The SENIEUR protocol and the efficacy of hepatitis B vaccination in healthy elderly persons by age, gender, and vaccine route.

BACKGROUND: Reduced response to hepatitis B vaccines is associated with aging, confounding and comorbid conditions, as well as inadvertent subcutaneous (SC) inoculation. We hypothesized that the antibody and T cell-mediated immune responses (T-CMI) of elderly adults to a vaccine intended for intramuscular (IM) administration would be attenuated when deposited into SC fat, independent of confounding conditions. RESULTS: Fifty-two healthy, community dwelling elderly adults (65-82 years), seronegative for HBV, were enrolled in the SENIEUR protocol as a strictly healthy population. These seniors were randomized to receive a licensed alum-adjuvanted recombinant HBV vaccine either SC or IM, with the inoculum site verified by imaging. The response rates, defined as hepatitis B surface antibodies (HBsAb) ≥10 IU/L, were significantly lower in the elderly than in young adults, a group of 12, healthy, 21-34-year-old volunteers. Moreover, elderly participants who received the vaccine IM were significantly more likely to be responders than those immunized SC (54% versus 16%, p = 0.008). The low seroconversion rate in the IM group progressively declined with increasing age, and responders had significantly lower HBsAb titers and limited isotype responses. Moreover, T-CMI (proliferation and cytokine production) were significantly reduced in both percentage of responders and intensity of the response for both Th1 and Th2 subsets in the elderly. CONCLUSIONS: Our data demonstrate the blunted immunogenicity of SC inoculation as measured by peak titers and response rates. Further, the qualitative and quantitative deficits in B- and T-CMI responses to primary alum adjuvanted protein antigens persisted even in strictly healthy elderly populations with verified IM placement compared to younger populations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04162223. Registered 14 November 2019. Retrospectively registered.

Exploratory study on oxygen consumption on-kinetics during treadmill walking in women with systemic lupus erythematosus.

OBJECTIVE: To determine whether oxygen consumption (V o(2)) on-kinetics differed between groups of women with systemic lupus erythematosus (SLE) and sedentary but otherwise healthy controls. DESIGN: Exploratory case-control study. SETTING: Medical school exercise physiology laboratory. PARTICIPANTS: Convenience samples of women with SLE (n=12) and sedentary but otherwise healthy controls (n=10). INTERVENTION: None. MAIN OUTCOME MEASURES: V o(2) on-kinetics indices including time to steady state, rate constant, mean response time (MRT), transition constant, and oxygen deficit measured during bouts of treadmill walking at intensities of 3 and 5 metabolic equivalents (METs). RESULTS: Time to steady state and oxygen deficit were increased and rate constant was decreased in the women with SLE compared with controls. At the 5-MET energy demand, the transition constant was lower and MRT was longer in the women with SLE than in controls. For a similar relative energy expenditure that was slightly lower than the anaerobic threshold, the transition constant was higher in controls than in women with SLE. CONCLUSION: V o(2) on-kinetics was prolonged in women with SLE. The prolongation was concomitant with an increase in oxygen deficit and may underlie performance fatigability in women with SLE.

Innate immune responses in lupus-prone Palmerston North mice: differential responses to LPS and bacterial DNA/CpG oligonucleotides.

Inadequate immune response to infectious danger may contribute to the pathogenesis of systemic autoimmune diseases, e.g., systemic lupus erythematosus. To test this hypothesis, we studied innate responses of prediseased lupus-prone Palmerston North (PN) mice to lipopolysaccharide (LPS), bacterial DNA, and synthetic CpG oligonucleotides. LPS and bacterial DNA/CpG oligodeoxyribonucleotides (ODNs) drove PN splenocytes into the cell cycle and protected B cells against spontaneous apoptosis, as in control lupus-free DBA-1 mice. LPS induced significantly higher IL-6 production in PN than in control splenocytes. In contrast, in PN splenocytes bacterial DNA and CpG ODNs induced approximately four- to sixfold lower IL-12p40 and approximately twofold lower IL-6 secretion than controls. This reduction in cytokine secretion in PN mice was not due to delayed kinetics but was related to significantly higher constitutive and CpG-inducible IL-10 secretion. Neutralizing anti-IL-10 antibodies almost completely restored PN IL-6 and IL-12p40 secretion to DBA-1 levels, whereas exogenous IL-10 inhibited in vitro IL-6 and IL-12p40 production in DBA-1 mice. Importantly, treatment with either IL-10 or anti-IL-10 antibody did not modulate CpG-induced cell cycle entry and apoptosis protection in either strain. In conclusion, lupus-prone PN mice show abnormal innate responses through their pattern-recognition TLR9 receptors, characterized by higher inducible IL-10 and lower IL-12p40 and IL-6 secretion, thus implying that response to infectious danger in PN mice is inappropriate and may be linked to lupus pathogenesis.

Evidence for aerobic insufficiency in women with systemic Lupus erythematosus.

OBJECTIVE: To determine if fatigue is associated with diminished aerobic capacity in women with systemic lupus erythematosus (SLE). METHODS: Eighteen women (age 35 +/- 9 years) with mild SLE (Systemic Lupus Activity Measure = 3.1 +/- 2.1) and 16 healthy but sedentary controls (age 38 +/- 8 years) completed peak treadmill exercise tests to determine aerobic capacity and Fatigue Severity Scales to quantify the severity of fatigue. Measures of oxygen consumption (VO(2)) were recorded during the treadmill tests. RESULTS: Peak VO(2) was lower in patients with SLE (19.2 +/- 4.4 ml/kg/minute) as compared with controls (27.4 +/- 4.7 ml/kg/minute) and expected values (30.7 +/- 3.1 ml/kg/minute; P < 0.0006 versus controls and P < 0.0001 versus expected). Functional aerobic impairment was observed in 14 of the 18 patients with SLE. In patients with SLE, ventilatory threshold, a marker for the onset of lactic acidemia, was observed at the lowest energy requirement for instrumental activities of daily living. Peak VO(2) in the patients with SLE was similar to the highest energy requirements for instrumental activities of daily living, leaving little or no reserve for more intense occupational and recreational activities. Peak VO(2) was significantly higher (P < 0.0001) than the activity of daily living requirements in controls, providing a substantial energy reserve. Fatigue severity score (FSS) was 5.0 +/- 1.4 in patients with SLE, with 14 of the 18 patients having scores above 4.0, a score indicating that fatigue severity limited physical activity. Of the 14, 12 had functional aerobic impairment. An FSS of greater than 4.0 was not observed in controls (mean = 2.5 +/- 0.7). CONCLUSION: In women with SLE, aerobic capacity was diminished to levels that were insufficient for engaging in activities of daily living and below those expected to result from physiologic deconditioning. This functional aerobic impairment was strongly correlated with the perception of severe, activity-limiting fatigue.