Safety and Immunogenicity of Respiratory Syncytial Virus Prefusion F Protein Vaccine when Co-administered with Adjuvanted Seasonal Quadrivalent Influenza Vaccine in Older Adults: A Phase 3 Randomized Trial.

BACKGROUND: We evaluated co-administration of adjuvanted seasonal quadrivalent influenza vaccine (FLU-aQIV) and respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) in ≥65-year-olds. METHODS: This phase 3, open-label trial randomized ≥65-year-olds to receive FLU-aQIV and RSVPreF3 OA concomitantly (Co-Ad) or sequentially, 1 month apart (Control). Primary objectives were to demonstrate the non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration in terms of hemagglutination inhibition (HI) titers for each FLU-aQIV strain and RSV-A and RSV-B neutralization titers, 1 month post-vaccination. Reactogenicity and safety were also assessed. RESULTS: Overall, 1045 participants were vaccinated (Co-Ad: 523; Control: 522). Non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration was demonstrated in terms of HI titers for the A/Victoria(H1N1), B/Victoria, and B/Yamagata influenza strains and RSV-A neutralization titers (upper limits [ULs] of 95% confidence intervals [CIs] for adjusted geometric mean titer [GMT] ratios [Control/Co-Ad] ≤1.50) but not for A/Darwin(H3N2) HI titers (95% CI UL = 1.53). The immune response to A/Darwin(H3N2) was further assessed post-hoc using a microneutralization assay; the post-vaccination adjusted GMT ratio (Control/Co-Ad) was 1.23 (95% CI: 1.06-1.42, ie, UL ≤1.50), suggesting an adequate immune response to A/Darwin(H3N2) following co-administration. RSV-B neutralization titers were comparable between groups (95% CI UL for adjusted GMT ratio ≤1.50). Solicited adverse events were mostly mild or moderate and transient; unsolicited and serious adverse event rates were balanced between groups. CONCLUSIONS: Adjuvanted FLU-aQIV and RSVPreF3 OA had acceptable reactogenicity/safety profiles when co-administered in ≥65-year-olds, without clinically relevant interference with the immune responses to either vaccine. CLINICAL TRIALS REGISTRATION: NCT05568797.

Immunogenicity, Reactogenicity, and Safety of AS01E-adjuvanted RSV Prefusion F Protein-based Candidate Vaccine (RSVPreF3 OA) When Co-administered With a Seasonal Quadrivalent Influenza Vaccine in Older Adults: Results of a Phase 3, Open-Label, Randomized Controlled Trial.

BACKGROUND: Co-administration of vaccines against respiratory syncytial virus (RSV) and influenza can be considered given their overlapping seasonality, and may increase vaccine uptake and compliance. In this phase 3, open-label, randomized study, we evaluated the immunogenicity, reactogenicity, and safety of the AS01E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) when co-administered with a seasonal quadrivalent influenza vaccine (FLU-QIV) in older adults. METHODS: Participants aged ≥60 years (randomized 1:1) received either RSVPreF3 OA and FLU-QIV simultaneously on day 1 (Co-Ad group) or FLU-QIV on day 1 followed by RSVPreF3 OA on day 31 (sequential administration [SA] group). The co-primary objectives were to demonstrate noninferiority of RSVPreF3 OA in terms of RSV-A neutralization geometric mean titer (GMT) ratio and FLU-QIV in terms of hemagglutination inhibition GMT ratio for each FLU-QIV strain, when co-administered versus when administered alone at 1-month post-vaccination. Noninferiority was demonstrated if the upper limit of the 95% confidence interview of the group GMT ratio (SA/Co-Ad) was ≤1.5. Secondary descriptive objectives comprised additional immunogenicity assessments, reactogenicity, and safety. RESULTS: Of the 885 participants who received one dose of the study vaccines, 837 were included in the per protocol set. Demographic and baseline characteristics were balanced between the groups. Both co-primary objectives were met for both vaccines. Reported adverse events in both groups were mild-to-moderate, with a low frequency of grade 3 events. CONCLUSIONS: Data from this study demonstrate that RSVPreF3 OA can be co-administered with FLU-QIV. Co-administration is well tolerated, with an acceptable safety profile. CLINICALTRIALS.GOV REGISTRATION: NCT04841577.

Validation of a Harmonized Enzyme-Linked-Lectin-Assay (ELLA-NI) Based Neuraminidase Inhibition Assay Standard Operating Procedure (SOP) for Quantification of N1 Influenza Antibodies and the Use of a Calibrator to Improve the Reproducibility of the ELLA-NI With Reverse Genetics Viral and Recombinant Neuraminidase Antigens: A FLUCOP Collaborative Study.

Current vaccination strategies against influenza focus on generating an antibody response against the viral haemagglutination surface protein, however there is increasing interest in neuraminidase (NA) as a target for vaccine development. A critical tool for development of vaccines that target NA or include an NA component is available validated serology assays for quantifying anti-NA antibodies. Additionally serology assays have a critical role in defining correlates of protection in vaccine development and licensure. Standardisation of these assays is important for consistent and accurate results. In this study we first validated a harmonized enzyme-linked lectin assay (ELLA)- Neuraminidase Inhibition (NI) SOP for N1 influenza antigen and demonstrated the assay was precise, linear, specific and robust within classical acceptance criteria for neutralization assays for vaccine testing. Secondly we tested this SOP with NA from influenza B viruses and showed the assay performed consistently with both influenza A and B antigens. Third, we demonstrated that recombinant NA (rNA) could be used as a source of antigen in ELLA-NI. In addition to validating a harmonized SOP we finally demonstrated a clear improvement in inter-laboratory agreement across several studies by using a calibrator. Importantly we showed that the use of a calibrator significantly improved agreement when using different sources of antigen in ELLA-NI, namely reverse genetics viruses and recombinant NA. We provide a freely available and detailed harmonized SOP for ELLA-NI. Our results add to the growing body of evidence in support of developing biological standards for influenza serology.

Efficacy of Cognitive Rehabilitation in Alzheimer Disease: A 1-Year Follow-Up Study.

INTRODUCTION: The benefit of cognitive rehabilitation (CR) for patients with early-stage Alzheimer disease (AD) remains difficult to assess. METHOD: An observational, prospective study was conducted in a sample of 52 patients with AD included in a clinical, individualized CR program. Cognitive rehabilitation consisted of 1 weekly session during 3 months at home, followed by 1 monthly contact for 9 months. Rehabilitation techniques were used by experienced therapists to adapt activities important for the patient. Evaluation of patient's dependence in activities and objective and subjective caregiver's burden was performed with a research quantitative scale immediately after the intervention and at 6-month and 1-year follow-up. RESULTS: Analyses with repeated measure analysis of variance showed decreased patient's dependence for adapted activities at 3 months, 6 months, and 1 year. Objective and subjective percentage of caregiver's burden was also decreased at all evaluations with our research functional scale, while there was no change on Zarit's burden scale. Global cognition slightly decreased over 1 year. CONCLUSIONS: This observational study in a clinical setting is in line with the benefit of CR for patients with mild AD reported in recent randomized controlled trials. The benefit obtained for adapted activities remained after 1 year, even if global cognition declined. Moreover caregiver's burden related to all individually relevant daily activities (from a list of 98) evaluated within the CR program was decreased after 1 year. Those preliminary results emphasize the importance of choice for the measurement instrument to report CR efficacy and claim for further validation of such tools.

Less is more: The availability heuristic in early childhood.

This study examined whether young children are influenced by the subjective experience associated with an easy or difficult recall when making memory decisions. Seventy-one children, aged 4, 6, and 8 years, were asked to generate either a small (easy condition) or large (hard condition) number of first names. Statistical analyses revealed that participants in the hard condition were more likely to infer that they did not know many names than participants in the easy condition, contrary to what would be expected if children based their memory judgement on the objective number of recalled items. Overall, our results support the hypothesis that children as young as 4 years old rely on the subjective experience of ease to regulate their decision-making processes. Theoretical implications of these findings are discussed.

Protein antigens increase the protective efficacy of a capsule-based vaccine against Staphylococcus aureus in a rat model of osteomyelitis.

Staphylococcus aureus is an invasive bacterial pathogen, and antibiotic resistance has impeded adequate control of infections caused by this microbe. Moreover, efforts to prevent human infections with single-component S. aureus vaccines have failed. In this study, we evaluated the protective efficacy in rats of vaccines containing both S. aureus capsular polysaccharides (CPs) and proteins. The serotypes 5 CP (CP5) and 8 CP (CP8) were conjugated to tetanus toxoid and administered to rats alone or together with domain A of clumping factor A (ClfA) or genetically detoxified alpha-toxin (dHla). The vaccines were delivered according to a preventive or a therapeutic regimen, and their protective efficacy was evaluated in a rat model of osteomyelitis. Addition of dHla (but not ClfA) to the CP5 or CP8 vaccine induced reductions in bacterial load and bone morphological changes compared with immunization with either conjugate vaccine alone. Both the prophylactic and therapeutic regimens were protective. Immunization with dHla together with a pneumococcal conjugate vaccine used as a control did not reduce staphylococcal osteomyelitis. The emergence of unencapsulated or small-colony variants during infection was negligible and similar for all of the vaccine groups. In conclusion, addition of dHla to a CP5 or CP8 conjugate vaccine enhanced its efficacy against S. aureus osteomyelitis, indicating that the inclusion of multiple antigens will likely enhance the efficacy of vaccines against both chronic and acute forms of staphylococcal disease.

Exploration of perceptual and motor inhibition in children with traumatic brain injury.

Perceptual and motor inhibition were examined using conflict resolution tasks for 12 children with traumatic brain injury and 24 matched controls. Direct comparisons of inhibition performances between the two groups showed a specific and disproportionate impairment of motor inhibition (compared with perceptual inhibition) for the children with traumatic brain injury, which suggests that inhibition processes might be differentially impaired in children after traumatic brain injury.

Does cognitive impairment influence burden in caregivers of patients with Alzheimer's disease?

Alzheimer's disease (AD) is characterized by a progressive deterioration of various cognitive and behavioral abilities, and it also has a health impact on the patients' caregiver. Our aim was to determine the patient (and to a lesser extent the caregiver) characteristics that contribute most to the caregiver burden. We used the baseline data from the ICTUS study, a European longitudinal cohort of patients with mild to moderate AD. Data from 1091 patients and their caregivers was used for analysis. Three principal components analyses were performed on variables from the domains of cognition, neuropsychiatric symptoms, and daily function using the MMSE plus the ADAS-Cog, NPI, and IADL subscores, respectively. These were followed by a stepwise logistic regression to identify patient characteristics which best predict caregiver burden. The regression model (R2 = 0.35, p < 0.001) shows that the best explanatory variables are: 1) neuropsychiatric symptoms (NPI); 2) difficulties in the IADL; 3) time taken by caregiving; 4) demographic variables such as caregiver's age and patient sex; and 5) severity of cognitive impairment. In conclusion, our results demonstrate that although the strongest determinant of the caregiver burden is behavioral disturbance, the impact of the degree of cognitive impairment on burden is also significant.

Patients with Alzheimer's disease use metamemory to attenuate the Jacoby-Whitehouse illusion.

Patients with Alzheimer's disease (AD) relying predominantly on familiarity for recognition, research has suggested that they may be particularly susceptible to memory illusions driven by conceptual fluency. Using the Jacoby and Whitehouse [Jacoby, L.L., & Whitehouse, K. (1989). An illusion of memory: False recognition influenced by unconscious perception. Journal of Experimental Psychology: General, 118, 126-135] illusion paradigm, we extended these findings and found that AD patients were also sensitive to perceptually driven false recognition. However, AD patients were equally able to disregard perceptual fluency when there was a shift in the sensory modality of the study and test stages. Overall, these findings support the notion that patients with AD can be susceptible to fluency-based memory illusions but these patients can strategically control the fluency attribution following their metamemory expectation in exactly the same way as elderly adults and young adults.

Inhibitory control of memory in normal ageing: dissociation between impaired intentional and preserved unintentional processes.

The aim of this study was to compare the performance of elderly and young participants on a series of memory tasks involving either intentional or unintentional inhibitory control of memory content. Intentional inhibition processes in working and episodic memory were explored with directed forgetting tasks and in semantic memory with the Hayling task. Unintentional inhibitory processes in working memory, long-term memory, and semantic memory were explored with an interference resolution task, the retrieval practice paradigm, and the flanker task, respectively. The results indicate that elderly participants' performance on the two directed forgetting tasks and the Hayling task is lower than that of young ones, and that this impairment is not related to their initial memory capacity. This suggests that there is a specific dysfunction affecting intentional inhibitory control of memory contents in normal ageing.

Dissociation of perceptual and motor inhibitory processes in young and elderly participants using the Simon task.

Deficits in inhibitory abilities are frequently observed in normal aging. However, few studies have explored the generality of these deficits in a single group of participants. Here, we used an adaptation of the Simon task to differentially assess perceptual and motor inhibition using the same stimuli and task design and to determine whether these processes use separate or shared cognitive resources. We were interested in determining whether (1) normal aging is associated with the use of separate (as previously evidenced in young participants) or similar cognitive resources to perform perceptual and motor inhibition tasks; (2) older participants present a specific impairment in one of these two processes. Analyses of reaction times indicated that motor and perceptual inhibitory processes share some cognitive resources and both are impaired in normal aging. These results can be interpreted by considering that a dedifferentiation process is responsible for the inhibitory deficits presented by older participants.