Priming Dose Research Articles

Pneumococcal carriage following PCV13 delivered as one primary and one booster dose (1+1) compared to two primary doses and a booster (2+1) in UK infants.

In January 2020 the UK changed from a 2+1 schedule for 13-valent pneumococcal conjugate vaccine (PCV13) to a 1+1 schedule (doses at 3 and 12months) based on a randomized immunogenicity trial comparing the two schedules. Carriage prevalence measured at the time of booster and 6months later in 191 of the 213 study infants was 57% (109/191) and 60% (114/190) respectively. There were eight episodes of vaccine-type (VT) or vaccine-related 6C carriage in the 2+1 and six in the 1+1 group; ≥4-fold rises in serotype-specific IgG in 71 children with paired post-booster and follow up blood samples at 21-33months of age were found in 20% (7/35) of the 2+1 and 15% (6/41) of the 1+1 group. VTs identified in carriage and inferred from serology were similar comprising 3, 19A and 19F. Dropping a priming dose from the 2+1 PCV 13 schedule did not increase VT carriage in the study cohort. Ongoing population level carriage studies will be important to confirm this.

The Effect of [(D-Ala6, Pro9NEt)mGnRH-a + Metoclopramide] (Ovopel) on Propagation Effectiveness of Two Breeding Lines of Common Carp (Cyprinus carpio L.) and on Luteinizing Hormone and 17α,20β-Dihydroxyprogesterone Levels in Females during Ovulation Induction.

The study evaluates the impact of Ovopel on the reproductive effectiveness of carp from Polish line 6 and Lithuanian line B and the release of luteinizing hormone (LH) and 17α,20β-dihydroxyprogesterone (17α,20β-DHP) in females from these lines during ovulation induction. The levels of both hormones were determined in blood plasma samples taken just before the priming injection of Ovopel (0 h), at the time of administering the resolving dose of Ovopel (12 h), and after the next 12 h (24 h). Following Ovopel treatment, the mean egg weight obtained for line 6 was higher, but not statistically different, than that observed for line B. Egg quality, on the other hand, was significantly higher in line B. Female provenance did not significantly affect the number of eggs and living embryos after 70 h incubation. However, the total egg number for line 6 was higher. The mean number of living embryos (70 h) was similar for both lines. LH concentrations at 0, 12, and 24 h were not statistically different between the lines. A comparison of LH concentrations between ovulated and non-ovulated females at different sampling times revealed no significant differences either within or between the lines. Statistically significant differences in LH levels were found for both ovulated and non-ovulated females from a given line between the sampling times. The results for 17α,20β-DHP were similar, with only one difference: 24 h after the priming dose of Ovopel, 17α,20β-DHP levels in ovulated fish were significantly higher compared with non-ovulated females, but only in line 6.

Abstract 2798: Simplifying selection and optimization of step-up dosing of subcutaneous Epcoritamab to mitigate CRS risk using repeated time-to-event modeling

Abstract Background: Epcoritamab, a bispecific antibody, binds to CD3 on T cells and CD20 on B cells to induce T-cell-mediated killing of CD20+ malignant B cells. For T-cell engagers, CRS is a potential adverse event. Step-up dosing (SUD) is used to mitigate potential severe CRS symptoms. Identification of optimal SUD is challenging because multiple steps of dose escalation are needed to manage CRS. Based on a dose-escalation study of epcoritamab, 2-step SUD (weekly priming and intermediate dose prior to administering the target dose) was necessary to effectively mitigate the risk of CRS. A wide range of priming (0.004-0.16 mg) and intermediate (0.0128-1.6 mg) doses for 17 combinations was explored; the 0.16/0.8/48-mg regimen was selected based on the CRS event rate. We further explored optimization of the SUD regimen using a model-based approach to inform clinical evaluation. Methods: A repeated time-to-event model was developed using pharmacokinetic and CRS event data collected in the phase 1/2 EPCORE NHL-1 monotherapy trial. The model was required to predict the onset of 1 or more CRS events (all-grade and grade ≥2) over time and to describe the impact of epcoritamab concentration on CRS risk over time and the development of tolerance after multiple doses. To capture these dynamics, the hazard function (risk of CRS event) was modeled as the product of 2 components: the first component addressed the risk of a CRS event and allowed for increasing hazard with increasing epcoritamab plasma concentrations, and the second component described the inhibition of the hazard to capture development of CRS tolerance over time after multiple doses. Simulations assessed the performance of different SUD regimens, measured by the probability of a grade ≥2 CRS event. Results: The model was able to predict the observed CRS events over time and confirmed that the SUD regimen used in the recommended phase 2 dose regimen for epcoritamab (0.16/0.8/48 mg) provided similar or better potential to reduce the risk of grade ≥2 CRS events versus other priming and intermediate dose permutations tested during dose escalation in the EPCORE NHL-1 trial. The validated model was used to further explore a large number of SUD regimens not studied in clinical trials. Based on model predictions, alternative SUD regimens can potentially lead to a small reduction in risk of grade ≥2 CRS. To further assess this, alternative SUD regimens were selected for potential clinical assessment. Conclusions: A dynamic model for CRS was successfully developed, validated, and applied to aid the optimization of an epcoritamab SUD regimen. The model-based optimization of SUD informed and narrowed down the number of doses/cohorts to be tested in clinical trials, simplified study design, and played a critical role in expediting the optimization of the epcoritamab SUD regimen. Citation Format: Tommy Li, Daniel Polhamus, Craig Thalhauser, Apurvasena Parikh, Manish Gupta, Mariana Sacchi, Steven Xu. Simplifying selection and optimization of step-up dosing of subcutaneous Epcoritamab to mitigate CRS risk using repeated time-to-event modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2798.

Abstract 855: Model-informed drug design (MIDD) exploration of a theoretical CD47xTAA bispecific antibody using available data from magrolimab, an anti-CD47 monoclonal antibody

Abstract Purpose: The goal of this study is to outline the process and utility of using fit-for-purpose, semi-mechanistic PK/PD modeling to inform the design of a theoretical CD47 bispecific antibody targeted to a generic tumor-associated antigen (CD47xTAA bsAb) with improved efficacy, tolerability, and PK compared to single target anti-CD47 therapies. Approach: To help guide the CD47xTAA bsAb design, a 3-compartment human model was built to include a target-mediated drug disposition (TMDD) component from CD47 expressed on red blood cells (RBC), white blood cells (WBC), and cells in the peripheral compartment. The model was parameterized using available literature data and calibrated against magrolimab human PK data that exhibited potential TMDD. The magrolimab model was used to identify key CD47 receptor occupancy (RO) thresholds associated with tolerability (the priming dose threshold) and efficacy (the recommended Phase 2 dose/RP2D threshold). Next, assumed drug properties and TAA expression levels for a CD47xTAA bsAb were implemented in a similar human model and drug PK and doses required to match key CD47 RO thresholds were explored across a range of single-arm binding affinities. Results: The calibrated magrolimab model projected target engagement levels on RBCs and WBCs and showed rapid antibody-induced CD47 pruning on RBCs that is consistent with clinical PD measurements. At TAA binding affinities that produce sufficient binding to tumor antigen, the model predicts that lowering the CD47 binding affinity allows for a higher starting dose that matches the priming threshold, while lowering the dose required to match the RP2D threshold. The model also shows that lowering the binding affinity to CD47 may improve PK exposure in the tumor compartment by reducing systemic CD47 TMDD. Conclusions: This modeling exercise demonstrates how semi-mechanistic PK/PD models can be used in model-informed drug design (MIDD) by leveraging the targeting advantage of avid bispecific antibody therapies and by using publicly available preclinical and clinical data. Furthermore, these model projections can help inform future studies with bispecific CD47 drug candidates. Citation Format: Emily A. Pace, Bjorn L. Millard. Model-informed drug design (MIDD) exploration of a theoretical CD47xTAA bispecific antibody using available data from magrolimab, an anti-CD47 monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 855.

Willingness to receive COVID-19 booster dose and its associated factors in Ghana: A cross-sectional study.

The COVID-19 booster dose has been cited as an important supplement for the control of the COVID-19 pandemic due to reports of waning immunity among fully vaccinated persons. Determining factors that would affect its acceptability is necessary for initiating successful vaccination programs. In this study, we aimed to evaluate the factors associated with the acceptability of the COVID-19 booster dose in Ghana. We conducted an online cross-sectional survey among the public. A self-administered questionnaire was used to collect information on demographic characteristics, willingness to vaccinate, perceptions toward COVID-19 vaccines, and trust in the government. Participants provided reasons and sources of advice that may affect their willingness to accept a booster dose. Using IBM SPSS and R Statistic; descriptive, univariate, and multivariate analyses were performed. Out of 812 respondents, 375 (46.2%) intended to accept the booster dose. Individuals who were males (adjusted odds ratio [aOR] 1.63, 95% confidence interval [CI] 1.07-2.48), had previously received other forms of vaccination twice (aOR 1.96, 95% CI 1.07-3.57) or in most years (aOR 2.51, 95% CI 1.38-4.57), tested positive for COVID-19 (aOR 3.46, 95% CI 1.23-10.52), have high trust in government (aOR=1.77, 95% CI: 1.15-2.74) and had positive perceptions regarding COVID-19 vaccines (OR = 14.24, 95% CI: 9.28-22.44) were more likely to accept a booster dose. Experiencing side effects from the primer dose (aOR 0.12, 95% CI 0.08-0.18) was associated with reduced acceptance. Concerns about vaccine safety and efficacy were the common reasons impeding willingness, while advice from health professionals would be the most considered. Low intention to accept the booster dose which is associated with a range of factors including the perception of vaccines and trust in the government, is a cause for concern. Thus, more effort would have to be taken through education and policy interventions to increase booster vaccine acceptability.

Distinct suppressing effects of deep brain stimulation in the orbitofrontal cortex on the development, extinction, and reinstatement of methamphetamine-seeking behaviors

AimsThe orbitofrontal cortex (OFC) is implicated in compulsive drug-seeking and relapse, the characteristics that result in addiction treatment failure. Structural and functional impairments within the OFC have been detected in many substance use disorders (SUDs). Deep brain stimulation (DBS) is proposed as a promising therapeutic option in treating SUDs. Therefore, the present study aimed to investigate the potential efficacy of DBS application on the various stages of the methamphetamine-conditioned place preference (CPP) paradigm in rats. Main methodsElectrodes were implanted unilaterally in the rat's right OFC. DBS in the form of high- or low-frequency stimulation (HFS: 130 Hz, LFS: 13 Hz) was applied during the 5-day conditioning phase (a daily 30-min session) or extinction period (30-min session, daily, ten days) of methamphetamine-induced CPP in two separate sets of experiments. Following extinction, place preference was reinstated by injecting a priming dose of methamphetamine (0.25 mg/kg). Key findingsThe HFS and LFS significantly decreased the methamphetamine place preference when applied over the conditioning period. In the extinction experiment, only HFS could remarkably accelerate the extinction of reward-context associations and even reduce the methamphetamine-induced reinstatement of seeking behaviors. SignificanceConclusively, DBS administration in the OFC demonstrated some positive results, including suppressing effects on the development, maintenance, and relapse of methamphetamine-seeking behavior. These findings encourage conducting more preclinical studies to strongly suggest a wide range of DBS applications in cortical areas such as OFC as an efficient treatment modality for psychostimulant use disorder.

Warfarin prophylaxis for arterial thromboembolism: Age is the prime dose determinant and atrial fibrillation is the main indication in an Afro-Arab Ethinic community

Arterial Thromboembolism (TE), is due to a heterogeneous group of disorders that associate with faulty hemostasis with consequent vascular thrombosis and embolism [1], the sequel of the latter are sometimes lethal.

Radio-adaptive Response Induced by Low-dose Ionizing Radiation in Innate Immunity for Radiotherapy.

Radio-adaptive response (RAR) is a mechanism by which low doses of ionizing radiation (IR) protect cells from subsequent high doses. This study aimed to compare the immuno-radiological effects of 0.25, 0.5, and 5 Gy to 0.25 or 0.5 Gy as priming and 5 Gy as challenging doses. Thirty-five rats were irradiated whole-body with 0.25 and 0.5 Gy followed by 5 Gy, and the same single IR doses with non-irradiated animals serving as controls. Serum interferon-gamma (INF-γ), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and malondialdehyde (MDA) levels were measured 4 d post both priming and challenge doses. A 0.25-Gy priming dose significantly (P < 0.05) reduced serum TNF-α, MDA, and NO levels compared to all single-irradiated groups. Surprisingly, there was no difference in IFN-γ serum levels between the RAR-induced and non-irradiated groups (P ≥ 0.05). Compared to the same low priming dose (0.25 and 0.5 Gy), the effect of the challenging dose (5 Gy) remains unchanged or decreases. Serum IFN-γ, MDA, and NO concentrations, on the other hand, were significantly (P < 0.05) lower in the 0.5 Gy pre-challenging dose, whereas IL1β had no effect (P ≥ 0.05) compared to 5 Gy alone. The post-RAR group had significantly (P < 0.05) lower oxidative stress indicators than the other irradiation groups. The findings suggested that priming with low IR could help mitigate the negative effects on the hematopoietic system. Finally, RAR has significantly impacted endogenous cytokines, oxidative stress biomarkers, and lipid peroxidation parameters. RAR can improve patients' radiological safety profiles by mitigating adverse radiotherapy effects.

Evaluation of the effect of mesenchymal stem cells injection in the nucleus accumbens on the morphine reinstatement behavior in a conditioned place preference model in Wistar rat: Expression changes of NMDA receptor subunits and NT-3

Mesenchymal stem cells (MSCs) have been recently shown to improve functional recovery in animal models of CNS disorders and are currently being examined in clinical studies for sclerosis, stroke, and CNS lesions. The activation of endogenous CNS protection and repair mechanisms is unclear. MSC-based approaches are considered a new potential target for neurodegenerative disorders. This study was designed to discover the effect of MSCs injection in the nucleus accumbens (NAc) on the reinstatement of behavior in morphine-induced conditioned place preference (CPP) in male rats. The CPP was induced via intra-peritoneal (i.p.) morphine injection (5 mg/kg) for three consecutive days. After being tested for CPP induction, animals received MSCs or culture medium (DMEM F-12) in their NAc using stereotaxic surgery. Following extinction, a priming dose of morphine (2 mg/kg) was administered to induce reinstatement. Expression of GluN1, GluN2A, and GluN2B subunits of the NMDA receptor and the NT-3 gene in the NAc was assessed on the last day of extinction and following CPP reinstatement. The results showed that local injection of MSCs attenuated reinstatement after receiving a priming dose of morphine, and also shortened the period of CPP extinction. The mRNA expression of the NT-3 gene in the group receiving MSCs was increased compared to control animals, as was observed for GluN1 and GluN2B, but not GluN2A. It is concluded that intra-NAc injection of MSCs may facilitate morphine extinction and alleviate reinstatement behavior which may be via expression changes in NMDA receptor subunits and NT-3 gene.

A Priming Dose of Oral Vitamin A Given to Preschool Children May Extend Protection Conferred by a Subsequent Large Dose of Vitamin A

A randomized trial tested whether a priming dose of vitamin A would extend the protection of a subsequent 60,000-micrograms retinol equivalent (RE) oral dose. Seventy-five xerophthalmic and 74 age- and neighborhood-matched non-xerophthalmic preschool children were randomized to one of three oral regimens of vitamin A, receiving peanut oil only (Group A), 7500 micrograms RE (Group B) or 60,000 micrograms RE (Group C), followed in all instances by 60,000 micrograms RE 1 wk later. Serum retinol was measured 2, 4, 6 and 12 mo following the second dose by technicians unaware of the children's treatment status. Among xerophthalmic children, mean values differed across treatment groups at 2 mo (C > A) and tended to be different at 12 mo (C > A and B > A). Among non-xerophthalmic children mean retinol concentrations differed across treatment groups at 6 mo, but not in a consistent way (A > C > B), and at 12 mo (C > A and B > A). Xerophthalmic children reverted to biochemical deficiency faster than non-xerophthalmic children. A small or large priming dose may extend the protection conferred by a 60,000-micrograms RE dose, supporting the use of repeated, spaced doses of vitamin A for treating xerophthalmia. Similar retinol concentrations in Groups B and C at 12 mo suggest the 60,000-micrograms RE prophylactic dose currently recommended by the World Health Organization need not be increased.

Mechanistic Modelling of DNA Damage Repair by the Radiation Adaptive Response Mechanism and Its Significance

The radiation adaptive response effect is a biophysical phenomenon responsible for the enhancement of repair processes in irradiated cells. This can be observed in dedicated radiobiological experiments, e.g., where the small priming dose of ionising radiation is given before the high challenging one (the so-called Raper–Yonezawa effect). The situation is more complicated when the whole complex system (the organism) is taken into consideration; many other mechanisms make the adaptive response weaker and—in some cases—practically insignificant. The recently published simplified Monte Carlo model of human lymphocytes irradiation by X-rays allows for the calculation of the level of repair enhancement by the adaptive response when every other cellular biological mechanism is implemented. The qualitative results show that the adaptive response phenomenon, observed with some probability on a basic level, usually blurs among other effects and becomes weaker than expected. Regardless, the radiation adaptive response is still an important biophysical effect which needs to be taken into consideration in low-dose radiobiological studies.

Evaluation of DNA Vaccine Candidates against Foot-and-Mouth Disease Virus in Cattle.

We evaluated four DNA vaccine candidates for their ability to produce virus-like particles (VLPs) and elicit a protective immune response against Foot-and-mouth disease virus (FMDV) in cattle. Two traditional DNA plasmids and two DNA minicircle constructs were evaluated. Both the pTarget O1P1-3C plasmid and O1P1-3C minicircle encoded a wild-type FMDV 3C protease to process the P1-2A polypeptide, whereas the O1P1-HIV-3CT minicircle used an HIV-1 ribosomal frameshift to down-regulate expression of a mutant 3C protease. A modified pTarget plasmid with a reduced backbone size, mpTarget O1P1-3CLT, used a 3C protease containing two mutations reported to enhance expression. All constructs produced mature FMDV P1 cleavage products in transfected cells, as seen by western blot analysis. Three constructs, O1P1-3C minicircles, pTarget O1P1-3C, and mpTarget O1P1-3CLT plasmids, produced intracellular VLP crystalline arrays detected by electron microscopy. Despite VLP formation in vitro, none of the DNA vaccine candidates elicited protection from clinical disease when administered independently. Administration of pTarget O1P1-3C plasmid enhanced neutralizing antibody titers when used as a priming dose prior to administration of a conditionally licensed adenovirus-vectored FMD vaccine. Further work is needed to develop these DNA plasmid-based constructs into standalone FMD vaccines in cattle.

Alcohol craving in the natural environment: Moderating roles of cue exposure, drinking, and alcohol sensitivity.

Effects of cue exposure and alcohol consumption (e.g., priming doses) on craving for alcohol have been examined in largely separate literature, limiting what is known about their potential interaction. Individuals with low alcohol sensitivity, a known risk factor for alcohol use disorder (AUD), exhibit stronger cue-elicited craving than their higher-sensitivity (HS) peers in both laboratory and real-world contexts. Here, underage drinkers (N = 155) completed a 21-day ecological momentary assessment (EMA) protocol in which they recorded exposure to alcohol cues and levels of craving during both nondrinking and postdrinking moments. Multilevel modeling detected a significant interaction of cue exposure and postdrinking status on craving. Cue-induced craving was increased in postdrinking moments compared to nondrinking moments. Contrary to prediction, cue-elicited increase in craving during nondrinking moments was stronger in participants reporting higher sensitivity to alcohol. In the presence of cues, lower sensitivity was robustly related to craving intensity in the postdrinking state but unrelated to craving during nondrinking moments. Craving during drinking episodes in the natural environment is magnified by the presence of alcohol cues, potentially contributing to the maintenance or acceleration of drinking episodes. Moreover, lower-sensitivity drinkers may be particularly susceptible to the combined effects of cue exposure and postdrinking status on alcohol craving. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Combination treatment of intratumoral vidutolimod (CMP-001), radiosurgery, nivolumab, and ipilimumab for metastatic colorectal carcinoma.

123 Background: Microsatellite stable (MSS) or mismatch repair proficient (MMR-P) metastatic colorectal cancer is refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response. Methods: In this single institution investigator-initiated phase I study, patients with MSS / MMR-P metastatic colorectal cancer were treated with a priming dose of subcutaneous (s.c.) vidutolimod, three intratumoral injections of vidutolimod, and radiosurgery to a metastasis, combined with nivolumab 3mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Following conclusion of intratumoral therapy, s.c. injections of vidutolimod commenced. Efficacy endpoints were based upon a non-irradiated and non-injected lesion. Cytokine levels were measured at baseline and at 7 (± 2) weeks. Patients were placed in 4 cohorts: (1) Safety run-in without radiosurgery (No RT); (2) Radiosurgery prior to intratumoral therapy (Early Liver RT Slow). An amendment was made due to early patient fall-out due to progressive disease; (3) Radiosurgery prior to intratumoral therapy with a condensed timeline (Early Liver RT Quick). An additional amendment was made due to unacceptable liver toxicity; (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy (Late Extrahepatic RT). ClinicalTrials.gov Identifier NCT03507699. Results: A total of 19 patients were accrued (No RT, n=2; Early Liver RT Slow, n=7; Early Liver RT Quick, n=4; Late Extrahepatic RT, n=6). Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2 – 5). None of the patients responded, aside from one patient in cohort #4 who achieved complete response, and was subsequently found to have a high tumor mutational burden (TMB) 79 mutations / Mb. Grade 3 liver toxicity, including elevated transaminases and hyperbilirubinemia, was reported in 0%, 0%, 75% and 17% in cohorts 1-4, respectively. Reactions following intratumoral injections, typically within 12 hours, included fever (68%), tachycardia (21%), chills (63%) and hypotension (47%). There was an increase in systemic CXCL10 levels at 7 (± 2) weeks compared to baseline, with a median of 407 versus 78 pg/ml, respectively, p&lt;0.01. Conclusions: Intratumoral liver injection of vidutolimod was associated with acute systemic symptoms attributed to cytokine release. The juxtaposition of liver irradiation and intratumoral vidutolimod injection to the same lesion was associated with unacceptable hepatic toxicity. The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS / MMR-P colon cancer. Clinical trial information: NCT03507699 .

No: 5935 The effect of rocuronium priming dose based on actual versus corrected body weight in modified rapid sequence intubation

No: 5935 The effect of rocuronium priming dose based on actual versus corrected body weight in modified rapid sequence intubation

Combined 13-valent pneumococcal conjugate and 23-valent pneumococcal polysaccharide vaccine regimens for adults with systemic lupus erythematosus: Does the sequence of pneumococcal vaccination affect immunogenicity responses? A single-center cohort study in Brazil.

A combination of 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) is currently recommended for adults with systemic lupus erythematosus (SLE). However, data on the immunogenicity elicited by sequential pneumococcal vaccination in this patient population are scarce. In this study, we compared short-term antibody responses to both PCV13/PPSV23 (≥8-week interval) and PPSV23/PCV13 (≥12-month interval) vaccination strategies in pneumococcal vaccine-naive adults with SLE. This longitudinal, open-label, quasi-randomized study was performed in a single-center cohort of adults (18 years or older) with SLE. In both vaccination groups, blood samples were collected immediately before administering the first dose of the pneumococcal vaccine (timepoint T0), 4-6 weeks after the priming dose (T1), and 4-6weeks after the booster dose (T2). We focused on the 12 shared serotypes between PCV13 and PPSV23, and compared the following immunogenicity outcomes between the groups at T2: anti-pneumococcal antibody geometric mean concentration (ApAb GMC), fold increase in ApAb levels (FI-ApAb), overall seroprotection rate, and overall seroconversion rate. The protective level for each pneumococcal serotype was set at 1.3 μg/mL. We used the multi-analyte immunodetection method to determine serum levels of ApAbs. Thirty-four patients with SLE were screened between April 2019 and January 2020, and 16 of them (mean age: 39.4 years, 87.5% female, and 100% on immunosuppressants) had evaluable immunogenicity results at T2. The median time elapsed between the pneumococcal vaccinations was 56 days in the PCV13/PPSV23 group (n = 11 patients) and 16 months in the PPSV23/PCV13 group (n = 5 patients). Priming with PCV13 (PCV13/PPSV23 group), as opposed to PPSV23 (PPSV23/PCV13 group), yielded significantly better results regarding FI-ApAb, overall seroconversion rate, and overall seroprotection rate 4-6 weeks after each pneumococcal vaccination. A trend toward augmented ApAb GMC in the patients who received the PCV13/PPSV23 sequence was also observed. No relevant safety issues were identified with sequential pneumococcal vaccination. The PCV13-priming PPSV23-boost strategy in adults with SLE induced greater antibody responses for most immunogenicity outcomes than those elicited by the PPSV23/PCV13 strategy.

The effectiveness of Ovaprim, Ovopel, and their combinations in artificial reproduction of common rudd Scardinius erythrophthalmus under controlled conditions

In this study, a practical protocol for artificial reproduction was developed for the rudd, Scardinius erythrophthalmus, to help to produce this fish for aquaculture industries and also for restocking programs. For this purpose, the efficiency of different hormonal agents and their combinations for spawning induction of female breeders of rudd was evaluated. Ovulations were stimulated using different treatments as: two injections of Ovaprim (Ova), two injections of Ovopel (Ovo), a priming dose of Ovopel with a resolving dose of Ovaprim (Comb1), a priming dose of Ovaprim with a resolving dose of Ovopel (Comb2), and two injections of sterile 0.9% NaCl solution as a control group. During the study, ovulation success, egg developmental competence as well as the performance of the freshly hatched larvae were recorded. There was no ovulation in females from the control group. In hormone-treated groups, 84–100% of fish ovulated, but no differences were observed in ovulation success (P > 0.05). The shortest latency period in treated fish was recorded in the Ovo group (431.6 degree-hour, P < 0.05). The best results in terms of working fecundity (number of obtained eggs per fish), relative fecundity, fertilization success, hatching rate, and embryo survival up to the eyed stage were achieved in the Ova and Comb1 groups (P < 0.05). Moreover, better survival rates up to the absorbing yolk sac stage and the lowest abnormality of larvae were observed in Ova and Comb1 groups (P < 0.05). There was no significant difference in the incubation time among different groups (P > 0.05). The obtained results indicate that two injections of Ovaprim and/or a priming dose of Ovopel with a resolving dose of Ovaprim are suitable for the artificial reproduction of rudd female breeders. Due to the proper effects and ease of use, two injections of Ovaprim could be recommended for the production of this species for restocking or aquaculture programs.

Immunogenicity and safety in healthy adults of full dose versus half doses of COVID-19 vaccine (ChAdOx1-S or BNT162b2) or full-dose CoronaVac administered as a booster dose after priming with CoronaVac: a randomised, observer-masked, controlled trial in Indonesia

Inactivated COVID-19 vaccines effectively prevent death, but their effectiveness for preventing infection or severe illness is known to decrease within 3-6 months following the second priming dose. Here we aimed to evaluate the immunogenicity and safety of three potential booster vaccines administered as a full-dose homologous booster or full-dose or half-dose heterologous boosters among individuals primed with CoronaVac. We did an observer and participant masked, randomised controlled trial study of healthy Indonesian adults from five recruitment sites in Bandung and Jakarta, Indonesia, aged 18 years and older who had previously received two doses of CoronaVac within 3 to less than 6 months or 6 to 9 months before the booster dose. Participants were randomly assigned (1:1:1:1:1) by means of stratified randomisation with random block size to a homologous booster with full-dose CoronaVac or heterologous boosters with ChAdOx1-S or BNT162b2 in full dose or half dose. The primary outcome was to evaluate the seropositive, seroconversion rate, and the geometric mean titres of IgG anti-spike-receptor binding domain and neutralising antibodies, 28 days after booster dose vaccination in the per-protocol population. Safety was assessed as a secondary outcome in all vaccinated booster participants by the incidence rate and intensity of adverse events within 24 h, 7 days, and 28 days after the booster dose. This study is registered with ina-registry.org, INA-GO0HLGB, and is complete. Between Nov 26 and Dec 16, 2021, 1015 people were screened, and 960 healthy adults were enrolled; 190-193 were included in each group. 28 days after receiving the booster, combining the 3 to less than 6 months and 6 to 9 months groups, the proportions of seroconversion rates in each vaccine group were ChAdOx1-S 75 (82%) of 92 to 87 (88%) of 99 for full dose and half dose, BNT162b2 92 (92%) of 100 to 90 (98%) of 92 for full dose and half dose, and CoronaVac in 38 (41%) of 92 to 65 (66%) of 98. All booster groups achieved 100% seropositivity 28 days after the booster dose. Participants in the 6 to 9 months priming group achieved higher titres compared with participants in the 3 to less than 6 months priming group. The geometric mean titres in participants in the 6 to 9 months priming group in each vaccine group were ChAdOx1-S 11258·69 (9562·43-13 255·85) and 7853·04 (6698·92-9206·00) for full dose and half dose, BNT162b2 19999·84 (17 720·58-22 572·25) and 17 017·62 (14 694·40-19 708·16) for full dose and half dose and CoronaVac 1440·55 (1172·81-1769·42) achieved higher titres compared with participants in the 3 to less than 6 months priming group which in each vaccine group were ChAdOx1-S 7730·39 (6401·87-9334·60) and 6684·34 (5678·94-7867·73) for full dose and half dose, BNT162b2 16594·08 (13 993·08-19 678·55) and 12 121·67 (9925·21-14 804·19) for full dose and half dose, and CoronaVac 1210·23 (976·49-1499·92). The median percentage inhibition for the surrogate virus neutralisation test against the delta B.1.617.2 and wild-type (WT) variant before the booster and 28 days after the booster dose was very high in all groups (p<0·001), all with greater than 90% inhibition against both delta and WT strains. No serious adverse events were associated with the vaccines. Within the heterologous booster groups, the adverse event rates in the half-dose groups were lower compared with the full-dose groups. Geometric mean titre values between participants in the 6 to 9 months priming group and the 3 to less than 6 months priming group before the booster dose and between half-dose and full-dose groups 28 days before the booster were not significantly different for half-dose ChAdOx1-S, full-dose BNT162b2, and CoronaVac and were significantly different for full-dose ChAdOx1-S and half-dose BNT162b2. Among individuals primed with CoronaVac, boosting with BNT162b2 (full dose or half dose) or ChAdOx1-S (full dose or half dose) produces substantially better immune responses than in those boosted with CoronaVac. Full-dose and half-dose boosting with either BNT162b2 or ChAdOx1-S produced similar responses. Heterologous booster with half-dose might be considered in adults primed with two doses of CoronaVac vaccine. Ministry of Health, Indonesia. For the Indonesian translation of the abstract see Supplementary Materials section.

Transcriptomic response and immunological responses to chimpanzee adenovirus- and MVA viral-vectored vaccines for RSV in healthy adults.

Cohorts of healthy younger adults (18-50yrs) and healthy older adults (60-75yrs) were immunized intramuscularly or intranasally with an adenovirus-vectored RSV vaccine (PanAd3-RSV) as a prime dose and boosted with PanAd3-RSV or a poxvirus-vectored vaccine (MVA-RSV) encoding the same insert. Whole blood gene expression was measured at baseline, 3- and 7-days post vaccination. Intramuscular prime vaccination with PanAd3-RSV induced differential expression of 643 genes (DEGs, FDR < 0.05). Intranasal prime vaccination with PanAd3-RSV did not induce any differentially expressed genes (DEGs) in blood samples at 3 days post vaccination. Intranasally primed participants showed greater numbers of DEGS on boosting than intramuscularly primed participants. The most highly enriched biological processes related to DEGs after both prime and boost vaccination were type-1 interferon related pathways, lymphocytic and humoral immune responses.

Continuous organ perfusion monitoring using indocyanine green in a piglet model.

Unrecognized organ hypoperfusion may cause major postoperative complications with detrimental effects for the patient. The use of Indocyanine Green (ICG) to detect organ hypoperfusion is emerging but the optimal methodology is still uncertain. The purpose of this study was to determine the feasibility of real-time continuous quantitative perfusion assessment with Indocyanine Green (ICG) to monitor organ perfusion during minimally invasive surgery using a novel ICG dosing regimen and quantification software. In this experimental porcine study, twelve subjects were administered a priming dose of ICG, followed by a regimen of high-frequency (1 dose per minute), low-dose bolus injections with weight-adjusted (0.008mg/kg) ICG allowing for continuous perfusion monitoring. In each pig, one randomly assigned organ of interest [stomach (n = 3), ascending colon (n = 3), rectum (n = 3) and spleen (n = 3)] was investigated with varying camera conditions. Video recording was performed with the 1588 AIM Stryker camera platform and subsequent quantitative analysis of the ICG signal were performed using a research version of a commercially available surgical real-time analysis software. Using a high-frequency, low-dose bolus ICG regimen, fluorescence visualization and quantification in abdominal organs were successful in the stomach (3/3), ascending colon (1/3), rectum (2/3), and the spleen (3/3). ICG accumulation in the tissue over time did not affect the quantification process. Considerable variation in fluorescence signal was observed between organs and between the same organ in different subjects. Of the different camera conditions investigated, the highest signal was achieved when the camera was placed 7.5cm from the target organ. This proof-of-concept study finds that real-time continuous perfusion monitoring in different abdominal organs using ICG is feasible. However, the study also finds a large variation in fluorescence intensity between organs and between the same organ in different subjects while using a fixed weight-adjusted dosing regimen using the same camera setting and placement.