Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.

BACKGROUND: SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. METHODS: In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 µg SARS-CoV-2 recombinant spike protein and 50 µg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 µg of NVX-CoV2373 plus 2·5 µg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588. FINDINGS: Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated. INTERPRETATION: All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. FUNDING: Novavax.

Immunogenicity and safety of heterologous Omicron BA.1 and bivalent SARS-CoV-2 recombinant spike protein booster vaccines: a phase 3, randomized, clinical trial.

BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone, or as a bivalent preparation in combination with the prototype vaccine (NVX-CoV2373), to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated superior neutralizing antibody response to BA.1 versus NVX-CoV2373 (n = 274) at Day 14 (geometric mean titer ratio [95% CI]: 1.6 [1.33, 2.03]). Seroresponse rates [n/N; 95% CI] were 73.4% [91/124; 64.7, 80.9] for NVX-CoV2515 versus 50.9% [59/116; 41.4, 60.3] for NVX-CoV2373. All formulations were similarly well-tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373.

A Family Study of Trauma and Coping Strategies in Gambling Disorder.

Family studies can provide a wealth of information regarding risk factors in psychological disorders. No studies have compared the trauma experiences and coping strategies of problem gamblers with those of their first-degree relatives. Therefore, in this study, childhood trauma and coping strategies were investigated among participants with gambling disorder, their first-degree biological relatives, and community controls. Participants completed diagnostic interviews and symptom severity assessments. Participants also completed the Childhood Trauma Questionnaire (CTQ) which assesses history of abuse and neglect, and the Coping Inventory for Stressful Situations (CISS) which assesses task, emotion, and avoidance oriented coping strategies. Analysis of variance showed that there was a significant effect for group, but not gender, on the CTQ. Multivariate analysis of variance revealed a significant effect for group on coping style. Post-hoc tests showed that probands and relatives were less likely to use task-oriented coping compared to controls, but probands and relatives did not differ from each other on task-oriented coping. Mediation analysis showed that task-oriented coping did not mediate the relation between childhood trauma and gambling severity. By using a family study design, this study was able for the first time to delineate familial and disease-specific effects associated with childhood trauma and coping strategies in gambling disorder.

The effects of dysphoria and personality on negative self-referent attitudes and perceptions of the attitudes of others.

The cognitive model of depression posits that depressed individuals harbor more dysfunctional self-referent attitudes, but little is known about how depressed individuals perceive the attitudes and perceptions of others in their social arena. This study examined whether dysphoric individuals perceive others to hold equally negative attitudes about themselves, and whether such perceptions depend on sociotropic (i.e., highly invested in social approval and relationship success) and autonomous (i.e., highly invested in vocational or academic achievement and goal attainment) personality styles. A sample of undergraduate students (N = 197) was recruited, and after the assessment of their depression symptoms and personality style, participants read vignettes that described negative scenarios, and imagined that these scenarios occurred to themselves or the general university student. After reading each vignette, participants also rated their agreement with a number of statements that assessed dysfunctional attitudes. Results indicated that elevated dysphoria (i.e., showing signs of depression) scores were positively associated with dysfunctional self-referent attitudes. Further, moderational analyses examining the interaction of sociotropy and dysphoria did not support the hypothesis that individuals higher on dysphoria and sociotropy were less likely to perceive others as harboring negative attitudes about themselves in comparison to those with elevated dysphoria and lower levels of sociotropy. Last, individuals showing elevated dysphoria and higher scores on subdomains of autonomy were more likely to perceive others as exhibiting negative attitudes about themselves than those with low levels of the trait. These findings, their implications, and strengths and limitations of the current investigation are further discussed.

Use of Cryopreserved, Particulate Human Amniotic Membrane and Umbilical Cord (AM/UC) Tissue: A Case Series Study for Application in the Healing of Chronic Wounds.

Human amniotic membrane and umbilical cord tissues (AM/UC) are fetal tissues that contain proteins, cytokines, and growth factors that, when transplanted, can modulate inflammation and promote healing. Lyophilized, particulate AM/UC tissues can be used as wound coverings for chronic dermal ulcers or defects to promote granulation tissue formation and rapid re-epithelialization. This study reviews a case series of 5 patients presenting with chronic nonhealing wounds that received particulate AM/UC tissues (NEOX® FLO, Amniox Medical, Atlanta, GA). For all cases, wounds were debrided in the office setting and a single application of lyophilized particulate was used with minimal additional dressings. The lyophilized AM/UC tissue was placed within the wound bed and a dressing consisting of Adaptic®, 2x2 or 4x4 (Systagenix, Quincy, MA), Kling® (Johnson & Johnson, New Brunswick, NJ), and ACE™ (3M, St. Paul, MN) wrap were applied. Dressings were kept in place until weekly follow-up appointments in which a new Adaptic, 2x2 and Kling were applied. Overall, healing of wounds was noted to have a mean of 5 weeks to complete epithelialization. Upon complete healing patients were able to return to planned postoperative care and rehabilitation. Wound complications occur despite the best standard of care. Chronic wounds that remain weeks after surgery inhibit patients from progressing to physical rehabilitation and significantly affect patients both physically and mentally. These case presentations demonstrate how use of human AM/UC tissue may help wounds heal quickly and help patients return to normal function.

B cell depletion therapy for new-onset opsoclonus-myoclonus.

Twelve immunotherapy-naïve children with opsoclonus-myoclonus syndrome and CSF B cell expansion received rituximab, adrenocorticotropic hormone (ACTH), and IVIg. Motor severity lessened 73% by 6 mo and 81% at 1 yr (P < 0.0001). Opsoclonus and action myoclonus disappeared rapidly, whereas gait ataxia and some other motor components improved more slowly. ACTH dose was tapered by 87%. Reduction in total CSF B cells was profound at 6 mo (-93%). By study end, peripheral B cells returned to 53% of baseline and serum IgM levels to 63%. Overall clinical response trailed peripheral B cell and IgM depletion, but improvement continued after their levels recovered. All but one non-ambulatory subject became ambulatory without additional chemotherapy; two relapsed and remitted; four had rituximab-related or possibly related adverse events; and two had low-titer human anti-chimeric antibody. Combination of rituximab with conventional agents as initial therapy was effective and safe. A controlled trial with long-term safety monitoring is indicated.

Therapeutic down-regulation of central and peripheral B-cell-activating factor (BAFF) production in pediatric opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) is an autoimmune, paraneoplastic, central nervous system disorder, characterized by cerebrospinal fluid (CSF) B-cell expansion and various putative autoantibodies. To investigate the role of B-cell activating factor (BAFF) in OMS and the effect of disease-modifying immunotherapies used to treat it, BAFF was measured by enzyme-linked immunoadsorbent assay in the CSF and serum of 161 children with OMS and 116 pediatric controls. The mean concentration of CSF BAFF and the CSF/serum BAFF ratio were significantly higher in untreated OMS compared to neurological controls. CSF and serum BAFF levels were significantly lower in children treated with ACTH or corticosteroids, as was the CSF/serum BAFF ratio. There was a strong, negative correlation between CSF or serum BAFF levels and ACTH dose. Monthly IVIg infusions had no net impact on BAFF levels, and the combination of IVIg with ACTH or steroids did not reduce or enhance their anti-BAFF effects. These data indicate that BAFF production is increased centrally, not peripherally, in OMS, implying astrocytic over production. The novel dose-related central and peripheral anti-BAFF properties of ACTH, especially, have implications for other BAFF-related autoimmune disorders, infectious diseases, and cancers.

Single-cell RT-PCR gene expression profiling of acutely dissociated and immunocytochemically identified central neurons.

Identification of neurons for single-cell mRNA profiling is difficult when cells of interest are located in heterogeneous brain regions. We developed a protocol in which acutely dissociated neurons are immunocytochemically labeled prior to single-cell reverse transcription-polymerase chain reaction (RT-PCR). We tested the protocol on hypothalamic melanin-concentrating hormone (MCH) and prepro-orexin (PPO) neurons, which are similarly distributed but functionally different. Cells dissociated from the perifornical region of the posterior hypothalamus of juvenile or adult rats were incubated with anti-MCH or anti-PPO primary antibodies, followed by washout and incubation with fluorescein-tagged secondary antibodies. Individual labeled cells were subjected to RT-PCR with primers for PPO and MCH. MCH mRNA was detected in 26 out of the 38 successfully reverse-transcribed cells identified as MCH-containing, and 28 cells out of the 42 identified as PPO-containing expressed PPO mRNA. No cell expressed both mRNAs. Most MCH neurons tested (five out of six) expressed the adrenergic alpha2A receptor mRNA, whereas it was absent from all seven PPO neurons tested. Neither PPO (n = 11) nor MCH (n = 6) cells expressed the type 2 orexin receptor mRNA. Thus, the method allows, with at least 66% confidence, immunocytochemical cell identification prior to mRNA studies of single neurons located in heterogeneous brain regions.