BACKGROUND:Despite the incorporation of atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, into first-line chemotherapy regimen, survival in patients with extensive-stage small cell lung cancer (ES-SCLC) remains poor. Given the role of dendritic cells (DCs) in modulating responses to anti-programmed cell death protein 1 (PD-1) antibodies, a promising avenue is the development of vaccines based on DCs, together with the evaluation of how DC phenotypic modifications shape treatment efficacy. MATERIALS AND METHODS:This is a single-arm, phase Ib/II, open-label clinical trial investigating the safety and activity of combining autologous tumor lysate pulsed DCs administered intradermally with intravenous atezolizumab as maintenance therapy for patients with ES-SCLC. Following leukapheresis, monocytes were differentiated ex vivo into mature DCs and loaded with irradiated autologous tumor lysate. After standard induction therapy (four cycles of carboplatin, etoposide, and atezolizumab), patients received up to six doses of mature DCs intradermally, along with intravenous atezolizumab 1,200 mg every 3 weeks, until disease progression. RESULTS:20 patients were enrolled, including six patients with brain metastases. 18 patients received DC vaccination, with a median of three doses (range 1-6). Most grade 3-4 treatment-related adverse events were hematological and related to chemotherapy. DC vaccination was well tolerated, with only grade 1-2 transient skin irritation at the injection site. Among 18 evaluable patients, 17 (94.4%) achieved an objective response. After a median follow-up of 31.4 months, progression-free survival at 2 years (PFS2y) was 20% (95% CI 6.4% to 39.1%), median overall survival (OS) 11.2 months (95% CI 6.3 to 26.0) and OS3y 22.5% (95% CI 6.8% to 43.6%). Six patients achieved long survival (median 30.5 months, range 23.4-36.2). Expansion of conventional type DC1 (cDC1s) XCR1+ and stem-like progenitor-exhausted (CXCR5+PD-1+) CD8+ T cells following chemotherapy plus atezolizumab was associated with improved PFS (HR 0.94, 95% CI 0.90 to 0.99 and HR 0.59, 95% CI 0.39 to 0.89). CONCLUSION:DC immunization combined with atezolizumab maintenance following standard chemotherapy plus atezolizumab treatment is well tolerated. Its clinical activity cannot be definitively determined in this study, as it was administered as maintenance therapy; however, the observed rate of long-term survivors suggests a potential benefit. Our findings suggest a pivotal role for cDC1s in mediating the antitumor activity in long-term survivors. TRIAL REGISTRATION NUMBER:NCT04487756.

A detailed mathematical model has been developed for the dynamics of hepatitis B virus (HBV) infection in a single cell. It provides a platform for a better quantitative understanding of the biochemical kinetics of the HBV lifecycle. The model is used to study the sensitivity of virus growth, providing a clear ranking of intracellular virus replication processes with respect to their contribution to net viral production. The stochastic formulation of the model enables the quantification of the variability characteristics in viral production, the probability of productive infection and the secretion of protein- and genome-deficient viral particles. An essential difference in infection efficiency between deterministic and stochastic models has been revealed. For example, in the case of MOI=1, the mean value of the total number of mature virions released during the lifecycle of the infection in the stochastic model is 1.06, whereas, in the deterministic model, its value is less than one thousandth and thus close to 0. The model is also used to quantitatively predict the effect of combinations of direct-acting antivirals, such as small interfering RNAs, capsid inhibitors and nucleoside analogues. The model shows that the inhibitory effect of siRNA on viral production is approximately two orders of magnitude higher than that of nucleoside analogues and capsid inhibitors.

BACKGROUND:Well-designed cohort studies are crucial for pandemic preparedness, informing evidence-based infection prevention and treatment strategies. OBJECTIVES:Following the 2022 mpox outbreak in Europe, this scoping review critically evaluates the design, implementation, and characteristics of cohort studies focusing on mpox. The aim is to inform recommendations for the Cohort Coordination Board and the COordination MEchanism for Cohorts and Trials (CoMeCT) to enhance cohort study research and improve preparedness. SOURCES:A comprehensive literature search was conducted in PubMed, Scopus, ClinicalTrials.gov, the European Union Clinical Trials Register, and the European Clinical Research Infrastructure Network (ECRIN) metadata repository up to December 2024. CONTENT:Forty-nine cohorts were identified, encompassing 10 728 individuals with primary or breakthrough mpox and 34 010 individuals without mpox (vaccinated and unvaccinated). The majority of cohorts collected data prospectively (30, 63%) and were multicentre (25, 52%). The primary aims were the natural history of mpox (31, 65%); effectiveness of vaccination (15, 31%); and treatment (2, 4%). The most frequent target population was individuals at increased risk of sexually transmitted infection (18, 38%). Follow-up of participants varied widely among cohorts. Significant data heterogeneity, stemming from the inconsistent use of standardized data dictionaries, impeded data sharing and meta-analyses. Under-representation of vulnerable populations and limited biobanking further compounded these challenges. IMPLICATIONS:This review underscores critical gaps in the research response during the mpox outbreak. Based on these findings, we propose the following recommendations: (1) establishing and maintaining "ever-warm" cohorts of high-risk individuals during inter-epidemic periods to enable rapid data collection during future outbreaks; (2) promoting data interoperability through the development and adoption of standardized data collection tools and ontologies; (3) improving the quality of study reporting through strict adherence to relevant guidelines; and (4) strengthening European and global coordination through the establishment of collaborative research networks. Sustained investment in research infrastructure is essential for a more effective, equitable, and timely public health response to future outbreaks.

Efficient control of HIV-1 infection relies on highly active antiretroviral therapy (HAART). However, this therapy is not curative and requires continuous drug administration. Application of HIV-1 defective interfering particles (DIPs), engineered with ablations in key viral protein expressions (e.g., Tat, Rev, Vpu, and Env), suggests a therapeutic potential transforming them into Therapeutic Interfering Particles (TIPs). A recent animal HIV model study in non-human primates reports a substantial reduction in viral load after a single intravenous injection of TIPs. In contrast, human clinical trials demonstrate no beneficial effect of defective interfering particles (DIPs) in people living with HIV-1. This discrepancy highlights the importance of further investigation of HIV-TIP interactions. A quantitative view of intracellular replication for HIV-1 in the presence of TIPs is still missing. Here, we develop a high-resolution mathematical model to study various aspects of the interference of a specific engineered TIP-2 particle characterized by a 2.5-kb deletion in the HIV pol-vpr region with HIV-1 replication within infected CD4+ T cells. We define the conditions in terms of the number of homozygous HIV-1 virions and TIP-2 particles that enable the reduction of the wild-type virus replication number to the value of about one. The deterministic model predicts that at a ratio of 1 HIV-1 to 10 TIP-2 particles, the infected cell still produces some viruses, although in a minor quantity, i.e., about two virions per cycle. Pre-activation of the interferon type I (IFN-I) system results in a complete block of HIV-1 production by TIP-2 co-infected cells. Overall, the modelling results suggest that to improve the effectiveness of TIPs in reducing HIV infection, their combination with other types of antiviral protection should be considered. Our results can be used in the development of combination therapy aimed at treating HIV-1 infection.

Vaccination of people living with an HIV infection (PLWH) remains a worldwide challenge. The reason is the heterogeneity of this group that comprises people with and without highly active retroviral treatment and varying degrees of immunosuppression. In this review, we (i) highlight the impact of antiviral treatment success on vaccination outcomes, (ii) describe the current vaccine recommendations for PLWH, and (iii) summarize immunotherapeutic strategies for improved HIV immune control.

Vaccines based on mRNA technology have revolutionized the field. In fact, lipid nanoparticles (LNP) formulated with mRNA are the preferential vaccine platform used in the fight against SARS-CoV-2 infection, with wider application against other diseases. The high demand and property right protection of the most potent cationic/ionizable lipids used for LNP formulation of COVID-19 mRNA vaccines have promoted the design of alternative nanocarriers for nucleic acid delivery. In this study we have evaluated the immunogenicity and efficacy of different rationally designed lipid and polymeric-based nanoparticle prototypes against SARS-CoV-2 infection. An mRNA coding for a trimeric soluble form of the receptor binding domain (RBD) of the spike (S) protein from SARS-CoV-2 was encapsulated using different components to form nanoemulsions (NE), nanocapsules (NC) and lipid nanoparticles (LNP). The toxicity and biological activity of these prototypes were evaluated in cultured cells after transfection and in mice following homologous prime/boost immunization. Our findings reveal good levels of RBD protein expression with most of the formulations. In C57BL/6 mice immunized intramuscularly with two doses of formulated RBD-mRNA, the modified lipid nanoparticle (mLNP) and the classical lipid nanoparticle (LNP-1) were the most effective delivery nanocarriers at inducing binding and neutralizing antibodies against SARS-CoV-2. Both prototypes fully protected susceptible K18-hACE2 transgenic mice from morbidity and mortality following a SARS-CoV-2 challenge. These results highlight that modulation of mRNAs immunogenicity can be achieved by using alternative nanocarriers and support further assessment of mLNP and LNP-1 prototypes as delivery vehicles for mRNA vaccines.

Despite the high efficiency of current SARS-CoV-2 mRNA vaccines in reducing COVID-19 morbidity and mortality, waning immunity and the emergence of resistant variants underscore the need for novel vaccination strategies. This study explores a heterologous mRNA/Modified Vaccinia virus Ankara (MVA) prime/boost regimen employing a trimeric form of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein compared to a homologous MVA/MVA regimen. In C57BL/6 mice, the RBD was delivered during priming via an mRNA vector encapsulated in nanoemulsions (NE) or lipid nanoparticles (LNP), followed by a booster with a replication-deficient MVA-based recombinant virus (MVA-RBD). This heterologous mRNA/MVA regimen elicited strong anti-RBD binding and neutralizing antibodies (BAbs and NAbs) against both the ancestral SARS-CoV-2 strain and different variants of concern (VoCs). Additionally, this protocol induced robust and polyfunctional RBD-specific CD4 and CD8 T cell responses, particularly in animals primed with mLNP-RBD. In K18-hACE2 transgenic mice, the LNP-RBD/MVA combination provided complete protection from morbidity and mortality following a live SARS-CoV-2 challenge compared with the partial protection observed with mNE-RBD/MVA or MVA/MVA regimens. Although the mNE-RBD/MVA regimen only protects half of the animals, it was able to induce antibodies with Fc-mediated effector functions besides NAbs. Moreover, viral replication and viral load in the respiratory tract were markedly reduced and decreased pro-inflammatory cytokine levels were observed. These results support the efficacy of heterologous mRNA/MVA vaccine combinations over homologous MVA/MVA regimen, using alternative nanocarriers that circumvent intellectual property restrictions of current mRNA vaccine formulations.

Immunotherapy with checkpoint inhibitors, albeit commonly used against tumors, is still at its infancy against chronic virus infections. It relies on the reinvigoration of exhausted T lymphocytes to eliminate virus-infected cells. Since T cell exhaustion is a physiological process to reduce immunopathology, the reinvigoration of these cells might be associated with an augmentation of pathological changes. To test this possibility, we here analyzed in the model system of chronic lymphocytic choriomeningitis virus (LCMV)-infected mice whether treatment with the checkpoint inhibitor anti-PD-L1 antibody would increase CD8 T cell-dependent fibrosis. We show that pre-existing spleen fibrosis did not worsen under conditions that increase CD8 T cell functionality and reduce virus loads suggesting that the CD8 T cell functionality increase remained below its pathogenicity threshold. These promising findings should further encourage immunotherapeutic trials against chronic virus infections.

People living with human immunodeficiency virus (HIV) are the individuals most affected by the current Monkeypox virus outbreak that was first announced in May 2022. Here we report Pan-pox-specific T-cell responses in a cohort of HIV-1-infected individuals after receiving the nonreplicative, attenuated smallpox vaccine JYNNEOS from Bavarian Nordic. Intradermal (i.d.) and subcutaneous (s.c.) vaccination was safe without major side effects. Dose-sparing i.d. vaccination was superior to s.c. vaccination and promoted T-cell polyfunctionality, and the expression of the gut-homing marker alpha 4 beta 7 integrin on lymphocytes. HIV-1-infected individuals with CD4 T-cell counts <= 500/mm3 blood required at least a booster vaccination to exhibit efficient virus-specific T-cell responses. The magnitude of the Th1 response after this booster directly correlated with the CD4 T-cell count of the vaccinees. Further studies with a larger number of participants are warranted to confirm and expand our observations.

SARS-CoV-2 still presents a global threat to human health due to the continued emergence of new strains and waning immunity among vaccinated populations. Therefore, it is still relevant to investigate potential therapeutics, such as therapeutic interfering particles (TIPs). Mathematical and computational modeling are valuable tools to study viral infection dynamics for predictive analysis. Here, we expand on the previous work on SARS-CoV-2 intra-cellular replication dynamics to include defective interfering particles (DIPs) as potential therapeutic agents. We formulate a deterministic model that describes the replication of wild-type (WT) SARS-CoV-2 virus in the presence of DIPs. Sensitivity analysis of parameters to several model outputs is employed to inform us on those parameters to be carefully calibrated from experimental data. We then study the effects of co-infection on WT replication and how DIP dose perturbs the release of WT viral particles. Furthermore, we provide a stochastic formulation of the model that is compared to the deterministic one. These models could be further developed into population-level models or used to guide the development and dose of TIPs.

SARS-CoV-2 emerged in December 2019 and quickly spread worldwide, continuously striking with an unpredictable evolution. Despite the success in vaccine production and mass vaccination programs, the situation is not still completely controlled, and therefore accessible second-generation vaccines are required to mitigate the pandemic. We previously developed an adjuvanted vaccine candidate coded PHH-1V, based on a heterodimer fusion protein comprising the RBD domain of two SARS-CoV-2 variants. Here, we report data on the efficacy, safety, and immunogenicity of PHH-1V in cynomolgus macaques. PHH-1V prime-boost vaccination induces high levels of RBD-specific IgG binding and neutralizing antibodies against several SARS-CoV-2 variants, as well as a balanced Th1/Th2 cellular immune response. Remarkably, PHH-1V vaccination prevents SARS-CoV-2 replication in the lower respiratory tract and significantly reduces viral load in the upper respiratory tract after an experimental infection. These results highlight the potential use of the PHH-1V vaccine in humans, currently undergoing Phase III clinical trials.

Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control.

Acute infection and chronic infection are the two most common fates of pathogenic virus infections. While several factors that contribute to these fates are described, the critical control points and the mechanisms that underlie infection fate regulation are incompletely understood. Using the acute and chronic lymphocytic choriomeningitis virus (LCMV) infection model of mice, we find that the early dynamic pattern of the IFN-I response is a differentiating trait between both infection fates. Acute-infected mice generate a 2-wave IFN-I response while chronic-infected mice generate only a 1-wave response. The underlying cause is a temporal difference in CD8 T cell-mediated killing of splenic marginal zone CD169+ macrophages. It occurs later in acute infection and thus enables CD169+ marginal zone macrophages to produce the 2nd IFN-I wave. This is required for subsequent immune events including induction of inflammatory macrophages, generation of effector CD8+ T cells and virus clearance. Importantly, these benefits come at a cost for the host in the form of spleen fibrosis. Due to an earlier marginal zone destruction, these ordered immune events are deregulated in chronic infection. Our findings demonstrate the critical importance of kinetically well-coordinated sequential immune events for acute infection control and highlights that it may come at a cost for the host organism.

The lymphocytic choriomeningitis virus (LCMV) is a non-cytopathic virus broadly used in fundamental immunology as a mouse model for acute and chronic virus infections. LCMV remains a cause of meningitis in humans, in particular the fatal LCMV infection in organ transplant recipients, which highlights the pathogenic potential and clinical significance of this neglected human pathogen. Paradoxically, the kinetics of the LCMV intracellular life cycle has not been investigated in detail. In this study, we formulate and calibrate a mathematical model predicting the kinetics of biochemical processes, including the transcription, translation, and degradation of molecular components of LCMV underlying its replication in infected cells. The model is used to study the sensitivity of the virus growth, providing a clear ranking of intracellular virus replication processes with respect to their contribution to net viral production. The stochastic formulation of the model enables the quantification of the variability characteristics in viral production, probability of productive infection and secretion of protein-deficient viral particles. As it is recognized that antiviral therapeutic options in human LCMV infection are currently limited, our results suggest potential targets for antiviral therapies. The model provides a currently missing building module for developing multi-scale mathematical models of LCMV infection in mice.

The systemic bio-organization of humans and other mammals is essentially "preprogrammed", and the basic interacting units, the cells, can be crudely mapped into discrete sets of developmental lineages and maturation states. Over several decades, however, and focusing on the immune system, we and others invoked evidence - now overwhelming - suggesting dynamic acquisition of cellular properties and functions, through tuning, re-networking, chromatin remodeling, and adaptive differentiation. The genetically encoded "algorithms" that govern the integration of signals and the computation of new states are not fully understood but are believed to be "smart", designed to enable the cells and the system to discriminate meaningful perturbations from each other and from "noise". Cellular sensory and response properties are shaped in part by recurring temporal patterns, or features, of the signaling environment. We compared this phenomenon to associative brain learning. We proposed that interactive cell learning is subject to selective pressures geared to performance, allowing the response of immune cells to injury or infection to be progressively coordinated with that of other cell types across tissues and organs. This in turn is comparable to supervised brain learning. Guided by feedback from both the tissue itself and the neural system, resident or recruited antigen-specific and innate immune cells can eradicate a pathogen while simultaneously sustaining functional homeostasis. As informative memories of immune responses are imprinted both systemically and within the targeted tissues, it is desirable to enhance tissue preparedness by incorporating attenuated-pathogen vaccines and informed choice of tissue-centered immunomodulators in vaccination schemes. Fortunately, much of the "training" that a living system requires to survive and function in the face of disturbances from outside or within is already incorporated into its design, so it does not need to deep-learn how to face a new challenge each time from scratch. Instead, the system learns from experience how to efficiently select a built-in strategy, or a combination of those, and can then use tuning to refine its organization and responses. Efforts to identify and therapeutically augment such strategies can take advantage of existing integrative modeling approaches. One recently explored strategy is boosting the flux of uninfected cells into and throughout an infected tissue to rinse and replace the infected cells.

A mathematical model of the human immunodeficiency virus Type 1 (HIV-1) life cycle in CD4 T cells was constructed and calibrated. It describes the activation of the intracellular Type I interferon (IFN-I) response and the IFN-induced suppression of viral replication. The model includes viral replication inhibition by interferon-induced antiviral factors and their inactivation by the viral proteins Vpu and Vif. Both deterministic and stochastic model formulations are presented. The stochastic model was used to predict efficiency of IFN-I-induced suppression of viral replication in different initial conditions for autocrine and paracrine effects. The probability of virion excretion for various MOIs and various amounts of IFN-I was evaluated and the statistical properties of the heterogeneity of HIV-1 and IFN-I production characterised.