Vaccines最新文献

Background/Objectives: An effective universal influenza vaccine is urgently needed to overcome the limitations of current seasonal influenza vaccines, which are ineffective against mismatched strains and unable to protect against pandemic influenza. Methods: In this study, bovine and human adenoviral vector-based vaccine platforms were utilized to express various combinations of antigens. These included the H5N1 hemagglutinin (HA) stem region or HA2, the extracellular domain of matrix protein 2 of influenza A virus, HA signal peptide (SP), trimerization domain, excretory peptide, and the autophagy-inducing peptide C5 (AIP-C5). The goal was to identify the optimal combination for enhanced immune responses and cross-protection. Mice were immunized using a prime-boost strategy with heterologous adenoviral (Ad) vectors. Results: The heterologous Ad vectors induced robust HA stem-specific humoral and cellular immune responses in the immunized mice. Among the tested combinations, Ad vectors expressing SP + HA stem + AIP-C5 conferred significant protection against group 1 (H1N1 and H5N1) and group 2 (H3N2) influenza A viruses. This protection was demonstrated by lower lung viral titers and reduced morbidity and mortality. Conclusions: The findings support further investigation of heterologous Ad vaccine platforms expressing SP + HA stem + AIP-C5. This combination shows promise as a potential universal influenza vaccine, providing broader protection against influenza A viruses.

Background: Inefficient cellular uptake is a significant limitation to the efficacy of DNA vaccines. In this study, we introduce S-Cr9T, a stearyl-modified cell-penetrating peptide (CPP) designed to enhance DNA vaccine delivery by forming stable complexes with plasmid DNA, thereby protecting it from degradation and promoting efficient intracellular uptake.

Methods and results: In vitro studies showed that S-Cr9T significantly improved plasmid stability and transfection efficiency, with optimal performance at an N/P ratio of 0.25. High-content imaging revealed that the S-Cr9T-plasmid complex stably adhered to the cell membrane, leading to enhanced plasmid uptake and transfection. In vivo, S-Cr9T significantly increased antigen expression and triggered a robust immune response, including a threefold increase in IFN-γ secretion and several hundred-fold increases in antibody levels compared to control groups.

Conclusions: These findings underscore the potential of S-Cr9T to enhance DNA vaccine efficacy, offering a promising platform for advanced gene therapy and vaccination strategies.

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.

Background/objectives: Human papillomavirus (HPV) is the primary cause of high-grade cervical lesions and cervical cancer worldwide. In Norway, HPV vaccination was introduced in 2009 for seventh-grade girls and extended through a catch-up program from 2016 to 2019 for women born between 1991 and 1996. This study evaluates the impact of the catch-up vaccination program on the incidence of HPV and high-grade cervical lesions in Troms and Finnmark.

Methods: We analyzed data from 40,617 women aged 26 to 30 who underwent cervical screening between 2009 and 2023 in Troms and Finnmark, including 1850 women with high-grade cervical lesions (CIN2+) on biopsy. Using linear regression, we assessed trends in high-grade lesion incidence per 1000 screened women and the association between vaccination status and HPV-16/18 incidence.

Results: Between 2017 and 2023, the incidence of high-grade cervical lesions significantly decreased: CIN2+ decreased by 33.4%, and CIN3+ decreased by 63.4%. Significant reductions in HPV-16/18-associated high-grade cervical lesions were observed among vaccinated women, with the proportion of CIN2+ cases due to HPV-16 and 18 decreasing from 56.8% in 2017 to 40.7% in 2023, reflecting a 55.8% reduction in the absolute number of cases caused by these high-risk HPV types. Comparing unvaccinated women aged 25-26 in 2016 and vaccinated women in 2023, HPV-16 incidence decreased from 5.1% to 0.1%, and HPV-18 incidence decreased from 3.3% to 0.0%.

Conclusions: The catch-up vaccination program significantly reduced the incidence of HPV-16/18 and high-grade cervical lesions in Troms and Finnmark, even with the lower vaccination coverage observed in the catch-up program. These findings demonstrate the effectiveness of HPV vaccination programs in reducing HPV infections and associated cervical lesions.

Human papillomavirus (HPV) is a major global health issue and is recognized as the leading cause of cervical cancer. While prophylactic vaccination programs have led to substantial reductions in both HPV infection rates and cervical cancer incidence, considerable burdens of HPV-related diseases persist, particularly in developing countries with inadequate vaccine coverage and uptake. The development of therapeutic vaccines for HPV represents an emerging strategy that has the potential to bolster the fight against cervical cancer. Unlike current prophylactic vaccines designed to prevent new infections, therapeutic vaccines aim to eradicate or treat existing HPV infections, as well as HPV-associated precancers and cancers. This review focuses on clinical studies involving therapeutic HPV vaccines for cervical cancer, specifically in three key areas: the treatment of cervical intraepithelial neoplasia; the treatment of cervical cancer in combination with or without chemotherapy, radiotherapy, or immune checkpoint inhibitors; and the role of prophylaxis following completion of treatment. Currently, there are no approved therapeutic HPV vaccines worldwide; however, active progress is being made in clinical research and development using multiple platforms such as peptides, proteins, DNA, RNA, bacterial vectors, viral vectors, and cell-based, each offering relative advantages and limitations for delivering HPV antigens and generating targeted immune responses. We outline preferred vaccine parameters, including indications, target populations, safety considerations, efficacy considerations, and immunization strategies. Lastly, we emphasize that therapeutic vaccines for HPV that are currently under development could be an important new tool in fighting against cervical cancer.

Background: The Influenza A virus (IAV), a pathogen affecting the respiratory system, represents a major risk to public health worldwide. Immunization remains the foremost strategy to control the transmission of IAV. The virus has two primary antigens: hemagglutinin (HA) and neuraminidase (NA). Our previous studies have demonstrated that an IAV NA mRNA vaccine can induce Th1-type immune responses in mice. This research examined the immune responses elicited by an mRNA vaccine targeting both HA and NA antigens in murine models.

Methods: In this study, we used two dual-antigen immunization strategies: single-site immunization with an IAV HA+NA mRNA vaccine and multi-site immunization with an IAV HA mRNA vaccine and IAV NA mRNA vaccine. Hemagglutination-inhibiting antibody titer and neutralizing antibody titer in the sera of immunized mice were evaluated, and a viral challenge experiment was conducted. Additionally, the immune responses elicited by the two immunization strategies were characterized using flow cytometry and ELISA. Comparative analyses were performed with mice immunized individually with the IAV HA mRNA vaccine, IAV NA mRNA vaccine, and inactivated vaccine.

Results: The results showed that by using a multi-site immunization strategy, mice were able to generate higher levels of hemagglutination-inhibiting and neutralizing antibodies, and were protected in a viral challenge experiment. Moreover, the multi-site regimen also promoted the generation of cytotoxic T cells and maintained a balanced Th1/Th2 immune response.

Conclusions: Using mRNA vaccine based on a HA and NA antigen with multi-site immunization strategy can induce higher levels of hemagglutination-inhibiting and neutralizing antibodies, and multi-type immune responses in mice, providing new theoretical and experimental support for advancing upcoming influenza vaccines.

Background: This study aimed to assess the antibody response to SARS-CoV-2 vaccines among healthcare workers (HCWs) from multiple outpatient clinics in Japan, examining the effects of baseline characteristics (e.g., sex, age, underlying condition, smoking history, occupation) and prior infections.

Methods: A total of 101 HCWs provided serum at four time points between October 2020 and July 2023. HCWs received two to six doses of mRNA vaccine (BNT162b2 or mRNA-1273). Anti-nucleocapsid (N) and anti-spike (S) IgG antibodies against the ancestral Wuhan strain were measured using the Abbott Architect™ SARS-CoV-2 IgG assay. Univariate and regression analysis evaluated factors such as past infections, age, sex, smoking, underlying condition, and occupation.

Results: After four to six doses, the median anti-S IgG titer in uninfected HCWs was 1807.30 BAU/mL, compared to 1899.89 BAU/mL in HCWs with prior infections. The median anti-N IgG titer was 0.10 index S/C in uninfected HCWs and 0.39 index S/C in infected HCWs. HCWs with prior infection had anti-S IgG titers 1.1 to 5.8 times higher than those without. Univariate and multivariate analyses indicated infection and vaccination significantly increased anti-S and anti-N IgG titers. Age, sex, smoking history and occupation did not influence antibody titers while underlying conditions were associated with lower anti-N IgG titers.

Conclusions: Infection and vaccination were strongly associated with an increase in anti-S and anti-N IgG titers; however, the impact of hybrid immunity appeared to be limited and varied depending on the timing of the sampling. These findings provide valuable insights for developing personalized vaccination strategies and future vaccine development.

Background: Anthrax is a serious disease caused by Bacillus anthracis (B. anthracis) with a very high mortality when the spores of B. anthracis are inhaled (inhalational anthrax). Aerosolized B. anthracis spores can be used as a deadly bioweapon. Vaccination against anthrax is the only effective preventive measure and, hence, the anthrax vaccine was administered to United States (and other) troops during the 1990-91 Gulf War. However, the anthrax vaccine is not harmless, and the anthrax vaccination has been linked to the occurrence and severity of Gulf War Illness (GWI), a debilitating Chronic Multisymptom Illness (CMI). We hypothesized that this is partly due to the combination of two factors, namely (a) the cytotoxicity of the antigen (anthrax Protective Antigen, PA) contained in the vaccine, and (b) the Human Leukocyte Antigen (HLA) genotype of susceptible vaccinees, reducing their ability to make antibodies against the cytotoxic PA.

Method: Here, we tested this hypothesis by determining the association between severity of GWI symptoms in 458 GW veterans and the overall strength of the binding affinity of the PA epitopes to the specific six Human Leukocyte Antigen (HLA) Class II alleles carried by each individual (two of each of the HLA-II genes: DPB1, DQB1, DRB1), responsible for initiating the process of antibody production in otherwise immunocompetent individuals, estimated in silico.

Results: We found that the severity of GWI symptomatology was negatively and significantly correlated with the strength of the predicted binding affinity of PA peptides to HLA-II molecules (r=-0.356, p<0.001); the stronger the overall binding affinity, the weaker the symptoms. Since the binding of a peptide to an HLA-II molecule is the first and necessary step in initiating the production of antibodies, the findings above support our hypothesis that the severity of GWI symptomatology is partly due to a lack of HLA-II protection.

Conclusions: Reduced HLA protection against the toxic anthrax vaccine may underlie GWI.

On 14-15 November 2023, the National Institute of Allergy and Infectious Diseases (NIAID) organized a workshop entitled "Systematic Approaches for ESKAPE Bacteria Antigen Discovery". The goal of the workshop was to engage scientists from diverse relevant backgrounds to explore novel technologies that can be harnessed to identify and address current roadblocks impeding advances in antigen and vaccine discoveries for the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). The workshop consisted of four sessions that addressed ESKAPE infections, antigen discovery and vaccine efforts, and new technologies including systems immunology and vaccinology approaches. Each session was followed by a panel discussion. In total, there were over 260 in-person and virtual attendees, with high levels of engagement. This report provides a summary of the event and highlights challenges and opportunities in the field of ESKAPE vaccine discovery.

Background/objective: Chlamydia abortus, the cause of ovine enzootic abortion, is a zoonotic bacterial pathogen and one of the most infectious causes of foetal death in sheep worldwide. Although the disease can be controlled using commercial inactivated and live whole-organism vaccines, there are issues with both, particularly concerning efficacy and safety. Recently, we have described the development of a new COMC (chlamydial outer membrane complex) vaccine based on a detergent-extracted outer membrane protein preparation of the pathogen, which can be delivered in a single inoculation and is both efficacious and safe.

Methods: In this study, we have evaluated the COMC vaccine further in a dose-response titration of the chlamydial antigen content of the vaccine (from 20 to 2.5 µg in seven experimental groups) using an established pregnant sheep challenge model.

Results: No obvious dose-response relationship was observed across the groups, with a single abortion event occurring in four of the groups and three in the lowest dose group (2.5 µg). No abortions occurred in the 15 and 10 µg groups. The abortion rates (0-14%) were significantly below that of the challenge control group (33%). A similar reduction in bacterial shedding of infectious organisms following parturition was observed in the vaccinated groups compared to the challenge control group, which is important in terms of reducing potential transmission to naive animals.

Conclusions: The results show that a dose of 10 µg antigen in the vaccine will be optimal in terms of maximising efficacy, reducing shedding at parturition, and ensuring it is cost-effective to produce for commercial manufacture.