Search Results (55)

Background/Objectives: HIV-exposed uninfected (HEU) infants experience increased severe respiratory syncytial virus lower respiratory tract illness (RSV-LRTI) rates compared with HIV-unexposed infants. Maternal bivalent RSVpreF vaccination can prevent infant RSV-LRTI but data from HEU infants are lacking. Methods: This phase 3 randomized, double-blinded trial assessed RSVpreF safety and immunogenicity in pregnant participants from South Africa living with HIV and their infants. Maternal participants with stable HIV disease taking antiretroviral therapy received RSVpreF or placebo (24–36 weeks’ gestation). Primary safety endpoints included reactogenicity through 7 days after vaccination (maternal participants), adverse events (AEs) through 1 month after vaccination (maternal participants) or birth (infants), and serious AEs (SAEs) throughout the study (maternal participants) or through 6 months after birth (infants). Immune responses were evaluated by 50% RSV-A and RSV-B neutralizing titers prevaccination and at delivery (maternal participants) or birth (infants). Results: Overall, 343 maternal participants received RSVpreF (n = 172) or placebo (n = 171). Most reactogenicity events were mild/moderate. AEs and SAEs were generally reported at similar frequencies in maternal RSVpreF and placebo groups including percentages of hypertensive disorders of pregnancy. There were no safety concerns in infants; percentages of reported AEs and SAEs were generally similar between RSVpreF and placebo groups and no difference in preterm birth. RSVpreF elicited high maternal neutralizing RSV-A and RSV-B immune responses, with efficient RSV antibody transplacental transfer to infants demonstrated by levels greater than the placebo group at birth (geometric mean ratios (GMRs) of RSVpreF to placebo were 7.8 for RSV-A and 6.8 for RSV-B) and by comparison with a cohort of HIV-unexposed infants from the pivotal phase 3 efficacy trial (GMRs of HEU to HIV-unexposed infants were 0.86 for RSV-A and 0.72 for RSV-B). Conclusions: These results support maternal RSVpreF vaccination among those living with stable HIV for preventing RSV-LRTI in HEU infants. (NCT06325657). Full article

Background: Children are at high risk of influenza infections and may spread the disease to vulnerable family members. Quadrivalent influenza vaccines (QIV) provide protection against four strains of influenza recommended annually by the World Health Organization (WHO) and have the potential to provide improved protection during seasons with B-strain mismatch between vaccine and circulating virus strains. Methods: We evaluated the reactogenicity and safety of a QIV (Afluria Quad and Afluria Quad Junior, Seqirus, Parkville, Australia) in children aged 6 months to <3 years and 3 to <9 years over two Southern Hemisphere influenza seasons (2019 and 2020). The rates of solicited local and systemic adverse events (AEs) occurring on Days 1–7 after each vaccine dose were compared between three vaccine batches during each of the two seasons. Results: Overall, 73.7% of participants aged 6 months to <3 years and 77.5% of those aged 3 to <9 years reported any solicited AE between Day 1 and 7 of SH2019, and 66.7% and 69.2%, respectively, reported any solicited AE in SH2020, consistent with results from prior paediatric studies of QIV. The majority of solicited AEs were mild to moderate in severity. No consistent patterns of batch variation in solicited local or systemic reactogenicity were observed, suggesting no clinically significant differences between vaccine batches. No serious AEs or AEs of special interest (i.e., anaphylactic reaction or febrile convulsion) were reported during Days 1–7 after each vaccination, and no new safety concerns were identified. Conclusions: Together, these results support a clinically acceptable safety and tolerability profile of QIV in children aged 6 months to <9 years. Full article

Influenza vaccines are the primary strategy to prevent severe influenza disease; however, their efficacy is often suboptimal, particularly in older adults (OAs). LiteVax Adjuvant (LVA), a novel adjuvant containing carbohydrate fatty-acid monosulphate ester (CMS) as the active ingredient, has demonstrated a favourable safety profile and enhanced immunogenicity when combined with a low-dose seasonal influenza vaccine in adults aged 18 to 50 years in a first-in-human phase 1 study. The present study investigates the reactogenicity and immunogenicity of CMS-based adjuvanted seasonal influenza vaccine in OAs, with a comparison to responses in younger adults (YAs). In this phase 1b, double-blind, active-controlled clinical trial, 36 YAs (18–50 years) and 48 OAs (≥60 years) were randomized (1:1:1) to receive either 0.5 mg or 1 mg LVA combined with VaxigripTetra, or VaxigripTetra alone. Solicited adverse events (AEs) were recorded using an electronic diary for 7 days following vaccination. Hemagglutination inhibition (HI) titers against four influenza strains were measured at baseline (pre-vaccination) and at 7-, 28-, and 180-days post-vaccination. All 24 YAs and 31 out of 32 OAs receiving CMS-based adjuvanted vaccines reported pain post-vaccination, compared to 8/12 YAs and 4/16 OAs receiving VaxigripTetra. Systemic AEs were more frequently reported among YAs receiving CMS-based adjuvanted vaccines (22/24) compared to those receiving VaxigripTetra (8/12). In OAs, the number of systemic AEs was similar regardless of CMS-based adjuvant administration. Most AEs were mild to moderate and resolved within 3 days. Both CMS-based adjuvanted formulations elicited increased HI titers at Day 7, peaking at Day 28, with a decline thereafter that remained above baseline at Day 180. In YAs, HI titers were comparable between the CMS-based adjuvanted and non-adjuvanted vaccines across all strains and timepoints. In contrast, CMS-based adjuvanted vaccination in OAs induced higher HI titers at Days 28 and 180 for all influenza strains tested. LVA shows an acceptable safety profile in both age cohorts and enhances humoral immune responses in older adults. The 1 mg dose of LVA was more immunogenic, highlighting its potential utility in this target population. Future research will focus on elucidating the mechanisms underlying the immunostimulatory effect of the CMS-based adjuvant. Full article

Messenger RNA (mRNA) vaccine technology has revolutionized the field of immunization, offering a non-infectious, non-genome-integrating platform that addresses many limitations of traditional vaccine modalities. Recent advancements in chemical modifications, delivery systems, and manufacturing processes have enhanced the stability, efficacy, and safety of RNA-based therapeutics, expanding their application beyond infectious diseases to include genetic disorders, cancer, and rare diseases. Central to the success of RNA vaccines is their ability to orchestrate a finely tuned immune response, leveraging both innate and adaptive immunity to achieve robust and durable protection. This review synthesizes current knowledge on the immunological mechanisms underpinning RNA vaccine efficacy, with a focus on the roles of pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) in sensing exogenous RNA, the impact of RNA modifications and manufacturing impurities on innate immune activation, and the subsequent cytokine and chemokine milieu that shapes adaptive responses. We also discuss the dual role of lipid nanoparticle (LNP) delivery systems as both carriers and adjuvants, highlighting their contribution to the vaccine’s immunogenicity and reactogenicity profile. Understanding these complex immune interactions is critical for optimizing RNA vaccine design, minimizing adverse effects, and expanding their therapeutic potential. This review aims to provide a comprehensive overview of the immune symphony orchestrated by RNA vaccines and to identify key areas for future research to further refine and expand the utility of this transformative technology. Full article

There is a need for safe and effective vaccines against the Venezuelan equine encephalitis virus that infects both humans and equines. However, development of a live-attenuated vaccine using the TC-83 strain has been hampered by substantial reactogenicity and the potential for neuroinvasion. In this study, we demonstrate that V4020, a new TC-83-based investigational VEEV vaccine with redundant safety features preventing neuroinvasion and reversion, exhibited no neuroinvasion potential in a murine model. Following subcutaneous or intramuscular administration, a subset of mice that received the TC-83 vaccine succumbed to central nervous system infection, with replicating virus detected in the CNS, demonstrating a low, yet detectable neuroinvasion potential of the TC-83 vaccine in vivo. Sequencing analysis of the TC-83 virus recovered from the brains identified a pseudoreversion of E2 R120I, as E2 R120 is known to confer attenuation for TC-83. In contrast, V4020 showed no evidence of virus in the CNS, highlighting one of the V4020 features, a new synonymous codon to minimize reversion to the wild-type residue. Overall, our study establishes V4020 as a rationally designed, safe vaccine candidate for VEEV with significantly reduced neuroinvasion risk. Full article

Background/Objectives: This overview provides a comprehensive safety evaluation of the approved live-attenuated vaccine VLA1553 (IXCHIQ^®) for active immunization for the prevention of disease caused by chikungunya virus (CHIKV) in clinical trials. Methods: Protocol-defined solicited systemic events (i.e., fever, arthralgia, myalgia, fatigue, and headache) and other unsolicited arthralgia-related events were evaluated. Additionally, during a regulatory review, a broader definition of adverse events of special interest (broad-definition AESIs) (fever and ≥1 AESI symptom within 30 days post-vaccination) was evaluated post hoc. Results: The most frequently reported solicited systemic events post-VLA1553 included fever (13.5%), arthralgia (17.2%), myalgia (23.9%), fatigue (28.5%), and headache (31.6%), with very few prolonged symptoms. The incidence of unsolicited arthralgia-related events (arthritis, osteoarthritis, musculoskeletal stiffness, joint stiffness, and joint swelling) was comparable between VLA1553 and placebo groups. Broad-definition AESIs were observed in 11.7% (361/3082) participants (VLA1553) and 0.6% (6/1033) participants (placebo), with a duration of 1–182 days (median: 4 days; prolonged broad-definition AESI [≥1 symptom lasting ≥ 30 days] occurred in 0.5% of participants) (VLA1553) and 4–27 days (median: 8 days) (placebo). Most symptoms contributing to broad-definition AESIs were solicited. In the VLA1553 group, the most common of these symptoms, in addition to fever, were headache (9.1% of participants), fatigue (8.6%), myalgia (7.0%), and arthralgia (5.2%). There were few severe cases (1.6% of participants in the VLA1553 group). Conclusions: In clinical trials, VLA1553 showed an acceptable safety profile that was consistent with other live-attenuated vaccines. The incidence of broad-definition AESIs was mainly limited to the immediate post-vaccination period, and broad-definition AESI symptoms were mostly solicited systemic adverse events. Full article

Background/Objectives: The combination of a hemagglutinin antigen (HA)-based inactivated influenza vaccine (IIV; Fluarix^® Tetra; GlaxoSmithKline) with a nucleoprotein (NP)-based vaccine, such as OVX836, should increase the efficacy of influenza vaccines since it leverages two complementary immunological mechanisms: HA antibodies targeting the virus envelope and neutralizing it, and an NP cell-mediated immune (CMI) response destroying infected cells. Methods: This was a randomized, double-blind, Phase 2a study (ClinicalTrials.gov NCT05284799) including three groups of 60 healthy subjects (18–55 years old) receiving either IIV + placebo, IIV + OVX836 (480 µg), or OVX836 + placebo intramuscularly and concomitantly into the same deltoid muscle. The endpoints were reactogenicity, safety, and immunogenicity (hemagglutination inhibition assay [HAI], anti-NP immunoglobulin G [IgG], and NP-specific cell-mediated immunity [CMI]). Results: The co-administration of IIV + OVX836 was safe and well-tolerated. The HAI response was strong and similar in the two IIV groups with no interference of OVX836. The humoral anti-NP IgG and NP-specific CMI responses to OVX836 were strong in the two OVX836 groups, and no major interference of IIV was observed. Conclusions: This study supports further clinical development of OVX836 as a combined IIV/OVX836 seasonal vaccine capable of inducing robust and complementary HAI and CMI NP-specific responses. Full article

Background: The COVID-19 pandemic highlighted the need for innovative vaccine platforms that elicit durable immunity. Self-amplifying RNA (saRNA) vaccines offer rapid production and dose-sparing advantages over traditional mRNA platforms. In Uganda’s first SARS-CoV-2 vaccine trial (NCT04934111), we assessed the safety and immunogenicity of a saRNA vaccine encoding the SARS-CoV-2 spike (S) glycoprotein in seronegative and seropositive adults. Methods: This non-randomised phase 1 trial (December 2021–April 2022) enrolled 42 healthy adults (18–45 years), including 12 seronegative and 30 seropositive for SARS-CoV-2. Participants received two 5 μg doses of saRNA vaccine, four weeks apart. Reactogenicity was assessed using diary cards for seven days post-vaccination, and adverse events were monitored throughout the 24-week study. Binding and neutralising antibody levels were quantified using ELISA and pseudovirus neutralisation assays. Findings: The vaccine was well tolerated, with only mild-to-moderate adverse events, including fatigue, headache, and chills. No serious vaccine-related events occurred. Among seronegative participants, 91.6% seroconverted after two doses (median S-IgG: 3695 ng/mL, p < 0.001). In the seropositive participants, S-IgG rose modestly from 7496 to 11,028 ng/mL after the second dose. Neutralising titres increased modestly across WT, BA.2, and A.23.1 variants, with no significant differences between groups. Conclusion: The saRNA SARS-CoV-2 vaccine was safe and immunogenic, inducing robust spike glycoprotein-specific antibody responses, particularly in seronegative participants. This trial demonstrates the potential of saRNA vaccines for broader use. Full article

Background: Influenza is a serious contagious disease caused by influenza virus. It is particularly dangerous for children, potentially leading to severe and even fatal complications. The aim of this study was to evaluate the safety and immunogenicity of two candidate quadrivalent influenza subunit vaccines in children aged 6–35 months. Methods: The subjects were randomly divided into three groups at a 1:1:1 ratio and received the corresponding vaccines: QIV-Sub-HD (Quadrivalent Influenza Subunit Vaccine, High Dose), QIV-Sub-LD (Quadrivalent Influenza Subunit Vaccine, Low Dose) and QIV-Split-LD (Quadrivalent Influenza Split-Virion Vaccine, Low Dose). Adverse events were recorded at 30 min, 0–7 days and 8–28 and 30 days after each dose of immunization. Serious adverse events (SAEs) were collected and reported within 6 months after the full vaccination. Blood samples were collected before the first dose and on 28 days, 3 months and 6 months after full vaccination for antibody detection to evaluate the immunogenicity and duration of immune responses. Results: The results showed that the relative and absolute criteria met the goals set by the clinical trial protocol, indicating that both vaccines are immunogenic. From the first dose to 30 days after full vaccination, the total incidence of adverse reactions in the QIV-Sub-HD, QIV-Sub-LD and QIV-Split-LD groups was 29.64%, 33.33% and 29.64%, respectively. The main symptoms were fever, cough, diarrhea and vomiting. No new safety concerns were identified. Conclusions: The quadrivalent influenza subunit vaccines candidate, manufactured by Ab&B Bio-tech Co., Ltd. JS., are safe and immunogenic in children aged 6–35 months. Full article

Background/Objectives: Circulating influenza strains antigenically differing from vaccine antigens increase disease burden by decreasing vaccine efficacy. Nucleoside-modified mRNA (modRNA) influenza vaccines may facilitate rapid production allowing later antigen selection and improved antigenic similarity compared to circulating strains. We studied different influenza modRNA vaccine (IRV) formulations and dose levels. Methods: This phase 1/2 randomized study evaluated IRV safety/tolerability and immunogenicity in healthy 18- through 85-year-olds. Based on safety and immunogenicity for different IRV doses, schedules, and valencies versus the quadrivalent influenza vaccine (QIV; Fluzone High-Dose Quadrivalent, Sanofi Pasteur) in phase 1 (65–85-year-olds), quadrivalent IRV (qIRV) was further evaluated in 65- through 85-year-olds and 18- through 64-year-olds in phase 2, leading to phase 3 dose selection. Results: Phase 1 (65–85-year-olds) safety/tolerability and immunogenicity findings supported qIRV 30-µg and 60-µg phase 2 assessment (18–85-year-olds, N = 610). qIRV was well tolerated. Injection site pain was the most frequently reported local reaction. Reactogenicity event incidences ≤ 7 days postvaccination for qIRV were generally higher versus QIV, observed more frequently in 18- through 64-year-olds than 65- through 85-year-olds, and showed dose-related trends (60 μg > 30 μg). qIRV and QIV adverse event profiles in 65- through 85-year-olds were similar. There were higher postvaccination hemagglutination inhibition assay geometric mean titers and fold rises and seroconversion rates observed with qIRV versus QIV for A strains, with no consistent pattern for B strains. Cell-mediated immune responses to qIRV by Day 7 showed overall higher T-cell responses against all strains versus QIV. Antibody and cell-mediated immune responses showed comparable trends across qIRV doses in 18- through 85-year-olds; a dose-related pattern was observed in 65- through 85-year-olds (60 μg > 30 μg). Conclusions: Phase 3 investigations of qIRV 60 µg in older adults and qIRV 30 µg in younger adults are warranted (ClinicalTrials.gov Identifier: NCT05052697). Full article

Background/Objectives: Co-administration of BNT162b2 with licensed seasonal influenza vaccines (SIVs) is recommended by health authorities. We provide a comprehensive summary of the data supporting this practice in adults. Methods: This systematic review consolidates available evidence on the prevalence, safety, immunogenicity, efficacy, and effectiveness of co-administering BNT162b2 and SIVs. Searches were conducted for English studies in adults ≥ 18 years of age between January 2021 and August 2024, with no geographic restriction. Study quality was assessed using Cochrane RoB 2.0 and the Newcastle–Ottawa Scale. Results: Twenty studies (15 observational and 5 clinical trials) were included, mainly conducted in seven countries in Europe and North America. Eight observational studies reported prevalence, twelve reported safety/reactogenicity, six reported immunogenicity, and three evaluated efficacy/effectiveness. Reported co-administration of BNT162b2 vaccines with SIVs increased over time. Of persons receiving BNT162b2, the proportion that reported co-administered SIVs increased from 2.7% in 2021 to 34.1% in 2023. Although variability in outcomes was observed, no consistent pattern indicating a negative impact on immunogenicity from same-day co-administration was identified. Effectiveness was not observed to change when BNT162B2 was co-administered with SIVs. The incidence of systemic and local adverse events was comparable between individuals receiving the vaccines separately and those receiving them co-administered. Conclusions: The findings from this review indicate that the co-administration of BNT162B2 with SIVs is both safe and effective. This highlights the value of co-administration, which could enhance vaccine uptake by streamlining immunization protocols and reducing health visits. 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

Concomitant administration may improve vaccination rates. This analysis of a phase 1/2 randomized study included 1073 healthy ≥65-year-olds who previously received ≥3 mRNA COVID-19 vaccine doses. Participants received concomitantly administered RSVpreF and bivalent BA.4/BA.5-adapted BNT162b2 vaccine (concomitant administration) with or without quadrivalent influenza vaccine (QIV), admixed combined RSVpreF + BNT162b2 vaccine (combined vaccine) with or without QIV, RSVpreF, BNT162b2, or QIV. Immunogenicity objectives included demonstrating the noninferiority of neutralizing antibody titers elicited by concomitant administration and combined vaccine compared with RSVpreF or BNT162b2 administered alone, and by concomitant administration and combined vaccine given with QIV compared with RSVpreF, BNT162b2, and QIV alone. Reactogenicity (≤7 days) and safety ≤1 month (adverse events (AEs)) and ≤6 months (serious AEs (SAEs)) after vaccination were assessed. Noninferiority for all immunogenicity comparisons was demonstrated. All vaccine groups were well tolerated; no new safety concerns were identified. Reactogenicity was mostly mild/moderate with rates generally similar across groups, except injection site pain and fatigue, which were less frequent with RSVpreF + placebo vs. other groups. AEs were infrequent, mostly mild/moderate, occurring at similar frequencies across groups. No AEs leading to study withdrawal or vaccine-related SAEs were reported. Favorable safety and tolerability alongside similar immunogenicity provide support for concomitant or combined use of RSVpreF and BNT162b2, with or without QIV, to help protect older adults from these important respiratory pathogens (NCT05886777). Full article

Q fever is a zoonotic disease caused by the obligate intracellular bacterium Coxiella burnetii that presents significant challenges for global public health control. Current prevention relies primarily on the whole-cell vaccine “Q-VAX”, which despite its effectiveness, faces important limitations including pre-screening requirements and reactogenicity issues in previously sensitized individuals. This comprehensive review examines the complex interplay between pathogen characteristics, host immune responses, and vaccine development strategies. We analyze recent advances in understanding C. burnetii’s molecular pathogenesis and host–pathogen interactions that have informed vaccine design. The evolution of vaccine approaches is evaluated, from traditional whole-cell preparations to modern subunit, DNA, and multi-epitope designs. Particular attention is given to innovative technologies, including reverse vaccinology and immunoinformatics, that have enabled the identification of novel antigenic targets. Recent clinical data demonstrating the safety and immunogenicity of next-generation vaccine candidates are presented, alongside manufacturing and implementation considerations. While significant progress has been made in overcoming the limitations of first-generation vaccines, challenges remain in optimizing immunogenicity while ensuring safety across diverse populations. This review provides a critical analysis of current evidence and future directions in Q fever vaccine development, highlighting promising strategies for achieving more effective and broadly applicable vaccines. Full article

During the last 100 years, vaccine development has evolved from an empirical approach to one of the more rational vaccine designs where the careful selection of antigens and adjuvants is key to the desired efficacy for challenging pathogens and/or challenging populations. To improve immunogenicity while maintaining a favorable reactogenicity and safety profile, modern vaccine design must consider factors beyond the choice of target antigen alone. With new vaccine technologies currently emerging, it will be possible to custom-design vaccines for optimal efficacy in groups of people with different responses to vaccination. It should be noted that after a fairly long period of overwhelming dominance of papers devoted to subunit plague vaccines, materials devoted to the development of live plague vaccines have increasingly been published. In this review, we present our opinion on reasonable tactics for the development and application of live, safe, and protective human plague vaccines causing an enhanced duration of protection and breadth of action against various virulent strains in vaccination studies representing different ages, genders, and nucleotide polymorphisms of the genes responsible for immune response. Full article