Adjuvanting a subunit COVID-19 vaccine to induce protective immunity.

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).

Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates.

The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor-binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.

No Difference Between Noxious and Innocuous Thermal Stimulation on Motor Recovery of Upper Extremity in Patients With Acute Stroke: A Randomized Controlled Trial With 6-Month Follow-up.

BACKGROUND: Thermal stimulation (TS) has been developed and incorporated into stroke rehabilitation. However, whether noxious and innocuous TS induce the same effects on motor function recovery after stroke is still unknown. A comparative study of different temperature combination regimens is needed. OBJECTIVE: To compare the short- and long-term effectiveness between noxious and innocuous TS on motor recovery of upper extremity in patients with acute stroke. DESIGN: Randomized, controlled trial with concealed allocation, intention-to-treat analysis and blinded outcome assessors. SETTING: A university hospital rehabilitation department in Taiwan. PARTICIPANTS: A total of 79 patients with acute ischemic stroke were recruited. The majority had moderate to severe motor impairment of the upper extremity (UE). INTERVENTION: In addition to traditional rehabilitation, the experimental group (n = 39) underwent noxious TS (heat pain 46-47°C/cold pain 7-8°C), and the control group (n = 40) received innocuous TS (heat 40-41°C/cold 20-21°C). TS intervention was applied for 30 minutes once per day and for a total of 20-24 times during hospital stay. A custom-made TS instrument, comprising 2 thermal stimulators and their respective thermal pads constructed in a closed-loop system, was used. OUTCOMES: The Fugl-Meyer upper extremity score (the primary outcome), Action Research Arm Test, Motricity Index, Barthel Index, and modified Ashworth scale (the secondary outcomes) were administered by a blinded assessor at baseline, post-12th TS, post-intervention, 1-month, and 6-month follow-ups. RESULTS: No significant differences between groups were found on the primary outcome at postintervention and follow-up assessments. At 1-month follow-up, the innocuous group showed a small effect (partial η2 = 0.02) that was greater than that of the noxious group, but that effect was eliminated at 6 months. Both groups presented significant within-group improvements over time (both P < .001). CONCLUSIONS: Combining noxious TS with traditional rehabilitation did not yield better short-term or long-term results than combining innocuous TS with traditional rehabilitation on UE functional recovery for individuals with acute stroke. LEVEL OF EVIDENCE: II.

Effects of noxious versus innocuous thermal stimulation on lower extremity motor recovery 3 months after stroke.

OBJECTIVE: To examine the effects of thermal stimulation (TS) on the lower extremity (LE) movement and function in patients with stroke. DESIGN: A double-blinded randomized controlled trial. SETTING: A university hospital. PARTICIPANTS: Patients (N=34) at least 3 months after stroke were randomly assigned into the experimental and the control groups. INTERVENTIONS: In addition to regular rehabilitation, the experimental group received a 30-minute noxious TS protocol (heat pain 46-47°C/cold pain 2-3°C) 3days/wk for 8 weeks, and the control group received a 30-minute innocuous TS protocol (heat 40-41°C/cold 23-24°C) 3d/wk for 8 weeks. MAIN OUTCOME MEASURES: The Low Extremity subscale of the Stroke Rehabilitation Assessment of Movement (LE-STREAM), the Mobility subscale of STREAM (Mob-STREAM), the Functional Ambulation Category (FAC), the Barthel Index (BI), the Postural Assessment Scale for Stroke Patients (PASS), and the Modified Ashworth Scale (MAS) were administered by a blinded rater at baseline, posttreatment (8wk), and follow-up (12wk). RESULTS: Twenty-three participants completed the study protocol and all outcome measurements. No preexisting group differences between the experimental group (n=11) and the control group (n=12) were found on demographic and clinical variables. Compared with baseline, the experimental group showed significant improvements at posttreatment and follow-up on the LE-STREAM, Mob-STREAM, FAC, and BI (P<.05) while the control group showed no significant improvements for all outcome measures. As for the between-group comparison, significant differences were seen at follow-up (12wk) on the LE-STREAM, Mob-STREAM, BI, and MAS. CONCLUSIONS: Our findings indicate that an 8-week program of noxious TS combined with a traditional stroke rehabilitation program can improve the LE-related movement and function in patients with stroke for more than 3 months.

Effects and predictors of shoulder muscle massage for patients with posterior shoulder tightness.

BACKGROUND: Clinical approaches like mobilization, stretching, and/or massage may decrease shoulder tightness and improve symptoms in subjects with stiff shoulders. We investigated the effect and predictors of effectiveness of massage in the treatment of patients with posterior shoulder tightness. METHODS: A randomized controlled trial was conducted in a hospital-based outpatient practice (orthopedic and rehabilitation). Forty-three women and 17 men (mean age = 54 years, range 43-73 years) with posterior shoulder tightness participated and were randomized into massage and control groups (n = 30 per group). A physical therapist provided the massage on the posterior deltoid, infraspinatus, and teres minor of the involved shoulder for 18 minutes [about 6 minutes for each muscle] two times a week for 4 weeks. For the control group, one therapist applied light hand touch on the muscles 10 minutes two times a week for 4 weeks. Glenohumeral internal rotation ROM, functional status, and muscle tightness were the main outcomes. Additionally, the potential factors on the effectiveness of massage were analyzed by multivariate logistic regression. For this analysis, patients with functional score improvement at least 20% after massage were considered responsive, and the others were considered nonresponsive. RESULTS: Fifty-two patients completed the study (29 for the massage and 23 for the control). The overall mean internal rotation ROM increased significantly in the massage group compared to the control (54.9° v.s. 34.9°; P ≤ 0.001). There were 21 patients in the responsive group and 8 in the nonresponsive group. Among the factors, duration of symptoms, functional score, and posterior deltoid tightness were significant predictors of effectiveness of massage. CONCLUSIONS: Massage was an effective treatment for patients with posterior shoulder tightness, but was less effective in patients with longer duration of symptoms, higher functional limitation, and less posterior deltoid tightness. TRIAL REGISTRATION: This clinical trial is registered at Trial Registration "Trial registration: Clinicaltrials.gov NCT01022827".

Dosage of neuromuscular electrical stimulation: is it a determinant of upper limb functional improvement in stroke patients?

OBJECTIVE: To investigate the predictors related to upper extremity functional recovery, with special emphasis on neuromuscular electrical stimulation dose-response in patients after stroke. SUBJECTS: Ninety-five patients with stroke who received a 4-week neuromuscular electrical stimulation intervention. DESIGN: Prospective predictive analysis. METHODS: The change score of the Action Research Arm Test (ARAT) was used as the main outcome. Baseline subject characteristics, stroke-related data, and intervention-related data were collected. Multiple linear regression analysis was applied to identify the potential predictors related to main outcome. RESULTS: The regression model revealed that the initial Fugl-Meyer upper limb score was the most important predictor for ARAT change score post-test, followed by time since stroke onset and location of stroke lesion. At 2-month follow-up, the neuromuscular electrical stimulation dosage became a significant determinant in addition to the above predictors. CONCLUSION: Initial motor severity and lesion location were the main predictors for upper limb functional improvement in stroke patients. Neuromuscular electrical stimulation dosage became a significant determinant for upper limb functional recovery after stroke at 2-month follow-up. More intensive neuromuscular electrical stimulation therapy during early rehabilitation is associated with better upper limb motor function recovery after stroke.

Dose-response relation between neuromuscular electrical stimulation and upper-extremity function in patients with stroke.

BACKGROUND AND PURPOSE: The purpose of our study was to investigate the effects of different doses of neuromuscular electrical stimulation (NMES) on upper-extremity function in acute stroke patients with severe motor deficit. METHODS: Sixty-six acute stroke patients were randomized to 3 groups: high NMES, low NMES, or control. The low-NMES group received 30 minutes of stimulation per day, and the high-NMES group received 60 minutes per day, for 4 weeks. The Fugl-Meyer Motor Assessment Scale, Action Research Arm Test, and Motor Activity Log were used to assess the patients at baseline, 4 weeks, and 12 weeks post baseline (follow-up). RESULTS: Both NMES groups showed significant improvement on Fugl-Meyer Motor Assessment and Action Research Arm Test scales compared with the control group at week 4 and follow-up. The high-NMES group showed treatment effects similar to those of the low-NMES group. CONCLUSIONS: Higher and lower doses of NMES led to similar improvements in motor function. A minimum of 10 hours of NMES in combination with regular rehabilitation may improve recovery of arm function in stroke patients during the acute stage.