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The COVID-19 pandemic has exemplified that rigorous evaluation in large animal models is key for translation from promising in vitro results to successful clinical implementation. Among the drugs that have been largely tested in clinical trials but failed so far to bring clear evidence of clinical efficacy is favipiravir, a nucleoside analogue with large spectrum activity against several RNA viruses in vitro and in small animal models. Here, we evaluate the antiviral activity of favipiravir against Zika or SARS-CoV-2 virus in cynomolgus macaques. In both models, high doses of favipiravir are initiated before infection and viral kinetics are evaluated during 7 to 15 days after infection. Favipiravir leads to a statistically significant reduction in plasma Zika viral load compared to untreated animals. However, favipiravir has no effects on SARS-CoV-2 viral kinetics, and 4 treated animals have to be euthanized due to rapid clinical deterioration, suggesting a potential role of favipiravir in disease worsening in SARS-CoV-2 infected animals. To summarize, favipiravir has an antiviral activity against Zika virus but not against SARS-CoV-2 infection in the cynomolgus macaque model. Our results support the clinical evaluation of favipiravir against Zika virus but they advocate against its use against SARS-CoV-2 infection. Repurposed antiviral drugs present as a valuable resource in the defence during outbreaks, with rigorous evaluation in large animal models keys for translation to clinical implementation. Here, the authors explore the antiviral activity of favipiravir against Zika virus and SARS-CoV-2 in cynomolgus macaques, in order to support future clinical investigations into this RNA polymerase inhibitor.

In human medicine, bronchoalveolar lavage is the main non-traumatic procedure allowing an insight into the respiratory Dendritic Cells (DC) and Macrophages populations. However, it has never been demonstrated in a relevant model that alveolar DC subpopulations were comparable to their interstitial counterparts. In a precedent work we observed that respiratory pig DC and Macrophages were more similar to the human ones than to the mouse ones. In the present work, thanks to our animal model, we were able to collect the rare bronchoalveolar DC and compare them to their interstitial counterparts. We observed that DC presented very similar gene-expression patterns in the alveolar and interstitial compartments, validating the study of human bronchoalveolar DC as surrogate of their interstitium counterparts.

Non-human primates infected with SARS-CoV-2 exhibit mild clinical signs. Here we used a mathematical model to characterize in detail the viral dynamics in 31 cynomolgus macaques for which nasopharyngeal and tracheal viral load were frequently assessed. We identified that infected cells had a large burst size (>10 4 virus) and a within-host reproductive basic number of approximately 6 and 4 in nasopharyngeal and tracheal compartment, respectively. After peak viral load, infected cells were rapidly lost with a half-life of 9 hours, with no significant association between cytokine elevation and clearance, leading to a median time to viral clearance of 10 days, consistent with observations in mild human infections. Given these parameter estimates, we predict that a prophylactic treatment blocking 90% of viral production or viral infection could prevent viral growth. In conclusion, our results provide estimates of SARS-CoV-2 viral kinetic parameters in an experimental model of mild infection and they provide means to assess the efficacy of future antiviral treatments.

The definition of correlates of protection is critical for the development of next-generation SARS-CoV-2 vaccine platforms. Here, we propose a model-based approach for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication.

The influenza A virus (IAV) PB1-F2 protein is a virulence factor contributing to the pathogenesis observed during IAV infections in mammals. In this study, using a mouse model, we compared the host response associated with PB1-F2 with an early transcriptomic signature that was previously associated with neutrophils and consecutively fatal IAV infections. This allowed us to show that PB1-F2 is partly involved in neutrophil-related mechanisms leading to death. Using neutropenic mice, we confirmed that the harmful effect of PB1-F2 is due to an excessive inflammation mediated by an increased neutrophil mobilization. We identified the downstream effects of this PB1-F2-exacerbated neutrophil recruitment. PB1-F2 had no impact on the lymphocyte recruitment in the airways at day 8 pi. However, functional genomics analysis and flow cytometry in broncho-alveolar lavages at 4 days pi revealed that PB1-F2 induced a NK cells deficiency. Thus, our results identify PB1-F2 as an important immune disruptive factor during the IAV infection.

The impact of variants of concern (VoC) on SARS-CoV-2 viral dynamics remains poorly understood and essentially relies on observational studies subject to various sorts of biases. In contrast, experimental models of infection constitute a powerful model to perform controlled comparisons of the viral dynamics observed with VoC and better quantify how VoC escape from the immune response. Here we used molecular and infectious viral load of 78 cynomolgus macaques to characterize in detail the effects of VoC on viral dynamics. We first developed a mathematical model that recapitulate the observed dynamics, and we found that the best model describing the data assumed a rapid antigen-dependent stimulation of the immune response leading to a rapid reduction of viral infectivity. When compared with the historical variant, all VoC except beta were associated with an escape from this immune response, and this effect was particularly sensitive for delta and omicron variant (p<10 −6 for both). Interestingly, delta variant was associated with a 1.8-fold increased viral production rate (p = 0.046), while conversely omicron variant was associated with a 14-fold reduction in viral production rate (p<10 −6 ). During a natural infection, our models predict that delta variant is associated with a higher peak viral RNA than omicron variant (7.6 log 10 copies/mL 95% CI 6.8–8 for delta; 5.6 log 10 copies/mL 95% CI 4.8–6.3 for omicron) while having similar peak infectious titers (3.7 log 10 PFU/mL 95% CI 2.4–4.6 for delta; 2.8 log 10 PFU/mL 95% CI 1.9–3.8 for omicron). These results provide a detailed picture of the effects of VoC on total and infectious viral load and may help understand some differences observed in the patterns of viral transmission of these viruses.

A protective vaccine is urgently needed to curb the ongoing global HIV-1 epidemic. There is increased interest to develop a vaccine able to induce both neutralizing antibodies and antibody-mediated effector functions for additional efficacy. We investigated the ability of a group M consensus envelope glycoprotein (Env) trimer vaccine ConM SOSIP.v7 to induce antibodies that mediate effector functions in preclinical and clinical studies. We found that the ConM SOSIP.v7 protein immunogen in combination with MPLA adjuvant induced diverse antibody-mediated effector functions in human volunteers participating in a phase 1 trial. Moreover, the functional antibody response was higher in female compared to male participants. The same immunogen induced similar antibody-mediated effector functions in preclinical studies using rabbits and non-human primates. In these preclinical models, we demonstrated that alterations in the vaccine regimen, including immunization route and adjuvant, could modulate vaccine immunogenicity and lead to functionally different antibody responses. Specifically, we observed that intramuscular immunization led to more functional antibody responses compared to subcutaneous vaccine administration, and that the MPLA liposomes and squalene emulsion adjuvants induced functionally different antibody responses. In conclusion, this study shows that HIV-1 native-like Env trimers are able to elicit antibody-mediated effector functions in humans and that preclinical studies had predictive value. Furthermore, the preclinical studies revealed that different vaccine formulations and administration routes yield qualitatively different antibody-mediated effector functions. Our findings should guide interpretation of preclinical HIV-1 vaccine studies and can inform the design of HIV-1 vaccine regimens aimed at inducing antibody-mediated effector functions in addition to neutralization capacity.

Vaccines represent one of the major advances of modern medicine. Despite the many successes of vaccination, continuous efforts to design new vaccines are needed to fight “old” pandemics, such as tuberculosis and malaria, as well as emerging pathogens, such as Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccination aims at reaching sterilizing immunity, however assessing vaccine efficacy is still challenging and underscores the need for a better understanding of immune protective responses. Identifying reliable predictive markers of immunogenicity can help to select and develop promising vaccine candidates during early preclinical studies and can lead to improved, personalized, vaccination strategies. A systems biology approach is increasingly being adopted to address these major challenges using multiple high-dimensional technologies combined with in silico models. Although the goal is to develop predictive models of vaccine efficacy in humans, applying this approach to animal models empowers basic and translational vaccine research. In this review, we provide an overview of vaccine immune signatures in preclinical models, as well as in target human populations. We also discuss high-throughput technologies used to probe vaccine-induced responses, along with data analysis and computational methodologies applied to the predictive modeling of vaccine efficacy.

Background Porcine reproductive and respiratory syndrome (PRRS) remains a major concern for the swine industry worldwide due to its significant economic impact and its association with respiratory co-infections. Vaccination is a key strategy for PRRS control; however, the most effective commercial anti-PRRSV vaccines to date—live attenuated vaccines, also named modified live virus (MLV) vaccines—provide only partial protection. This study investigates whether oral supplementation with formulated Ulva -derived seaweed extracts can enhance immune responses to PRRSV-1 MLV vaccination. Methods Two supplementation protocols using commercial seaweed extracts formulated with vitamin A and D (Searup®) were tested: one starting one day post-vaccination for five consecutive days (post-vaccination), and another beginning one day before vaccination and continuing for two days post-vaccination (pre-vaccination). In this exploratory farm-based experimental setting, pigs were divided into six groups: three vaccinated groups (supplemented with seaweed either pre- or post-vaccination or not supplemented), and three non-vaccinated control groups receiving the same supplementation regimes. Serum cytokine levels, PRRSV viral loads, and anti-PRRSV antibody responses were measured to assess immune modulation. Results Post-vaccination supplementation had no significant effect on vaccine viral load or humoral response, though a modest reduction in viral persistence was noted at 12 days post-vaccination (dpv). In contrast, pre-vaccination supplementation significantly increased vaccine virus levels at 4 dpv ( p =  0.048) and enhanced anti-PRRSV IgG levels ( p =  0.029). This protocol also induced an early and sustained decrease in pro-inflammatory cytokines, suggesting an immunomodulatory effect of algal extract supplemented with Vitamins A and D. We present here for the first time, in field conditions and in the target species, significant immune modifications upon realistic oral supplementation with Searup®. These findings are consistent with previous studies demonstrating the potential of pre-vaccination seaweed supplementation as a cost-effective, practical strategy to enhance humoral responses to PRRSV vaccination. Further studies are needed to evaluate its impact on neutralizing antibody production, cellular responses and protection against heterologous field PRRSV strains.

Purinergic receptors and NOD-like receptor protein 3 (NLRP3) inflammasome regulate inflammation and viral infection, but their effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain poorly understood. Here, we report that the purinergic receptor P2X7 and NLRP3 inflammasome are cellular host factors required for SARS-CoV-2 infection. Lung autopsies from patients with severe coronavirus disease 2019 (COVID-19) reveal that NLRP3 expression is increased in host cellular targets of SARS-CoV-2 including alveolar macrophages, type II pneumocytes and syncytia arising from the fusion of infected macrophages, thus suggesting a potential role of NLRP3 and associated signaling pathways to both inflammation and viral replication. In vitro studies demonstrate that NLRP3-dependent inflammasome activation is detected upon macrophage abortive infection. More importantly, a weak activation of NLRP3 inflammasome is also detected during the early steps of SARS-CoV-2 infection of epithelial cells and promotes the viral replication in these cells. Interestingly, the purinergic receptor P2X7, which is known to control NLRP3 inflammasome activation, also favors the replication of D614G and alpha SARS-CoV-2 variants. Altogether, our results reveal an unexpected relationship between the purinergic receptor P2X7, the NLRP3 inflammasome and the permissiveness to SARS-CoV-2 infection that offers novel opportunities for COVID-19 treatment.