Challenge Trials Research Articles

Parameter Optimization of a Viral Dynamics Model in the Mucus Layer of the Human Nasal Cavity-Nasopharynx Based on Computational Fluid-Particle and Host-Cell Dynamics

Respiratory diseases, such as COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), have posed a threat to human health. For infection control and a better understanding of the pathogenesis, this study mainly focused on elucidating the virus dynamics in the mucus layer of the human nasal cavity-nasopharynx, using coupled computational fluid-particle dynamics (CFPD) and host-cell dynamics (HCD) analyses. To reproduce virus transportation in the mucus layer by mucociliary motion, a three-dimensional-shell model was created using the data obtained from computed tomography (CT) of the human upper airway. By considering the mucus milieu, the target-cell-limited model was coupled with the convection-diffusion term to develop the HCD model. Parameter optimization has been shown to have a great impact on the accuracy of model prediction; therefore, this study proposes a method that divides the geometric model into multiple regions and uses Monolix for nonlinear mixed effects modeling for pharmacometrics. The results showed that data from human inoculation challenge trials could be used to estimate the corresponding parameters. The models developed and used with optimized parameters can provide relatively accurate predictions of virus dynamics, which could contribute to the prevention and treatment of respiratory diseases.

Accelerating Vaccine Innovation for Emerging Infectious Diseases via Parallel Discovery

The COVID-19 pandemic has raised awareness about the global imperative to develop and stockpile vaccines against future outbreaks of emerging infectious diseases (EIDs). Prior to the pandemic, vaccine development for EIDs was stagnant, largely due to the lack of financial incentives for pharmaceutical firms to invest in vaccine research and development (R&D). This R&D requires significant capital investment, most notably in conducting clinical trials, but vaccines generate much less profit for pharmaceutical firms compared with other therapeutics in disease areas such as oncology. The portfolio approach of financing drug development has been proposed as a financial innovation to improve the risk/return trade-off of investment in drug development projects through the use of diversification and securitization. By investing in a sizable and well-diversified portfolio of novel drug candidates, and issuing equity and securitized debt based on this portfolio, the financial performance of such a biomedical “megafund” can attract a wider group of private-sector investors. To analyze the viability of the portfolio approach in expediting vaccine development against EIDs, we simulate the financial performance of a hypothetical vaccine megafund consisting of 120 messenger RNA (mRNA) vaccine candidates in the preclinical stage, which target 11 EIDs, including a hypothetical “disease X” that may be responsible for the next pandemic. We calibrate the simulation parameters with input from domain experts in mRNA technology and an extensive literature review and find that this vaccine portfolio will generate an average annualized return on investment of −6.0% per annum and a negative net present value of −$9.5 billion, despite the scientific advantages of mRNA technology and the financial benefits of diversification. We also show that clinical trial costs account for 94% of the total investment; vaccine manufacturing costs account for only 6%. The most important factor of the megafund’s financial performance is the price per vaccine dose. Other factors, such as the increased probability of success due to mRNA technology, the size of the megafund portfolio, and the possibility of conducting human challenge trials, do not significantly improve its financial performance. Our analysis indicates that continued collaboration between government agencies and the private sector will be necessary if the goal is to create a sustainable business model and robust vaccine ecosystem for addressing future pandemics.

Comparative effects of different bacterial lipopolysaccharides on modulation of immune levels to improve survival of the black tiger shrimp

To prevent loss from disease, immunostimulants have been used as dietary supplements to improve immunity and survival of shrimps. Among the various types of immunostimulants, there is increasing evidence that a diet enriched with bacterial lipopolysaccharide can reduce the mortality rate of shrimp under exposure to pathogens. Here, the immunostimulatory effects of bacterial lipopolysaccharide (LPS) from various bacterial sources were explored. Bacterial LPS was extracted from a shrimp pathogen, Vibrio harveyi and its effects were compared with the commercially available LPS from the non-shrimp pathogen, Escherichia coli. Our results revealed that the LPS from V. harveyi was different in molecular size but contained similar functional groups to that from E. coli. To understand their molecular mechanisms, bacterial LPS from the two sources were applied as a supplementary diet and fed to juvenile shrimp for 4-week feeding period before tissue samples were collected for transcriptomic analysis by next generation sequencing. Gene expression profiling revealed that major immune-related genes such as pattern recognition proteins (PRPs), proteinases and proteinase inhibitors, prophenoloxidase systems (proPO system), antimicrobial peptides (AMPs), signaling transduction pathways, heat shock proteins (HSPs), oxidative stress responses, and other immune-related molecules such as mucins and peritrophins were modulated in the groups of shrimp fed with bacterial LPS from both sources, but at different levels. The results suggest that bacterial LPS could modulate shrimp immune system, and different LPS sources led to different activation of immune pathways. Additionally, metabolic-related genes were affected by LPS, suggesting that energy was required for immune stimulation. In the V. harveyi pathogen challenge trial, all shrimp groups fed with diets containing LPS from both bacterial sources showed better survival than the control group without LPS. When comparing groups fed with LPS supplemented diets, the higher concentration of LPS (8 μg/body weight) from E. coli resulted in a better survival rate than a lower concentration (4 μg/body weight). Conversely, shrimp fed with a diet containing LPS from V. harveyi showed a lower survival rate when a higher dose of LPS (8 μg/body weight) was administered than the group fed with a lower concentration of LPS (4 μg/body weight). This could be due to overstimulation of shrimp immune responses, especially by LPS derived from shrimp pathogens, resulting in a reverse effect. These results confirm that immunity in shrimp upon administration of bacterial LPS depends on the origin and dose of the LPS administered.

LB747. Immune Responses of the Recombinant MVA-BN-RSV Vaccine against Respiratory Syncytial Virus Infection in an RSV Human Challenge Trial (HCT) in Healthy Adult Participants

Abstract Background Respiratory Syncytial Virus (RSV) causes considerable morbidity and mortality in infants and older adults. Even though throughout life multiple infections occur, there is no natural protection. The MVA-BN vector-based RSV vaccine was designed to induce humoral and cellular RSV-specific immune responses against 5 RSV proteins (F, G [A and B subtype], M2-1 and N). We present immune response data after vaccination and challenge with an RSV-A strain in a human challenge trial conducted in healthy, young adults. Methods In a double-blinded, placebo controlled, HCT (EudraCT-no. 2020-004814-36) subjects (N=61) were randomly vaccinated with MVA-BN-RSV or placebo (30 MVA-BN-RSV and 31 placebo), intranasally challenged with RSV-A (Memphis-37b strain) after 28 days and quarantined for 12 days. Exploratory endpoints included RSV specific humoral and cellular immune responses after vaccination and after challenge throughout follow up until Day 155 assessed by treatment group and infected vs non infected in subjects receiving either MVA-BN-RSV or placebo. Results For all serum-based RSV specific antibody assays including ELISA IgG, IgA and neutralizing antibody assays PRNT A and B, antibody titers increased after vaccination in the MVA-BN-RSV group and stayed above baseline level over the entire study without being influenced by the challenge with Memphis-37b. In the placebo group, the antibody titers increased after challenge and were not affected by vaccination. The geometric mean spot forming units (GMSFUs) based on IFN-γ producing PBMCs for the stimulating agents pool F, G(A), G(B), N, M2-1 and RSV increased after vaccination in the MVA-BN-RSV group, peaking at Day 7 post vaccination for most peptide pools without any effect after challenge. In the placebo group, there was no increase after vaccination, but an increase with a peak on Day 10 post challenge was observed for all pools. Conclusion The results confirmed the broad humoral and cellular immune response elicited by the vaccination with MVA-BN-RSV which was not further boosted by the challenge virus. Disclosures Darja Schmidt, PhD, Bavarian Nordic: Employed|Bavarian Nordic: Warrants Günter Silbernagl, MSc, Bavarian Nordic: Employed|Bavarian Nordic GmbH: employee Employee and received warrants Elke Jordan, PhD, Bavarian Nordic: Employed Victoria A. JENKINS, PhD MBA, Bavarian Nordic: Employed Stephanie Schultz, Dipl Biol, Bavarian Nordic: Employed Heinz Weidenthaler, Dr med, Bavarian Nordic: Employed.

Clinical trials for accelerating pandemic vaccines

AbstractWe provide a short overview of clinical trials of vaccines, with particular focus on (i) adaptive and platform trials, (ii) human challenge trials, and (iii) vaccine use optimization, especially fractional dosing. We describe their relationship with regulatory approval and review main developments during Covid-19. We review the literature on risk–benefit analyses of alternative testing approaches but find few results, suggesting need for further quantitative research. We conclude by discussing some lessons for the next pandemic, such as the need for pre-pandemic R&D and clear guidelines; improving capability to use new trial approaches; arguments for diversifying research methods; research incentives and disincentives; and the need to use risk–benefit in approving new vaccines and targeting.

Vitamin D serves as a modulator of immune organs in grass carp (Ctenopharyngodon idella) infected with Aeromonas hydrophila

Vitamin D regulates biological processes via vitamin D receptors (VDRs) and exerts a pleiotropic effect in the prevention of pathogen infections. In various fish, the existence of two unique VDR isoforms (VDRa and VDRb) has been reported; however, the effects of vitamin D and VDR isoforms on the function of immune-related organs (e.g., the head kidney and spleen) remain poorly understood. In the present study, diets containing different vitamin D concentrations (0, 364.3, 782.5, 1167.9, 1573.8, and 1980.1 IU/kg) were provided to on-growing grass carp for 70 d. Subsequently, each group was subjected to a challenge trial by infection with Aeromonas hydrophila for 14 d. Dietary vitamin D decreased the oxidative biomarker content and upregulated the transcriptional responses of antioxidant enzymes potentially involved in Nrf2 signaling; alleviated cell apoptosis by down-regulating caspase expression, potentially in relation to the inhibition of p38MAPK molecules; enhanced immune component activity; downregulated the transcriptional levels of pro-inflammatory cytokines; and upregulated those of anti-inflammatory cytokines. Furthermore, the optimal vitamin D dose decreased the expression of nuclear factor kappa B p65, c-Rel, IKKα, IKKβ, and IKKγ and increased the transcriptional levels of iκBα, VDRb (but not VDRa), macrophage stimulating 1 (MST1), and signal transducers and activators of transcription (STAT) 3b1 and 3b2. Moreover, the protein levels of VDR, p-STAT3Tyr705, and p-MST1Thr108 were elevated both in the head kidney and spleen after treatment. In summary, vitamin D protected the immune organs from oxidative stress, apoptosis, and immunological injury. Based on lysozyme activity in the head kidney and spleen, the vitamin D requirements of on-growing grass carp (256.89–1129.67 g) were estimated to be 1150.71 and 1355.37 IU/kg, respectively. In conclusion, our findings confirmed that vitamin D can regulate molecular pathways related to immune organ function and pathogen defense in an aquaculture setting, supporting the feasibility of vitamin D supplementation to support immunological functions under infection conditions.

Effects of a Specific Pre- and Probiotic Combination and Parent Stock Vaccination on Performance and Bacterial Communities in Broilers Challenged with a Multidrug-Resistant Escherichia coli.

Antibiotic resistance poses a risk for human and animal health, leading to a growing demand for effective alternatives. Combining nutritional tools and parent stock vaccination could be an approach to achieve sufficient protection against bacterial infections in poultry. In an Escherichia coli O1/O18 challenge trial, we investigated the protective effects of feeding diets containing Enterococcus faecium DSM 7134 and fructooligosaccharides (FOS) combined with specific parent stock vaccination in 225 ROSS 308 broilers. Data on performance parameters, intestinal microbial composition and metabolites, and antibiotic resistance genes (sul1-3, dhfr1a, SHV-12) were obtained. E. faecium and FOS combined with parent stock vaccination led to the highest body weights, which were significantly higher than those of controls throughout the experiment and decreased the relative abundance of Proteobacteria in the crop digesta compared to that in the positive control. However, cumulative feed conversation remained unaffected by the strategies. Birds receiving the pre-/probiotic combination showed lower cecal pH levels and higher crop L-lactate concentrations than the controls, whereas copy numbers of dhfr1a (trimethoprim resistance) and SHV-12 (extended-spectrum beta-lactamase) genes were only decreased in broilers from vaccinated hens compared to those in the challenged control. In conclusion, prophylactic administration of E. faecium and FOS in combination with parent stock vaccination can have complementary effects by improving broiler weight gain and stimulating intestinal bacterial metabolism, which may be beneficial for maintaining gut health in terms of Escherichia coli infection.

Emerging fish pathogens Lactococcus petauri and L. garvieae in Nile tilapia (Oreochromis niloticus) farmed in Brazil

Lactococcosis in fish has been associated with Lactococcus garvieae and the recently described L. petauri. However, the relevance of these emerging fish pathogens to Nile tilapia still requires thorough understanding. This study investigated lactococcosis outbreaks in Nile tilapia on Brazilian farms and characterized the isolates through multilocus sequence typing (MLST), virulence to Nile tilapia, and antimicrobial susceptibility. Lactococcosis outbreaks were monitored from 2019 to 2022 throughout Brazil. The outbreaks occurred mainly during warmer months, and co-infections were observed in four farms, whereas concurrent bacterial infections were identified in all farms. Since the sequence of the 16S rRNA was not capable of differentiating between L. petauri and L. garvieae, Lactococcus spp. isolates were identified at the species level using the gyrB gene sequence. In total, 30 isolates were classified as L. petauri and two as L. garvieae. According to the MLST, all L. petauri isolates were grouped in the sequence type (ST) 24, except for one isolate which belonged to the newly described ST47. A new ST was also described for the L. garvieae isolates identified, ST46. The L. petauri ST24 and ST47 were characterized as singletons, whereas L. garvieae ST46 was grouped with ST16 and ST17 and formed CC17. For the challenge trial, an L. petauri ST24 isolate was chosen considering that this MLST lineage was the most frequently observed. Fish were challenged by intraperitoneal injection and different bacterial doses were used (106 to 102 CFU per fish). The infection in the challenged fish progressed very rapidly, and within 48 h post-challenge clinical signs and the first mortalities were observed. The pathogenicity of L. petauri to Nile tilapia was confirmed. The estimated LD50 was 5.74 × 103 CFU 15 days post-challenge. Provisional epidemiological cutoff values were determined for L. petauri for six antimicrobial agents from different drug classes. All isolates were characterized as wild type (WT) for neomycin and oxytetracycline, whereas 96.67% of the isolates were characterized as WT for amoxicillin, erythromycin, and florfenicol, and 83.33% were WT for norfloxacin. The L. petauri ST24 was observed in different regions of the country, illustrating a rapid expansion of this bacterial lineage.

Exploring the multimodal role of Cnicus benedictus extract in the modulation of growth, hematobiochemical, histopathological, antioxidative performance, and immune-related gene expression of Oreochromis niloticus challenged with Aeromonas hydrophila

This study explored the growth efficiency and the intracellular pathways by which Cnicus benedictus extract (CBE) acts. It investigated the antioxidant effects and efficacy of CBE as a fish supplement in attenuation of Aeromonas hydrophila in Oreochromis niloticus fish. Mono-sex Nile tilapia fish (n = 225) were randomly allocated to five groups in triplicate aquaria (n = 3 tanks per group, 15 fish per tank, with 120 L of water per tank) with a daily water exchange rate of 20%. After adaption for 2 weeks and body weight measuring, the experimental groups were fed isonitrogenous and isocaloric diets with different dosages of the ethanolic extract of C. benedictus for 10 weeks. The five groups were identified as the control group (CBE0.0), which was fed on the basal diet, while the second (CBE0.1), the third (CBE0.2), the fourth (CBE0.4), and the fifth (CBE0.6) groups were fed the basal diet supplemented with 0.1%, 0.2%, 0.4%, and 0.6% of C. benedictus extract, respectively. After the 10-week feeding trial was completed, the fish were inoculated with the PCR-identified pathogenic A. hydrophila in a challenge trial which lasted 15 days. A. hydrophila, one of the septicemic bacteria, causes severe economic losses, high mortality rates, and hemorrhages in Nile tilapia and other cultured freshwater fishes worldwide. The CBE was found to significantly increase the body mass, weight gain, and the specific growth rate, as well as the protein efficiency ratio of the fish. Increased survival percentage, accompanied by post challenge lymphocytosis with decreased liver enzyme levels, increased total protein, and improved kidney function markers were also seen. Additionally, CBE supplementation showed significant increases in phagocytic activity, phagocytic index, and lysosomal activity post challenge, accompanied by increases in antioxidant activity and the mRNA expression of cytokines genes hsp70 and tlr7 mRNA. The desirable effects of CBE treatment were confirmed by a histopathological examination of the height of intestinal villi and enterocytes lining the middle intestine and increases in the size of liver cells. We conclude that CBE increases the growth performance and modulates the antioxidant, inflammatory, stress, and immune-related genes in Nile tilapia. Moreover, the dietary inclusion of 0.42–0.47% CBE showed a better protective effect with the A. hydrophila challenge.

Characterizing altruistic motivation in potential volunteers for SARS-CoV-2 challenge trials.

In human challenge trials (HCTs), volunteers are deliberately infected with an infectious agent. Such trials can be used to accelerate vaccine development and answer important scientific questions. Starting early in the COVID-19 pandemic, ethical concerns were raised about using HCTs to accelerate development and approval of a vaccine. Some of those concerns pertained to potential exploitation of and/or lack of truly informed consent from volunteers. Specific areas of concern arose around individuals who may be unusually risk-seeking or too economically vulnerable to refuse the payments these trials provide, as opposed to being motivated primarily by altruistic goals. This pre-registered study is the first large-scale survey to characterize people who, early in the pandemic, expressed interest and intention to volunteer to participate in COVID-19 HCTs. We found that individuals expressing interest in SARS-CoV-2 HCTs exhibit consistently altruistic motivations without any special indication of poor risk perception or economic vulnerability. In finding that, early in the pandemic, COVID-19 HCTs were able to attract volunteers whose values align with the nature of these trials, and who are not unusually vulnerable to exploitation, this study may allay some ethical concerns about the volunteers interested in participating in such trials.

A Systematic Review of Human Challenge Trials, Designs, and Safety.

Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective. A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021. Of 2838 articles screened, 276 were reviewed in full. A total of 15 046 challenged participants were described in 308 studies that met inclusion criteria; 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies that reported on SAEs, 0.2% of participants experienced at least 1 challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. Eighty percent of studies published after 2010 were registered in a trials database. HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218.

THE SUCCESSFUL MAJOR SURGERY IN A PATIENT WITH INHERITED FVII DEFICIENCY AND A HUGE NASOPHARYNGEAL ANGIOFIBROMA

The bleeding phenotype of patients with inherited FVII deficiency is variable, and epistaxis is one of the most frequent symptoms. Interestingly, the bleeding risk does not correlate with the level of FVII activity. The severity of FVII deficiency and the type of surgery are not determinants of the optimal management of surgery, the doses and the duration of rFVIIa therapy are widely variable. The aim of this study is to present our successful experience in a 16-year-old boy with inherited FVII deficiency and a huge nasopharyngeal angiofibroma with a very high risk of bleeding The patient was referred with recurrent epistaxis in the last 6 months and he was diagnosed as an inherited FVII deficiency (FVIIC:29%, FVII inhibitor negative with positive family history). Tranexamic acid (10days) and rFVIIa (2doses) were used with success in the management of this surgery. Since this surgery may cause life-threatening bleeding, endovascular particle embolization was done to the important vessels feeding the mass one day before surgery without rFVIIa support. No bleeding or thrombosis were observed in our patient. In conclusion, a life-threatening major surgery was successfully done for a patient with inherited FVII deficiency and a huge angiofibroma. However, perioperative management of patients with FVII deficiency still remains a major challenge and clinical trials are needed to provide evidence-based optimal management of surgeries. And, angiofibroma should be thought in the differential diagnosis of epistaxis.

The CHALLENGE trial: the effects of a virtual reality-assisted exposure therapy for persistent auditory hallucinations versus supportive counselling in people with psychosis: study protocol for a randomised clinical trial

BackgroundMany patients suffering from schizophrenia spectrum disorders continue having distressing auditory hallucinations in spite of treatment with antipsychotic medication. The aim of this trial is to examine the effect of a targeted virtual reality therapy for persistent auditory hallucinations in individuals with psychosis. The trial explores whether this type of therapy can decrease the severity, frequency and distress of auditory hallucinations and, additionally, whether it can reduce clinical symptoms and enhance daily functioning in individuals with psychosis.MethodsThe study is a randomised, assessor-blinded parallel-group superiority clinical trial, allocating a total of 266 patients to either the experimental intervention or supportive counselling. The participants will be randomised to either (1) seven sessions of virtual reality therapy or (2) seven sessions of supportive counselling to be delivered within the first 12 weeks after inclusion in the study. All participants will be assessed at baseline and 12 and 24 weeks post-baseline. Independent assessors blinded to the treatment allocation will evaluate the outcome. The primary outcome is the level of auditory hallucinations measured with the Psychotic Symptoms Rating Scales (PSYRATS-AH) total score at the cessation of treatment at 12 weeks. Secondary outcomes are frequency of auditory hallucinations, the distress caused by auditory hallucinations, perceived voice power, patient acceptance of voices, patients’ ability to respond to voices in an assertive way and social and daily function.DiscussionPromising evidence of the efficacy of this immersive virtual reality-based therapy for auditory hallucinations exist, but evidence needs to be established in a large, methodological rigorous trial. If the therapy proves to be beneficial in reducing the severity of refractory auditory hallucinations, a large group of patients with schizophrenia and related disorders could be the target group of this short-term psychotherapeutic intervention.

Risk Dilution: Or, How to Run a Minimal‐Risk HIV Challenge Trial

ABSTRACTBioethicists broadly agree that there is a limit to the level of net risk that biomedical research may permissibly impose on participants, even in cases where the potential of that research to improve the health of the population health would be great. Although some may permissibly volunteer to take on some degree of pro‐social risk, no one, not even a willing volunteer, may ever be outright sacrificed for others. One might think this perspective, if correct, makes it effectively impossible to study interventions with high intrinsic risks. But I describe a method – risk dilution – by which an extremely high‐risk intervention can nonetheless be effectively studied in the context of an acceptably low‐risk trial. I then defend risk dilution from objections.

Efficacy of vaccination against equine herpesvirus type 1 (EHV-1) infection: Systematic review and meta-analysis of randomised controlled challenge trials.

Equid herpesvirus type 1 (EHV-1) infection can cause a range of disease syndromes of variable severity that can result in a lethal outcome and restriction of horse movements, especially in the case of outbreaks involving neurological disease. Vaccination is one of the tools used to control the infection. It is widely known that vaccination is not completely effective in ensuring protection against disease caused by this virus. In fact, the real efficacy of vaccination against EHV-1 related disease has not been measured and no systematic reviews exist on this topic. To perform a systematic review and meta-analysis on the efficacy of commercial or candidate vaccines against EHV-1 in randomised controlled trials (RCT) all of which involved experimental challenge of the test subjects. Systematic review and meta-analysis. RCTs were searched using the search algorithm (([equid herpesvirus* OR equine herpesvirus* OR EHV-1]) AND vaccin*) AND (trial OR experimental OR challenge) on PubMed, Science Citation Index Expanded, Scopus, and CAB Abstracts. Where appropriate, meta-analysis was performed using RevMan 5.4. Eight studies were selected and were analysed for their respective characteristics and possible shortcomings. The results of RCTs revealed that there was a general improvement in the clinical and virological outcomes of EHV-1 infection following vaccination, but that the effects were very slight. The reduced beneficial effect is probably amplified by the paucity of detailed data reported in the studies that did not allow for the comparison of parameters in many of the cases analysed. The remarkable heterogeneity and the poor quality of reporting of the selected studies. Meta-analysis has shown that EHV-1 vaccination generally results in a slight improvement in clinical and virological outcomes, although not to a significant extent. The cumulative results have probably been affected by the lack of information on some parameters not systematically reported in the studies. An improvement in the standard of reporting and better standardisation of the data collected would likely have improved the quality of each study and enabled more effective comparison of the studies with each other.

Field Experiment: Synbiotic Microcapsule Dietary Supplementation Improved the Health Status of the White Shrimp under the Challenge of Coinfection Diseases through Improvement the Beneficial Microbial Composition.

This study aimed to evaluate the effectivity of microencapsulated synbiotic (MS), Bacillus sp. NP5 and mannan oligosaccharide (MOS) dietary in different feeding frequencies in Pacific white shrimp culture field experiment. The MS was administered as a feed supplementation to enhance the immunity for prevention against co-infection with WSSV (White Spot Syndrome Virus) and Vibrio harveyi. The synbiotic was microencapsulated by the spray dryer method. Shrimps were reared in the floating net cages in the pond. Treatments included the administration of MS at different frequencies i.e, daily (A), twice a week (B), once a week (C), and without MS supplementation (consisted of negative and positive controls) with a feeding rate of 6% of shrimp biomass (5 times a day). During the challenge trial, shrimps were removed and further reared in plastic tanks, for 7 days. The shrimps (except negative control treatment) were intramuscularly injected by WSSV filtrate at the infective dosage of 10-4 copies.ml-1. Twenty four hours after WSSV injection the shrimps were immersed in the water-containing cells suspension of V. harveyi at the cell’s population dosage of 106 CFU.ml-1. Immune responses were observed for 7 days after experimental infection. The shrimps that have been treated with daily MS supplementation (A) showed better immune responses i.e., total haemocyte counts, phenoloxidase, respiratory burst, and the lower pathogenic cells abundance in the intestine compared to other treatments groups.

The past, present, and future of human challenge trials

Human challenge trials (HCTs) have the potential to lay groundwork for critical advances in medicine. For centuries, physicians and researchers have intentionally infected human subjects to study disease transmission and design life-saving vaccines and treatments. Historically, many controlled infections occurred without informed consent from participants, but in the last century, several HCTs have been conducted which included full risk assessment, informed consent, and patient compensation. The COVID-19 pandemic has elevated the topic of establishing human challenge trials to accelerate the design and testing of protective vaccines. Thousands of people have expressed willingness to be infected with SARS-CoV-2, risking their health to help the global effort of ending the pandemic. Conducting such a study during a pandemic involves additional scientific and ethical precautions to minimize the risk to volunteers and to prevent community transmission; however, HCTs are not directly regulated. Here, we assess the scientific, ethical, and regulatory considerations of implementing HCTs for infectious disease models, particularly in pandemic settings.

Bridging Animal and Human Data in Pursuit of Vaccine Licensure.

The FDA Animal Rule was devised to facilitate approval of candidate vaccines and therapeutics using animal survival data when human efficacy studies are not practical or ethical. This regulatory pathway is critical for candidates against pathogens with high case fatality rates that prohibit human challenge trials, as well as candidates with low and sporadic incidences of outbreaks that make human field trials difficult. Important components of a vaccine development plan for Animal Rule licensure are the identification of an immune correlate of protection and immunobridging to humans. The relationship of vaccine-induced immune responses to survival after vaccination and challenge must be established in validated animal models and then used to infer predictive vaccine efficacy in humans via immunobridging. The Sabin Vaccine Institute is pursuing licensure for candidate filovirus vaccines via the Animal Rule and has convened meetings of key opinion leaders and subject matter experts to define fundamental components for vaccine licensure in the absence of human efficacy data. Here, filoviruses are used as examples to review immune correlates of protection and immunobridging. The points presented herein reflect the presentations and discussions during the second meeting held in October 2021 and are intended to address important considerations for developing immunobridging strategies.

Dietary of Lactobacillus paracasei and Bifidobacterium longum improve nonspecific immune responses, growth performance, and resistance against Vibrio parahaemolyticus in Penaeus vannamei

This study investigated the effects of two probiotics, namely Lactobacillus paracasei and Bifidobacterium longum, as feed additives on growth performance, nonspecific immunity, immune-related gene expression, and disease resistance against Vibrio parahaemolyticus in Penaeus vannamei. The experimental diets were prepared using L. paracasei and B. longum at concentrations of 105 and 107 CFU/g; these diets were referred to as P5, P7, B5, and B7. After 8 weeks of the diets, regarding growth performance, the B7 group showed the highest weight gain rate (890.34 ± 103.65%), special growth rate (4.08 ± 0.19%), and feed conversion rate (1.52 ± 0.19%) compared with the other groups. Moreover, the total hemocyte counts were significantly increased (p < 0.05) in the P7 groups on day 14 during the 28-day feeding trial. The phagocytosis rate in all experimental groups was increased on day 14 and was persistently significantly activated to day 21, especially in the P7 and B5 group. The phagocytic index of the P7 group showed a significant increase on day 14 and persistent activation to day 21. In the analysis of respiratory burst activity and phenoloxidase activity, the P7 and B5 groups showed a significant increase on day 7 and persistent activation to day 21. The expression level of the immune-related genes of superoxide dismutase, clotting protein, Penaeidin2, Penaeidin3, Penaeidin4, anti-LPS factor, crustin, and lysozyme was significantly increased in the experimental groups, especially in the P7 group. Furthermore, the optimum conditions of feed additives were determined in challenge trials conducted using P7 and B5. Shrimps fed P7 and B5 showed an increased survival rate (72.73% and 66.67%) after the V. parahaemolyticus challenge. In sum, the results revealed that B. longum, as a feed additive at 107 CFU/g, enhanced growth performance. L. paracasei at 107 CFU/g and B. longum at 105 CFU/g can enhance nonspecific immune responses and immune-related gene expression, and 107 CFU/g L. paracasei has the highest resistance ability for V. parahaemolyticus. Thus, dietary supplementation with L. paracasei and B. longum may be a valuable approach in white shrimp aquaculture.

Novel development of cationic surfactant-based mucoadhesive nanovaccine for direct immersion vaccination against Francisella noatunensis subsp. orientalis in red tilapia (Oreochromis sp.)

Francisella noatunensis subsp. orientalis (Fno) is one of the infectious diseases that causes economic losses associated with tilapia mortality. Even though direct immersion administration of vaccines is more practicable for small fish and fry compared with oral and injection vaccination in the fields, the efficacy is still insufficient due to lower potency of antigen uptake. Herein, we accomplished the development of a mucoadhesive nanovaccine platform using cetyltrimethylammonium bromide (CTAB), a cationic surfactant, to improve the efficiency of immersion vaccination against Fno in tilapia. Cationic Fno nanovaccine (CAT-Fno-NV) was prepared though emulsification using an ultrasonic method. In our investigation, the CAT-Fno-NV increased the opportunity of Fno vaccine uptake by extending the contact time between vaccine and mucosal surface of fish gills and enhancing the protective efficacy against Fno infection. Fish were vaccinated with the CAT-Fno-NV by a direct immersion protocol. The challenge trial by Fno injection revealed that CAT-Fno-NV at the concentration 1:100 ratio (approximately 1 × 106 cfu/mL) had the highest efficacy to protect fish from Fno infection at day 30 after post challenge period according to the total number of Fno detected in head kidney, spleen and liver. A significant upregulation of IgM gene was observed in gills, skin, head kidney, serum and peripheral blood lymphocytes (PBLs) and spleen tissues treated with WC and CAT-Fno-NV (1:100) vaccines, while IgT gene was highly expressed in only gills and skin tissues for treated WC and CAT-Fno-NV (1:100) groups. We anticipate that the cationic surfactant-based nanovaccine developed in this study could become an efficient alternative for direct immersion vaccination to induce humoral immune responses against Fno in vaccinated tilapia.