Search Results (41)

Background: Respiratory syncytial virus (RSV) is a major pathogen of acute lower respiratory tract infection (LRTI) in infants, the elderly, and immunocompromised individuals. This review focuses on the progress of RSV vaccine development, especially subunit vaccines targeting the fusion protein (F) and attachment glycoprotein (G), aiming to summarize key strategies, challenges, and future directions in the field. Methods: The review is based on a comprehensive literature search and analysis of recent studies on RSV vaccine development, with a specific focus on subunit vaccines and related technologies. Results: Approved vaccines such as Abrysvo and Arexvy utilize structural engineering to stabilize the prefusion conformation of the F protein (PreF), thereby exposing neutralizing epitopes. Subunit vaccine candidates such as DS-Cav1 and DT-PreF enhance stability through disulfide bonds and dityrosine linkages, while ADV110 targets the conserved domain of the G protein to elicit cross-strain immunity. Virus-like particle (VLP) vaccines like IVX-A12 combine RSV and human metapneumovirus antigens to provide broad-spectrum immunity. However, challenges exist, including maintaining PreF stability, overcoming immunosenescence in the elderly, and addressing safety concerns like Guillain-Barré syndrome (GBS). Conclusions: Future RSV vaccine development should center on combined PreF-G protein vaccines, VLP technology, and optimizing cold-chain logistics to improve global accessibility and overcome existing challenges, thereby providing more effective prevention and control of RSV infections. Full article

Background/Objectives: In response to the COVID-19 pandemic, we developed a vaccine candidate against SARS-CoV-2. Spike Ferritin Nanoparticle (SpFN) comprises 24 identical prefusion-stabilized spike proteins anchored to a self-assembled nanoparticle. Organized along the three-fold axis of the ferritin particle, eight SARS-CoV-2 spike trimers are presented per nanoparticle. Methods: Here, we describe the CGMP processes for manufacturing SpFN using transient transfection of Expi293F cells. Results: The final yield of SpFN was ~10 mg per liter of media supernatant. The resulting protein is stable in cold storage for two years at −20 °C, as well as for a month at room temperature, and can withstand multiple freeze/thaw cycles. SpFN material produced using the CGMP protocols adjuvanted with Army Liposomal Formulation-QS-21 (ALFQ) elicited potent neutralizing antibodies against WA-1, Alpha, Beta, and Delta variants in mice as measured by a pseudovirus neutralization assay. Conclusions: This work demonstrates rapid development and scaled-up production of clinical-grade SARS-CoV-2 vaccine protein material, allowing permissive storage and transport conditions, and serves as a framework for recombinant protein production for future emergent pathogens. Full article

Background: The current assessment method of the protective efficacy of adjuvanted vaccines remains slow and labor-intensive, hindered by prolonged immunization protocols and complex assays. Methods: To overcome this bottleneck, we demonstrate that early segregated cellular biomarkers enable rapid prediction of protection, using a respiratory syncytial virus (RSV) pre-fusion F (pre-F) protein model with diverse adjuvants in mice. Results: We identified that germinal center (GC) B cell responses (Days 7 and 9 post-immunization) strongly aligned with protective efficacy, except for Alum, which achieved MF59-level protection despite lower GC responses. Crucially, follicular dendritic cell (FDC) abundance at day 7 universally predicted protection across all adjuvants, including Alum, drastically shortening discovery time and effort from at least 4–6 weeks to within 1 week. Conclusions: FDCs and GC B cells serve as complementary early biomarkers that accurately forecast vaccine efficacy. This approach could potentially reduce the need for prolonged immunization regimens by cellular profiling on days 7–9, offering a modest step toward streamlining adjuvant selection and informing vaccine design. Full article

Background: As of 2024, three approved respiratory syncytial virus (RSV) vaccines are licensed for use in adults in the United States: Arexvy™, Abrysvo™, and mRESVIA™. These vaccines are specifically designed to prevent lower respiratory tract disease caused by RSV in adults aged 60 and older. All licensed vaccines rely on stabilized RSV pre-fusion F (pre-F) as the sole antigen. RSV vaccines targeted to the other key RSV surface protein, the G glycoprotein, have been slow to advance because of sequence diversity and a historical association with vaccine-enhanced disease in animal models of infection. The recent development of structure-guided subunit immunogens and immune-modulating adjuvants has renewed interest in RSV G, as the combination of both F and G glycoproteins appears to improve vaccine efficacy over either one individually. RSV G is extensively O-glycosylated, with two mucin-like regions. Methods: This study investigated the effects of manipulation of O-linked glycosylation on a recombinant RSV G vaccine antigen in an RSV/A2 challenge study in BALB/c mice. Conclusions: We found that restricting the O-linked glycosylation on a recombinant RSV G vaccine antigen enhances its immunogenicity and protective efficacy in BALB/c mice. Full article

Background: Human Metapneumovirus (HMPV) is a respiratory virus in the Pneumoviridae family. HMPV is an enveloped, negative-sense RNA virus encoding three surface proteins: SH, G, and F. The highly immunogenic fusion (F) protein is essential for viral entry and a key target for vaccine development. The F protein exists in two conformations: prefusion and postfusion. The prefusion form is highly immunogenic and considered a potent vaccine antigen. However, this conformation needs to be stabilized to improve its immunogenicity for effective vaccine development. Specific mutations are necessary to maintain the prefusion state and prevent it from changing to the postfusion form. Methods: In silico mutagenesis was performed on the C-terminal domain of the pre-F protein, focusing on five amino acids at positions 469 to 473 (LVDQS), using the established pre-F structure (PDB: 8W3Q) as the reference. The amino acid sequence was sequentially mutated based on hydrophobicity, resulting in mutants M1 (IIFLL), M2 (LLIVL), M3 (WWVLL), and M4 (YMWLL). Increasing hydrophobicity was found to enhance protein stability and structural rigidity. Results: Epitope mapping revealed that all mutants displayed significant B and T cell epitopes similar to the reference protein. The structure and stability of all mutants were analyzed using molecular dynamics simulations, free energy calculations, and secondary structure analysis. Based on the lowest RMSD, clash score, MolProbity value, stable radius of gyration, and low RMSF, the M1 mutant demonstrated superior structural stability. Conclusions: Our findings indicate that the M1 mutant of the pre-F protein could be the most stable and structurally accurate candidate for vaccine development against HMPV. Full article

Background/objectives: This was a post hoc analysis of safety data across the bivalent respiratory syncytial virus prefusion F (RSVpreF) vaccine clinical trial development program. Methods: Data from eight clinical trials in 46,913 immunocompetent adults who received RSVpreF or placebo were analyzed. Local reactions and systemic events were assessed among non-pregnant ≥18-year-olds (n = 9517); adverse events (AEs) among pregnant and non-pregnant 18–59-year-olds (n = 9238); and vaccine-related AEs among non-pregnant ≥18-year-olds (n = 39,314). Post-marketing data in non-pregnant adults were considered. Results: Local reactions and systemic events were reported more frequently in RSVpreF versus placebo recipients; injection site pain was the most common local reaction (RSVpreF, 18.9%; placebo, 7.4%), and fatigue (23.5%; 18.4%) and headache (19.5%; 15.0%) were the most common systemic events. Percentages of AEs within 1 month after vaccination were similar across groups (RSVpreF, 12.8%; placebo, 13.1%); severe AEs were reported in ≤1.5% of participants. Differences in percentages of individuals reporting vaccine-related AEs between the RSVpreF and placebo groups were <0.2% for all related AEs. Serious AEs throughout the study were reported in ≤14.0% (RSVpreF, 12.6%; placebo, 14.0%). No atrial fibrillation, Guillain-Barré syndrome, or acute polyneuropathy cases were reported. The AE data from post-marketing data sources were consistent with the safety profile from the clinical trial program, with no new safety concerns. Conclusions: Integrated data demonstrated that RSVpreF was well tolerated with a favorable safety profile in non-pregnant and pregnant adults. Ongoing surveillance through real-world use and clinical trial experience continue to support the safety profile of RSVpreF. ClinicalTrials.gov: NCT03529773/NCT04071158/NCT04785612/NCT05035212/NCT05096208/NCT05842967/NCT04032093/NCT04424316. Full article

Background: The transmembrane fusion (F) protein of RSV plays important roles in RSV pathogenesis as it mediates the fusion between the virus and the target cell membrane. During the fusion process, the F protein transits from a metastable state (prefusion, preF) to a stable state (postfusion, postF) after the merging of the virus and cell membranes. The majority of highly neutralizing antibodies induced by natural infection or immunization target the preF form, which makes it the preferred antigen for vaccine development. Methods: Here, we designed an effective RSV mRNA vaccine, STR-V003, consisting of mRNA encoding preF protein in lipid nanoparticles (LNPs). The immunogenicity, protection efficacy and toxicity were measured in multiple animal models. Results: STR-V003 demonstrated robust immunogenicity in both mice and cotton rats, inducing high levels of neutralizing antibodies and RSV preF-specific IgG antibodies and significantly reducing the RSV viral loads in the lung and nose tissue of challenged animals. In addition, STR-V003 did not show significant enhancement of lung pathology without causing vaccine-enhanced disease (VED). The repeated dose general toxicology studies and local tolerance studies of STR-V003 were evaluated in rats and non-human primate (NHP). Conclusions: STR-V003 demonstrates a favorable safety profile and induces robust protective immunity against RSV. Full article

Background/Objectives: Respiratory syncytial virus (RSV) poses a substantial global health threat, particularly impacting infants and vulnerable pediatric populations through severe respiratory morbidity. Methods: We developed a novel adenoviral vector vaccine platform utilizing chimpanzee adenovirus 68 (AdC68) to deliver prefusion F (pre-F) antigens from RSV subtypes A and B, generating three vaccine candidates: AdC68-A (subtype A), AdC68-B (subtype B), and AdC68-A+B (bivalent formulation). Results: Single intranasal (i.n.) immunization and prime–boost immunizations via intramuscular (i.m.) routes in BALB/c mice induced robust immune activation, with single i.n. administration conferring durable protection evidenced by an 85% reduction in pulmonary viral loads (p < 0.05) at 134 days post-immunization. All vaccine formulations via i.n. single administration elicited potent subtype-specific IgG responses (geometric mean titers 50–12,800) and Th1-polarized cellular immunity (552–1201 IFN-γ+ spot-forming units/10⁶ PBMCs, IgG2a/IgG1 > 1) in bivalent formulation group, while i.m. boosting enhanced cellular responses 3-fold versus prime immunization alone (p < 0.01). Notably, despite undetectable serum-neutralizing antibodies and absent mucosal IgA in bronchoalveolar lavage at 7 days post-i.n. immunization, the sustained viral control highlights non-neutralizing antibody-mediated protective mechanisms. Conclusions: These findings establish the proof-of-concept for adenoviral-vectored intranasal vaccines against RSV, though optimization of humoral response induction and mucosal immunity duration require further investigation. Full article

Background/Objectives: Human metapneumovirus (hMPV) is a leading cause of respiratory infections in the elderly, with high morbidity and mortality and with no vaccines or specific therapies available. The primary protective antigen of hMPV is the fusion protein, and its prefusion conformation (pre-F) is considered the most promising target for vaccine development. Methods: Utilizing computational design strategies focused on intraprotomer interface stabilization, we designed hMPV pre-F recombinant subunit vaccine candidates based on the most prevalent A2 subtype and characterized them in vitro and in vivo, benchmarking to the prototypical hMPV pre-F stabilized by an introduction of a proline at site 185. Results: The top candidate (N46V_T160F) yielded 14.4 mg/L with a melting temperature of 79.3 °C as compared to 5.7 mg/L and 70.4 °C for the benchmark. By employing monoclonal antibody binding to all six antigenic sites of hMPV pre-F, we confirmed this construct retained all pre-F specific antigenic sites and that the key sites Ø and V were stable at 4 °C for up to 6 months. When immunogenicity of N46V_T160F was evaluated in mice, it induced higher binding and neutralizing antibody titers than the benchmark, which stemmed in part from increased levels of site Ø and site II targeting Abs. Further, this A2 based construct induced cross-neutralizing Abs against all four hMPV subtypes. Lastly, our construct exhibited similar immunogenicity as the recently published next-generation hMPV pre-F constructs, DS-CavEs2 and v3B_Δ12_D454C-V458C. Conclusions: N46V_T160F is a promising hMPV vaccine candidate paving the way for further development and optimization. Full article

Background/Objectives: Individuals with immunocompromising conditions are at high risk of developing severe respiratory syncytial virus (RSV) illness. This phase 3, single-arm study assessed the safety and immunogenicity of the bivalent RSV prefusion F protein−based (RSVpreF) 120-µg vaccine in immunocompromised and renally impaired adults. Methods: Participants were stratified by age group (18−<60-year-olds; ≥60-year-olds) and received two RSVpreF doses 1 month apart (i.e., Dose 1 and Dose 2, respectively). Reactogenicity events were collected for 7 days after each dose; adverse events through 1 month after the last dose; and serious adverse events, adverse events of special interest, and newly diagnosed chronic medical conditions throughout the study. Results: One month after Dose 1, RSVpreF elicited robust immune responses overall and across age and immunocompromised subgroups. Overall, geometric mean fold rises from before to 1 month after Dose 1 were high for RSV A and RSV B (8.3 and 9.0, respectively); no additional increases 1 month after Dose 2 (7.5 and 7.8) were observed. The most frequent local reaction was pain at the injection site, which was more common after Dose 2 than after Dose 1. The most frequent systemic event after any dose was fatigue. Most local reactions and systemic events were mild or moderate in severity. Adverse event and serious adverse event rates were 13.5% and 7.3% among 18−<60-year-olds and 22.4% and 14.0% among ≥60-year-olds, respectively. Conclusions: A single dose of the RSVpreF vaccine conferred robust immune responses in immunocompromised and renally impaired adults with no safety concerns. (ClinicalTrials.gov Identifier: NCT05842967). Full article

Respiratory syncytial virus (RSV) remains a significant global health threat, especially to infants, the elderly, and immunocompromised individuals. This review comprehensively explores the progress in RSV vaccine development, the immune evaluation methods, and immunological surrogate. The RSV fusion (F) protein, a primary target for vaccine development, has been engineered in prefusion conformation to elicit potent neutralizing antibodies, while the attachment (G) glycoprotein and other immunogens are also being explored to broaden immune responses. Advances in diverse vaccine platforms, ranging from live attenuated and protein subunit vaccines to cutting-edge mRNA- and nanoparticle-based formulations, highlight the field’s progress, yet challenges in balancing safety, immunogenicity, and durability persist. Central to these efforts is the identification and validation of immunological surrogates, which may serve as critical benchmarks for vaccine efficacy. Neutralizing antibody titers, multifunctional T cell responses, and B cell memory have emerged as key correlates of protection. However, the feasibility of these surrogates depends on their ability to predict clinical outcomes across diverse populations and settings. While neutralizing antibodies block the virus directly, T cell responses are essential for clearing infected cells and preventing severe disease, and B cell memory ensures long-term immunity. Integrating these immunological markers into a cohesive framework requires standardized assays, robust clinical validation, and an in-depth understanding of RSV-induced immune response. Full article

Background: Respiratory syncytial virus (RSV) is a common cause of acute respiratory infection (ARI). The risk of severe RSV outcomes is higher among older adults (OAs) and individuals with chronic diseases (high risk, HR). AS01_E-adjuvanted RSV preFusion protein 3 OA vaccine (adjuvanted RSVPreF3 OA is approved for the prevention of lower respiratory tract disease [LRTD] due to RSV in OAs). The objective of this study was to assess the potential public health impact of an RSV vaccination program using adjuvanted RSVPreF3 OA in adults ≥75 years (y) and HR adults ≥60 y in Italy. Methods: A static multi-cohort Markov model was used to estimate the number of RSV cases and associated health outcomes projected in adults ≥75 y and HR adults ≥60 y with no RSV vaccination or with a single dose of adjuvanted RSVPreF3 OA. Epidemiological, healthcare resource use and cost data were obtained from the scientific literature. Vaccine efficacy and waning inputs were based on results from the AReSVi-006 phase III clinical trial. Several scenarios for vaccine coverage were explored. Results: Assuming the target vaccination rate for influenza vaccination in Italy (75%), the model predicted that vaccinating Italian adults ≥75 y and the HR population ≥ 60 y with adjuvanted RSVPreF3 OA would reduce the number of RSV-LRTD events by 43%, leading to a reduction in associated emergency department visits, hospitalizations, complications, deaths, and direct healthcare costs over a 3-year period. Conclusions: The vaccination of Italians aged ≥ 75 y and HR individuals aged ≥ 60 y using the adjuvanted RSVPreF3 OA vaccine has the potential to offer substantial public health benefits by reducing the burden of RSV disease. Full article

Respiratory syncytial virus (RSV) causes significant morbidity and mortality, especially in young children and the elderly. RSV vaccine development puzzled vaccinologists for years. Safety concerns of initial formulations, the lack of an absolute correlate of protection, and the need for selecting appropriate virus attenuation and antigen–adjuvant combinations contributed to delayed vaccine production. The recent stabilization of the RSV-F glycoprotein in the prefusion (preF) conformation that constitutes the primary target of RSV-neutralizing antibodies was key for efficient vaccine design. Two protein subunit vaccines (GSK’s Arexvy and Pfizer’s Abrysvo) and one mRNA RSV vaccine (Moderna’s mRESVIA) are now available. This article aims to provide a comparative overview of the safety and efficacy of novel RSV vaccines that are approved for the prevention of RSV-lower respiratory tract disease (LRTD) in adults 60 years of age and older, with updated recommendations calling for the expansion of vaccination to all adults at increased risk for severe RSV disease. Abrysvo is the only vaccine indicated for use in pregnancy to prevent RSV-LRTD in infants from birth to 6 months of age. We provide a comparative assessment of the efficacy of approved RSV vaccines over a maximum of three seasons, summarizing currently available data. We conclude that despite the decreasing vaccine efficacy over time, which should be anticipated for a virus that is characterized by short-term immunity, efficacy was clinically meaningful over placebo. The increased risk of Guillain–Barré syndrome post vaccination with Abrysvo or Arexvy, which prompted the FDA to require the inclusion of such warnings in the prescribing information of these two RSV vaccines, should be prioritized and investigated thoroughly. Furthermore, ongoing vaccine surveillance and further evaluation, particularly among immunocompromised patients, frail elderly subjects, and young infants that were under- or not represented in pivotal clinical trials, are necessary. As in the success story of combined pediatric vaccines, combination vaccines, conferring protection against several respiratory illnesses in one dose, could help improve vaccine acceptance and coverage rates in older adults. Full article

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and children. mRNA vaccines based on the lipopolyplex (LPP) platform have been previously reported, but they remain unapplied in RSV vaccine development. In this study, we developed a novel LPP-delivered mRNA vaccine that expresses the respiratory syncytial virus prefusion protein (RSV pre-F) to evaluate its immunogenicity and protective effect in a mouse model. We synthesized mRNAs with gene modification for RSV pre-F and prepared mRNA vaccines using the LPP delivery platform, referred to as RSV pre-F LPP-mRNA. RSV pre-F protein expression in mRNA vaccines was characterized in vitro. Then, we evaluated the effects of the immune response and protection of this mRNA vaccine in mice up to 24 weeks post-vaccination. Following booster immunization, robust and long-lasting RSV pre-F-specific IgG antibodies were detected in the serum of mice, which exhibited Th1/Th2 balanced IgG response and cross-neutralizing antibodies against different subtypes (RSV A2, B18537, and clinical isolate hRSV/C-Tan/BJ 202301), with a clear dose–response relationship observed. RSV pre-F-specific IgG antibodies were maintained in the mice for an extended period, lasting up to 18 weeks post-immunization. Concurrently, multifunctional RSV F-specific CD8⁺ T cells (IFN–γ, IL-2, and TNF-α) were detected in the mice. After RSV A2 challenge, the RSV pre-F LPP-mRNA vaccine led to a significant reduction in viral replication, while reduced pathological damage was observed in lung tissue. The LPP-delivered mRNA vaccine expressing RSV pre-F induces a robust and long-lasting immune response and protection, indicating good prospects for further development and application. Full article

Background/Objectives: Respiratory syncytial virus (RSV) is a leading cause of respiratory infections in children. A novel RSVpreF vaccine for use among pregnant women for the prevention of RSV in infants is expected to be licensed in Mexico. Hence, the clinical and economic burden of RSV among infants in Mexico, with and without a year-round RSVpreF maternal vaccination program, was estimated. Methods: A cohort model was developed to project clinical and economic outcomes of RSV from birth to 1 year of age for maternal vaccination and no intervention. Incremental cost-effectiveness ratios were calculated from direct cost outcomes, life years, and quality-adjusted life years (QALYs). The value per dose of the RSVpreF for which the program would be cost-effective was explored. Analyses were conducted from the healthcare system perspective, with direct costs (2024 Mexican Pesos [MXN]) and outcomes discounted at 5% annually; scenario and sensitivity analyses tested the robustness of model settings and inputs. Results: Compared to no intervention, a year-round RSVpreF vaccine administered to 1891 M pregnant women would prevent 15,768 hospitalizations, 5505 emergency department cases, and 5505 physician office visits annually, averting MXN 1754 M in direct medical costs with an increase of 3402 life years or 3666 QALYs. The RSVpreF vaccine would be cost-saving up to MXN 1301/dose and cost-effective up to MXN 2105–MXN 3715/dose under an assumed cost-effectiveness threshold range of 1–3× the gross domestic product (GDP) per capita (MXN 247,310) per QALY gained. Conclusions: Year-round RSVpreF maternal vaccination would substantially reduce RSV’s clinical and economic burden among infants in Mexico and likely be a cost-effective program. Full article