Cell-based Vaccines Research Articles

Cell-based influenza vaccines: An effective vaccine option for under 60-year-olds.

Seasonal influenza poses a significant burden of disease, affecting not only older adults but also individuals under the age of 60. It carries a high economic burden, mainly driven by influenza-associated productivity losses in the working population. Conventional egg-based influenza vaccines may have reduced effectiveness due to antigen adaptation in eggs. In contrast, cell-based influenza vaccines are less likely to be affected by such antigen adaptation. This review aims to present real-world data (RWD) comparing the effectiveness of quadrivalent cell-based (QIVc) and egg-based (QIVe) influenza vaccines over three consecutive seasons. A comprehensive review was conducted, analyzing RWD from retrospective cohort and case-control studies on the relative vaccine effectiveness (rVE) of QIVc versus QIVe during the 2017/18-2019/20 seasons. This study included six retrospective cohort studies and one case-control study, with a combined total of approximately 29 million participants. A cohort study involving people aged ≥4 years during the 2017/18 season showed a statistically significant rVE of QIVc compared to QIVe in preventing influenza-like illness, with a value of 36.2%. QIVc demonstrated statistically significant superiority over QIVe in preventing outpatient and inpatient medical encounters as observed in two cohort studies conducted during the 2018/19 and 2019/20 seasons. The rVE of QIVc compared to QIVe was found to be 7.6% in individuals aged ≥4 years and 9.5% in individuals aged ≥18 years. Three additional cohort studies conducted between 2017/18-2019/20 reported a statistically significant improvement in rVE (5.3-14.4%) of QIVc compared to QIVe in preventing influenza-related hospitalizations and emergency department visits due to influenza in individuals aged 4-64 years. In a case-control study across all three seasons, QIVc showed statistically significantly higher effectiveness compared to QIVe in preventing test-confirmed influenza, with rVEs of 10.0-14.8%. RWD from the 2017/18-2019/20 seasons demonstrated that QIVc is more effective than QIVe in preventing influenza-related outcomes in individuals aged 4-64 years. Preferential use of cell-based influenza vaccines, as opposed to conventional egg-based vaccines, could reduce the burden of influenza-related symptoms on individuals and alleviate the economic impact on the German population under 60 years of age.

Cost-effectiveness analysis of cell-based versus egg-based quadrivalent influenza vaccines in the pediatric population in Taiwan.

Cell-based influenza vaccines avoid egg-adaptive mutations, potentially improving vaccine effectiveness. We assessed the one-season cost-effectiveness of cell-based quadrivalent influenza vaccine (QIVc) against that of egg-derived quadrivalent influenza vaccines (QIVe) in children (6 months to 17 years of age) from payer and societal perspectives in Taiwan using an age-stratified static model. Base case and high egg adaptation scenarios were assessed. Deterministic and probabilistic sensitivity analyses were performed. The incremental cost-effectiveness ratio (ICER) threshold in Taiwan was assumed to be USD 99 177/quality-adjusted life year (QALY). Compared to QIVe, QIVc would prevent 15 665 influenza cases, 2244 complicated cases, and 259 hospitalizations per year. The base case ICER was USD 68 298/QALY and USD 40 085/QALY from the payer and societal perspective, respectively. In the high egg adaptation scenario, the ICER was USD 45 782/QALY from the payer's perspective and USD 17 489/QALY from the societal perspective. Deterministic sensitivity analyses indicated that infection incidence rate, vaccination coverage, and prevalence of the A/H3N2 strain were the main drivers of ICER. In conclusion, switching the immunization strategy from QIVe to QIVc is predicted to reduce the influenza-associated disease burden and be cost-effective for the pediatric population in Taiwan. The potential benefits of QIVc would be even higher during influenza seasons with high levels of egg adaptation.

Assessing Antigen-Specific T Cell Responses Through IFN-γ Enzyme-Linked Immune Absorbent Spot (ELISpot).

T cells are instrumental in protecting the host against invading pathogens and the development of cancer. To do so, they produce effector molecules such as granzymes, interleukins, interferons, and perforin. For the development and immunomonitoring of therapeutic applications such as cell-based therapies and vaccines, assessing T cell effector function is paramount. This can be achieved through various methods, such as 51Cr release assays, flow cytometry, and enzyme-linked immune absorbent spot (ELISpot) assays. For T cell ELISpots, plates are coated with antibodies directed against the effector molecule of interest (e.g., IFN-g). Subsequently, peripheral blood mononuclear cells (PBMCs) or isolated T cells are cultured on the plate together with stimuli of choice, and the production of effector molecules is visualized via labeled detection antibodies. For clinical studies, ELISpot is currently the gold standard to determine antigen-specific T cell frequencies. In contrast to 51Cr release assays, ELISpot allows for the exact enumeration of responding T cells, and compared to flow cytometry, ELISpot is more cost-effective and high throughput. Here, we optimize and describe, in a step-by-step fashion, how to perform a controlled IFN-γ ELISpot experiment to determine the frequency of responding or antigen-specific T cells in healthy human volunteers. Of note, this protocol can also be employed to assess the frequency of antigen-specific T cells induced in, e.g., vaccination studies or present in cellular products.

The Interaction of Immune System in Tumour Microenvironment and Possible Role of Cancer Cell Immnunosensitization for Better Treatment Efficacy: A Review

Unlike haematologic malignant cells which express cell surface common antigens uniformly and are susceptible to targeted cancer immunotherapy, solid tumours either lack such antigens or have been mutated due to chemotherapy or other therapeutic interventions. Moreover, rapidly dividing tumour cells present complex and dynamic tumour metabolism, which hampers immune cells' reactivity against the tumour cells. Hence solid tumours other than immune-sensitive cancers such as melanoma and renal cell carcinoma are less responsive towards current cellular immunotherapy strategies, including cytokine therapy, dendritic cell-based vaccines, and immune-activating antibodies. Nonetheless, emerging evidence supports combined approaches that target immunosuppressive or antiapoptotic molecules, involving sensitization of the cancer cells by immunosensitizing drugs to express specific ligands that will be recognized by the immune cells via trafficking. This review highlights the immune system's involvement in the tumour microenvironment and the potential significance of cancer cell immunosensitization for improved treatment outcomes.

PERSPECTIVE FOR APPLYING ANTITUMOR VACCINES

One of the promising areas in immunotherapy are tumour-specific vaccines based on immunocompromised cells. DC-based personalized neoantigenic cellular vaccines have promising antitumor effects in clinical practice. Dendritic cell-based vaccines have a number of advantages, one example being the ability to engage both innate and adaptive immunity, as well as to develop long-term immunological memory against tumor recurrence. DCs are the most professional and consistent antigens and are more effective in activating resting T cells. The review provides the most up-to-date information on cancer vaccines, as well as an analysis of the types of cancer vaccines from domestic and foreign sources. The conclusion of this brief review is the wide variety of types of tumor-specific vaccines and their rapid improvement.

Modelling the population-level benefits and cost-effectiveness of cell-based quadrivalent influenza vaccine for children and adolescents aged 6 months to 17 years in the US

ABSTRACT Background Cell-based quadrivalent influenza vaccines (QIVc) can increase effectiveness against seasonal influenza by avoiding mismatch from egg adaption of vaccine viruses. This study evaluates the population-level cost-effectiveness and impacts on health outcomes of QIVc versus an egg-based vaccine (QIVe) in children aged 6 months to 17 years in the US. Research Design and Methods A dynamic age-structured susceptible-exposed-infected-recovered model was used to simulate influenza transmission in low and high incidence seasons for two scenarios: 1. QIVe for 6 months–17 year-olds, QIVc for 18–64 year-olds, and adjuvanted QIV (aQIV) for ≥ 65 year-olds, and 2. QIVc for 6 months–64 year-olds, and aQIV for ≥ 65 year-olds. Probabilistic sensitivity analysis was performed to account for uncertainty in parameter estimates. Cost-effectiveness was evaluated as incremental cost-effectiveness ratios (ICERs). Results Extension of QIVc to children resulted in 3–4% reductions in cases (1,656,271), hospitalizations (16,688), and deaths (2,126) at a population level in a high incidence season, and 65% reductions (cases: 2,856,384; hospitalizations: 31667; deaths: 4,163) in a low incidence season. Use of QIVc would be cost-saving, with ICERs of -$16,427/QALY and -$8,100/QALY from a payer perspective and -$22,669/QALY and -$15,015/QALY from a societal perspective, for low and high incidence seasons respectively. Cost savings were estimated at approximately $468 million and $1.366 billion for high and low incidence seasons, respectively. Conclusion Use of QIVc instead of QIVe in children > 6 months of age in the US would reduce the disease burden and be cost-saving from both a payer and societal perspective.

Abstract IA015: Leveraging mRNA to design a next-generation cell-based therapeutic cancer vaccine

Abstract Monocyte-derived dendritic cell (DC)-based cancer vaccines were shown to activate T cell-mediated antitumor immune responses. To ensure high tumor specificity and potency of the DC-vaccine, we leveraged mRNA for the delivery of tumor antigens and proteins that enhance the DCs’ T-cell stimulatory capacity. With regard to tumor antigens, we studied neoantigens. These originate from erroneous DNA in tumor cells, creating a message for novel and unique tumor antigens of which neoepitopes could be presented by the tumor cells to T cells. Identifying neoepitopes has become possible through advances in next-generation sequencing and bioinformatic prediction algorithms. We developed a synthetic DNA template (SDT) to manufacture in vitro transcribed neoepitope mRNA. A benefit of this platform is the high flexibility and speed to create a neoepitope mRNA library. We showed that mRNA produced with the SDT could be used to validate bioinformatically predicted neoepitopes and could potentially be used to produce a DC-vaccine. With regard to potency, we developed a novel mRNA-based adjuvant, building on the knowledge that interleukin-12 produced by DCs correlates with T-cell activation. The novel mRNA mix, referred to as TetraMix, consists of 4 mRNA molecules encoding (1) constitutively active toll-like receptor 4, (2) CD40 ligand, (3) interferon-gamma and (4) a decoy receptor for interleukin-10. DCs electroporated with TetraMix mRNA showed a viral response gene expression profile. The obtained DC-maturation state enabled activation of tumor killing T cells. In summary, we developed a personalized cancer vaccine consisting of mRNA-engineered DCs, which is ready for evaluation in a clinical setting.</aaff> Citation Format: Karine Breckpot. Leveraging mRNA to design a next-generation cell-based therapeutic cancer vaccine [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA015.

2640. Estimated Additional Burden Averted from Use of Cell-Based Influenza Vaccines Compared to Egg-Based Influenza Vaccines Among People 0-64 Years of Age in the United States: 2017-2020 Seasons

Abstract Background Influenza vaccines have traditionally been produced in eggs, which can introduce egg-adaptive mutations. Cell-based influenza vaccines avoid egg-adaptive mutations, potentially improving match to circulating influenza viruses and therefore vaccine effectiveness. This study modeled the public health impact if all vaccinated people 0-64 years of age in the United States received cell-propagated inactivated quadrivalent influenza vaccine (IIV4c) compared to egg-propagated inactivated quadrivalent influenza vaccine (IIV4) across the 2017-2018 through 2019-2020 Influenza Seasons. Methods The modeling method used by the US Centers for Disease Control and Prevention (CDC) for estimating overall burden averted due to influenza vaccination was extended to a relative vaccine effectiveness (rVE) context. The model utilized CDC data on influenza vaccine uptake, influenza incidence, influenza-related healthcare resource use and deaths. CDC estimates of absolute vaccine effectiveness (aVE) (any vaccine) were used as the aVE of IIV4. Based on previously published rVE estimates generated from the same real-world database, the rVE of IIV4c vs IIV4 was assumed to be 19.3% (95% Confidence interval: 9.5 to 28) in 2017-2018, 7.6% (6.5 to 8.6) in 2018-2019, and 17.2% (15.8 to 18.6) in 2019-2020. Base-case results were validated with deterministic (DSA) and probabilistic (PSA) sensitivity analyses. Results Figure 1 shows the anticipated number influenza-related cases and complications that would be averted if all vaccinated people 0-64 years of age received IIV4c or IIV4. Across the 3 influenza seasons, use of IIV4c would result in prevention of an additional 12,706,837 symptomatic illnesses, 6,222,820 outpatient visits, 80,390 hospitalizations, and 2,765 deaths. DSA results showed that the rVE estimate was associated with the most variability while the burden estimates were most influential in the other two seasons. Mean PSA results were all within a 0.5% difference of base-case results.Figure 1.Number of Outcomes Prevented from Use of IIV4c Compared to IIV4 Among People 0-64 Years of Age: 2017-2018 Through 2019-2020 Seasons Conclusion Use of IIV4c instead of IIV4 during the 2017-2020 influenza seasons in the US would have had a substantial public health impact due to a 28.5% to 49.1% increase in influenza cases prevented. Disclosures Ian McGovern, MPH, CSL Seqirus: Employment|CSL Seqirus: Stocks/Bonds Alexandra Taylor, MSc, CSL Seqirus: Advisor/Consultant Aditya Sardesai, MSc, CSL Seqirus: Advisor/Consultant|Merck & Co. Inc: Grant/Research Support|Merck & Co. Inc: Grant/Research Support Hector Toro-Diaz, PhD, CSL Seqirus: Advisor/Consultant Mendel Haag, PhD, PharmD, CSL Seqirus: Stocks/Bonds

1732. The Value of the Influenza Cell-Based Vaccine in the Pediatric Population. A Dynamic Transmission Modelling Approach in the U.S.

Abstract Background Seasonal influenza poses a huge public health issue for children globally, resulting in significant disease and economic burdens. In addition, children are major influenza spreaders across the multiple age groups because they may pass on more of the virus for a longer period. This research aimed to evaluate the economic and health impacts of the cell-based quadrivalent influenza vaccine (QIVc) compared to the standard-dose egg-based quadrivalent influenza vaccine (QIVe) in U.S. children (6 months-17 years), from the payers and societal perspective. Methods The public health and cost outcomes of QIVc and QIVe was estimated using a dynamic age-structured susceptible-exposed-infected-recovered transmission model. The model was calibrated to a low (2011-2012) and high incidence (2017-2018) influenza seasons, matching Centers for Disease Control and Prevention (CDC) reported data. The relative vaccine effectiveness of QIVc over QIVe in children was taken from a meta-analysis based on observational studies in the U.S. Within the dynamic model, adults (18-64yrs) received QIVc and older adults (65yrs+) the adjuvanted influenza vaccine; only vaccination type differences were accounted in the 6mons-17yrs age group. Probability of events, costs and utility values were obtained from U.S. literature. Coverage rates for all age-groups was taken from official CDC pre-pandemic reports. The robustness of the results was assessed in probabilistic sensitivity analyses. Results Within a low incidence season (LIS), switching from QIVe to QIVc in 6 months- to 17-year-olds may prevent 2.9 million symptomatic cases, 1.1 million outpatient visits, 31,667 hospitalizations, and 4,163 deaths annually. As an opposite, within a high incidence season (HIS), switching from QIVe to QIVc may prevent 1.7 million symptomatic cases, 648,263 outpatient visits, 16,688 hospitalizations, and 2,126 deaths. In both scenarios, LIS and HIS, QIVc would be a cost-saving strategy with US$1.4B and US$468.7M savings from a societal perspective and US$989.8M and US$252.8M savings from a payer perspective, respectively. Conclusion The analysis shows that QIVc in children is expected to prevent hospitalizations and deaths, and result in substantial savings in healthcare costs. Disclosures Joaquin F. Mould-Quevedo, PhD, CSL Seqirus Inc.: Employee|CSL Seqirus Inc.: Employee|CSL Seqirus Inc.: Stocks/Bonds|CSL Seqirus Inc.: Stocks/Bonds Van Nguyen, PhD, CSL Seqirus Inc.: Advisor/Consultant|CSL Seqirus Inc.: Advisor/Consultant|CSL Seqirus Inc.: Honoraria

Unlocking Dendritic Cell-Based Vaccine Efficacy through Genetic Modulation-How Soon Is Now?

The dendritic cell (DC) vaccine anti-cancer strategy involves tumour-associated antigen loading and maturation of autologous ex vivo cultured DCs, followed by infusion into the cancer patient. This strategy stemmed from the idea that to induce a robust anti-tumour immune response, it was necessary to bypass the fundamental immunosuppressive mechanisms of the tumour microenvironment that dampen down endogenous innate immune cell activation and enable tumours to evade immune attack. Even though the feasibility and safety of DC vaccines have long been confirmed, clinical response rates remain disappointing. Hence, the full potential of DC vaccines has yet to be reached. Whether this cellular-based vaccination approach will fully realise its position in the immunotherapy arsenal is yet to be determined. Attempts to increase DC vaccine immunogenicity will depend on increasing our understanding of DC biology and the signalling pathways involved in antigen uptake, maturation, migration, and T lymphocyte priming to identify amenable molecular targets to improve DC vaccine performance. This review evaluates various genetic engineering strategies that have been employed to optimise and boost the efficacy of DC vaccines.

Effectiveness of Cell-Based Quadrivalent Seasonal Influenza Vaccine: A Systematic Review and Meta-Analysis.

Cell-based seasonal influenza vaccine viruses may more closely match recommended vaccine strains than egg-based options. We sought to evaluate the effectiveness of seasonal cell-based quadrivalent influenza vaccine (QIVc), as reported in the published literature. A systematic literature review was conducted (PROSPERO CRD42020160851) to identify publications reporting on the effectiveness of QIVc in persons aged ≥6 months relative to no vaccination or to standard-dose, egg-based quadrivalent or trivalent influenza vaccines (QIVe/TIVe). Publications from between 1 January 2016 and 25 February 2022 were considered. The review identified 18 relevant publications spanning three influenza seasons from the 2017-2020 period, with an overall pooled relative vaccine effectiveness (rVE) of 8.4% (95% CI, 6.5-10.2%) for QIVc vs. QIVe/TIVe. Among persons aged 4-64 years, the pooled rVE was 16.2% (95% CI, 7.6-24.8%) for 2017-2018, 6.1% (4.9-7.3%) for 2018-2019, and 10.1% (6.3-14.0%) for 2019-2020. For adults aged ≥65 years, the pooled rVE was 9.9% (95% CI, 6.9-12.9%) in the egg-adapted 2017-2018 season, whereas there was no significant difference in 2018-2019. For persons aged 4-64 years, QIVc was consistently more effective than QIVe/TIVe over the three influenza seasons. For persons aged ≥65 years, protection with QIVc was greater than QIVe or TIVe during the 2017-2018 season and comparable in 2018-2019.

Vaccine Effectiveness of Cell-Based Quadrivalent Influenza Vaccine in Children: A Narrative Review.

Cell-based manufacturing of seasonal influenza vaccines eliminates the risk of egg-adaptation of candidate vaccine viruses, potentially increasing vaccine effectiveness (VE). We present an overview of published data reporting the VE and cost-effectiveness of a cell-based quadrivalent influenza vaccine (QIVc) in preventing influenza-related outcomes in the pediatric population. We identified 16 clinical studies that included data on the VE of a QIVc or the relative VE (rVE) of a QIVc versus an egg-based QIV (QIVe) in children and/or adolescents, 11 of which presented estimates specifically for the pediatric age group. Of these, two studies reported rVE against hospitalizations. Point estimates of rVE varied from 2.1% to 33.0%, with studies reporting significant benefits of using a QIVc against influenza-related, pneumonia, asthma, and all-cause hospitalization. Four studies reported rVE against influenza-related medical encounters, with point estimates against non-strain specific encounters ranging from 3.9% to 18.8% across seasons. One study evaluated rVE against any influenza, with variable results by strain. The other four studies presented VE data against laboratory-confirmed influenza. Three health economics studies focusing on a pediatric population also found the use of QIVc to be cost-effective or cost-saving. Overall, using a QIVc is effective in pediatric patients, with evidence of incremental benefits over using a QIVe in preventing hospitalizations and influenza-related medical encounters in nearly all published studies.

Seasonal quadrivalent mRNA vaccine prevents and mitigates influenza infection

Annually, seasonal influenza is responsible for millions of infections and hundreds of thousands of deaths. The current method for managing influenza is vaccination using a standardized amount of the influenza virus’ primary surface antigen, hemagglutinin (HA), as the intended target of the immune response. This vaccination strategy results in vaccines with variable efficacy year to year due to antigenic drift of HA, which can be further exacerbated by manufacturing processes optimizing growth of vaccine virus in eggs. Due to these limitations, alternative vaccine platforms are actively being explored to improve influenza vaccine efficacy, including cell-based, recombinant protein, and mRNA vaccines. mRNA’s rapid, in vitro production makes it an appealing platform for influenza vaccination, and the success of SARS-CoV-2 mRNA vaccines in the clinic has encouraged the development of mRNA vaccines for other pathogens. Here, the immunogenicity and protective efficacy of a quadrivalent mRNA vaccine encoding HA from four seasonal influenza viruses, A/California/07/2009 (H1N1), A/Hong Kong/4801/2014 (H3N2), B/Brisbane/60/2008 (B-Victoria lineage), and B/Phuket/3073/2013 (B-Yamagata lineage), was evaluated. In mice, a 120 μg total dose of this quadrivalent mRNA vaccine induced robust antibody titers against each subtype that were commensurate with titers when each antigen was administered alone. Following A/California/04/2009 challenge, mice were fully protected from morbidity and mortality, even at doses as low as 1 μg of each antigen. Additionally, a single administration of 10 μg of quadrivalent mRNA was sufficient to prevent weight loss caused by A/California/04/2009. These results support the promise of this mRNA vaccine for prevention and mitigation of influenza vaccine.

The Landscape of Adoptive Cellular Therapies in Ovarian Cancer.

Ovarian cancers are typically poorly immunogenic and have demonstrated disappointing responses to immune checkpoint inhibitor (ICI) therapy. Adoptive cellular therapy (ACT) offers an alternative method of harnessing the immune system that has shown promise, especially with the success of chimeric antigen receptor T-cell (CAR-T) therapy in haematologic malignancies. So far, ACT has led to modest results in the treatment of solid organ malignancies. This review explores the possibility of ACT as an effective alternative or additional treatment to current standards of care in ovarian cancer. We will highlight the potential of ACTs, such as CAR-T, T-cell receptor therapy (TCR-T), tumour-infiltrating lymphocytes (TILs) and cell-based vaccines, whilst also discussing their challenges. We will present clinical studies for these approaches in the treatment of immunologically 'cold' ovarian cancer and consider the rationale for future research.

Construction of Candida albicans Adhesin-Exposed Synthetic Cells for Preventing Systemic Fungal Infection.

The development of efficient fungal vaccines is urgent for preventing life-threatening systemic fungal infections. In this study, we prepared a synthetic, cell-based fungal vaccine for preventing systemic fungal infections using synthetic biology techniques. The synthetic cell EmEAP1 was constructed by transforming the Escherichia coli chassis using a de novo synthetic fragment encoding the protein mChEap1 that was composed of the E. coli OmpA peptide, the fluorescence protein mCherry, the Candida albicans adhesin Eap1, and the C-terminally transmembrane region. The EmEAP1 cells highly exposed the mChEap1 on the cell surface under IPTG induction. The fungal vaccine was then prepared by mixing the EmEAP1 cells with aluminum hydroxide gel and CpG. Fluorescence quantification revealed that the fungal vaccine was stable even after 112 days of storage. After immunization in mice, the vaccine resided in the lymph nodes, inducing the recruitment of CD11c+ dendritic cells. Moreover, the vaccine strongly activated the CD4+ T splenocytes and elicited high levels of anti-Eap1 IgG. By the prime-boost immunization, the vaccine prolonged the survival time of the mice infected by the C. albicans cells and attenuated fungal colonization together with inflammation in the kidneys. This study sheds light on the development of synthetic biology-based fungal vaccines for the prevention of life-threatening fungal infections.

Generating and measuring effective vaccine-elicited HIV-specific CD8 + T cell responses.

There is growing consensus that eliciting CD8 + T cells in addition to antibodies may be required for an effective HIV vaccine for both prevention and cure. Here, we review key qualities of vaccine-elicited CD8 + T cells as well as major CD8 + T cell-based delivery platforms used in recent HIV vaccine clinical trials. Much progress has been made in improving HIV immunogen design and delivery platforms to optimize CD8 + T cell responses. With regards to viral vectors, recent trials have tested newer chimp and human adenovirus vectors as well as a CMV vector. DNA vaccine immunogenicity has been increased by delivering the vaccines by electroporation and together with adjuvants as well as administering them as part of a heterologous regimen. In preclinical models, self-amplifying RNA vaccines can generate durable tissue-based CD8 + T cells. While it may be beneficial for HIV vaccines to recapitulate the functional and phenotypic features of HIV-specific CD8 + T cells isolated from elite controllers, most of these features are not routinely measured in HIV vaccine clinical trials. Identifying a vaccine capable of generating durable T cell responses that target mutationally vulnerable epitopes and that can rapidly intercept infecting or rebounding virus remains a challenge for HIV. Comprehensive assessment of HIV vaccine-elicited CD8 + T cells, as well as comparisons between different vaccine platforms, will be critical to advance our understanding of how to design better CD8 + T cell-based vaccines for HIV.

Active inoculation with an inactivated Coxsackievirus A2 vaccine induces neutralizing antibodies and protects mice against lethal infection

Coxsackievirus A2 (CVA2) is one of the causative agents of hand-foot-and-mouth disease (HFMD), which poses a great challenge for global public health. However, presently, there are no available commercial vaccines or antivirals to prevent CVA2 infection. Here, we present an inactivated Vero cell-based whole CVA2 vaccine candidate and evaluate its safety and efficacy in this study. Neonatal BALB/c mice were vaccinated at 5 and 7 days old, respectively, and then challenged with either homologous or heterologous strain of CVA2 at a lethal dose at 10 days old. The inactivated whole CVA2 vaccine candidate showed a high protective efficacy. Additionally, our inactivated vaccine stimulated the production of CVA2-specific IgG1 and IgG2a antibodies in vivo and high titers of neutralization antibodies (NtAbs) in the serum of immunized mice. Maternal immunization with the inactivated CVA2 vaccine provided full protection to pups against lethal infection. Compared with mice inoculated with only alum, the viral loads were decreased, and pathological changes were relieved in tissue samples of immunized mice. Moreover, the transcription levels of some genes related to cytokines (IFN-γ and TNF-α, MCP-1, IL-6, CXCL-10 etc.) were significantly reduced. The number of immune cells and levels of cytokines in peripheral blood of mice inoculated with only alum were higher than that of immunized mice. It is noteworthy that this vaccine showed a good cross-immunity efficacy against Enterovirus A71 (EVA71) challenge. In conclusion, our findings suggest that this experimental inactivated CVA2 vaccine is a promising component of polyvalent vaccines related to HFMD in the near future.

Advances in immunotherapy for osteosarcoma: a review of emerging treatment strategies

Advances in immunotherapy for osteosarcoma have shown promising results, with the use of monoclonal antibodies and immune checkpoint inhibitors. These strategies are aimed at targeting specific molecules and pathways involved in tumour immune evasion and promoting anti-tumour immune responses. Other emerging immunotherapeutic approaches include autophagy and pyroptosis induction, chimeric antigen receptor T-cell therapy, gadolinium-bisphosphonate nanoparticles and dendritic cell-based vaccines. Continued research into these emerging treatment strategies is essential for developing effective therapies for patients with high-grade osteosarcoma.

The Adenylyl Cyclase Activator Forskolin Increases Influenza Virus Propagation in MDCK Cells by Regulating ERK1/2 Activity.

Vaccination is the most effective method for preventing the spread of the influenza virus. Cell-based influenza vaccines have been developed to overcome the disadvantages of egg-based vaccines and their production efficiency has been previously discussed. In this study, we investigated whether treatment with forskolin (FSK), an adenylyl cyclase activator, affected the output of a cell-based influenza vaccine. We found that FSK increased the propagation of three influenza virus subtypes (A/H1N1/California/4/09, A/H3N2/Mississippi/1/85, and B/Shandong/7/97) in Madin-Darby canine kidney (MDCK) cells. Interestingly, FSK suppressed the growth of MDCK cells. This effect could be a result of protein kinase A (PKA)-Src axis activation, which downregulates extracellular signal-regulated kinase (ERK)1/2 activity and delays cell cycle progression from G1 to S. This delay in cell growth might benefit the binding and entry of the influenza virus in the early stages of viral replication. In contrast, FSK dramatically upregulated ERK1/2 activity via the cAMP-PKA-Raf-1 axis at a late stage of viral replication. Thus, increased ERK1/2 activity might contribute to increased viral ribonucleoprotein export and influenza virus propagation. The increase in viral titer induced by FSK could be explained by the action of cAMP in assisting the entry and binding of the influenza virus. Therefore, FSK addition to cell culture systems could help increase the production efficiency of cell-based vaccines against the influenza virus.

Dendritic cell-based vaccine prepared with recombinant Lactococcus lactis enhances antigen cross-presentation and antitumor efficacy through ROS production.

Lactococcus lactis (L.L) is safe and can be used as vehicle. In this study, the immunoregulatory effect of L.L on dendritic cell (DC) activation and mechanism were investigated. The immune responses and antigen cross-presentation mechanism of DC-based vaccine prepared with OVA recombinant L.L were explored. Confocal microscopy and flow cytometry were used to analyze the mechanism of L.L promoting DC maturation, phagosome membrane rupture and antigen presentation. The antitumor effect of DC vaccine prepared with L.L-OVA was assessed in the B16-OVA tumor mouse model. L.L significantly promoted DC maturation, which was partially dependent on TLR2 and downstream MAPK and NF-κB signaling pathways. L.L was internalized into DCs by endocytosis and did not co-localized with lysosome. OVA recombinant L.L enhanced antigen cross-presentation of DCs through the phagosome-to-cytosol pathway in a reactive oxygen species (ROS)- and proteasome-dependent manner. In mouse experiments, L.L increased the migration of DCs to draining lymph node and DC vaccine prepared with OVA recombinant L.L induced strong antigen-specific Th1 and cytotoxic T lymphocyte responses, which significantly inhibited B16-OVA tumor growth. This study demonstrated that recombinant L.L as an antigen delivery system prepared DC vaccine can enhance the antigen cross-presentation and antitumor efficacy.