Vaccine Research Articles

A phase 2, multicenter, open-label study of AlloStim in-situ cancer vaccine immunotherapy as 3L therapy in MSS/pMMR metastatic colorectal cancer.

TPS317 Background: Neoantigen therapeutic cancer vaccines have had limited clinical benefit in metastatic tumor settings. Tumor immunoediting selects tumor clones over time that are non-immunogenic. In addition, the metastatic tumor microenvironment (TME) becomes profoundly immunosuppressive. Microsatellite stable (MSS) and mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) tumors do not accumulate mutations, resulting in low mutational burden (TMB) and a lack of neoantigen targets. Consequently, therapeutic vaccine approaches for mCRC have had difficulty in demonstrating clinical effectiveness. Novel approaches that boost the immune response in low TMB tumors may benefit mCRC patients. AlloStim is an allogeneic, non-genetically manipulated, living Th1-like cell immunotherapy. The Th1-like cells are ex-vivo differentiated and expanded from healthy blood donors and activated prior to infusion. These cells are designed to be rejected upon intradermal (ID) injection. Repeated ID injections elicit high titers of allo-specific Th1 memory cells in circulation. In allo-primed patients, intravenous (IV) infusion of AlloStim causes a rejection response that releases cytokines, such as IL-12, which non-specifically activate circulating memory T cells and NK cells. Activated host memory T-cells and NK cells extravasate and traffic to metastatic tumor sites. This creates the conditions for “in-situ vaccination”. Activated NK cells cause disruption of the cell membrane and release of chaperoned neoantigens into the tumor microenvironment, a process known as immunological cell death (ICD). The release of neoantigens into the microenvironment in the context of inflammation mediated by infiltrating Th1 memory cells creates conditions for in-situ vaccination. In situ vaccination represents an alternative immunotherapy approach in which a therapeutic cancer vaccine is generated in vivo without the need to previously identify and isolate tumor neoantigens. Methods: To investigate this novel in-situ vaccine mechanism, a phase 2, multicenter, single-arm clinical trial in 3L MSS/pMMR mCRC subjects that have been previously treated with oxaliplatin-containing and irinotecan-containing chemotherapy regimens, anti-EGFR (RAS wt and left-sided) and anti-VEGF was initiated. Patients were administered weekly AlloStim in three 28-day cycles consisting of 4 ID injections and a combination ID and IV infusion on the final week in each cycle to create self-amplifying waves of allo-specific and tumor-specific host immune cells in circulation which traffic to tumors upon IV infusion. The primary end-point is overall survival. 21 evaluable patients have been enrolled and are currently being followed for maturity of the survival data. Clinical trial information: NCT04444622 .

Modelling the impact and cost-effectiveness of upcoming Zika virus vaccines on congenital Zika syndrome.

Zika virus (ZIKV) continues to circulate in Southeast Asia following the 2015-2016 global epidemic, posing an ongoing risk of importation and disease spread for Singapore, a tropical city-state in the region. The virus remains a threat to pregnant women and their fetuses due to the risk of Congenital Zika Syndrome (CZS). Vaccines currently in development offer hope for reducing ZIKV infections and CZS cases. We developed an agent-based compartmental model, incorporating Singapore's demographic dynamics, to simulate ZIKV epidemic trajectories and project the national disease burden of CZS over the next decade. We proposed eight vaccination strategies targeting females of child-bearing age and evaluated their cost-effectiveness-in terms of the incremental cost-effectiveness ratio (ICER)-across scenarios with varying vaccine efficacy, protection duration, coverage rate, vaccination cost, and pre-existing immunity levels in the population. Continuous high importation of ZIKV could lead to multiple small outbreaks in the next decade. Total CZS case numbers over the next decade were projected to be 68 (95% confidence interval [CI]: 66-70), 51 (95% CI: 49-52), and 32 (95% CI: 31-33) under scenarios of 0%, 2%, and 5% pre-existing immunity, respectively. While mass vaccination for females would avert up to 66 (95% CI: 64-69), 49 (95% CI: 48-50), and 31 (95% CI: 30-31) CZS cases, respectively, the cost-effectiveness of these strategies should be evaluated on a case-by-case basis. The pre-pregnancy vaccination strategy demonstrated consistent cost-effectiveness regardless of vaccine protection duration, vaccine efficacy, vaccine price, or pre-existing immunity level in the population. Localised outbreaks driven by importation are likely to persist in Singapore. The pre-pregnancy vaccination strategy is consistently cost-effective and should be considered. Mass vaccination may also be viable with the availability of a low-cost vaccine providing long-term protection.

Nucleotide analogues and mpox: Repurposing the repurposable.

While the COVID-19 crisis is still ongoing, a new public health threat has emerged with recent outbreaks of monkeypox (mpox) infections in Africa. Mass vaccination is not currently recommended by the World Health Organization (WHO), and antiviral treatments are yet to be specifically approved for mpox, although existing FDA-approved drugs (Tecovirimat, Brincidofovir, and Cidofovir) may be used in severe cases or for immunocompromised patients. A first-line of defense is thus drug repurposing, which was heavily attempted against SARS-CoV-2 - albeit with limited success. This review focuses on nucleoside analogues as promising antiviral candidates for targeting of the viral DNA-dependent DNA polymerase. In contrast to broad-spectrum screening approaches employed for SARS-CoV-2, we emphasize the importance of understanding the structural specificity of viral polymerases for rational selection of potential candidates. By comparing DNA-dependent DNA polymerases with other viral polymerases, we highlight the unique features that influence the efficacy and selectivity of nucleoside analogues. These structural insights provide a framework for the preselection, repurposing, optimization, and design of nucleoside analogues, aiming to accelerate the development of targeted antiviral therapies for mpox and other viral infections.

HeterologousPrime-Boost immunizationwithAdenoviral vector and recombinant subunit vaccines strategies against dengue virus type2.

Dengue virus (DENV) remains a significant public health threat in tropical and subtropical regions, with effective antiviral treatments and vaccines still not fully established despite extensive research. A critical aspect of vaccine development for DENV involves selecting proteins from both structural and non-structural regions of the virus to activate humoral and cellular immune responses effectively. In this study, we developed a novel vaccine for dengue virus serotype 2 (DENV2) using a heterologous Prime-Boost strategy that combines an adenoviral vector (Ad) with subunit vaccines. The vaccine design included non-structural protein 1 (NS1), envelope protein domain III (EDIII), and the bc-loop of envelope domain II (EDII) as conserved epitopes. These antigens were fused into a single construct P1 and inserted into the pAdTrack-CMV vector to produce a recombinant adenovirus (rAd5-P1) via homologous recombination in E. coli. The examination of the immune response indicated that strong humoral and cellular immunity was generated in various groups of mice. Additionally, the group receiving a heterologous regimen of recombinant adenovirus and protein showed a superior balance of humoral and cellular immunity in terms of IgG2a/IgG1 and INF-γ /IL-4 ratios. These findings validate the vaccine design's ability to utilize both structural and non-structural proteins to generate strong immune responses on two platforms. The promising results from the heterologous regimen highlight its potential as an effective DENV2 vaccine candidate. This research offers significant insights into developing safe and effective DEN vaccines, contributing to efforts to control DENV infections.

Preclinical development of the lipid nanoparticle–based mRNA vaccine with multiple natural T cell epitopes for pancreatic cancer.

752 Background: Immunotherapy has recently emerged as a promising avenue in cancer treatment; however, its effectiveness on pancreatic ductal adenocarcinoma (PDAC) is hindered by the lack of effector T cells in the tumor microenvironment. One of the strategies to overcome the resistance of PDAC to immunotherapy involves identifying immunogenic tumor-associated and specific antigens for the development of personalized cancer vaccines. The mRNA platform has become an attractive platform for antigen presentation. The delivery of mRNA cancer vaccines via lipid nanoparticles (LNPs) enables intracellular delivery and controlled release of the payload, offering improved vaccine efficacy. However, mRNA vaccines presenting human T cell epitopes often lack a preclinical model for antitumor immune efficacy testing. Methods: A syngeneic mouse model of PDACs was established by implanting KPC tumor cells into the livers by hemispleen surgery. mRNA vaccine expressing five 25-mer peptide regions were synthesized. Two mouse CD8+ T cell epitopes were predicted. Their MHC binding was tested by the T2 binding assay. CD8+ T cells specific for these two epitopes were examined by ELISpot assays and were quantified by ImmunoSpot ELISpot Reader to identify changes in IFN-g secretion. Results: Using mass spectrometry analysis, we successfully identified natural HLA class I and class II-binding epitopes in the neoplastic tissues of human PDACs. For the design of mRNA vaccine, we chose five 25-mer peptide regions that each contains both class I and class II epitopes punctuated by AAY and GPGPG linkers and followed by an MITD sequence, which all aim to improve the efficiency of antigen presentation to dendritic cells. Using NetMHC, we predicted H2Kb or H2Db-binding epitopes LYPFPLAL and SMVQMTFL, within these five human peptide regions. The T2 binding assay showed a lack of evident binding of both peptides to the T2-Kb or T2-Db cells. However, the ELISpot assay showed that LYPFPLAL, but not SMVQMTFL, can induce the IFN-g expression from CD8+ T cells derived from splenocytes of the KPC tumor mice vaccinated by a peptide vaccine containing both peptides. Therefore, this result confirmed that LYPFPLAL is a mouse CD8+ T cell epitope and can be used to monitor antigen-specific CD8+ T cell response in response to the mRNA vaccine treatment in the syngeneic mouse model of PDACs. Conclusions: Antitumor efficacy of our above-designed mRNA vaccine can be tested in the syngeneic mouse hemispleen model of KPC tumors. Mouse LYPFPLAL epitope-specific CD8+ T cell response can serve as a surrogate marker for the antitumor efficacy of this mRNA vaccine in mouse models for PDAC.

An in vitro nanocarrier-based B cell antigen loading system; tumor growth suppression via transfusion of the antigen-loaded B cells in vivo.

B cell-based vaccines are expected to provide an alternative to DC-based vaccines. However, the efficacy of antigen uptake by B cells in vitro is relatively low, and efficient antigen-loading methods must be established before B cell-based vaccines are viable in clinical settings. We recently developed an in vitro system that efficiently loads antigens into isolated splenic B cells via liposomes decorated with hydroxyl PEG (HO-PEG-Lips). Therefore, the purpose of this study was to expand this system in order to achieve another approach to in vivo tumor growth suppression. By using HO-PEG-Lips as a carrier for model antigen OVA along with an adjuvant, α-galactosylceramide (GC), the amount of antigen loading to the B cells in vitro was increased compared with that of both free OVA and free GC. Transfusion of B cells treated with HO-PEG-Lips that encapsulated OVA and GC suppressed the growth of OVA-expressing murine thymoma (E.G7-OVA) tumors in vivo through strong induction of OVA-specific T cells. Under fluorescence microscopic observation, migration of the transfused B cells in the spleens of recipient mice were confirmed. Our results indicate that our novel antigen-loading system could become a promising approach to facilitate the development of cell-based therapeutic cancer vaccines utilizing B cells as alternative APCs.

Impact of neoadjuvant radiation therapy modalities on post-surgical lymphopenia in operable pancreatic cancer.

710 Background: Recent advances in therapeutic vaccines show promise for KRAS -mutated pancreatic cancer (PC), with ongoing clinical trials exploring their potential further. Lymphocytes are essential in generating vaccine-induced immune response. Patients who develop lymphopenia following neoadjuvant radiation therapy (RT) are frequently excluded from these vaccine trials. We aimed to assess how different modalities of neoadjuvant RT impact the severity and incidence of lymphopenia. Methods: We identified patients with PC who received neoadjuvant therapy including RT followed by surgery at our institution between March 2009 and June 2024. Patients were stratified by the type of RT they received: conventional long-course chemo-RT (LCRT) with 50.4 Gy over 28 fractions (Fr), short-course chemo-RT (SCRT) with 36 Gy over 15 Fr, and stereotactic body RT (SBRT) with 30 Gy over 5 Fr. The absolute lymphocyte count (ALC, 10 3 cells/µL) was compared at various timepoints: baseline, during RT, 6-weeks after surgery (post-op), and every 3-month interval up to 1 year post-op. Moderate lymphopenia was defined as ALC <1.0 and severe lymphopenia as ALC <0.5. Results: Among the 627 patients included in the study, 522 had baseline pre-RT ALC data available for analysis. There was no difference in baseline ALC among the different RT groups (Table). During RT, patients receiving LCRT experienced a higher incidence of severe lymphopenia (86.1%; median ALC (mALC) nadir 0.28) compared to SCRT (41.9%; mALC nadir 0.50) or SBRT (20.0%; mALC nadir 0.72, p<0001). No difference in the mALC or rates of lymphopenia was observed beyond 6 weeks post-op. Notably, 53% of the patients experienced lymphopenia for as long as 1 year after surgery. Conclusions: LCRT resulted in more severe lymphopenia compared to SCRT or SBRT during RT, but this difference in severity diminished 6 weeks after surgery. Alternatives in treatment sequencing for operable pancreatic cancer can have profound effects on patterns of disease recurrence. When applying multiple treatments in series, toxicities such as lymphopenia may impact receipt of therapy. Techniques to mitigate such toxicities, while maximizing response, will be important to consider. Absolute lymphocyte count (ALC, 10 3 cells/µL) at different time point. Patients with baseline ALC LCRT (n=454) SCRT (n=34) SBRT (n=34) P-value Baseline ALC, median (IQR) 1.48 (0.74) 1.27 (0.94) 1.51 (0.74) 0.74 6-week lymphopenia, n (%) No Moderate Severe 173 (37)219 (46)79 (17) 13/27 (48)11/27 (41)3/27 (11) 18/35 (51)16/35 (46)1/35 (3) 0.10 1-year lymphopenia, n (%) No Moderate Severe 101/217 (47)90/217 (41)26/217 (12) 3/8 (37)5/8 (63)0/8 (0) 9/13 (69)1/13 (8)3/13 (23) 0.054

Individualized Neoantigen-Directed Melanoma Therapy.

Individualized neoantigen-directed therapy represents a groundbreaking approach in melanoma treatment that leverages the patient's own immune system to target cancer cells. Thisinnovative strategyinvolvesthe identification of unique immunogenic neoantigens (mutated proteins specific to an individual's tumor) and the development of therapeutic vaccines that either consist of peptide sequences or RNA encoding these neoantigens. The goal of these therapies is to induce neoantigen-specific immune responses, enabling the immune system to recognize and destroy cancer cells presenting the targeted neoantigens. This individualized approach is particularly advantageous given the genetic heterogeneity of melanoma, which exhibits distinct mutations among different patients. In contrast to traditional therapies, neoantigen-directed therapy offers a tailored treatment that potentially reduces off-target side effects and enhances therapeutic efficacy. Recent advances in neoantigen prediction and vaccine development have facilitated clinical trials exploring the combination of neoantigen vaccines with immune checkpoint inhibitors. These trials have shown promising clinical outcomes, underscoring the potential of this personalized approach. This review provides an overview of the rationale behind neoantigen-directed therapies and summarizes the current state of knowledge regarding personalized neoantigen vaccines in melanoma treatment.

In silico design of a multi-epitope vaccine against Mycobacterium avium subspecies paratuberculosis

In silico design of a multi-epitope vaccine against Mycobacterium avium subspecies paratuberculosis

Global Impact of Mass Vaccination Campaigns on Circulating Type 2 Vaccine-Derived Poliovirus Outbreaks: An Interrupted Time-Series Analysis.

Between 2016 and 2023, 3248 cases of circulating vaccine-derived type 2 poliomyelitis (cVDPV2) were reported globally and supplementary immunization activities (SIAs) with monovalent type 2 oral poliovirus vaccine (mOPV2) and novel type 2 oral poliovirus vaccine (nOPV2) targeted an estimated 356 and 525 million children, respectively. This analysis estimates the community-level impact of nOPV2 relative to mOPV2 SIAs. We fitted interrupted time-series regressions to surveillance data between January 2016 and November 2023 to estimate the impact of nOPV2 and mOPV2 SIAs on cVDPV2 poliomyelitis incidence and prevalence in environmental surveillance across 37 countries, directly comparing the impact of SIAs in 13 countries where both vaccines were used. We did not find any statistically significant differences between nOPV2 and mOPV2 SIA impact except for in the Democratic Republic of Congo (DRC), where nOPV2 SIAs had lower impact (adjusted relative risk [aRR] for cVDPV2 poliomyelitis incidence per nOPV2 SIA, 0.505; 95% confidence interval [CI], .409-.623) compared to mOPV2 (aRR, 0.193; 95% CI, .137-.272); P value for difference in RRs = 3e-6. We find variation in OPV2 SIA impacts globally, with greater certainty about Nigeria and DRC, where large outbreaks provided an opportunity to assess impact at scale. In most countries, we find no significant difference between nOPV2 and mOPV2 SIA impact. We are unable to identify the reason for the significant difference in DRC, which could include differential SIA coverage, timing, vaccine effectiveness, or outbreak dynamics.

Inhibiting NLRP3 enhances cellular autophagy induced by outer membrane vesicles from Pseudomonas aeruginosa.

The bacterium Pseudomonas aeruginosa is able to invade lung epithelial cells and survive intracellularly. During this process, it secretes outer membrane vesicles (OMVs), however, it is currently unclear how OMVs from P. aeruginosa (PA-OMVs) affect lung epithelial cells and their impact on oxidative stress, autophagy, and other physiological activities of lung epithelial cells. In this study, we found that PA-OMVs activated oxidative stress and autophagy in cells. We demonstrated that the NLRP3 (NLR family, pyrin domain containing 3) inhibitor MCC950 can enhance autophagy induced by PA-OMVs. The main function of NLRP3 is related to the body's immune response and inflammation regulation. MCC950 is the most common inhibitor of NLRP3. Additionally, we showed that PA-OMVs not only enhanced the expression of AMP-activated protein kinase, a key regulator of cellular energy homeostasis, and reactive oxygen species, which play a crucial role in cellular signaling and oxidative stress, but also significantly enhanced the expression of NLRP3. Inhibiting the expression of NLRP3 further enhanced the process of PA-OMVs induced autophagy. These results demonstrate that PA-OMVs activate both autophagy and the NLRP3 inflammasome, with NLRP3 suppressing autophagy to a certain extent, hoping to provide broad ideas for the future applications of PA-OMVs.IMPORTANCEThe discovery that lung epithelial cells exposed to outer membrane vesicles from Pseudomonas aeruginosa (PA-OMVs) activate cellular autophagy and induce protective immunity is significant. Specifically, the addition of an NLRP3 inhibitor, MCC950, has been found to decrease NLRP3 targets while simultaneously enhancing the autophagy activity induced by PA-OMVs. This finding unveils a novel theoretical framework for the development of PA-OMVs vaccines, highlighting new targets for enhancing the body's anti-infective responses. By elucidating the mechanisms through which PA-OMVs trigger autophagy and bolster immune defenses, this research opens avenues for innovative vaccine design strategies aimed at combatting infections effectively.

Exploring the potential of homologous epitopes from gut microbes for SARS-CoV-2 vaccine design, using molecular modelling to gain critical insights

Exploring the potential of homologous epitopes from gut microbes for SARS-CoV-2 vaccine design, using molecular modelling to gain critical insights

State of the Art and Emerging Technologies in Vaccine Design for Respiratory Pathogens.

In this review, we present the efforts made so far in developing effective solutions to prevent infections caused by seven major respiratory pathogens: influenza virus, respiratory syncytial virus (RSV), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Bordetella pertussis, Streptococcus pneumoniae (pneumococcus), Mycobacterium tuberculosis, and Pseudomonas aeruginosa. Advancements driven by the recent coronavirus disease 2019 (COVID-19) crisis have largely focused on viruses, but effective prophylactic solutions for bacterial pathogens are also needed, especially in light of the antimicrobial resistance (AMR) phenomenon. Here, we discuss various innovative key technologies that can help address this critical need, such as (a) the development of Lung-on-Chip ex vivo models to gain a better understanding of the pathogenesis process and the host-microbe interactions; (b) a more thorough investigation of the mechanisms behind mucosal immunity as the first line of defense against pathogens; (c) the identification of correlates of protection (CoPs) which, in conjunction with the Reverse Vaccinology 2.0 approach, can push a more rational and targeted design of vaccines. By focusing on these critical areas, we expect substantial progress in the development of new vaccines against respiratory bacterial pathogens, thereby enhancing global health protection in the framework of the increasingly concerning AMR emergence.

Adenoviral Therapy for Cervical Cancer: From Targeted Modification to Immunotherapy.

Cervical cancer is a significant global health threat, ranking as the fourth most common malignancy among women and resulting in over 300,000 deaths annually. Although screening and vaccination initiatives have led to a decline in incidence rates, treatment options for advanced or recurrent cervical cancer remain inadequate, often proving ineffective and costly. In this context, adenoviral therapy has emerged as a promising strategy to enhance therapeutic outcomes. Adenoviruses are non-enveloped viruses that can efficiently infect a wide range of cells, including tumor cells, while exhibiting a favorable safety profile, making them suitable candidates for clinical applications. Adenoviral vectors possess the unique ability to package large segments of therapeutic genes, allowing for diverse treatment approaches, including oncolytic virotherapy, which selectively targets and destroys tumor cells while stimulating robust immune responses. By engineering adenoviruses to express tumor suppressor genes such as p53, researchers can restore critical apoptotic pathways often disrupted in cervical cancer. Furthermore, genetic modifications to capsid proteins can enhance the targeting of tumor cells and reduce the immunogenicity associated with these viral vectors. Additionally, adenoviral vectors can serve as delivery systems for therapeutic vaccines against HPV oncogenes E6 and E7, promoting effective immune responses and potentially preventing disease progression. The combination of adenoviral therapy with immune checkpoint inhibitors offers a novel approach to overcoming the immunosuppressive tumor microenvironment, enhancing overall antitumor immunity. Overall, this review highlights the significant advancements in adenoviral therapy for cervical cancer, emphasizing the need for further research to optimize these strategies and translate preclinical successes into effective clinical applications. By harnessing the full potential of adenoviral vectors, we can improve treatment options for patients who have cervical cancer, paving the way for more personalized and effective therapeutic interventions.

In vivo determination of protective antibody thresholds for SARS-CoV-2 variants using mouse models

ABSTRACT Neutralizing antibody titers have been shown to correlate with immune protection against COVID-19 and can be used to estimate vaccine effectiveness. Numerous studies have explored the relationship between neutralizing antibodies and protection. However, there remains a lack of quantitative data directly assessing the minimum effective protective neutralizing antibody titer in in vivo. In this study, we utilized eight cohorts of participants with diverse immune backgrounds for evaluation of protective antibody response. To precisely assess the lower threshold of neutralizing antibody titers required for effective protection against SARS-CoV-2 infections, we employed plasma adoptive transfer from different cohorts into mice. This study demonstrated that neutralizing titers in the plasma of recipient mice correlated well with those in human donors, and a positive linear correlation was observed between the human and mouse recipients of transferred plasma neutralizing titer. A pseudotyped virus neutralizing titers greater than 7 was identified as the minimum threshold necessary to reduce viral titers in infected mice, establishing a crucial baseline for effective protection. Furthermore, despite the variability in immune backgrounds, these diverse cohorts’ plasma exhibited a similar neutralizing antibody threshold necessary for protection. This finding has significant implications for vaccine design and the assessment of immune competence.

The combined immunization of cervical cancer therapeutic vaccine based on Listeria balanced lethal system has a significant therapeutic effect on tumor model mice.

Cervical cancer is the fourth most common cancer and the fourth leading cause of cancer death in women. Effective treatment of cervical cancer is urgently needed. Tumor therapeutic vaccine is a research hotspot in tumor immunotherapy, and the tumor therapeutic vaccine based on attenuated live bacteria carrier has clinical application prospect because of its clear action site and high safety. The bacterial balanced lethal system uses nutritional screening instead of antibiotic screening to avoid the risk of the spread of antibiotic resistance. So it is generally recognized as a green carrier. In our early research, we have constructed two cervical cancer therapeutic vaccine candidates (LM-HPVCW-1 and LI-HPVCW-1) based on Listeria balanced lethal system via transforming the nutrient-deficient strains with nutrition gene complementary plasmid. The complementary plasmid contained the nutrition complementary gene, LM dal gene, and its Amp gene was replaced with asd gene to delete the antibiotic resistance. Besides, it carried the shuffled HPV-16 E6E7 fusion protein gene. In vitro experiments showed that the plasmid carried by the candidate strain could be stably passaged and the target protein could be successfully expressed. In this study, we proved that the two candidate strains were safe in vivo and induced cellular immune response. At the same time, by establishing a tumor-bearing mouse model, it was proved that the two vaccine strains combined immunization could effectively inhibit mouse tumors. The mechanism of tumor suppression may be related to breaking the immunosuppression of tumor microenvironment and inducing CD8+ T cell infiltration. The therapeutic vaccine for cervical cancer constructed in this study is expected to be further applied in clinical practice.

A Methodological Approach to Measuring the Impact of TAK-003 for the Prevention of Dengue in Dourados, Brazil: Optimizing Strategies for Public Health

Background/Objectives: Takeda’s tetravalent dengue vaccine TAK-003 has been approved by the Brazilian regulatory agency ANVISA for dengue disease prevention in individuals aged 4 to 60 years. Dourados, in the state of Mato Grosso do Sul, became the world’s first city to implement a mass vaccination campaign targeting approximately 120,000 individuals. An ongoing collaborative, observational, population-based study using national surveillance and vaccination data was planned to measure the impact of the vaccine on the reduction in dengue incidence. Methods: In this manuscript, the study’s methodology, including its programmatic steps and public health relevance, is described. A collaborative assessment with multidisciplinary researchers in Brazil was conducted to identify key programmatic areas for the successful implementation of the study. These areas included feasibility and site selection assessment, methodology selection, vaccination program implementation, and public health importance. Results/Conclusions: Identification of the public health problem and understanding the disease burden, local healthcare infrastructure, and strategic partnerships were critical for a robust feasibility assessment. One of the feasibility criteria identified was the ability of the Dourados Municipal Health Secretary and the principal investigator to conduct an active vaccination campaign, utilizing extramural activities and diverse communication channels to increase vaccine acceptance and coverage. The selection of analytical methods, such as time series analysis, was dependent on the national and local structures of the databases and data availability.

Computational design of multi-epitope vaccine against Hepatitis C Virus infection using immunoinformatics techniques.

Hepatitis C Virus (HCV) is a blood borne pathogen that affects around 200 million individuals worldwide. Immunizations against the Hepatitis C Virus are intended to enhance T-cell responses and have been identified as a crucial component of successful antiviral therapy. Nevertheless, attempts to mediate clinically relevant anti-HCV activity in people have mainly failed, despite the vaccines present satisfactory progress. In this study, we used an array of immunoinformatics approaches to design a multiepitope peptide-based vaccine against HCV by emphasizing 6 conserved epitopes from viral protein NS5B. The potential epitopes were examined for their possible antigenic combination with each other along with GPGPG linkers using structural modeling and epitope-epitope interaction analysis. An adjuvant (β-defensin) was introduced to the N-terminus to increase the immunogenicity of the vaccine construct. Molecular dynamics simulation discloses the most stable structure of the proposed vaccine. The designed vaccine is potentially antigenic in nature and can form stable and significant interaction with both receptors TLR2 and TLR3. The vaccine construct was also subjected to In-Silico cloning which confirmed its expression efficiency in a vector. The findings indicate that the designed multi-epitope vaccine have a great potential for preclinical and clinical research, which is an important step in addressing the problems related to HCV infection.

Vvax001, a Therapeutic Vaccine for Patients with HPV16-positive High-grade Cervical Intraepithelial Neoplasia: a Phase II Trial.

Human papillomavirus (HPV) infection is the major cause of (pre)malignant cervical lesions. We previously demonstrated that Vvax001, a replication-incompetent Semliki Forest virus (SFV) vaccine encoding HPV type 16 (HPV16) E6 and E7, induced potent anti-E6 and -E7 cytotoxic T-cell responses. Here, we investigated the clinical efficacy of Vvax001 in patients with HPV16-positive cervical intraepithelial neoplasia grade 3 (CIN3). Patients with newly diagnosed HPV16-positive CIN3 were eligible for participation. Patients received 3 immunizations of Vvax001 (5x107 infectious particles) at a three-week interval. Up to 19 weeks after the last immunization patients were monitored for regression of CIN3 by colposcopy. A colposcopy-guided biopsy was taken at the last visit and a standard of care loop excision was performed only in case of remaining CIN2/3. Histopathologic response rates, HPV16 clearance, treatment-related adverse events (trAEs), and vaccine-induced immune responses were assessed. A total of 18 patients were enrolled and fully immunized. Colposcopic examination revealed a reduction in CIN3 lesion sizes in 17/18 patients (94%) already evident from 3 weeks onwards after the last immunization. A histopathological complete response (regression to CIN1 or no dysplasia) was observed in 9/18 patients (50%), and HPV16 clearance in 10/16 patients (63%). Vvax001 did not induce clearance of other HPV types. To date, no recurrences have been observed, with a median and longest disease-free survival of 20 and 30 months, respectively. No serious AEs were observed. Treatment with Vvax001 is safe, feasible, and shows preliminary clinical effectiveness in patients with HPV16-associated CIN3 lesions.

Pandemic preparedness in Vietnam: a review of health system resilience and areas for improvement.

In this viewpoint, we explore Vietnam's health system vulnerabilities and its national response to the COVID-19 pandemic, as well as critical areas of health system resilience, including health financing, workforce distribution, information systems, and governance. While Vietnam achieved early success through strong governance and mass vaccination campaigns, the pandemic revealed weaknesses in resource procurement, workforce imbalance, and limitations of its health information system. There are challenges in ensuring the rapid disbursement of financial resources and reliance on imported medical supplies, which delayed response times. Uneven healthcare workforce distribution, particularly in rural areas, further strained the health system. Although telemedicine and digital health solutions were implemented, weak digital infrastructure and inadequate information technology literacy hindered their effectiveness. Governance efforts, while generally strong, highlighted the need for better coordination and role clarity during health emergencies. Our findings identify areas for improvement, including effective resource mobilisation and allocation, enhanced digital infrastructure, expanded telemedicine access, and better support for healthcare workers. Governance enhancements, such as improved priority setting and interagency coordination, were also critical. These insights offer valuable guidance for strengthening Vietnam's health system and ensuring greater preparedness for future pandemics, but could also help other low- and middle-income countries facing similar challenges.