Central cone design demonstrates greater micromotion compared to keel design in cementless tibial baseplates: A biomechanical analysis.

PURPOSE: The purpose of this study was to compare micromotion of two new cementless tibial baseplates to a cementless design with well-published clinical success. METHODS: Three cementless tibial baseplate designs (fixed-bearing [FB] with keel and cruciform pegs, rotating-platform with porous central cone and pegs, FB with cruciform keel and scalloped pegs) were evaluated on sawbone models. Loading was applied to the baseplate at a rate of 1 Hz for 10,000 cycles, which represents 6-8 weeks of stair descent. This time frame also represents the approximate time length for the induction of biologic fixation of cementless implants. Compressive and shear micromotion at the sawbone-implant interface were measured. RESULTS: At the end of the loading protocol, the central cone rotating-platform design exhibited greater micromotion at the anterior (p < 0.001), posterior (p < 0.001) and medial locations (p = 0.049) compared to the other two implants. The central cone design also exhibited greater translational micromotion in the sagittal plane at the medial (p = 0.001) and lateral locations (p = 0.034) and in the coronal plane anteriorly (p = 0.007). CONCLUSION: The cementless central cone rotating-platform baseplate demonstrated greater vertical and translational micromotion compared to the two FB baseplates with a keel underloading. This may indicate lower initial mechanical stability in implants without a keel, which possibly affects osseointegration. The implication of this is yet unknown and requires further long-term clinical follow-up to correlate these laboratory findings. LEVEL OF EVIDENCE: V (biomechanical study).

Discrimination Experiences and All-Cause and Cardiovascular Mortality: Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Epidemiologic studies have documented the associations between experiences of discrimination and adverse health outcomes. However, the relationship between discrimination and mortality, and the factors that may moderate this relationship are not well understood. This study examined whether lifetime and everyday discrimination were associated with all-cause and cardiovascular mortality and whether these associations differed by race and ethnicity, gender, and racial and ethnic residential segregation. METHODS: The study included 1633 Black, 1403 Hispanic/Latino, and 2473 White participants aged 45 to 84 years from the Multi-Ethnic Study of Atherosclerosis, enrolled from 2000 to 2002 and followed across 5 exams (2002-2018). Discrimination was measured using the lifetime discrimination (major experiences of unfair treatment) and everyday discrimination (day-to-day experiences of unfair treatment) scales. Racial and ethnic residential segregation was measured using the Gi* statistic. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, adjusting for sociodemographic characteristics, health behaviors, and clinical risk factors. RESULTS: Each increase in reports of lifetime discrimination was associated with increased all-cause (HR, 1.06 [95% CI, 1.00-1.11]) and cardiovascular (HR, 1.15 [95% CI, 1.04-1.27]) mortality, adjusting for sociodemographic factors, health behaviors, and clinical risk factors. Associations between lifetime discrimination and cardiovascular mortality were observed across all racial and ethnic groups but were strongest and only statistically significant among Black participants (HR, 1.18 [95% CI, 1.02-1.37]). Additionally, in the fully adjusted model, each increase in reports of everyday discrimination was strongly associated with increased cardiovascular mortality (HR, 1.21 [95% CI, 1.03-1.43]). Associations for lifetime and everyday discrimination with all-cause and cardiovascular mortality were not modified by race and ethnicity, gender, or racial and ethnic residential segregation. CONCLUSIONS: These findings suggest that experiences of discrimination are associated with increased all-cause and cardiovascular mortality.

Efficacy of PECS block in addition to multimodal analgesia for postoperative pain management in patients undergoing outpatient elective breast surgery: A retrospective study.

Background: Pectoralis nerve blocks (PECS) have been shown in numerous studies to be a safe and effective method to treat postoperative pain and reduce postoperative opioid consumption after breast surgery. However, there are few publications evaluating the PECS block effectiveness in conjunction with multimodal analgesia (MMA) in outpatient breast surgery. This retrospective study aims to evaluate the efficacy of PECS's blocks on perioperative pain management and opioid consumption. Methods: We conducted a retrospective study to assess the efficacy of preoperative PECS block in addition to preoperative MMA (oral acetaminophen and/or gabapentin) in reducing opioid consumption in adult female subjects undergoing outpatient elective breast surgery between 2015 and 2020. A total of 228 subjects were included in the study and divided in two groups: PECS block group (received PECS block + MMA) and control Group (received only MMA). The primary outcome was to compare postoperative opioid consumption between both groups. The secondary outcome was intergroup comparisons of the following: postoperative nausea and vomiting (PONV), incidence of rescue antiemetic medication, PACU non-opioid analgesic medication required, length of PACU stay and the incidence of 30-day postoperative complications between both groups. Results: Two hundred and twenty-eight subjects (n = 228) were included in the study. A total of 174 subjects were allocated in the control group and 54 subjects were allocated in the PECS block group. Breast reduction and mastectomy/lumpectomy surgeries were the most commonly performed procedures (48% and 28%, respectively). The total amount of perioperative (intraoperative and PACU) MME was 27 [19, 38] in the control group and 28.5 [22, 38] in the PECS groups (p = 0.21). PACU opioid consumption was 14.3 [7, 24.5] MME for the control group and 17 [8, 23] MME (p = 0.732) for the PECS group. Lastly, the mean overall incidence of postsurgical complications at 30 days was 3% (N = 5), being wound infection, the only complication observed in the PECS groups (N = 2), and hematoma (N = 2) and wound dehiscence (N = 1) in the control group. Conclusion: PECS block combined with MMA may not reduce intraoperative and/or PACU opioid consumption in patients undergoing outpatient elective breast surgery.

The impact of different step rate threshold methods on physical activity intensity in older adults.

BACKGROUND: Older adults benefit most from engaging in higher-intensity physical activity, which is often determined using step rate thresholds. Fixed step rate thresholds that correspond to moderate (MPA) and vigorous-intensity physical activity (VPA) have been developed for heuristic activity promotion. The activPAL monitor uses step rate thresholds to determine activity intensity. Stepping thresholds may also vary based on body mass index (BMI) or aerobic fitness level in older adults. Despite the various thresholds used in the literature, it is unclear whether they produce similar outcomes. RESEARCH QUESTION: How does time spent in physical activity intensities compare between different step rate thresholds in older adults? METHODS: Thirty-eight participants (24♀; 67 ± 4 years; BMI: 26.6 ± 4.4 kg/m2) wore an activPAL monitor 24-hr/day for up to 7-d (total: 205-d). Aerobic fitness (V̇O2max: 23 ± 8 ml/kg/min) was determined via indirect calorimetry during a maximal, graded cycling test. Time spent in each intensity category (light-physical-activity [LPA], MPA, VPA) was determined using the fixed (MPA/VPA) 100/130, 110/130, and activPAL step rate thresholds (74/212), as well as BMI-adjusted absolute (108.5 ± 2.5/134.0 ± 4.8) and BMI-adjusted relative (40%/60% V̇O2max; 111.4 ± 14.7/132.0 ± 19.0) cut-offs. Times spent in each intensity category were compared between methods. RESULTS: The activPAL and 100/130 thresholds yielded less LPA and more MPA than all other methods. The activPAL had no time spent in VPA at all. The BMI-adjusted absolute and relative thresholds produced statistically equivalent time in LPA and MPA (via equivalence testing), but not VPA. No two methods yielded similar time spent in LPA, MPA, or VPA. SIGNIFICANCE: The choice of step rate threshold has a major impact on physical activity intensity outcomes in older adults. Inherently, strategies that adjust for older adults' body size and/or aerobic fitness level provide a more individualized data processing strategy than fixed thresholds that assume the same threshold for all older adults.

Impact of habitual sedentary patterns on popliteal artery endothelial-dependent vasodilation in healthy adults.

INTRODUCTION: Acute, laboratory-based bouts of prolonged sitting attenuate lower-limb arterial endothelial-dependent vasodilation. However, the impact of habitual sedentary patterns on popliteal artery endothelial health is unclear. We tested the hypothesis that greater habitual total sedentary time, more time spent in prolonged sedentary bouts, and fewer sedentary breaks would be associated with worse popliteal flow-mediated dilation (FMD) responses. METHODS: This cross-sectional study used 98 healthy participants (19-77 years, 53 females) that wore an activPAL monitor on the thigh for 6.4 ± 0.8 days to objectively measure sedentary activity and completed a popliteal ultrasound assessment to determine FMD. Both relative (%baseline diameter) and absolute (mm) FMD were calculated. Using bivariate correlation and multiple regression analyses, we examined if there were relationships between sedentary outcomes and FMD while statistically controlling for any potential confounders. RESULTS: In the multiple regression model, age (p = 0.006, ß = -0.030, 95% CI = -0.051, -0.009) and total time in sedentary bouts > 1 hour (p = 0.031, ß = -0.005, 95% CI = -0.009, -0.001) were independent predictors of relative FMD. Age (ß = -0.002, 95% CI = -0.003, -0.001), mean blood flow (ß = 0.013, 95% CI = 0.002, 0.024), moderate-intensity physical activity (ß = 155.9E-5, 95% CI = 22.4E-5, 289.4E-5), sedentary breaks (ß = 0.036, 95% CI = 0.007, 0.066), and total time spent in sedentary bouts > 1 hour (ß = -25.02E-5, 95% CI = -47.67E-5, -2.378E-5) were predictors of absolute FMD (all, p < 0.047). All independent outcomes remained significant after partially controlling for all other predictor variables (all, p < 0.031). CONCLUSIONS: Habitual prolonged sedentary bouts and sedentary breaks, but not total sedentary time, were predictors of popliteal endothelial-dependent vasodilatory function. The patterns by which sedentary time is accumulated may be more important than the total sedentary time on lower-limb arterial health.

A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50 µg) SpFN vaccine, given twice 28 days apart, induced a Th1-biased CD4 T cell helper response and elicited neutralizing antibodies against SARS-CoV-2 wild-type and variants of concern, as well as against SARS-CoV-1. These potent humoral and cell-mediated immune responses translated into rapid elimination of replicating virus in the upper and lower airways and lung parenchyma of nonhuman primates following high-dose SARS-CoV-2 respiratory challenge. The immune response elicited by SpFN vaccination and resulting efficacy in nonhuman primates supports the utility of SpFN as a vaccine candidate for SARS-causing betacoronaviruses.

Comparison of habitual stepping cadence analysis methods: Relationship with step counts.

BACKGROUND: Different approaches have been implemented to calculate stepping cadence (steps/min) that vary in the time demominator used. Given the differences in how stepping intensity are calculated, it is unclear if they are more so associated with total step counts. RESEARCH OBJECTIVE: This study compared three methods of calculating stepping cadence and determined their relationship with total step counts. METHODS: 132 participants (74♀; 35 ± 20 years; body mass index: 24.9 ± 4.0 kg•m-2) wore an activPAL monitor 24-hr/day for up to 8-d (total: 869-d). The total steps/day, time spent stepping (0.1 s resolution; to calculate bout stepping rate), time spent stepping in 60 s epochs (step accumulation), and awake time (awake cadence) were determined. Each cadence method (in steps/min) were compared via Spearman's rank correlation. The relationships versus total step count were determined, and the strength of these relationships compared between cadence measures (95% confidence interval of correlation differences). RESULTS: Bout stepping rate (85 ± 14 steps/min) was larger than step accumulation (34 ± 12 steps/min) and awake cadence (10 ± 5 steps/min, both: P < 0.001). Step accumulation was positively strongly related to bout stepping rate (ρ = 0.813; P < 0.001) whereas awake cadence was weakly related to bout stepping rate (ρ = 0.496; P < 0.001). Step accumulation (ρ = 0.634; P < 0.001) and awake cadence (ρ = 0.964; P < 0.001) were more related to step counts than bout stepping rate (ρ = 0.497; P < 0.001; 95% confidence intervals of correlation differences: step accumulation=0.10-0.17, awake cadence: 0.42-0.52). SIGNIFICANCE: Without a precise measure of time spent stepping, stepping cadence is lower using the step accumulation and awake cadence methods. Step accumulation and awake cadence are more related to total step counts than bout stepping rate. Bout stepping rate outcomes reflect continuous stepping rate, does not rely on a preset epoch, and may have less overlap with step counts, which may have implications for determining the unique contributions of step count versus stepping cadence on health outcomes.

Effects of Breaking up Deskwork with Physical Activity Combined with Tea Consumption on Cerebrovascular Function, Mood, and Affect

Abstract Background: Prolonged sitting, typical of desk work, decreases cerebral blood flow (CBF), mood and affect. Conversely, short physical activity breaks from sitting may prevent these detrimental effects and provide cardiometabolic benefits. Objective: We evaluated the effect of interrupting prolonged sitting with short breaks of light physical activity combined with tea consumption on CBF, cerebral autoregulation (CA), mood, and affect in desk workers. Methods: Nineteen healthy desk workers (ten male, 27±10 years) performed desk work in a laboratory for six hours on two separate intervention days: tea breaks (TEA-BREAK: short walk combined with ingestion of one cup of tea every hour) and sedentary (SED: ingestion of one cup of water every hour, while seated). Before and after desk work, we assessed mean arterial pressure (MAP), middle cerebral artery blood velocity (MCAv) and CA. Questionnaires were used to assess mood (Bond & Lader, PANAS) and affect (Affect grid) before and after the intervention. Data are expressed as mean ± standard deviation. Two-way ANOVA with repeated measurements followed by Sidak post hoc test was used for data analysis. Paired Student's t-test was also used to compare changes (Δ) between trials. Statistical significance was at p<0.05. Results: Desk work increased MAP (4.6±4.6 Δ mmHg; P<0.05), and decreased MCAv (-5.2±7.0 Δ cm/s; P<0.05), with no difference between interventions in these parameters. TEA-BREAKS, but not SED, decreased gain (-0.08±0.12 Δ cm.s−1.mmHg.−1) and increased phase (5.26±8.84 Δ radians) at very low frequency (P<0.05), but not at low frequency. Small changes in positive affect were found after the six hours of desk work (-5.5±7.3 Δ scale; P<0.05), with no differences between interventions. Conclusion: Changes in MCAv and positive affect induced by prolonged desk work could not be prevented by TEA-BREAKS. However, TEA-BREAKS improved CA, suggesting a higher efficiency in maintaining MCAv in response to blood pressure fluctuations.

Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques.

Emergence of novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean serum neutralizing antibody titers of 14,000 to 21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within 4 d in seven of eight animals receiving 50 µg of RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only approximately twofold relative to WA1/2020. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-CoV-like Sarbecovirus vaccine development.

Development and validation of an activPAL accelerometry count-based model of physical activity intensity in adults.

The activPAL linear cadence-metabolic equivalents (METs) equation poorly estimates activity intensity. The magnitude of acceleration in three directional planes may be a superior predictor of activity intensity than stepping cadence, with accelerometry count thresholds developed in children/adolescent populations. We extracted the proprietary accelerometer-derived information to develop a counts-METs model and cross-validates it in laboratory and free-living conditions. Forty adults (25±6 years) wore an activPAL during a 7-stage progressive treadmill protocol (criterion: indirect calorimetry). Tri-axial accelerometry-derived activity counts (vector magnitude) and METs data from a subset of participants (n = 20) were modelled (R2=0.76) and the regression equation evaluated in the remaining participants (n = 20). Thirty-two of these participants wore the activPAL during free-living conditions (n = 192-d; criterion: PiezoRxD monitor). The absolute percent error of the counts-METs model in the laboratory cross-validation was 18±13%, with equivalence testing determinining equivalent MET values to indirect calorimetry during the slowest (1.5 mph) and fastest (4.0-4.5 mph) stages. In free-living conditions, the model accurately quantified light- and moderate-intensity physical activity but underestimated vigorous-intensity activity (6.5±11.3 vs. 5.5±20.8 mins/day; p < 0.001). We developed and present a data analysis method using the activPAL tri-axial accelerometry counts to improve estimations of physical activity intensity in controlled laboratory settings and uncontrolled free-living settings.

Anesthetic Management of Treacher Collins Syndrome in an Outpatient Surgical Center.

BACKGROUND Treacher Collins syndrome is a rare autosomal dominant disorder characterized by micrognathia and abnormal development of the zygomatic arch, which may result in significant upper airway obstruction. As patients who have it age, their upper airway obstruction may worsen. Therefore, they typically require several surgeries throughout their lives to correct specific facial abnormalities. Anesthetic and airway management of patients with Treacher Collins syndrome can be challenging for anesthesia providers, especially in ambulatory settings. CASE REPORT A 15-year-old patient with Treacher Collins syndrome presented to our outpatient surgery center for midface fat grafting. He had undergone multiple surgical procedures at Nationwide Children's Hospital, which is affiliated with The Ohio State University Wexner Medical Center. A decision was made to proceed with the grafting surgery after: (1) the literature was thoroughly reviewed; (2) multidisciplinary planning had been done utilizing our comprehensive preoperative screening and assessment process; (3) the scope of care at our ambulatory surgery center, the patient's medical history, and relevant airway notes had been reviewed; (4) the case was discussed with the surgeon; and (5) relevant images of the patient had been gathered. Evaluation of the patient's airway on the day of surgery was reassuring and a plan for managing a potentially difficult airway had been developed. After anesthetic induction, mask ventilation without adjuvants was successful. Video and direct laryngoscopy (for purposes of education) revealed grade 1 views. Supraglottic airway device placement resulted in an effective seal and the remainder of the surgery and the patient's subsequent course were uneventful. CONCLUSIONS Improved airway approaches, combined with thorough preoperative screening and multidisciplinary planning and communication, may make it possible to perform ambulatory surgery on patients with Treacher Collins syndrome, whose condition typically represents a significant challenge to anesthesia providers.

Does aerobic fitness impact prolonged sitting-induced popliteal artery endothelial dysfunction?

PURPOSE: Acute prolonged bouts of sitting reduce popliteal artery blood flow and flow-mediated dilation (FMD). Individuals with higher aerobic fitness have enhanced popliteal FMD. Conflicting evidence regarding whether more aerobically fit individuals are protected from the negative impacts of sitting on popliteal endothelial function in male-dominated studies have been reported. We further explored the relationship between aerobic fitness and sitting-induced impairments in popliteal blood flow and FMD in a more sex-balanced cohort. METHODS: Relative peak oxygen consumption (V̇O2peak) was assessed using a cycling-based incremental test in 21 healthy adults (eight males; 23 ± 2 years; 23.9 ± 2.9 kg/m2). Popliteal blood flow and relative FMD (%) were measured via duplex ultrasonography before and after 3 h of uninterrupted sitting. Pearson correlations were performed separately between V̇O2peak versus pre-sitting and sitting-induced reductions in popliteal outcomes. RESULTS: Aerobic fitness (41.0 ± 9.7 ml/kg/min) was positively correlated with pre-sitting popliteal blood flow (65 ± 23 mL/min; R = 0.59, P = 0.005) and relative FMD (4.2 ± 1.5%; R = 0.49, P = 0.03). As expected, sitting reduced resting blood flow (19 ± 11 mL/min) and FMD (1.9 ± 0.7%) (both, P < 0.001). V̇O2peak was inversely related to sitting-induced declines in blood flow (Δ-46 ± 23 mL/min; R = - 0.71, P < 0.001) and FMD (Δ-2.4 ± 1.5%; R = - 0.51, P = 0.02). CONCLUSIONS: Although higher aerobic fitness was associated with more favorable popliteal endothelial-dependent vasodilator responses, it also corresponded with larger sitting-induced impairments in FMD. This suggests that being more aerobically fit does not protect against sitting-induced vascular endothelial dysfunction. As such, all young adults should minimize habitual prolonged sedentary bouts, regardless of their aerobic fitness level.

A larger low-flow-mediated constrictor response is associated with augmented flow-mediated dilation in the popliteal artery.

In the brachial artery, conflicting evidence exists regarding the relationship between the low-flow-mediated constriction (L-FMC) and subsequent flow-mediated dilation (FMD) responses, which may confound interpretation of the latter. The popliteal artery is a common site for atherosclerotic development, which is preceded by endothelial dysfunction. We aimed to determine whether the magnitude of popliteal L-FMC impacted FMD responses, which is currently unknown. L-FMC and FMD were assessed in the popliteal artery via high-resolution duplex ultrasonography and quantified as the percent change in diameter (from baseline) during ischaemia and in response to hyperaemia, respectively. Using partial correlations and multiple regression analyses, we evaluated the association between popliteal L-FMC on FMD in 110 healthy participants (60 females; 42 ± 22 [19-77] years). All variables univariately associated (p < 0.05) with popliteal relative FMD (relative L-FMC, log-SRAUC , age, systolic blood pressure, diastolic blood pressure, resting shear rate) were inputted into a model that explained 35% of the variance. The reactive hyperaemia stimulus (log-SRAUC : ß = 1.10) and relative L-FMC (ß = -0.39) were the only independent predictors of FMD (both, p < 0.01). Relative L-FMC was negatively correlated to relative FMD, after controlling for the significant univariate predictor variables listed above (R = -0.30; p = 0.002). An augmented (ie healthier) L-FMC response was linked with a larger FMD response as determined by the independent inverse association observed between these shear-stress-mediated measures of vasoreactivity.

The influence of habitual breaks in sedentary time on cardiovagal baroreflex function.

Sedentary time has recently been included in the 24-h activity guidelines. However, the impact of habitual sedentary patterns on autonomic cardiovascular regulation are unclear. We tested the hypothesis that more sedentary time and fewer sedentary breaks were associated with lower cardiovagal baroreflex sensitivity. More frequent sedentary breaks, but not total sedentary time, was independently and positively associated with vagally mediated blood pressure control. Breaking up sedentary time could be more important than total sedentary time for cardiovascular health. Novelty: Breaks in sedentary time is an independent predictor of cardiovagal baroreflex sensitivity, with more frequent breaks associated with better vagally mediated blood pressure regulation.

Efficacy of a Broadly Neutralizing SARS-CoV-2 Ferritin Nanoparticle Vaccine in Nonhuman Primates.

The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine in nonhuman primates (NHPs). High-dose (50 µ g) SpFN vaccine, given twice within a 28 day interval, induced a Th1-biased CD4 T cell helper response and a peak neutralizing antibody geometric mean titer of 52,773 against wild-type virus, with activity against SARS-CoV-1 and minimal decrement against variants of concern. Vaccinated animals mounted an anamnestic response upon high-dose SARS-CoV-2 respiratory challenge that translated into rapid elimination of replicating virus in their upper and lower airways and lung parenchyma. SpFN's potent and broad immunogenicity profile and resulting efficacy in NHPs supports its utility as a candidate platform for SARS-like betacoronaviruses. ONE-SENTENCE SUMMARY: A SARS-CoV-2 Spike protein ferritin nanoparticle vaccine, co-formulated with a liposomal adjuvant, elicits broad neutralizing antibody responses that exceed those observed for other major vaccines and rapidly protects against respiratory infection and disease in the upper and lower airways and lung tissue of nonhuman primates.

Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques.

Emergence of novel variants of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean neutralizing antibody titers of 14,000-21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within four days in 7 of 8 animals receiving 50 µg RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only ∼2-fold relative to USA-WA1. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-like betacoronavirus vaccine development. SIGNIFICANCE STATEMENT: The emergence of SARS-CoV-2 variants of concern (VOC) that reduce the efficacy of current COVID-19 vaccines is a major threat to pandemic control. We evaluate a SARS-CoV-2 Spike receptor-binding domain ferritin nanoparticle protein vaccine (RFN) in a nonhuman primate challenge model that addresses the need for a next-generation, efficacious vaccine with increased pan-SARS breadth of coverage. RFN, adjuvanted with a liposomal-QS21 formulation (ALFQ), elicits humoral and cellular immune responses exceeding those of current vaccines in terms of breadth and potency and protects against high-dose respiratory tract challenge. Neutralization activity against the B.1.351 VOC within two-fold of wild-type virus and against SARS-CoV-1 indicate exceptional breadth. Our results support consideration of RFN for SARS-like betacoronavirus vaccine development.

Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques

Emergence of novel variants of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean neutralizing antibody titers of 14,000-21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within four days in 7 of 8 animals receiving 50 {micro}g RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only [~]2-fold relative to USA-WA1. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-like betacoronavirus vaccine development. Significance StatementThe emergence of SARS-CoV-2 variants of concern (VOC) that reduce the efficacy of current COVID-19 vaccines is a major threat to pandemic control. We evaluate a SARS-CoV-2 Spike receptor-binding domain ferritin nanoparticle protein vaccine (RFN) in a nonhuman primate challenge model that addresses the need for a next-generation, efficacious vaccine with increased pan-SARS breadth of coverage. RFN, adjuvanted with a liposomal-QS21 formulation (ALFQ), elicits humoral and cellular immune responses exceeding those of current vaccines in terms of breadth and potency and protects against high-dose respiratory tract challenge. Neutralization activity against the B.1.351 VOC within two-fold of wild-type virus and against SARS-CoV-1 indicate exceptional breadth. Our results support consideration of RFN for SARS-like betacoronavirus vaccine development.