Human Vaccines & Immunotherapeutics最新文献

We previously demonstrated that native-like oligomers of Influenza A H1N1 M2e, expressed in Expi293F cells, elicit robust immune responses. Building on this foundation, we engineered a recombinant antigen comprising five tandem repeats of the M2e epitope (M2e-5x) fused to the tGCN4 domain, which promotes oligomerization and stability. BALB/c mice were immunized intramuscularly with M2e-5x antigen formulated in AddaVax^TM, in a prime-boost regimen, which elicited strong humoral and cellular responses. Despite this, vaccinated animals did not survive following high-dose lethal challenge with Influenza A/PR/8/34 (H1N1) and X-31 (H3N2) viruses. However, notable reductions in lung viral titers and less severe histopathological damage were observed compared to unvaccinated controls, suggesting partial viral clearance. Further evaluation of in vivo protective efficacy by combining M2e-5x (35 µg) with a low dose of soluble trimeric HA (5 µg) antigen showed complete protection in challenged mice. The overall results emphasized the importance of multi-antigen formulations for protective and robust influenza immunity. These findings highlight the importance of incorporating conserved and key viral epitopes into vaccine formulations to enhance broad and robust protection, providing valuable guidance for future influenza vaccine development.

Carriage of Neisseria meningitidis is essential in meningococcal transmission and is a prerequisite for invasive meningococcal disease (IMD). Meningococcal conjugate vaccines have been suggested to reduce acquisition of carriage in adolescents and young adults, contributing to herd protection. Mucosal immunity is considered key in protection against colonization. While mucosal antibody responses following parenteral meningococcal conjugate vaccination have been described in infants, adolescents and young adults, data in older adults, who are at increased risk for infectious diseases including IMD, are limited. This phase IV, open-label clinical trial (CTIS: 2024-513640-29-00) assessed antibody responses in saliva in 216 adults aged 65-85 y following primary meningococcal serogroup A, C, W, and Y conjugate vaccine (MenACWY-TT) vaccination. A booster dose was administered 1 y later in a sub-cohort (n = 100). MenACWY polysaccharide (ps)-specific IgA and IgG concentrations were measured in paired saliva and serum. Primary MenACWY-TT vaccination significantly increased salivary IgA and IgG concentrations for all serogroups. Salivary IgA concentrations returned to baseline within 1-2 y, whereas IgG concentrations remained elevated for at least 2 y. Booster vaccination enhanced salivary IgG concentrations, but failed to boost salivary IgA responses. Strong correlations were observed between post-vaccination salivary and serum IgG concentrations, and between salivary IgA and secretory component levels, suggesting systemic origin of IgG and mucosal origin of IgA. These findings highlight that MenACWY-TT vaccination induces durable salivary IgG and transient IgA responses in older adults, with limited enhancement of mucosal IgA after booster vaccination.

Nearly 85% of people will contract human papillomavirus (HPV) at some point in their lives. When given at the recommended ages, the HPV vaccine can prevent over 90% of HPV-related cancers. However, vaccination rates among young adults, including college students, remain low. Moreover, millions of international students enrolled in U.S. tertiary institutions may not have had access to preventive vaccines, including the HPV vaccine, in their countries of origin. This cross-sectional study conducted in October 2021, guided by the Theory of Planned Behavior (TPB), examined how attitudes, perceived behavioral control (PBC), and subjective norms relate to college students' intentions to receive the HPV vaccine. Conducted at a U.S. university, the study recruited 199 unvaccinated students through the university registrar's office and Amazon Mechanical Turk. Data were collected during the study period using an anonymous Qualtrics survey and analyzed using descriptive statistics, t-tests, and generalized linear models. We aimed to examine the influence of independent variables including attitude, subjective norms, and PBC, on the dependent variable, intention to receive the HPV vaccine. Of the 419 students who completed the survey, 199 (61 domestic and 138 international) who had not received the HPV vaccine were included in the study. The mean age of these participants was 21.27 y (SD = 3.29), with 135 males and 64 females. For both international and domestic students, attitudes toward HPV vaccination and subjective norms were significantly associated with higher vaccination intentions (international: attitude B = 0.11, p = .004; norms B = 0.38, p < .001; domestic: attitude B = 0.09, p = .027; norms B = 0.40, p < .001) in regression analyses. No significant differences were observed between the two groups in attitudes, perceived behavioral control, subjective norms, or vaccination intentions. These findings provide partial support for the TPB in explaining HPV vaccination intentions among college students. Public health initiatives and university-based programs may benefit from applying this framework by fostering positive attitudes and reinforcing supportive social norms. For routine practice, healthcare providers and campus health centers should integrate targeted education and outreach to improve vaccine uptake, particularly among international students. Future research should evaluate the effectiveness of TPB-based interventions in increasing actual vaccination rates and explore additional factors influencing vaccine intentions across diverse student populations.

Herpes zoster is caused by the reactivation of latent varicella-zoster virus (VZV), primarily affecting middle-aged and older individuals and often accompanied by severe pain and other complications. Vaccination is an effective preventive measure against this disease. In the present study, we evaluated the adjuvant activity of Toll-like receptor (TLR)9 and TLR7 agonists in combination with stimulator of interferon genes (STING) agonists for a VZV-glycoprotein E (gE)-based vaccine. Among the tested combinations, the CpG-2722 (TLR9 agonist) and 2'3'-c-di-AM(PS)2 (STING agonist) pairing exhibited potent immunostimulatory activity in immune cells and superior adjuvant activity for VZV-gE vaccines in a mouse models. Shingrix, a licensed herpes zoster vaccine, is administered intramuscularly. The CpG-2722/2'3'-c-di-AM(PS)2 combination adjuvanted VZV vaccine, administered intramuscularly, effectively induced higher gE-specific IgG responses than that induced by the Shingrix and imiquimod/2'3'-c-di-AM(PS)2 adjuvant vaccine. Notably, intranasal administration of the CpG-2722/2'3'-c-di-AM(PS)2 adjuvanted VZV vaccine to mice elicited a robust antigen-specific IgA response, which was barely detectable in intramuscularly administered vaccines. Two doses of the intranasal immunization, administered at a two-week interval, provided long-lasting protection, as antigen-specific IgG levels remained elevated for months without booster immunization. Further investigation into the functional mechanism revealed that CpG-2722 combined with 2'3'-c-di-AM(PS)2 induced a strong antigen-dependent T helper 1 (Th1) cytokine response, consistent with the antigen-independent cytokine-inducing properties of this adjuvant combination. This study demonstrates that the TLR9 and STING agonists formulated adjuvant induces a potent and long-lasting immune response, highlighting its potential as a promising adjuvant candidate for nasal VZV vaccines.

Rett syndrome (RTT) is a rare neurodevelopmental disorder of genetic origin characterized by chronic low-grade inflammation, immune imbalance, and frequently associated with compromised respiratory function. During the COVID-19 pandemic, individuals with RTT were classified as high-risk and invited to follow stringent vaccination protocols that included multiple booster doses. However, the immune response elicited by vaccination in this population has never been systematically investigated. Here, we provide the first characterization of spike-specific antibody and memory B cell responses in 23 RTT patients following two or three doses of SARS-CoV-2 mRNA vaccines. RTT patients developed spike-specific IgG levels comparable to those observed in healthy female controls (GMT 8476 [range 5120-20480] and 9213 [640-81920] after the first two vaccine doses, respectively). The frequencies and phenotype of spike-specific memory B cells were also similar between RTT and controls (mean frequency of 1.3 ± 0.6 and 1.6 ± 1.1, respectively) and these cells displayed functional reactivity upon antigenic stimulation in vitro. The assessment of vaccine-induced immunity in RTT addresses a critical knowledge gap by demonstrating the ability of these patients to develop an immune response to mRNA vaccination, thereby providing insights that may inform tailored vaccination strategies and improve understanding of immune competence in this rare disorder.

A multicomponent vaccine against seasonal influenza and COVID-19 could reduce disease burden in adults by providing simultaneous protection in a single-dose regimen. The first-generation, mRNA-based, multicomponent mRNA-1073 vaccine, combining antigens encoded by mRNA-1010 (influenza) and mRNA-1273 (COVID-19) vaccines, was investigated in a phase 1/2 clinical trial. This stratified, observer-blinded study randomly assigned healthy adults (18-75 years) to receive mRNA-1073 (25-µg, 50-µg, or 100-µg) + placebo, mRNA-1273 (50-μg) + placebo, mRNA-1010 (50-μg) + placebo, or co-administered mRNA-1010 (50-μg) + mRNA-1273 (50-μg) on day 1. Primary study objectives were safety and reactogenicity. Secondary study objectives assessed humoral immunogenicity against vaccine-matched influenza and SARS-CoV-2 strains at day 29 and all evaluable time points through day 181. An exploratory objective was to further characterize immune responses across the study vaccines. Overall, 550 participants were randomly assigned to receive study vaccination. mRNA-1073 exhibited dose-dependent reactogenicity. Most solicited adverse reactions were grade 1 or 2 in severity; no grade 4 events, serious adverse events related to study vaccination, or deaths were reported. A single dose of mRNA-1073 elicited durable immune responses through 6 months against all vaccine-matched influenza and SARS-CoV-2 strains. Systems serology analysis indicated that mRNA-1073 induced robust, balanced antibody responses with comparable immune profiles to mRNA-1010 + mRNA-1273. mRNA-1073 had an acceptable safety profile and elicited durable immune responses against all vaccine-matched influenza and SARS-CoV-2 strains, supporting ongoing evaluations of mRNA-based multicomponent vaccines that simultaneously protect against seasonal influenza and COVID-19 in a single dose.Registration: ClinicalTrials.gov identifier: NCT05375838 (https://clinicaltrials.gov/study/NCT05375838).

Achieving equitable access to life-course vaccination is a central objective of the global Immunization Agenda 2030 (IA2030). Ethiopia has made notable gains in routine immunization; however, disparities remain, particularly in underserved, pastoralist, and conflict-affected regions. This study assessed vaccination coverage, disparities, and barriers to service utilization across four regions of Ethiopia. A community-based cross-sectional survey was conducted in 57 woredas (districts) of Afar, Amhara, Oromia, and Tigray Regional states. Trained health workers administered digital questionnaires with GPS-enabled devices to caregivers, and eligible individuals subsequently received vaccines. The study enumerated 1.2 million households comprising 5.3 million individuals, including children under five, adolescent girls (9-14 y), pregnant women, and person aged 12 y and above. Descriptive and geospatial analyses were applied to examine coverage levels and disparities. The findings were revealed that 9.1% were zero dose, and 11.2% under-immunized, with measles-containing vaccine (MCV1) coverage at 88.3% among children aged 12-59 months. In addition, 79.6% of pregnant women were received tetanus-diphtheria (Td) vaccine, 75.3% of adolescent girls received Human Papilloma Virus (HPV) vaccine, while only almost half 53.8% of individuals aged 12 y and above received COVID-19 vaccine. Marked regional disparities were emerged: Afar recorded the highest zero-dose prevalence (24%), whereas Amhara and Tigray reported disparity levels below 10%. Despite progress in routine immunization, inequities persist, disproportionately affecting remote and marginalized populations. Addressing these gaps requires integrating geospatial microplanning, expanding mobile outreach, and applying culturally tailored demand-generation strategies to ensure equitable vaccine access and advance IA2030 targets.

The clinical manifestation of anogenital warts (AGW) resulting from Human Papillomavirus (HPV) infection is influenced by host immune responses. Interferon (IFN)-α contributes to antiviral activity, while Interleukin (IL)-2 plays an important role in cellular immunity. Tuberculin purified protein derivative (TPPD) has been investigated as an immunotherapeutic agent. This exploratory quasi-experimental study analyzed 12 AGW patients treated with intralesional TPPD (5 tuberculin units weekly for six injections). Tissue samples were collected at baseline and week 2, and serum samples at baseline and week 6. IFN-α and IL-2 expression in tissue was assessed using immunohistochemistry (IHC), and serum levels were measured using ELISA. TPPD therapy was associated with increased IFN-α and IL-2 expression in tissue (p = .047 and p = .019) and higher serum IL-2 levels (p = .030), while serum IFN-α did not change significantly. Clinically, 4 of 12 patients achieved complete response, whereas others showed partial, minimal, or no improvement, and 6 patients required subsequent destructive treatment. Local and systemic cytokine changes did not correlate with lesion regression. These findings suggest that cytokine upregulation reflects immune activation rather than determining lesion clearance, and between-group comparisons should be interpreted cautiously due to baseline.

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants, young children, and the elderly. Current licensed prefusogenic F-based RSV vaccines induce systemic immune responses through intramuscular injection. However, mucosal immunization will be required to elicit local sterilizing immunity to prevent virus replication in the nasopharynx and the lungs as well as virus shedding and transmission. Adenovirus vectors are a promising platform to develop RSV vaccines, but further evaluation of mucosal adenovirus-based prefusion F (preF) vaccines is still needed. In this study, we constructed a recombinant chimpanzee adenovirus serotype 68 vector expressing a second-generation disulfide-stabilized (DS2)trimeric preF protein (ChAd68-PreF). In mice, intranasal immunization with ChAd68-PreF induced dose-dependent increase in RSV-specific secretory IgA (sIgA) in the lower respiratory tract, demonstrating its capacity to elict mucosal immunity. Subsequently, in cotton rats, intratracheal instillation of ChAd68-PreF induced high cross-neutralizing antibody titers against RSV A and RSV B. After RSV A2 challenge, ChAd68-PreF vaccinated animals showed no detectable viral replication in the nose nor in the lungs. Moreover, ChAd68-PreF vaccination did not lead to enhanced respiratory disease (ERD) in cotton rats. These results demonstrate that mucosal delivery of ChAd68-PreF confers potent protective immunity against RSV with good safety profile, warranting further clinical development as a mucosa-targeting RSV vaccine for vulnerable populations.