Search Results (248)

Lenacapavir (LEN) is the first-in-class capsid inhibitor that inhibits HIV capsid function in vitro with picomolar activity. LEN has been approved for the treatment of HIV in combination with other antiretroviral agents (ARVs), as well as for the prevention of acquisition of HIV-1 in people who may benefit from pre-exposure prophylaxis (PrEP). In vitro investigations of the resistance profile of LEN have identified resistance-associated mutations (RAMs) at six residues in the HIV-1 capsid protein (CA), all found in the CA structural pocket where LEN binds and conferring LEN-resistance with various degrees of loss of susceptibility. LEN was initially evaluated in a clinical study (CAPELLA) of heavily treatment-experienced (HTE) people with HIV (PWH), in which 14 of 72 participants had emergence of in vitro-predicted LEN RAMs. Despite the presence of LEN RAMs in these participants with viral rebound, treatment with LEN led to viral suppression in a large majority of HTE PWH in CAPELLA. In treatment-naïve participants receiving subcutaneous LEN + asynchronous oral ARVs (CALIBRATE) 4 of 157 participants had emergence of LEN RAM after >2 years of study. In contrast, no cases of viral rebound with resistance to LEN have been observed in virologically suppressed PWH switching to the once-daily single-tablet regimen (STR) combining LEN with the integrase strand-transfer inhibitor (INSTI) bictegravir after up to 48 weeks in two Phase 3 studies, and for >3 years in Phase 2. Similarly, no resistance to LEN has been observed after up to 96 weeks in the Phase 2 study of once-weekly regimen of the deoxyadenosine analog RT inhibitor islatravir + LEN. Finally, in the Phase 2 study of the 6-monthly injectable LEN + 2 broadly neutralizing antibodies (bNAbs) combination, only one instance of resistance to LEN was observed in conjunction with loss of susceptibility to one of the bNAbs through 1 year of treatment. Overall, resistance to LEN in regimens using synchronous dosing (daily or weekly oral, or 6-monthly injectable) has been rare in clinical studies. As the use of LEN is predicted to increase in the near future with these potential new combinations, capabilities to test for capsid resistance are being developed through global commercial options as well as through regional health institutions. Full article

Background: The elicitation of broadly neutralizing antibodies against conserved antigenic epitopes has been a focus of universal vaccine research. To facilitate immunofocusing on the conserved influenza hemagglutinin (HA) stalk, we designed headless trimeric antigens, initially focusing on subtypes H1, H3, and H5, and subsequently expanding to eight additional HA subtypes. Results: The designs were first evaluated in silico; they were predicted to fold correctly by AlphaFold2, and remained stable in molecular dynamics simulations in isolation, as well as bound to a broadly neutralizing antibody. The antigens expressed in HEK293-derived cells in high yields, and eluted predominantly as trimers in SEC-HPLC. Future work will explore the use of mosaic nanoparticles decorated with headless antigens of various subtypes for the optimal elicitation of broadly neutralizing anti-influenza antibodies. Overall, our study advances the use of headless HA trimers as modular antigens toward a universal influenza vaccine. Full article

Mumps virus (MuV) genotype G is widely represented among circulating strains, but the evolutionary patterns of the hemagglutinin–neuraminidase (HN) gene remain incompletely understood. In this study, we analyzed publicly available full-length genotype G HN sequences using phylogenetic, phylodynamic, codon-based selection, and structure-guided epitope prediction approaches. The genotype G HN sequences were categorized into Clade 1, an operationally defined Diverse group, and Clade 2. Clade 1, which was composed mainly of Japanese strains, showed a relatively structured pattern over time. In contrast, Clade 2 showed more recent diversification and an overall increase in relative genetic diversity, although this phylodynamic pattern was sensitive to sampling structure. The Diverse group was phylogenetically heterogeneous, and its Bayesian skyline estimates were not used for biological interpretation because repeated analyses showed unstable posterior behavior. Root-to-tip regression supported temporal structure in the complete dataset, with the strongest signal in Clade 2. Bayesian molecular dating estimated the time to the most recent common ancestor of the sampled genotype G HN sequences at approximately 1932, and the mean evolutionary rate was 4.925 × 10⁻⁴ substitutions/site/year. Although the HN protein is a major surface antigen and a target of neutralizing antibodies, codon-based analyses showed no robust evidence of positive selection using multiple methods. Instead, many codon sites were inferred to be under purifying selection, suggesting that genotype G HN evolution is largely constrained by the need to maintain protein function. Predicted B-cell epitope regions were broadly similar among representative genotype G strains. Overall, these findings indicate that genotype G HN lineages have followed distinct evolutionary patterns, while the HN gene remains mainly shaped by purifying selection. These findings may help improve our understanding of MuV genotype G HN gene evolution and support future molecular surveillance. Full article

Messenger RNA (mRNA) vaccines represent a transformative platform in vaccinology, with applications extending beyond SARS-CoV-2 to other infectious diseases and cancer immunotherapy. However, patients with solid tumors receiving active anticancer treatment were largely underrepresented in pivotal vaccination trials, limiting understanding of vaccine-induced immunity in this population. In this prospective exploratory study, we assessed humoral and cellular immune responses after two doses of SARS-CoV-2 mRNA vaccines in 39 patients with solid tumors undergoing active treatment. Blood samples were collected before vaccination and approximately two months after the second vaccine dose, prior to the next treatment cycle. Anti-spike IgG, neutralizing antibodies, receptor-binding domain (RBD) levels, interleukin-6 (IL-6), hematological parameters, immune cell subsets, T-cell differentiation, and early apoptosis in αβ and γδ T-cell subsets were analyzed. Vaccination induced a robust humoral response, with high post-vaccination anti-spike IgG levels (median 988.69 BAU/mL), 97.44% seropositivity, 96.88% true seroconversion among baseline IgG−/NAb− patients, and strong neutralizing antibody activity (median 85.73%). Hematological parameters and IL-6 levels remained broadly stable, suggesting no detectable increase in systemic inflammation during the study period. Cellular analyses identified a reduction in peripheral CD19+ B-cell frequencies and decreased early apoptosis, particularly in CD8+ T cells and CD3+CD56+ NKT-like cells. Although changes in T-cell frequencies and differentiation profiles were also observed, these findings were attenuated after exclusion of participants with possible prior SARS-CoV-2 exposure and should be interpreted as exploratory. Overall, these results show that patients with solid tumors receiving active treatment can mount robust humoral responses to SARS-CoV-2 mRNA vaccination and suggest measurable post-vaccination changes in lymphocyte dynamics, including reduced early T-cell apoptosis. Full article

The continuous evolution of the SARS-CoV-2 virus, marked by the emergence of new variants, poses a significant threat to the efficacy of existing vaccines. However, a promising approach to addressing vaccine failure caused by viral mutations (particularly in the spike protein) is the development of a variant-proof (conserved), non-spike, multiepitope universal nanostructure vaccine with multifunctionality, biocompatibility, self-adjuvanticity, and structural similarity to pathogens in terms of size and shape. This study aimed to design a self-assembled nanostructure vaccine (SANV) featuring pentameric and trimeric coiled-coil peptide motifs, as well as other functional motifs, including epitopes, TAT, PADRE, and adjuvant. The cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B lymphocyte (BL) epitopes of SANV were screened from the IEDB with more than 50% individual predicted population coverage (PPC) and fused using linkers to enable self-assembly. The multimerization of the 24 SANV monomers was modeled using the GalaxyHomomer and AlphaFold web servers. Subsequently, the leading SANV constructs with (SANVa9) and without (SANVb6) adjuvant were analyzed for their physicochemical profiles and assessed for antigenicity, allergenicity, solubility, and antioxidant potential. Furthermore, the molecular interactions, specificity, and stability of SANVa9 and SANVb6 with the broadly neutralizing sarbecovirus antibody 5817 and toll-like receptors (TLR2, TLR3, and TLR7) were analyzed using molecular docking and simulation over a 100-nanosecond time scale. Finally, the comparative immune simulation profiles of SANVa9 and SANVb6 with controls indicated stronger, broad-spectrum immune responses that could be translated into in vitro and in vivo studies and warrant further evaluation before clinical use. Full article

Highly pathogenic avian influenza (HPAI) is a lethal disease of poultry that has recently spilled over into mammals, including dairy cattle and humans, heightening concerns for livestock health, food security, and pandemic emergence. While vaccines that induce neutralizing antibodies against hemagglutinin and neuraminidase provide strain-specific protection, durable cross-subtype immunity requires T-cell responses targeting conserved internal antigens such as nucleoprotein (NP). To leverage these conserved targets, we utilized a previously engineered mosaic nucleoprotein (MNP) incorporating T-cell epitopes from thousands of influenza A virus (IAV) strains, conferring broad protection against epidemic (H3N2) and pandemic (H1N1) IAV in mice. Here, we tested whether precision adjuvancy could differentially imprint adaptive immunity to MNP in cattle. Combination formulations paired the carbomer-based nano-emulsion Adjuplex (ADJ) with either a STING agonist (cyclic dinucleotides; CdN) or a TLR4 agonist (glucopyranosyl lipid A; GLA) to program distinct inflammatory milieus. Both formulations elicited circulating IFN-γ–producing T cell responses and NP-specific antibodies in serum and milk. However, STING activation via CdN generated more potent and consistent cellular and humoral immunity than TLR4 engagement. These data demonstrate that selective activation of innate sensing pathways functionally imprints adaptive immune magnitude and quality in a large animal host. By advancing a broadly protective, T-cell-focused vaccine strategy in cattle, this work supports a One Health framework to mitigate H5N1 transmission risk at the human–animal interface. Full article

Background: Monoclonal antibodies (mAbs) initially played a major role in outpatient COVID-19 management by providing rapid passive immunity and reducing progression to severe disease. However, continuous SARS-CoV-2 evolution progressively compromised the effectiveness of several anti-spike products. This narrative review summarizes the trajectory of COVID-19 mAbs across three phases: early clinical efficacy, loss of efficacy due to immune escape, and future directions. Methods: We conducted a narrative review focusing on mechanisms of action, pivotal clinical trials, and real-world effectiveness of neutralizing anti-spike mAbs and host-directed immunomodulatory mAbs. Emphasis was placed on the impact of variants—especially Omicron—on susceptibility and clinical use, as well as on emerging next-generation platforms. Results: First-generation neutralizing mAbs substantially reduced the hospitalization rates during the Alpha and Delta waves, while immunomodulatory mAbs became standard options for the hyperinflammatory phase in hospitalized patients. With the emergence of Omicron and its sub-lineages, extensive immune escape led to marked reductions in neutralization for many earlier anti-spike agents and consequent restrictions in use. Later-generation approaches targeting more conserved epitopes provided temporary solutions but were also challenged by ongoing antigenic drift. Host-directed immunomodulators retained clinical relevance because their mechanism is independent of viral spike mutations. Conclusions: The clinical role of monoclonal antibodies in COVID-19 has been dynamic and increasingly constrained by viral evolution. Future strategies should prioritize broadly neutralizing antibodies targeting conserved epitopes, innovative delivery platforms, and integration with real-time surveillance to preserve clinical utility in the endemic phase and improve preparedness for future outbreaks. Full article

The high-frequency mutation characteristics of SARS-CoV-2 have posed formidable challenges to the development of vaccines and therapeutic agents. Neutralizing antibodies, which serve as effective tools for prevention and control, have undergone continuous updates and iterations in response to viral mutations. This article provides a comprehensive review of researchers’ efforts to achieve both high neutralizing potency and high mutation tolerance in SARS-CoV-2–targeting neutralizing antibodies. Building on the characteristics of conventional antibodies directed against distinct epitopes on the S protein, it further discusses the research on nanobodies, antibody cocktails, multi-specific antibodies, and other antibody formats and engineering approaches, including artificial intelligence–enabled optimization. Each antibody-based strategy targeting SARS-CoV-2 has its own distinctive advantages and potential applications, providing an integrated perspective to support the continued development of antiviral neutralizing antibodies. Full article

This perspective outlines the ongoing necessity for an HIV vaccine and immune-based prevention strategies in an era of availability of multiple behavioral and pharmacological HIV prevention interventions, including safe and highly effective pre-exposure prophylaxis (PrEP). We describe the approach of the National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS (DAIDS), based on key scientific progress, critical steps, and persistent challenges in achieving broad and durable immune protection against HIV. We highlight DAIDS coordinated infrastructure, clinical trial networks, and partnerships that enable iterative development and de-risk innovation for these interventions. Finally, we consider implications for trial design and priorities for advancing scalable HIV immune-based prevention. Full article

The high case fatality rate, cross-species transmission, and ongoing evolution of H5 avian influenza viruses pose an imminent threat of an influenza pandemic, particularly with the currently predominant clade 2.3.4.4b lineage. Existing seasonal influenza vaccines and licensed H5 vaccines provide limited cross-protection against H5 viruses, underscoring an urgent need for the development of broadly protective H5 vaccines. In this study, we analyzed all human-infected H5 hemagglutinin (HA) sequences using bioinformatics approaches and subsequently designed a novel H5 influenza vaccine through algorithm optimization. The predicted structure of this vaccine closely resembles that of the wild-type H5 HA trimer. In animal studies, the algorithm-optimized H5 mRNA vaccine not only induced high levels of neutralizing antibodies against multiple clade 2.3.4.4b H5 viruses but also elicited cross-neutralizing antibodies against clade 2.3.4.4 and clade 2.2.1 H5 viruses, as well as robust cellular immune responses. These findings highlight the potential of algorithm-based approaches in developing broadly protective vaccines against pandemic viruses and suggest that this vaccine candidate could serve as a strategic stockpile for preventing H5 influenza pandemics. Full article

The continued evolution of SARS-CoV-2 has enabled an escape from most monoclonal antibodies, yet a subset of broadly neutralizing antibodies targeting three newly identified super-conserved RBD epitopes—SCORE-A, SCORE-B, and SCORE-C—retains remarkable activity against even the most recent JN.1-derived sublineages. Here, we employed an integrated computational framework combining conformational dynamics, mutational scanning, MM-GBSA binding energetics, and frustration profiling to dissect the molecular mechanisms by which XGI antibodies achieve broad neutralization and resistance to immune escape. Structural analysis revealed that all three SCORE epitopes share a common architecture: a highly conserved, minimally frustrated core that provides stable anchoring, flanked by peripheral regions that accommodate antibody-specific variations. Conformational dynamics showed that SCORE-A antibodies (XGI-183) rigidify the lateral epitope while leaving the RBM partially mobile; SCORE-B antibodies (XGI-198, XGI-203) clamp the RBM apex, directly blocking ACE2; and SCORE-C antibodies (XGI-171) allosterically loosen the RBM loop, impairing receptor engagement indirectly. Mutational scanning identified a hierarchical hotspot organization where primary hotspots (e.g., K356, T500, Y380, T385) are evolutionarily constrained and minimally frustrated, while secondary hotspots (e.g., V503, Y508, S383) are neutrally frustrated and represent the principal sites of immune-driven mutations. MM-GBSA decomposition revealed that van der Waals-driven hydrophobic packing dominates binding, with electrostatic interactions providing auxiliary stabilization. Critically, frustration analysis demonstrated that immune escape hotspots reside precisely in zones of neutral frustration—“energetic playgrounds” that permit mutational exploration without destabilizing the RBD—while minimally frustrated cores are evolutionarily locked. The comparative analysis of conformational versus mutational frustration distributions revealed a unifying principle: aligned neutral frustration yields permissive, escape-prone interfaces; decoupling enables the targeting of constrained cores; and the convergence of minimal frustration in both distributions creates invulnerable interfaces. These findings establish that broad neutralization arises not from ultra-high-affinity anchors but from strategic energy distribution across rigid, evolutionarily informed interfaces, providing a roadmap for designing next-generation therapeutics that target the invulnerable cores of viral surface proteins. Full article

Despite prolonged viral inhibition with combination antiretroviral therapy (ART), HIV-1 survives as genetically intact, replication-capable proviruses within durable CD4+ T-cell fractions, involving central memory, transitional memory, and stem cell-like memory populations, as well as within tissue-resident compartments including lymphoid follicles and gut-associated lymphoid tissue. Reservoir stability is preserved via clonal growth of infected cells and epigenetic processes that impose proviral transcriptional silencing. As a result, current therapeutic approaches seek to either directly alter proviral survival or to improve immune-driven elimination of infected cells. At the molecular level, investigational strategies such as CRISPR–Cas9 and CRISPR–Cas12 gene-editing systems are intended to remove or induce inactivating mutations inside embedded proviral DNA, as well as alter host entrance co-receptors such as CCR5 to provide cellular resistance to infection. In addition, pharmacologic latency regulation is being studied via histone deacetylase inhibitors, protein kinase C agonists, and bromodomain inhibitors to reverse latency, along with Tat inhibitors and other transcriptional repressors aimed to persistently silence proviral expression. Moreover, immunological techniques aim to counteract inefficient endogenous antiviral defenses. Broadly neutralizing antibodies with tailored Fc-driven effector functions are under examination for both neutralization and antibody-dependent cellular cytotoxicity. Therapeutic vaccine approaches seek to elevate polyfunctional HIV-specific CD8+ T-cell responses, while adoptive cellular approaches, involving CAR-T cells aiming HIV envelope epitopes, remain in early clinical research. Immune checkpoint blockade is also being investigated to reverse T-cell depletion inside reservoir-rich tissues. Nevertheless, the key obstacles continue to be the diverse reservoir composition, restricted tissue penetration, viral escape, and safety limitations. The molecular and translational obstacles that characterize attempts toward an HIV cure must be addressed through ongoing multidisciplinary research. Full article

Henipaviruses (HNVs), including Nipah virus (NiV) and Hendra virus (HeV), are highly pathogenic and often lethal zoonotic viruses with broad species tropism and no approved human vaccines. The emergence of genetically divergent HNVs—including Ghana virus (GhV), Langya virus (LayV), and Mojiang virus (MojV)—emphasizes the need for broadly protective countermeasures. Here, we evaluated the antibody (Ab) responses to sequential mRNA vaccines encoding the membrane-bound attachment glycoprotein (gG) from NiV, GhV, and/or LayV in a pilot study with Indian rhesus macaques. Serum binding Ab responses were quantified by ELISA against five soluble gG antigens (NiV, HeV, GhV, LayV, MojV). Functional activity was assessed by neutralization assays using NiV, HeV, and GhV pseudoviruses, and by receptor-blocking ELISA. Sequential vaccination induced high-titer IgG binding against all five HNV gGs with increasing breadth after each dose. Pan-genus regimens elicited moderate neutralizing Ab titers against NiV, HeV, and GhV, whereas the NiV-only regimen elicited potent but narrow neutralization against NiV and HeV. Conversely, the GhV-LayV-GhV regimen elicited strong binding to GhV, LayV, and MojV gG and robust neutralization of GhV pseudovirus, but limited cross-reactivity to NiV and HeV. In this pilot study, we demonstrated that mRNA vaccination can elicit broadly reactive binding and neutralizing Ab responses across phylogenetically distant HNVs. Additionally, we show GhV pseudovirus neutralization for the first time. Collectively, these data provide a foundation for the development of next-generation pan-genus HNV vaccines capable of mitigating future HNV outbreaks. Full article

People with HIV (PWH) may exhibit altered immune responses to SARS-CoV-2 vaccination due to persistent immune dysregulation despite antiretroviral therapy. We evaluated humoral immunogenicity following mRNA SARS-CoV-2 vaccination in PWH according to CD4 T-cell count and compared responses with HIV-negative controls. The study included 57 PWH stratified by CD4 count (<200 and ≥200 cells/µL), alongside 12 HIV-negative controls. Neutralizing antibody titers (NT50) against SARS-CoV-2 pseudoviruses expressing the D614G and Omicron BA.5 spike variants were measured using a luciferase-based neutralization assay one month (M1) and six months (M6) after primary vaccination with BNT162b2 or mRNA-1273. PWH with CD4 counts ≥ 200 cells/µL demonstrated higher neutralizing titers against D614G at M1 and M6, with significant differences observed between CD4 groups (M1: p = 0.03; M6: p = 0.02). Neutralization of BA.5 was lower overall; while no overall group differences were observed at M1, higher titers were detected among individuals with CD4 ≥ 200 cells/µL at six months (p = 0.04). Neutralizing titers correlated positively with CD4 counts among PWH. Responses were broadly comparable between PWH and HIV-negative controls and did not differ substantially by vaccine type. These findings indicate that immune status, reflected by CD4 T-cell count, is a key determinant of SARS-CoV-2 vaccine-induced humoral responses in PWH and support prioritizing vaccination strategies for individuals with advanced immunosuppression. Full article

While current influenza vaccines often lack broad protection against antigenically drifted strains, some modified hemagglutinin (HA) protein antigens have shown promise in eliciting broadly neutralizing antibodies against conserved epitopes. During infection, the mildly acidic environment of the late endosome triggers irreversible HA conformational changes resulting in a post-fusion structure with altered antigenicity. While enhancing the stability of other structural class I viral fusion protein antigens has been instrumental in improving the effectiveness of COVID-19 and RSV vaccines, the role of HA stability in influenza vaccine immunogenicity is relatively unclear. Here, we used the nucleoside-modified mRNA-LNP platform to test engineered HA antigens with specific acid-stabilizing mutations (E47K, K58I, R106K, and K153E) in the HA stalk. All mutations increased HA acid stability, but E47K and R106K did not increase immunogenicity. K153E and K58I, but not E47K and R106K, enhanced the cell-surface expression of the HA protein in vitro. In mice, K153E- and K58I-containing mRNA-LNP vaccines elicited increased neutralizing antibody titers against homologous virus. K153E conferred greater protection than wild-type vaccine against lethal heterologous A/PR/8/34 challenge at low doses (0.5–1.0 µg), despite the absence of neutralizing antibodies against the challenge strain. K153E also elicited greater expansion of antigen-specific antibody-secreting cells (ASCs) in the bone marrow, as well as cross-reactive T follicular helper (Tfh) cells in the spleen. For the vaccines studied, increased HA expression was a stronger correlate of mRNA-LNP enhancement than increased HA stability. Full article