Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies. METHODS: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete. FINDINGS: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related. INTERPRETATION: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose. FUNDING: Medical Research Council, Blood Cancer UK.

Concordance between clinical and radiographic evaluations of knee osteoarthritis.

BACKGROUND: Significant correlation has been previously demonstrated between radiographic and clinical diagnoses of knee osteoarthritis (OA); however, the specific findings on clinical examination that relate best to a radiographic diagnosis have not been fully elicited. AIMS: We aimed to explore the relationship between clinical symptoms and physical findings with radiographic diagnoses of tibiofemoral and patellofemoral OA. METHODS: This study was based on 409 individuals from the Hertfordshire Cohort Study, born between 1931 and 1939. Antero-posterior and lateral radiographs were taken of both knees. The presence of tibiofemoral and patellofemoral OA was defined according to the Kellgren and Lawrence score. Clinical symptoms, assessed using WOMAC, and physical findings were ascertained by examination. Relationships were assessed using multilevel univariate logistic regression. RESULTS: In the 775 knees studied, the prevalence of physical findings was crepitus (25%), tibiofemoral tenderness (15%), bony swelling (12%), and pain on flexion (10%). Thirty-one percent (n = 238) knees demonstrated tibiofemoral OA, 28% (n = 220) showed patellofemoral OA, and 16% demonstrated OA in both locations. A global clinical symptom score was associated with increased risk of tibiofemoral OA (OR 12.5, 95% CI 5.4-29.0) and patellofemoral OA (OR 5.1, 95% CI 2.3-13.1). On clinical examination, the presence of crepitus, tibiofemoral tenderness, bony swelling, and pain on flexion was associated with increased risk of tibiofemoral OA; however, only tenderness was found to be associated with patellofemoral OA. CONCLUSION: Global clinical symptom score was associated with radiographic tibiofemoral and patellofemoral OA. However, individual clinical signs were more strongly associated with tibiofemoral than patellofemoral OA.

Structural and Functional Changes of the Invariant NKT Clonal Repertoire in Early Rheumatoid Arthritis.

Invariant NKT cells (iNKT) are potent immunoregulatory T cells that recognize CD1d via a semi-invariant TCR (iNKT-TCR). Despite the knowledge of a defective iNKT pool in several autoimmune conditions, including rheumatoid arthritis (RA), a clear understanding of the intrinsic mechanisms, including qualitative and structural changes of the human iNKT repertoire at the earlier stages of autoimmune disease, is lacking. In this study, we compared the structure and function of the iNKT repertoire in early RA patients with age- and gender-matched controls. We analyzed the phenotype and function of the ex vivo iNKT repertoire as well as CD1d Ag presentation, combined with analyses of a large panel of ex vivo sorted iNKT clones. We show that circulating iNKTs were reduced in early RA, and their frequency was inversely correlated to disease activity score 28. Proliferative iNKT responses were defective in early RA, independent of CD1d function. Functional iNKT alterations were associated with a skewed iNKT-TCR repertoire with a selective reduction of high-affinity iNKT clones in early RA. Furthermore, high-affinity iNKTs in early RA exhibited an altered functional Th profile with Th1- or Th2-like phenotype, in treatment-naive and treated patients, respectively, compared with Th0-like Th profiles exhibited by high-affinity iNKTs in controls. To our knowledge, this is the first study to provide a mechanism for the intrinsic qualitative defects of the circulating iNKT clonal repertoire in early RA, demonstrating defects of iNKTs bearing high-affinity TCRs. These defects may contribute to immune dysregulation, and our findings could be exploited for future therapeutic intervention.

Does obesity predict knee pain over fourteen years in women, independently of radiographic changes?

OBJECTIVE: To examine longitudinal patterns in body mass index (BMI) over 14 years and its association with knee pain in the Chingford Study. METHODS: We studied a total of 594 women with BMI data from clinic visits at years (Y) 1, 5, 10, and 15. Knee pain at Y15 was assessed by questionnaire. Associations between BMI over 14 years and knee pain at Y15 were examined using logistic regression. RESULTS: BMI significantly increased from Y1 to Y15 (P < 0.0005) with medians (interquartile ranges) of 24.5 kg/m(2) (22.5-27.2 kg/m(2) ) and 26.5 kg/m(2) (23.9-30.1 kg/m(2) ), respectively. At Y15, 45.1% of subjects had knee pain. A greater BMI at Y1 (odds ratio [OR] 1.34, 95% confidence interval [95% CI] 1.05-1.69), at Y15 (OR 1.34, 95% CI 1.10-1.61), and change in BMI over 15 years (OR 1.40, 95% CI 1.00-1.93) were significant predictors of knee pain at Y15 (P < 0.05). BMI change was associated with bilateral (OR 1.61, 95% CI 1.05-1.76, P = 0.024) but not unilateral knee pain (OR 1.22, 95% CI 0.73-1.76, P = 0.298). The association between BMI change and knee pain was independent of radiographic knee osteoarthritis (OA). The strength of association between BMI and knee pain at Y15 was similar during followup measurements. CONCLUSION: Over 14 years, a higher BMI predicts knee pain at Y15 in women, independently of radiographic knee OA. When adjusted, the association was significant in bilateral, not unilateral, knee pain, suggesting alternative pathologic mechanisms may exist. The longitudinal effect of BMI on knee pain at Y15 is equally important at any time point, which may assist reducing the population burden of knee pain.