would never encounter the pathogen in the course of a real infection. The program will systematically evaluate how this targeting affects antigen presentation, immune stimulation, safety, and protection.

“VITAL is designed to directly support RAVEN’s objective by asking a broader question than whether we can make a vaccine against one virus,” said Gustavo Palacios, PhD, Professor of Microbiology at the Icahn School of Medicine and VITAL project lead. “Rather than focusing only on which antigens are delivered, we want to understand which biological principles can be incorporated into vaccination so that the same framework can eventually be adapted across different respiratory threats. H5N1 gives us a rigorous starting point to test those principles.”

The architecture of the program rests on five biological principles. The first is the exclusive targeting of immunogen expression to immune cells that help activate the body’s immune response, ensuring that antigen production occurs where it is immunologically useful. The second is the provision of appropriate stimulation to those cells, so that antigen presentation is paired with the right activation signals. The third involves engineering the antigens themselves to reduce toxicity and adverse responses without sacrificing expression or immunogenicity. The fourth principle matches antigen delivery to a pathogen’s natural route of entry, which in the case of respiratory viruses means delivering the vaccine intranasally rather than intramuscularly. The fifth is pulse immunization, a strategy intended to generate immune responses that mimic aspects of natural infection through controlled patterns of exposure over time.

Antigen detoxification occupies a central position in this design. Viral antigens can carry intrinsic toxic or inflammatory activities, and the VITAL team will engineer these molecules to reduce potential toxicity while preserving their ability to be expressed and to provoke a protective immune response. In parallel, the program will investigate different intranasal immunization schedules, including repeated low-dose regimens designed to reproduce aspects of the timing with which the immune system naturally encounters a respiratory virus. The underlying hypothesis is that the pattern of antigen exposure, not merely its identity, shapes the quality, breadth, and durability of the resulting immunity.

“One of the central challenges in influenza vaccination is achieving protection that is broad and durable rather than narrowly focused on a single circulating influenza virus variant,” said Adolfo García-Sastre, PhD, Irene and Dr. Arthur M. Fishberg Professor of Medicine and Director of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine. “VITAL gives us an opportunity to explore a different way of approaching that problem—by engineering not only the antigen, but also how, where, and over what time course the immune system encounters it.” García-Sastre’s long-standing work on influenza virus biology, virus-host interactions, and vaccine development anchors the program’s virological expertise.

To dissect the immune responses generated by this approach, VITAL will combine human immune tissue models and animal models with single-cell and spatial analysis, proteomics, and artificial intelligence and computational methods. The research will examine how targeted antigen-presenting cells, including macrophages and dendritic cells, respond to vaccination, how they interact with one another, and how those interactions drive downstream B cell and T cell responses. This systems-level view is intended to reveal which features of the engineered exposure correlate with durable, broad protection, providing the empirical basis for generalizing the framework beyond H5N1.

“A major strength of VITAL is the ability to study how vaccination shapes the immune response in physiologically relevant human systems,” said Ana Fernandez-Sesma, PhD, Chair of the Department of Microbiology at the Icahn School of Medicine. “By looking closely at macrophages, dendritic cells, and other immune populations using primary human tissues, we can predict whether a vaccine generates the appropriate immune response in humans as an alternative to animal models.” Her research on virus-host interactions and immune responses in human systems, including work with macrophages, dendritic cells, and human tonsil-based models, forms a core component of the program’s human immunology arm.

If the initial principles are successfully validated in the H5N1 prototype, VITAL is structured to scale toward a multivalent strategy encompassing at least 20 respiratory viruses, creating a framework that can be evaluated across a much broader spectrum of threats. Preclinical studies will assess the durability and breadth of immune responses across young and aged mice and ferrets, alongside the primary human systems, since animal models remain necessary under the current regulatory framework to characterize integrated immune responses, safety, and protection in vivo. These studies are positioned as a bridge toward a future in which validated human organoid systems may be accepted by regulatory agencies for defined aspects of preclinical evaluation. The program also incorporates regulatory planning and Investigational New Drug-enabling activities to support the potential clinical translation of selected vaccine candidates. The project agreement runs through August 28, 2031, giving the team a defined window to demonstrate whether engineering the where, when, and how of antigen presentation can yield a genuinely generalizable vaccine platform for respiratory disease.

Subject of Research: Development of a targeted mRNA vaccine platform for broad protection against respiratory pathogens, starting with H5N1 avian influenza

Article Title: Mount Sinai awarded five-year, $20.7 million vaccine development agreement to advance next-generation technologies against respiratory threats

Article References: Mount Sinai awarded five-year, $20.7 million vaccine development agreement to advance next-generation technologies against respiratory threats. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: Mount Sinai, VITAL, RAVEN program, H5N1, mRNA vaccine, intranasal delivery, macrophages, antigen presentation, pulse immunization, respiratory viruses, Defense Threat Reduction Agency, influenza

The research, led by Xuanjing Yu, Xinyu Jiang, and colleagues at Yunnan University’s Bio-X Center for Interdisciplinary Innovation and Yunnan Vaccine Laboratory, took advantage of a randomized clinical trial of mRNA booster vaccines. The team selected an outcome-balanced subset of 124 participants—62 who later developed a documented COVID-19 case during follow-up and 62 who did not—matched across sex, vaccine product, and age category. Peripheral blood mononuclear cells collected immediately before vaccination (Day 0) and again 24 hours later (Day 1) were stained with a metal-conjugated antibody cocktail and analyzed by mass cytometry, a technique that detects individual metal isotopes rather than overlapping fluorescent signals, allowing researchers to measure dozens of markers on millions of single cells simultaneously.

Seventeen major immune-cell populations were manually gated from the resulting data, spanning the full spectrum of circulating immunity: classical, intermediate, and non-classical monocytes; myeloid and plasmacytoid dendritic cells; natural killer cells; gamma-delta T cells; NKT-like cells; naive, central memory, effector memory, and terminally differentiated effector memory subsets of both CD4 and CD8 T cells; and B cells. Cell abundances were transformed using a centered log-ratio (CLR) method to account for the compositional nature of blood-cell counts, and marker expression was summarized as sample-level median arcsinh-transformed intensities. Composite module scores were built from markers associated with type I interferon signaling, Th1 chemokines, pro-inflammatory cytokines, CCL2–CCR2 axis, antigen presentation, activation, and cytotoxicity, alongside individual readouts for global H3K27ac—a histone modification marking active promoters and enhancers—and m6A, the most prevalent internal modification of eukaryotic mRNA.

The results revealed a strikingly rapid, lineage-specific redistribution of circulating immune cells. Within 24 hours, classical and intermediate monocytes showed the largest positive shifts in relative abundance, consistent with mobilization of the myeloid compartment in response to vaccine-derived signals. In contrast, plasmacytoid dendritic cells, natural killer cells, and selected CD8 and unconventional T-cell populations showed prominent negative shifts. The four major CD4 T-cell populations—naive, central memory, effector memory, and terminally differentiated effector memory—remained comparatively stable on this relative-composition scale. These changes were accompanied by distinct, lineage-restricted alterations in intracellular and phenotypic markers: classical monocytes displayed prominent changes in MCP-1, arginase-1, and H3K27ac; intermediate monocytes showed changes in CCR2, CD38, and IL-4; pDCs exhibited changes in granzyme B and CXCR3; and NK cells showed marked alterations in CD69 and CD56.

Crucially, the team found that early changes in global m6A and H3K27ac signals correlated with relative-abundance changes in selected innate and T-cell populations. m6A changes correlated positively with classical and intermediate monocyte abundance but inversely with pDC and NK-cell abundance. H3K27ac changes were also inversely correlated with pDC and NK-cell abundance. Within the T-cell compartment, both m6A and H3K27ac changes were inversely related to CD4 naive T-cell abundance, while m6A changes were positively associated with CD4 effector memory abundance but inversely associated with CD8 naive and CD8 central memory abundance. These correlations suggest that global modification signals track distinct differentiation-state trajectories across the immune landscape, though the authors caution that correlation does not establish causation.

When the researchers examined whether these early cellular and molecular changes predicted subsequent neutralizing-antibody responses, the picture became more nuanced. Both groups showed broad increases in serum neutralization against a panel of SARS-CoV-2 variants—including the prototype strain, Alpha, Beta, BA.4/5, BF.7, BQ.1.1, XBB.1.5, XBB.1.16, XBB.1.9.1, and JN.1—measured longitudinally through Day 180 using a vesicular stomatitis virus-based pseudovirus neutralization assay. However, after excluding antibody measurements obtained on or after documented breakthrough infection and applying Benjamini–Hochberg correction across the complete 340-test family of cell population–marker–strain combinations, no early H3K27ac- or m6A-associated signal change remained significantly associated with Day 14 or Day 180 neutralizing-antibody responses. The strongest nominal association—an inverse relationship between early H3K27ac change in CD4 central memory cells and the BF.7 response—did not survive correction.

The most compelling finding emerged when the team compared early immune trajectories between participants who subsequently developed documented breakthrough infection and those who did not. Major-cell abundance trajectories did not differ significantly between the two groups, indicating that the broad redistribution of circulating immune populations was shared regardless of later infection status. However, a focused screen of 13 prespecified feature readouts across all 17 major immune-cell populations—comprising 221 tests—revealed five feature–cell-population combinations that remained significant after global multiple-testing correction. Four of these were concentrated within the CD4 naive T-cell compartment: the IFN–Th1 chemokine-associated, cytotoxic–Th1-associated, and CCL2–CCR2-associated marker scores, and the m6A-associated readout. The fifth involved the cytotoxic–Th1-associated score in CD4 central memory cells. Relative to non-BTI participants, individuals who subsequently developed breakthrough infection showed smaller—more negative—Day 0-to-Day 1 changes in each of these features.

The authors emphasize that these composite scores represent combinations of measured markers rather than direct functional assays. Signal intensity varied substantially among constituent markers within CD4 naive cells: granzyme B was robustly detected, while MCP-1, CXCL9, and CD57 showed measurable intermediate-level signals, but IFN-γ, CD86, and CXCR3 exhibited relatively low absolute intensities. Unsupervised clustering further resolved 11 phenotypic subclusters within the CD4 naive compartment, demonstrating substantial internal heterogeneity, though the significant associations were identified at the total population level and cannot yet be assigned to specific subclusters. A sensitivity analysis adjusting for age, sex, and vaccine product using HC3 robust standard errors confirmed the direction of the BTI-associated differences for all four CD4 naive features.

The study’s implications extend beyond the immediate findings. By demonstrating that dynamic early immune states—captured within 24 hours of vaccination—can capture outcome-associated variation not evident from major-cell abundance alone, the work supports a broader paradigm shift in systems vaccinology: rather than relying on static baseline measurements or single downstream readouts, researchers may need to characterize the full temporal trajectory of immune responses to understand why some individuals remain protected while others experience breakthrough infection. The authors note that breakthrough infection is influenced by factors beyond measured immune features, including exposure intensity, circulating viral variants, mucosal immunity, and behavioral factors, and that illness-triggered surveillance may have missed asymptomatic infections. Future studies integrating antigen-specific assays, absolute cell counts, single-cell RNA sequencing, chromatin-accessibility profiling, and transcript-resolved m6A analysis will be necessary to define the biological pathways underlying these early CD4 naive T-cell associations and to establish their clinical relevance as correlates of vaccine-response heterogeneity.

Subject of Research: Mass cytometry study of early immune remodeling after mRNA booster vaccination and its association with breakthrough infection

Article Title: Mass cytometry of early immune remodeling after mRNA booster vaccination reveals exploratory CD4 naive T-cell associations with documented breakthrough infection

Article References: Yu, X., Jiang, X., Xue, Y., Ji, Y., Li, C., Zhang, Z. S., & Cheng, R. (2026). Mass cytometry of early immune remodeling after mRNA booster vaccination reveals exploratory CD4 naive T-cell associations with documented breakthrough infection. Frontiers in Cellular and Infection Microbiology, 16, Article 1966930. https://doi.org/10.3389/fcimb.2026.1966930

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1966930

Keywords: mRNA vaccine, mass cytometry, breakthrough infection, CD4 naive T cells, H3K27ac, m6A, Mass, cytometry, early, immune, remodeling, mRNA

The EG95 protein has occupied a special place in echinococcosis research since its discovery as a protective antigen from oncosphere-stage parasites. Recombinant EG95-based vaccines have shown efficacy in sheep and have been deployed in some control programs, but the platform has persistent weaknesses. Protein subunit vaccines tend to elicit immune responses that wane relatively quickly, requiring booster doses and careful scheduling to maintain protection in flocks. Their production depends on expression systems that can be technically demanding, and the immunogenicity of the purified antigen, while real, is modest compared with what newer vaccine technologies can achieve. For a neglected zoonotic disease whose control depends on vaccinating large numbers of livestock in resource-limited settings, those limitations matter enormously.

The Chinese research group, whose members span institutions working on parasitic diseases and veterinary science, reasoned that the mRNA-lipid nanoparticle platform, which transformed human vaccinology during the COVID-19 pandemic, could address these shortcomings. mRNA vaccines instruct the recipient’s own cells to manufacture the target antigen, which means the protein is produced in its native form, with appropriate folding and post-translational modifications, and presented to the immune system in a context that engages both antibody and T-cell arms of immunity. The lipid nanoparticles that deliver the messenger RNA also act as built-in adjuvants, stimulating innate immune sensors that amplify the adaptive response. Manufacturing is fast, scalable, and does not require cell culture systems specific to each antigen, making the platform attractive for diseases that have never attracted the commercial investment of human medicine.

From this starting point, the team designed three vaccine candidates. The first was a straightforward EG95 mRNA-LNP vaccine, encoding the canonical protective antigen. The second, an IL-4-EG95 mRNA-LNP vaccine, was more inventive: it encoded a fusion protein in which EG95 was joined to interleukin-4, an immune signaling molecule, via a flexible peptide linker. The idea was to exploit the cytokine as a molecular adjuvant, tethering an immunostimulatory signal directly to the antigen so that cells taking up the vaccine would present EG95 in a context primed to enhance immune activation. The third candidate, an EG95-EC95 mRNA-LNP vaccine, took a multivalent approach, incorporating EC95 antigens derived from Echinococcus canadensis, a related parasite species within the E. granulosus sensu lato complex. Because the parasite species complex encompasses organisms with antigenic variation, a formulation that covers multiple variants could broaden protection across the range of parasites circulating in different regions and host species.

The researchers confirmed that all three vaccine candidates were efficiently encapsulated in lipid nanoparticles and that the encoded antigens were robustly expressed both in cell culture and in vaccinated animals. Expression of the target protein is the essential first step for any mRNA vaccine, and the fusion constructs, despite their added complexity, performed well. With the platform validated in vitro, the team moved to animal studies, comparing the mRNA vaccines head-to-head with a commercial EG95 subunit vaccine, the benchmark against which any new echinococcosis vaccine must be measured.

The immunological results were striking. In both mice and lambs, the mRNA-LNP vaccines induced humoral and cellular immune responses that were significantly stronger than those provoked by the subunit vaccine. Antibody titers rose higher and, critically, persisted longer: the animals maintained high levels of EG95-specific antibodies for more than twelve months after vaccination. For a livestock vaccine intended to protect animals through the period when they are most vulnerable to infection and through the breeding cycles of a working flock, that durability is a decisive advantage. It suggests that a vaccination schedule built on the mRNA platform could achieve with fewer doses what currently requires repeated boosters, reducing the logistical burden on herders and veterinary services in endemic regions.

Cellular immunity, often the neglected dimension in evaluations of antiparasitic vaccines, also differed markedly between the platforms. The mRNA vaccines engaged T-cell responses to a degree the subunit formulation did not match, a consequence of the way lipid nanoparticles deliver their cargo into cells and stimulate innate immune pathways. Because the immune response to Echinococcus involves both antibodies that attack oncospheres as they attempt to establish infection and cellular mechanisms that shape the environment around developing parasites, the breadth of the response induced by the mRNA platform may explain much of its protective superiority.

The decisive test came from parasite challenge experiments. When vaccinated animals were exposed to Echinococcus infection, the three mRNA-LNP vaccines all conferred protection, but the IL-4-EG95 fusion vaccine stood out. In animals receiving that formulation, the survival of protoscoleces, the larval forms that seed hydatid cysts, was inhibited, and the growth of cysts that did establish was suppressed. The fusion of the cytokine to the antigen, an approach that might have backfired by skewing immunity in an unhelpful direction, instead delivered the most effective protection of any candidate tested. The result validates the concept of genetically adjuvanted mRNA vaccines for parasitic diseases and suggests that the IL-4-EG95 construct is the leading candidate for further development.

The implications extend beyond echinococcosis itself. Cystic echinococcosis is one of many neglected zoonotic diseases for which the economics of vaccine development have never worked in favor of conventional platforms. The mRNA approach offers safety, scalability, and flexibility: the same lipid nanoparticle technology can be adapted to new antigens simply by changing the encoded sequence, and manufacturing does not depend on the biological quirks of expression systems. For a disease whose control requires coordinated vaccination of livestock, deworming of dogs, and public health surveillance across vast rural landscapes, a vaccine that is both more effective and longer-lasting could shift the calculus of elimination programs that have struggled for decades.

The study, published in PLOS Pathogens, positions EG95-based mRNA vaccines as a promising strategy for reducing the transmission of E. granulosus sensu lato and, with it, the zoonotic burden of cystic echinococcosis in the communities where the parasite remains endemic. Challenges remain before the platform reaches the field, including the regulatory pathways for veterinary mRNA vaccines, cold-chain requirements for lipid nanoparticle formulations, and the scale-up of challenge studies in livestock under natural transmission conditions. But the demonstration that mRNA vaccines can outperform the established subunit benchmark in both magnitude and duration of immunity, and that a cytokine-antigen fusion can push protection even further, gives researchers and control programs a concrete new tool to pursue. For a neglected disease that has waited decades for a technological leap, the arrival of one may finally be at hand.

Subject of Research: Development of EG95-based mRNA-lipid nanoparticle vaccines inducing long-term protective immunity against cystic echinococcosis

Article Title: Novel EG95-based mRNA vaccines induce long-term protective immunity against echinococcosis

Article References: Chen, W.-G., Li, L., Dai, G.-D., Wu, Y.-D., Zhu, C.-G., Zhang, H., Li, X.-R., Li, L., Zhang, N.-Z., Wang, L.-Q., Li, G.-C., Ma, W.-L., Pan, J.-T., Tan, M.-L., Da, F.-L., Yin, H., Fu, B.-Q., Luo, X.-N., Yan, H.-B., & Jia, W.-Z. (2026). Novel EG95-based mRNA vaccines induce long-term protective immunity against echinococcosis. PLOS Pathogens, 22(10), e1014659. https://doi.org/10.1371/journal.ppat.1014659

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014659

Keywords: echinococcosis, Echinococcus granulosus, EG95, mRNA vaccine, lipid nanoparticles, zoonotic disease, veterinary vaccinology, humoral immunity, IL-4, parasitology, vaccine development, one health

HER2, a transmembrane receptor tyrosine kinase belonging to the EGFR family, is best known as a driver of breast and gastric cancers, but it is also overexpressed in roughly 7.7 to 23 percent of NSCLC patients. These tumors tend to be aggressive and respond poorly to chemotherapy and conventional targeted agents. Antibody-drug conjugates such as trastuzumab deruxtecan have shown promise, yet they are currently recommended only for HER2-mutant disease, and the DESTINY-Lung01 trial documented substantial grade 3 or higher toxicity and treatment-related deaths in HER2-overexpressing patients. The research team, led by investigators affiliated with Hebei Medical University, set out to fill this gap with a vaccine strategy that recruits the patient’s own immune system rather than relying on systemic drug exposure.

The vaccine itself is a classic product of the post-COVID mRNA era. The researchers synthesized mRNA encoding the human HER2 extracellular domain through in vitro transcription, capping, and polyadenylation, then encapsulated it in lipid nanoparticles built on the well-characterized MC3 ionizable lipid formulation, mixed at a molar ratio of DLin-MC3-DMA, DSPC, cholesterol, and DMG-PEG2000 of 50:10:38.5:1.5. Using a microfluidic device, they produced particles with a median diameter of about 71 nanometers, a polydispersity index of just 0.072, and an encapsulation efficiency of roughly 80 percent. Cryo-electron microscopy showed uniform, spherical particles with dense mRNA cores. Once injected intramuscularly, the nanoparticles deliver their cargo to dendritic cells and other host cells, where the HER2 protein is translated, processed by the proteasome, and presented on both MHC class I and class II molecules, priming cytotoxic T cells and antibody production against what is normally a self-antigen.

Immunogenicity was robust. In both BALB/c and C57BL/6 mice, three doses of the vaccine drove high serum titers of HER2-specific antibodies, and booster immunization pushed titers progressively higher over time. Crucially, the antibody response worked across two different MHC backgrounds, hinting that the antigen design may generalize beyond a single genetic context. Safety testing at the day 70 endpoint showed no pathological changes in heart, liver, lung, or spleen on histology, and complete blood counts, liver enzymes, renal markers, and cardiac enzymes all remained within normal ranges. The only notable finding was reduced spleen weight in vaccinated mice, which the authors attribute to relief of tumor-driven compensatory splenic enlargement rather than toxicity.

To test efficacy, the team engineered a Lewis lung carcinoma cell line stably overexpressing human HER2 using a transposon system, confirming expression levels that fell between the HER2-high breast cancer line SKBR3 and the moderate expresser A549, mirroring the clinical spectrum seen in NSCLC patients. In a prophylactic setting, mice vaccinated before tumor challenge showed significantly slower tumor growth from day 4 onward, and the addition of radiotherapy, delivered as three 8-Gy fractions totaling 24 Gy from a clinical linear accelerator, produced the smallest tumors of any group throughout the 24-day observation window. A striking inverse correlation emerged between antibody titer and final tumor volume, with a Pearson coefficient of -0.889, suggesting the humoral response tracks closely with tumor control.

The therapeutic arm of the study was arguably more clinically relevant. When vaccination began only after tumors were established, with radiotherapy administered on day 14, the combination again outperformed either modality alone, with significantly smaller tumor volumes from day 3 onward and the greatest reductions in both tumor weight and proliferative Ki67 staining. Splenic T lymphocytes from combination-treated mice showed the highest cytotoxic killing of HER2-LLC cells in co-culture assays. Immunohistochemistry confirmed that both HER2 expression and proliferation markers dropped most steeply in the combination group, consistent with the vaccine sensitizing tumors to radiation.

Flow cytometry revealed the mechanistic story underneath these outcomes. Within tumors, the combination therapy increased CD8-positive T cell infiltration beyond either monotherapy and raised the CD8-to-CD4 ratio significantly. Macrophages shifted decisively toward the antitumor M1 phenotype: the M1-to-M2 ratio rose twentyfold with the vaccine alone and thirtyfold with the combination, indicating that radiation amplifies a vaccine-driven reprogramming of the myeloid compartment. NK cells and B cells also expanded, while immunosuppressive regulatory T cells declined. In the spleen, the same pattern held, accompanied by elevated secretion of IFN-gamma, TNF-alpha, IL-2, and IL-4, painting a picture of coordinated systemic Th1-dominant activation with humoral support.

One of the most intriguing findings concerns T cell differentiation. The combination regimen reduced the fraction of CD44-negative CD62L-negative double-negative T cells, a short-lived terminally differentiated subset, while boosting CD8-positive effector memory cells and granzyme B-expressing cytotoxic cells. The authors interpret this as radiation-induced bystander activation at work: irradiated tumor cells undergo immunogenic cell death, releasing damage-associated molecular patterns that redirect quiescent T cells away from transient effector fates and toward durable, memory-like phenotypes with sustained killing capacity. If this holds in humans, the combination might not only shrink existing tumors but seed long-term immune memory against recurrence.

The authors are candid about the limitations of their model. Human HER2 is a xenogeneic antigen in mice, lacking a normal-tissue homolog, which likely inflates the apparent immunogenicity and prevents meaningful assessment of autoimmune risk, a critical concern for any self-antigen-targeted vaccine. The engineered cell line cannot reproduce the heterogeneity of HER2 expression in human tumors, all experiments used male mice to avoid hormonal confounders, and safety was assessed only at a single terminal time point. The team proposes follow-up work in HER2-transgenic or humanized models, dynamic toxicity monitoring, T cell depletion and antibody transfer experiments, epitope mapping, and combination studies with immune checkpoint inhibitors.

Even with those caveats, the study stakes out an important translational position. Only a handful of LNP-based mRNA vaccines have reached clinical testing in lung cancer, and none have specifically targeted HER2-overexpressing patients. Earlier mRNA approaches, such as the five-antigen vaccine BI 1361849 combined with radiotherapy in stage IV NSCLC, demonstrated tolerability and immune activation but did not focus on this molecular subtype. By showing that a single-antigen HER2 mRNA-LNP vaccine can both prevent tumor establishment and radiosensitize established disease, the researchers provide a preclinical rationale for a radio-immunotherapy strategy aimed at one of the most refractory corners of lung oncology, where the flexibility of the mRNA platform could eventually support personalized antigen selection and rapid clinical iteration.

Subject of Research: Combined HER2-targeted mRNA-LNP vaccine and radiotherapy immunotherapy for HER2-overexpressing non-small cell lung cancer in mice

Article Title: Combined HER2‐targeted mRNA‐LNP vaccine and radiotherapy suppress Lewis lung carcinoma growth in mice: Efficacy and mechanistic insights

Article References: Wang, S., Jing, S., Zou, S., Zhang, Y., Ge, M., Gao, K., Li, X., Zhao, L., & Wang, J. (2026). Combined HER2 ‐targeted mRNA ‐ LNP vaccine and radiotherapy suppress Lewis lung carcinoma growth in mice: Efficacy and mechanistic insights. Bioengineering & Translational Medicine, 11(5), Article e70160. https://doi.org/10.1002/btm2.70160

Image Credits: AI Generated

DOI: 10.1002/btm2.70160

Keywords: mRNA vaccine, lipid nanoparticles, HER2, non-small cell lung cancer, radiotherapy, radio-immunotherapy, CD8 T cells, M1 macrophage polarization, tumor microenvironment, Lewis lung carcinoma, immunogenic cell death, preclinical study

The scale and breadth of the data collection is what sets this study apart. Rather than measuring a handful of immune markers, the team assembled four complementary omics layers from the same longitudinal samples: transcriptomics, which captures gene expression patterns in circulating immune cells; metabolomics, which profiles the small molecules that fuel and regulate cellular chemistry; lipidomics, which maps the fat-based signaling molecules and membrane components that shift during inflammation; and cytokine measurements, which quantify the soluble messengers that immune cells use to communicate. Integrating these layers allowed the investigators to move beyond the question of whether a vaccine produces antibodies and toward a systems-level picture of how vaccination reorganizes host physiology. This approach, often called systems vaccinology, treats the immune response not as an isolated event but as a coordinated, body-wide program of gene regulation, metabolism and cellular signaling.

The headline finding is that the two vaccine platforms produce pronounced and persistent differences in their multiomic fingerprints. BNT162b2 induced far more profound changes across the omics landscape than CoronaVac, with particularly marked alterations in adaptive immunity and in metabolomic function. That is consistent with the mechanistic distinction between the platforms: an mRNA vaccine delivers genetic instructions that cause the recipient’s own cells to manufacture the SARS-CoV-2 spike protein, triggering a potent innate sensing response and driving strong T-cell help and B-cell maturation. An inactivated virus vaccine, by contrast, presents a killed, non-replicating virus that primarily stimulates antibody production through more contained innate signaling. The molecular consequences of those different entry points into the immune system, the study shows, ripple outward into gene expression programs and metabolic pathways that remain measurable for months.

Perhaps the most striking observation is durability. At six months after the second dose, recipients of BNT162b2 still displayed a durable immunological imprint, characterized by persistent modifications in immune gene expression and ongoing metabolic reprogramming. In other words, the mRNA vaccine did not simply provoke a transient burst of activity that faded back to baseline; it left a lasting signature in the transcriptome and metabolome of vaccinated individuals. The authors link this prolonged imprint to the vaccine’s known immunogenicity and to the durability of protection it confers. CoronaVac recipients, meanwhile, showed a more subdued and less persistent omics response, which aligns with clinical observations that inactivated-virus primary series generally elicit lower and more rapidly waning neutralizing antibody levels than mRNA vaccines, particularly against evolving variants of concern.

One of the study’s technical contributions lies in its analysis of crosstalk between omics layers. The researchers found substantially greater interplay between transcriptomic, metabolomic and lipidomic features in the BNT162b2 group, suggesting that the mRNA platform engages a more integrated, multi-system response. Crosstalk of this kind matters because immune outcomes rarely depend on a single molecule. Gene expression changes drive metabolic shifts; metabolites in turn feed back on signaling pathways that regulate cytokine production and lymphocyte differentiation. A vaccine that coordinates these layers coherently may be more effective at shepherding naive immune cells through the full program of activation, clonal expansion, germinal center reaction and memory formation. The enhanced crosstalk observed after BNT162b2 vaccination, the authors argue, is related to the platform’s stronger immunogenicity and longer-lasting protection.

Beyond describing group-level differences, the team asked whether a person’s baseline molecular state—measured before any vaccination—could predict how well they would respond to a given vaccine. Using predictive modeling on the multiomics data, they found that pre-vaccination profiles could forecast vaccine-specific performance with area under the curve values of 0.73 to 0.79. In practical terms, that means the metabolic and transcriptional state of an individual before vaccination carries meaningful information about the strength and character of the immune response they will mount. An AUC in this range is well above chance and, while not yet accurate enough for standalone clinical decision-making, it demonstrates that the concept of predicting vaccine responsiveness from a baseline blood draw is scientifically viable. It also hints at why vaccine responses vary so widely between individuals: differences in baseline metabolism, immune tone and inflammatory state shape how the same vaccine is interpreted by different bodies.

The study’s setting gives it particular epidemiological weight. Hong Kong was one of the few places where mRNA and inactivated-virus vaccines were deployed side by side in large numbers during the primary vaccination campaign, creating a natural comparative cohort that would have been difficult to assemble elsewhere. Because both groups lived through the same pandemic conditions, were exposed to the same circulating variants and were recruited through the same health system, confounding from environment and exposure history is reduced. The 553-participant cohort, with samples spanning half a year, therefore provides an unusually clean head-to-head comparison of the two dominant vaccine platforms used across Asia and much of the world, where CoronaVac and similar inactivated vaccines reached billions of arms.

The implications extend beyond COVID-19. The finding that mRNA vaccination produces a prolonged metabolic reprogramming and persistent immune gene modification adds to a growing body of literature on trained immunity, the concept that innate immune cells undergo long-term epigenetic and metabolic rewiring after stimulation, altering their responsiveness to future challenges. If mRNA vaccines induce a durable trained-immunity-like state, that could partly explain their robust performance and could inform the design of future mRNA vaccines against influenza, respiratory syncytial virus, cancer and other targets. Conversely, understanding the molecular reasons why inactivated vaccines elicit narrower and less durable signatures could guide adjuvant choices or prime-boost regimens that combine platforms to broaden and prolong protection.

The authors are explicit about the translational direction of the work. They advocate integrating multiomics data to tailor vaccination strategies to individual immune profiles, with the goal of enhancing public health outcomes. In a future shaped by this kind of systems vaccinology, a pre-vaccination blood test could, in principle, identify who is likely to respond poorly to a standard regimen and who might benefit from an alternative platform, an earlier booster or an adjusted dose. The predictive models reported here, with their moderate but real discriminatory power, are early proof of concept for that vision. Before such tests reach the clinic, they would need validation in independent cohorts, standardization of assays across laboratories and demonstration that acting on a prediction actually improves outcomes. The cost of multiomics profiling, while falling, also remains a barrier to population-scale deployment.

Limitations should temper interpretation of the results. The study captured the primary two-dose series and did not follow participants through boosters or breakthrough infections, both of which reshape the omics landscape further. Multiomics datasets are high-dimensional, and associations between molecular signatures and protection, however biologically plausible, are correlational rather than proof of mechanism. The published version of the article is also subject to final editorial processing, as it was shared early under Springer Nature’s open-access policy with a permanent DOI. Even so, the study stands as a landmark demonstration that two vaccines against the same pathogen, both highly effective at reducing severe disease, inscribe fundamentally different and enduring patterns on human biology. As vaccine development accelerates for emerging pathogens, the lesson is clear: the platform matters not only for how strong the response is, but for what kind of molecular memory it leaves behind.

Subject of Research: Longitudinal multiomic comparison of host immune responses to mRNA and inactivated virus COVID-19 vaccines

Article Title: Differential prolonged multiomic responses to mRNA and inactivated virus COVID-19 vaccines

Article References: Tun, H. M., Zhao, S., Chen, C., Chen, Y., Peng, Y., Lv, H., Zhu, J., Tang, Y. S., Chan, K. K. P., Ip, B. Y., Sun, Y., Liu, X., Yiu, K., Hui, D. S. C., & Mok, C. K. P. (2026). Differential prolonged multiomic responses to mRNA and inactivated virus COVID-19 vaccines. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06455-z

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06455-z

Keywords: COVID-19 vaccines, mRNA vaccine, BNT162b2, CoronaVac, inactivated virus vaccine, multiomics, transcriptomics, metabolomics, lipidomics, cytokines, systems vaccinology, immune durability

The strategy, termed Proactive Immune Training (PIT), draws its inspiration from an observation that has become increasingly clear over the course of the COVID-19 pandemic. People who experienced natural infection followed by vaccination—so-called hybrid immunity—tend to mount broader and more durable protection against reinfection and severe disease than those receiving either alone. The explanation lies in the evolutionary arms race that unfolds during a natural infection: as the virus mutates within the host, immune pressure selects for B cells capable of recognizing an expanding repertoire of antigenic shapes. This dynamic training drives somatic hypermutation and the eventual emergence of broadly neutralizing antibodies that can accommodate variant-level changes. The catch is obvious. Acquiring immunity through infection carries real risks of severe illness and death, and existing mRNA vaccines present only static antigens that cannot evolve inside the host, so they never recreate this dynamic antigenic landscape.

PIT was designed to reproduce that landscape synthetically, without the danger of infection. Using SARS-CoV-2 as a model, the research team, led by Xiangrong Song of Sichuan University, first turned to computational prediction. They applied the PyR0 pipeline, a hierarchical Bayesian regression framework trained on approximately 6.4 million SARS-CoV-2 genomes from GISAID, to estimate the fitness contribution of potential spike protein mutations. The model, which achieved an R-squared of 0.983 for fitness estimates in prior validation, ranks mutations by a Z-score that incorporates estimation uncertainty. From this global fitness landscape the researchers selected 30 high-probability mutation sites in the Spike protein, including well-characterized immune escape hotspots such as residues E484, K417, and N501, along with sites like L452, S477, N501, and P681 that have repeatedly defined variants of concern.

With the 30 sites in hand, the team performed saturation mutagenesis, systematically substituting every possible amino acid at each position to generate a DNA plasmid library of 600 distinct Spike antigens: 570 unique single-point mutants plus the wild-type sequence. Quality control was rigorous. Next-generation sequencing confirmed that residual wild-type had been reduced to 0.25 percent of the library, coverage of the intended mutants reached 98.4 percent, and a Gini coefficient of 0.17 indicated that the genetic diversity was evenly distributed rather than skewed toward a few dominant clones. Translational fidelity was verified by expressing ten representative mutants in HEK293T cells and quantifying Spike production by ELISA, which showed expression levels consistent with the wild-type protein. The plasmid pool was then transcribed in vitro into a matching mRNA library, ensuring that each training antigen retained its structural integrity while presenting deliberate variation at the key hotspots where immune escape is most likely to occur.

Delivering 600 different mRNA species simultaneously required an efficient and homogeneous delivery vehicle. The researchers formulated their library in lipid nanoparticles built around CMP1, an ionizable lipid developed in-house and protected under US Patent 11,839,657. Using microfluidic mixing, they produced particles averaging roughly 100 nanometers in diameter with a low polydispersity index of about 0.2. Nanoflow cytometry revealed an mRNA encapsulation efficiency of 90 percent and a remarkably low empty-particle ratio of 1.7 percent. In vitro, CMP1-based nanoparticles doubled the transfection efficiency achieved by the common reagent Lipofectamine 2000, and cryo-electron microscopy confirmed uniform, quasi-spherical particles with intact lipid bilayers. In mice, the platform showed preferential uptake by splenic dendritic cells and neutrophils, and confocal imaging demonstrated superior endosomal escape compared with the ALC-0315 lipid used in clinically approved mRNA vaccines, a critical property because mRNA trapped in lysosomes is degraded before it can be translated.

The immunization regimen itself was carefully staged. Mice first received a prime with a conventional single-antigen vaccine encoding the Delta variant Spike protein, establishing a foundational pool of memory B cells. Fourteen days later, a subset received a booster dose of the PIT vaccine containing the full 600-antigen m-library. The logic mirrors natural infection: the prime creates a high-quality substrate of memory, while the boost challenges that memory with a dense landscape of related but distinct variants, driving affinity maturation toward clones that can tolerate or recognize multiple mutational states. Control groups received two doses of the single-antigen vaccine, two doses of the PIT vaccine alone, or a hexavalent cocktail of six whole-Spike mRNAs spanning the wild-type, Alpha, Beta, Gamma, Delta, and Omicron BA.1 variants, providing a direct benchmark against a rational multivalent design.

The results of the prime-boost sequence were striking. The SA+PIT regimen elicited significantly higher serum IgG binding titers and pseudovirus neutralization titers across a panel of ten SARS-CoV-2 variants, including Alpha, Beta, Gamma, Delta, Omicron BA.2, BA.2.75, BA.5, and BF.7, compared with two doses of the single-antigen vaccine. Notably, BA.5 and BF.7 had not yet emerged when the PyR0 model was trained, so the breadth against these variants demonstrates genuine anticipatory capacity. When compared head-to-head with the hexavalent cocktail, the two strategies performed similarly against BA.2, which is antigenically close to the cocktail’s Omicron component, but the PIT-boosted group generated significantly higher binding and neutralizing titers against the more divergent BA.5 and BF.7 variants, with P values below 0.01. The authors interpret this as evidence that dense mutational coverage fills the antigenic gaps between discrete variants of concern, providing better protection against evolutionary drift within the predicted mutational space than a mixture of known strains.

Cellular immunity showed a parallel enhancement. Flow cytometry of splenocytes revealed that the SA+PIT regimen significantly increased the frequency of IFN-γ-producing CD4-positive and CD8-positive T cells, expanded the T follicular helper cell population that supports antibody maturation, and boosted IFN-γ production by B cells, while IL-2 responses remained comparable between vaccinated groups. Single-cell T cell receptor and B cell receptor sequencing, performed ten days after a rapid day-0/day-7 immunization schedule, showed markedly greater diversity in the BCR heavy chain and both kappa and lambda light chain repertoires, with a larger fraction of unique CDR3 sequences, the hypervariable regions that determine antigen specificity. The repertoires also displayed a transcriptomic shift toward the IgA subclass, hinting at broader isotype diversification, although mucosal IgA protein was not directly measured. Importantly, safety evaluations at a higher 50-microgram dose showed no significant changes in blood chemistry markers and no histopathological abnormalities in the heart, liver, spleen, lung, or kidney.

The authors are candid about the study’s limitations. The work remains a proof of concept based on surrogate endpoints such as ELISA binding and pseudovirus neutralization; no live-virus challenge experiments were performed, and protective efficacy must be confirmed in K18-hACE2 transgenic mice or non-human primates. Mechanistic cohorts were small, the BALB/c mouse model incompletely recapitulates human immunity, the study did not benchmark against clinically licensed mRNA vaccines such as BNT162b2 or mRNA-1273, and the manufacturing complexity of a 600-mutant library presents substantial hurdles for clinical-grade production. Germinal center dynamics, affinity maturation kinetics, and the precise epitopes underlying cross-reactivity also remain to be mapped. Yet the framework is inherently adaptable: the same combination of computational fitness prediction, saturation mutagenesis, and LNP delivery could, in principle, be extended to influenza or entirely novel pathogens, with artificial intelligence models predicting mutational landscapes directly from sequence data. The broader significance is conceptual. Vaccines have long been built to match the past; PIT suggests they could instead be built to anticipate the future, presenting the immune system with a cloud of evolutionary possibilities and letting it train against them before the virus ever gets the chance.

Subject of Research: A proactive mRNA vaccine strategy using a library of predicted SARS-CoV-2 Spike mutants to broaden antiviral immunity against future variants

Article Title: A proactive immune training strategy to generate anticipatory immunity against viral evasion

Article References: Qin, S., Teng, Y., Xin, J., Zhang, Y., Huang, L., Zhao, S., Jiao, X., Yin, X., Liu, S., Sun, J., Xu, W., Xie, Y., Liu, J., Kong, L., & Song, X. (2026). A proactive immune training strategy to generate anticipatory immunity against viral evasion. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.08.059

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.08.059

Keywords: SARS-CoV-2, mRNA vaccine, Proactive Immune Training, viral immune evasion, broadly neutralizing antibodies, lipid nanoparticles, saturation mutagenesis, variant of concern, BCR repertoire, hybrid immunity, PyR0 model, vaccinology

A new study published in the Journal of Translational Medicine reports a rational engineering strategy designed to break that tolerance. Researchers led by a Danish team spanning the University of Copenhagen and the biotechnology company HERVolution Therapeutics systematically mutated the envelope protein of HERV-K, focusing on a short stretch known as the immunosuppressive domain, or ISD. This domain, conserved among retroviral envelope proteins, is thought to dampen innate immune signaling and help the virus evade detection. The team hypothesized that disabling this domain without destroying the overall structure of the envelope protein could convert a poorly immunogenic self-antigen into a potent vaccine immunogen capable of awakening T cells against HERV-K-expressing tumors.

The engineering effort centered on a single amino acid substitution. Through a mutational screen across the ISD region, the researchers identified a mutation designated Q525A, in which the glutamine at position 525 of the envelope protein is replaced with alanine. This variant, termed ISDmut, had a measurable effect on innate immune signaling: cells expressing the mutated envelope showed enhanced activation of nuclear factor kappa B, or NF-κB, a central transcription factor in inflammatory and antiviral responses. Importantly, the mutation did not sabotage the assembly of virus-like particles, meaning the engineered envelope still formed the particulate structures that present antigen to the immune system in a native-like configuration. Preserving this architecture while removing immunosuppressive function was the key design goal.

To probe how the engineered antigen behaves in human immune cells, the team transduced monocyte-derived dendritic cells, the professional antigen-presenting cells that orchestrate T cell responses, with HERV-K-ISDmut constructs. Using flow cytometry, RNA sequencing, and transmission electron microscopy, they found that the mutated envelope increased antigen expression and shifted dendritic cell gene expression toward pathways associated with antigen presentation and cell death, both of which favor productive immune priming. The dendritic cells carrying the engineered antigen were then co-cultured with peripheral blood mononuclear cells from healthy human donors. The result was robust expansion of both CD4-positive and CD8-positive T cells, and critically, the expanded T cells recognized HLA-matched tumor cells that naturally express HERV-K. This demonstrated that the human T cell repertoire, despite lifelong exposure to HERV-K as a self-antigen, retains usable anti-HERV-K reactivity that can be mobilized with the right immunogen.

The next question was whether the engineered antigen could induce immune responses in living organisms, where tolerance mechanisms operate at full strength. The researchers evaluated two delivery platforms: adenoviral vectors and lipid nanoparticle-formulated messenger RNA. In mice, both mRNA and adenoviral vectors encoding HERV-K-ISDmut elicited strong cellular and humoral immune responses. More demanding still, the team tested the construct in HERV-K transgenic mice, animals engineered to carry the human HERV-K gene and therefore immunologically tolerant to it, a model that closely mimics the situation in human patients. Vaccination broke this tolerance, inducing responses against an antigen the immune system had been trained to ignore. The platform was also evaluated in cynomolgus macaques, non-human primates whose immune systems are more similar to our own, where the vaccine induced antibody responses, providing early evidence of translational feasibility across species.

Immunogenicity alone does not guarantee therapeutic benefit, so the team moved to a tumor model. They used a murine metastatic renal carcinoma model in which the tumor cells were made to express the HERV-K envelope, recreating the antigen profile of HERV-K-positive human cancers. In this setting, immunization with an adenovirus-vectored HERV-K-ISDmut vaccine conferred increased survival compared with controls. The researchers also examined how the vaccine interacted with checkpoint blockade, the class of drugs that releases the brakes on T cells. Combining the vaccine with anti-PD-1 antibody therapy provided additional benefit, suggesting that a therapeutic cancer vaccine targeting HERV-K could be rationally paired with existing immunotherapies rather than competing with them.

The biological logic underlying this strategy deserves attention. HERV-K expression in tumors is not a random curiosity. Hypomethylation of the genome, a hallmark of transformed cells, reactivates endogenous retroviral loci that are silenced in healthy tissues. This creates what immunologists call a tumor-associated antigen with viral characteristics: it is foreign in sequence, yet encoded by the patient’s own DNA and expressed almost exclusively in malignant tissue. Unlike personalized neoantigen vaccines, which require sequencing and manufacturing tailored to each patient’s tumor mutations, a shared antigen such as HERV-K could in principle support an off-the-shelf vaccine applicable to broad patient populations across multiple cancer types. The study’s authors argue that this breadth is precisely what makes the engineered ISDmut antigen a promising platform rather than a single-disease tool.

The work also illustrates a broader principle in retrovirology and vaccine design: the immunosuppressive domains of retroviral envelopes are not merely viral evasion tools but engineering handles. Related ISD sequences exist in other retroviruses, including murine leukemia virus, and their immunomodulatory function has been mapped to specific residues that interfere with innate immune pathways. By mutating a single residue in the HERV-K ISD, the Danish team effectively converted a stealth signal into an adjuvant-like trigger, enhancing NF-κB activation and downstream antigen presentation while leaving the global fold of the envelope intact. This kind of structure-guided rational design, in which immune evasion features are deliberately removed from an antigen, may be applicable to other endogenous retroviral targets and to viral vector platforms where envelope-mediated immunosuppression limits efficacy.

Significant hurdles remain before this approach reaches patients. The tumor models used were transplant models with engineered HERV-K expression, and spontaneous tumors with heterogeneous antigen expression may behave differently. Safety is a central consideration: any therapy that breaks immune tolerance to a self-encoded antigen must demonstrate that it does not attack healthy tissues that express low levels of HERV-K, such as germline cells and certain embryonic tissues, and the primate study represents only an early step in that assessment. The preclinical work was funded by HERVolution Therapeutics, and several authors hold patents and equity related to the technology, so independent replication will be important. Nevertheless, the study provides a complete proof of concept, from molecular engineering through dendritic cell biology, T cell priming in human cells, tolerance breaking in transgenic animals, and survival benefit in a tumor model. The authors propose that HERV-K-ISDmut antigens should now be explored in future clinical trials, where the central question will be whether an ancient viral fossil, deliberately reawakened and stripped of its immunosuppressive armor, can be turned into a broadly applicable weapon against cancer.

Subject of Research: Engineering the HERV-K envelope immunosuppressive domain as a cancer vaccine immunogen

Article Title: Engineering human endogenous retrovirus-K for improving immunogenicity and broad cancer targeting

Article References: Müller, M. D., Neukirch, L., Ragonnaud, E., Bermejo, A. V., Daradoumis, J., Jaded, V., Engdal, E. S., Faas, F., Perez-Penco, M., Picon-Jara, C., Nielsen, K. N., Duvnjak, L., Boilesen, D. R., Kusiński, S., Skandorff, I., Skeltved, N., Trinh, L. L. N., Turner, L., Grunddal, K. V., … Holst, P. J. (2026). Engineering human endogenous retrovirus-K for improving immunogenicity and broad cancer targeting. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09012-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09012-1

Keywords: HERV-K, human endogenous retrovirus, cancer immunotherapy, therapeutic vaccine, immunosuppressive domain, dendritic cells, T cell response, adenoviral vector, mRNA vaccine, anti-PD-1, tumor-associated antigen, NF-kB signaling

A new study from Korea University College of Medicine, published in Nature Immunology on June 15, 2026, offers a detailed molecular portrait of how an mRNA-based influenza vaccine may accomplish exactly that. Led by Associate Professor Jiwon Lee of the Department of Convergence Medicine and the Vaccine Innovation Center, and conducted in collaboration with Professor Ali Ellebedy and his group at Washington University in St. Louis, the investigation compared an investigational quadrivalent mRNA influenza vaccine, designated mRNA-1010, against the licensed conventional split-virion vaccine Fluarix in a head-to-head clinical evaluation. The central question was whether the mRNA platform could stimulate stronger and more persistent germinal-center responses than a conventional vaccine, and whether that persistence would translate into a measurably broader antibody repertoire in the blood.

The germinal center is the crucible where vaccine-induced immunity is forged. Within specialized microenvironments of draining lymph nodes, B cells that recognize vaccine antigen undergo rounds of proliferation, somatic hypermutation, and selection. Each cycle introduces random mutations into the genes encoding the B-cell receptor, and only those variants whose mutated receptors bind antigen with higher affinity are permitted to survive and expand. Over weeks, this Darwinian process generates plasma cells that secrete high-affinity antibodies and memory B cells that persist for years. The duration and intensity of germinal-center activity are therefore widely regarded as key determinants of both the breadth and the durability of antibody responses. A vaccine that keeps germinal centers active for longer gives B cells more opportunities to mutate, diversify, and explore antibody solutions that recognize conserved or varied features of the virus.

To test whether mRNA vaccination extends this critical phase, the researchers enrolled 75 healthy adults aged 20 to 50 years and followed them across two influenza seasons. Of these, 38 participants received mRNA-1010 and 37 received Fluarix. Blood samples were collected at multiple time points through 26 weeks after vaccination, allowing the team to track the evolution of circulating antibodies over nearly half a year. Crucially, a subset of participants also underwent ultrasound-guided fine-needle aspiration of draining axillary lymph nodes, an invasive but informative procedure that enabled direct sampling of germinal centers as they formed and matured. This combination of peripheral blood monitoring and lymph-node sampling is rare in human vaccine studies and gave the investigators an unusually complete view of the immune response as it unfolded in real time.

The laboratory analysis was correspondingly comprehensive. The team deployed flow cytometry to characterize immune cell populations, ELISpot assays to quantify antigen-specific antibody-secreting cells, single-cell RNA sequencing and B-cell receptor sequencing to resolve individual B-cell lineages, serum IgG proteomics to catalog circulating antibody clonotypes, and a battery of antibody binding and neutralization assays to test functional activity against antigenically diverse influenza strains. Together, these methods profiled the response at scales ranging from single cells to whole serum, providing a multidimensional dataset that conventional vaccine trials, which typically rely on bulk antibody titers alone, cannot match.

The findings were striking. The mRNA vaccine elicited a substantially more diverse and broader serum antibody repertoire than Fluarix, according to Dr. Lee. Most notably, influenza-specific germinal-center responses persisted for up to 26 weeks in 5 of 13 mRNA-1010 recipients whose draining lymph nodes were sampled, while persistent germinal centers were not detected among any of the Fluarix recipients sampled. Six months of sustained germinal-center activity after a single vaccination is an unusually long window of B-cell evolution, and it suggests that the mRNA platform provides antigen persistence and inflammatory signaling that keep the selection machinery running far longer than a conventional protein-based split-virion preparation.

That prolonged activity left a measurable imprint on the antibody repertoire. The mRNA vaccine increased the diversity of the serum IgG repertoire and promoted the diversification of pre-existing B-cell lineages through somatic hypermutation, meaning that antibodies the immune system had already learned to make against earlier influenza exposures were not merely recalled but actively refined and expanded. These molecular changes were associated with broader antibody binding across antigenically diverse influenza strains and with significantly greater increases in neutralization titers against 11 of 13 A/H1N1 viruses tested. In practical terms, the antibodies generated after mRNA vaccination recognized a wider range of viral variants and neutralized more of them, including strains that differed antigenically from those contained in the vaccine itself. Dr. Lee summarized the distinction succinctly: the mRNA platform does not simply produce more antibodies, it produces a more diversified antibody response, which leads to greater binding and neutralizing breadth.

A key methodological strength of the study was Ig-Seq, a mass-spectrometry-based technology that identifies individual antibody clonotypes circulating in the blood after vaccination. Conventional vaccine studies typically measure bulk binding or neutralization titers, aggregate numbers that reveal how much antibody activity is present but say little about its composition. Ig-Seq resolves the response down to individual antibody clonotypes, revealing which antibody lineages emerged, expanded, and diversified after vaccination. Combined with B-cell receptor sequencing, this molecular-level approach allowed the researchers to trace the genealogical trees of antibody families as they mutated and branched over the six-month observation period, directly linking sustained germinal-center activity in the lymph node to the diversification of antibodies measurable in the serum. The authors identify Ig-Seq as a defining strength of the work because it captures information that bulk serology fundamentally cannot.

The broader implications reach toward the long-sought goal of a more universal influenza vaccine. If mRNA vaccination can sustain germinal-center activity for months rather than weeks, it creates a temporal window in which B cells can accumulate mutations that broaden their recognition of the virus’s antigenic landscape. This mechanism could in principle support protection that carries over between seasons, reducing the need for annual reformulation and re-vaccination. However, the authors are careful to note that further studies are needed to determine whether these broadened responses translate into multi-season protection or permit longer vaccination intervals. The study population consisted of healthy adults aged 20 to 50, and future research must investigate whether the same benefits are maintained in older adults and immunocompromised populations, whose germinal-center function, B-cell repertoire diversity, and overall immune responsiveness differ substantially from those of healthy younger recipients.

What the study establishes, with unusual molecular resolution, is a mechanistic bridge between a vaccine platform and the quality of the immunity it generates. Persistent germinal centers, diversified B-cell lineages, and a broader serum antibody repertoire form a coherent causal chain, and tools such as Ig-Seq now make each link observable in humans. As mRNA technology matures beyond its first applications, findings like these suggest that its most consequential contribution to vaccinology may lie not in speed of development but in the depth and breadth of the immune memory it leaves behind, offering a rational template for influenza vaccines designed to stay ahead of a virus that never stops changing.

Subject of Research: A clinical study comparing mRNA-1010 and Fluarix influenza vaccines in healthy adults, examining germinal-center persistence and antibody repertoire breadth

Article Title: Korea University study uncovers how mRNA vaccination may broaden flu antibody responses

Article References: Korea University study uncovers how mRNA vaccination may broaden flu antibody responses. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: mRNA vaccine, influenza, germinal center, antibody breadth, B cells, somatic hypermutation, Ig-Seq, neutralization, vaccinology, Nature Immunology, Korea University, immune repertoire

The outbreak first came to the attention of the World Health Organization on May 2, 2026, when passengers aboard the MV Hondius, which carried 147 crew members and passengers from 23 countries, presented with fever and gastrointestinal symptoms that rapidly progressed to pneumonia, shock, and acute respiratory distress syndrome. Laboratory confirmation of Andes virus infection by polymerase chain reaction followed between May 4 and May 6. By July 2, 2026, 13 cases had been identified on the vessel, 12 confirmed and one probable, and three patients had died, yielding a case fatality ratio of 23 percent. Epidemiologists hypothesize that an initial case acquired the infection from a rodent before boarding, with subsequent human-to-human transmission occurring during the prolonged, close contact that confined shipboard conditions inevitably produce.

Andes virus, formally Orthohantavirus andesense, occupies a unique position among hantaviruses. While hantaviruses are typically transmitted from rodents to humans through contact with urine, feces, or saliva, and humans are generally considered dead-end hosts, Andes virus is the only hantavirus documented to spread efficiently between people. First identified in Argentina in 1995, the virus has an incubation period ranging from 7 to 42 days, with a median of 18 days, and viral RNA has been detected in blood, respiratory secretions, urine, and semen. Transmission can occur through mucosal or respiratory exposure to infectious respiratory particles, although the virus is not classified as highly airborne. Case fatality ratios have reached 50 percent in some settings, and the virus has a documented history of super-spreading events, most dramatically during Argentina’s 2018 to 2019 outbreak, when transmission at a large social gathering linked to three super-spreaders produced the largest Andes virus outbreak recorded to date, with a case fatality ratio of approximately 32 percent.

Genomic sequencing of viruses isolated from the MV Hondius passengers detected no new lineages, and the circulating strain closely resembled Andes virus lineages previously identified in Argentina and Chile. The outbreak’s reproductive number was estimated at 0.7, considerably lower than the median reproductive numbers of 2.12 and 0.96 observed before and after infection control measures during the Argentine outbreak. Because the incubation period can extend to six weeks, disembarked passengers were asked to quarantine for 42 days, a duration that health authorities calculate provides a 96 percent probability of safe release. The episode has nonetheless highlighted the vulnerability of international transportation systems, where restricted spaces, overcrowding, inadequate ventilation, and limited access to intensive care can amplify transmission. Experts now recommend screening passengers boarding from hantavirus-endemic regions, controlling rodents on ships and in harbors, and establishing approved protocols for managing infectious diseases in international waters.

The pathogenesis of Andes virus infection centers on endothelial dysfunction. Hantaviruses target endothelial cells, producing enhanced microvascular permeability in the principal target organs: the lungs in hantavirus cardiopulmonary syndrome, which predominates in the Americas, and the kidneys in hemorrhagic fever with renal syndrome, which prevails in Europe and Asia. Immune-mediated mechanisms play a pivotal role. CD8-positive T cell activation has been documented during acute phases of both syndromes, immunoblasts circulate in patients experiencing shock or pulmonary edema, and fatal cases show high densities of cytokine-releasing cells in lung tissue. Elevated levels of tumor necrosis factor alpha can drive capillary leakage, pulmonary edema, and shock, while high interleukin 2 levels increase vascular permeability. Hantavirus cardiopulmonary syndrome unfolds in three phases: a prodromal phase of non-specific flu-like symptoms, a cardiopulmonary phase marked by pulmonary capillary leak and hemodynamic compromise that can culminate in cardiogenic shock, and a convalescent recovery phase.

Early diagnosis is critical because no specific antiviral agent exists. Reverse transcription polymerase chain reaction can detect viral RNA in whole blood during the asymptomatic and prodromal phases, and serological confirmation relies on IgM and IgG assays performed with chemiluminescence immunoassay technology. IgM antibodies appear at symptom onset, rise within a week, and clear after one to three months, whereas IgG antibodies emerge three to seven days after symptoms begin and persist for years, making them unsuitable for early diagnosis. Notably, some polymerase chain reaction-positive cases have been entirely asymptomatic, and viremia can precede symptoms. Differential diagnoses during the prodromal phase include influenza, COVID-19, viral and atypical pneumonias, yellow fever, dengue, leptospirosis, endocarditis with pulmonary edema, sepsis with acute respiratory distress syndrome, and arenavirus infections, underscoring the diagnostic challenge clinicians face.

Clinically, initial symptoms of hantavirus cardiopulmonary syndrome typically emerge one to eight weeks after exposure and include chills, fever, gastrointestinal upset, nausea, vomiting, diarrhea, headache, dizziness, and myalgia, before sudden progression to respiratory distress, hypotension, and shock. A recent systematic review and meta-analysis identified prognostic factors for severe outcomes, including female sex, age over 18, rural residence, pulmonary infiltrates on chest radiographs, underlying disease with elevated serum creatinine and hematocrit, and signs of bleeding. For patients with severe disease, extracorporeal membrane oxygenation can be life-saving; in experienced centers in the United States, Argentina, and Chile, ECMO-supported survival has ranged from approximately 60 to 75 percent. Timely administration of antipyretics, vasopressors, fluid therapy, mechanical ventilation, and renal replacement therapy, tailored to infection severity and organ involvement, remains the foundation of care.

On the pharmacological front, favipiravir is the most studied antiviral under consideration for Andes virus, though most safety and efficacy data derive from its use against other viral infections. A recently published case report described a 69-year-old man, diagnosed through screening after repatriation from the cruise ship, who received a combination of oral favipiravir, subcutaneous icatibant, intravenous then oral ribavirin, and oral baricitinib over a proposed 10-day course. The patient developed hypoxemia, hyponatremia, thrombocytopenia, and bilateral interstitial infiltrates roughly 24 hours after diagnosis, but recovered clinically, radiologically, and laboratory-wise from day two without progressing to shock or requiring vasopressors or invasive ventilation. Ribavirin and favipiravir were discontinued on days five and nine, respectively, after recurrent diarrhea and hyponatremia. The authors caution that a single favorable outcome cannot establish efficacy, and larger studies are required. Icatibant, a selective bradykinin B2 receptor antagonist, is hypothesized to alleviate bradykinin-driven vascular leakage, while the interleukin 6 receptor antagonist tocilizumab showed striking signals in a MEURI case series: five of five untreated ICU patients with Andes virus cardiopulmonary syndrome died, compared with four of five survivors among those receiving a single 8 mg/kg intravenous dose within 24 hours of admission. By contrast, a double-blind randomized trial in Chile found that high-dose intravenous methylprednisolone provided no significant clinical benefit in hantavirus cardiopulmonary syndrome, and monoclonal antibodies, molnupiravir, and baloxavir remain at earlier stages of investigation.

Vaccine development remains an empty pipeline in Western nations, with no approved hantavirus vaccine in the United States or Europe, although the inactivated Hantavax vaccine is used in Korea and China. A DNA vaccine targeting the Andes virus glycoprotein has completed Phase I testing: in a randomized controlled trial of 48 healthy adults, needle-free administration of 2 mg or 4 mg doses in three- or four-dose schedules was generally well tolerated, induced neutralizing antibodies, and achieved seropositivity rates of 67 to 90 percent by day 337, with only mild to moderate adverse events. Viral vector vaccines based on vesicular stomatitis virus and mRNA vaccines using both uridine and N1-methylpseudouridine platforms are in preclinical development, and recombinant human monoclonal antibodies JL16 and MIB22 have provided high levels of post-exposure protection in animal models by neutralizing viral glycoproteins. The review’s authors conclude that while the public health risk from the current outbreak remains low, the MV Hondius episode demonstrates that Andes virus could become a broader global concern, and they urge accelerated development of specific antivirals and vaccines, particularly mRNA platforms, alongside sustained vigilance in isolation, physical distancing, rodent control, and global cooperation to manage unpredictable outbreaks in the years ahead.

Subject of Research: Epidemiology, pathogenesis, and pharmacological management of the 2026 Andes virus outbreak linked to a cruise ship

Article Title: Incidence, pathogenesis, clinical manifestations, and pharmacological management of the 2026 Andes virus outbreak

Article References: Ghasemiyeh, P., & Mohammadi-Samani, S. (2026). Incidence, pathogenesis, clinical manifestations, and pharmacological management of the 2026 Andes virus outbreak. Virology Journal, 23(1), Article 208. https://doi.org/10.1186/s12985-026-03298-9

Image Credits: AI Generated

DOI: 10.1186/s12985-026-03298-9

Keywords: Andes virus, hantavirus, hantavirus cardiopulmonary syndrome, MV Hondius, cruise ship outbreak, human-to-human transmission, favipiravir, tocilizumab, ECMO, DNA vaccine, mRNA vaccine, public health

The burden of sleeping sickness is considerable. The disease progresses in stages, beginning with fever, headaches and lymphadenopathy as parasites multiply in the blood and lymph, and advancing to neurological involvement once the parasites cross the blood-brain barrier, producing sleep disturbances, cognitive decline and, if untreated, death. The parasite’s most formidable weapon is antigenic variation: a dense coat of variant surface glycoproteins, or VSGs, that is continually reshuffled through gene conversion, allowing the parasite to stay one step ahead of the host antibody response. This immune evasion strategy, well documented in the literature, has long frustrated conventional vaccine development, which is one reason the researchers turned to conserved, functionally essential proteins as alternative targets.

Specifically, the team selected three T. brucei proteins as the basis for their construct: the variant surface glycoprotein itself, heat shock protein 70, and the vacuolar transporter chaperone complex. Heat shock protein 70 is a highly conserved molecular chaperone central to protein folding and stress responses, while the vacuolar transporter chaperone complex is involved in polyphosphate synthesis and acidocalcisome function, processes essential to parasite survival. By mining these proteins for immunogenic peptides, the researchers aimed to build a construct that combines surface exposure with conservation across strains, increasing the likelihood that an immune response raised against the vaccine would recognize the parasite before it can establish infection.

The design workflow followed the now-standard logic of reverse vaccinology. Protein sequences were retrieved from the UniProt database and aligned with tools such as Clustal Omega to assess conservation. Cytotoxic T lymphocyte epitopes were predicted for MHC class I presentation, and helper T lymphocyte epitopes for MHC class II, using the Immune Epitope Database analysis resource and related servers. B-cell epitopes were predicted with linear and discontinuous methods, including ElliPro for structure-based antibody epitope mapping. Each candidate epitope was then filtered for allergenicity with AllerTOP, for toxicity with dedicated peptide toxicity predictors, and for antigenicity with VaxiJen, ensuring that only immunogenic, non-allergenic and non-toxic peptides entered the final construct.

Population coverage analysis, which estimates how many people worldwide carry HLA alleles capable of presenting the chosen epitopes, returned a striking result: the vaccine candidate achieved 100 percent global population coverage. This metric matters because a vaccine that only fits a narrow slice of HLA diversity would leave large populations unprotected. Biophysical characterization of the final multi-epitope protein showed an aliphatic index of 71.23, indicating good thermal stability, and a GRAVY score of minus 0.719, indicating a hydrophilic, soluble protein likely to fold and express well. Solubility and instability assessments supported the view that the construct should behave as a stable, expressible protein in a cellular context.

Structural modeling came next. The tertiary structure of the vaccine construct was predicted and evaluated with a TM-score of 0.65 plus or minus 0.13 and a C-score of minus 0.50, values consistent with a reliable fold. The model was then refined, and validation metrics confirmed its quality: a Ramachandran score of 86.8 percent, meaning the vast majority of residues occupy favored or allowed backbone conformations, and a ProSA Z-score of minus 5.26, within the range expected for proteins of comparable size. Disulfide engineering was considered to further stabilize the fold, and secondary structure predictions from PSIPRED and SOPMA were used to cross-check the modeled architecture.

To test whether the vaccine could actually engage the innate immune sensors that trigger adaptive responses, the team docked the construct against Toll-like receptors 2 and 4, key pattern-recognition receptors on antigen-presenting cells. Molecular docking predicted strong binding, with energy scores of minus 1013.5 kJ/mol for TLR-2 and minus 1002.8 kJ/mol for TLR-4. These docked complexes were then subjected to molecular dynamics simulation, principal component analysis, dynamic cross-correlation matrix analysis and MM-GBSA binding free energy calculations, all of which supported the stability and favorable energetics of the receptor-vaccine interactions. In practical terms, the simulations suggest the vaccine construct should bind robustly to the very receptors that initiate the innate immune cascade.

Immune simulation provided the most direct readout of the construct’s potential immunogenicity. Using computational immune system modeling, the researchers predicted robust humoral and cell-mediated responses, including elevated B lymphocyte and T lymphocyte populations and rising titers of IgM and IgG antibodies over the simulated immunization course. Cytokine profiles indicated activation of both Th1-type and Th2-type pathways, the dual signature generally desired in a prophylactic vaccine. While such simulations are approximations of a vastly more complex biological reality, they serve as a critical screening step, allowing weak candidates to be discarded before any laboratory resource is spent.

Because the platform is mRNA, the team also optimized the nucleic acid sequence itself. Codon optimization for expression in Escherichia coli strain K12, conducted for in-silico cloning into the pET-28a(+) vector, yielded a codon adaptation index of 0.9688 and a GC content of 44.70 percent, both indicative of high expression potential. In-silico cloning confirmed that the construct could be inserted into the vector without disrupting restriction sites. Finally, minimum free energy analysis of the mRNA sequence was used to evaluate the structural integrity and stability of the transcript, an important consideration since mRNA secondary structure influences translation efficiency and vaccine performance.

The authors are careful to frame the work as a computational proof of concept rather than a finished vaccine. As they conclude, the in-silico designed candidate demonstrated strong structural stability, favorable receptor interactions and promising immunogenic potential against T. brucei, but experimental validation and in-vivo studies are required to verify its safety and efficacy. That caveat applies to the entire field of computational vaccinology: docking scores and immune simulations can prioritize candidates and dramatically shorten development timelines, but only animal studies and clinical trials can establish whether a designed construct protects against real infection. Still, for a disease with no licensed vaccine, in which drug therapy is costly, logistically difficult and increasingly challenged by resistance, a rationally designed mRNA candidate that clears every computational hurdle represents a meaningful step forward, and a template for applying the same pipeline to other neglected tropical parasites.

Subject of Research: Computational immunoinformatics design of an mRNA vaccine candidate against the sleeping sickness parasite Trypanosoma brucei

Article Title: Immunoinformatics Approach for the Designing of a Novel mRNA Vaccine Candidate Against Trypanosoma brucei

Article References: Nil, M. S., Khandker, S., Sadaf, S., Ahmed, N., Reja, S., Sayfullah, M., Ferdous, J., Saha, S., Alamri, A., Khan, M. S., Ahmed, S., Wajed, S., Mahdeen, A. A., & Siddiquee, N. H. (2026). Immunoinformatics Approach for the Designing of a Novel mRNA Vaccine Candidate Against Trypanosoma brucei. Acta Parasitologica, 71(5), Article 205. https://doi.org/10.1007/s11686-026-01388-w

Image Credits: AI Generated

DOI: 10.1007/s11686-026-01388-w

Keywords: Trypanosoma brucei, human African trypanosomiasis, mRNA vaccine, immunoinformatics, reverse vaccinology, epitope prediction, molecular docking, molecular dynamics simulation, TLR-2, TLR-4, codon optimization, neglected tropical disease