Impact of Vaccination, Prior Infection, and Therapy on Delta and Omicron Variants

We studied 249,070 patients who were tested for SARS-CoV-2 in the Cleveland Clinic Health System between October 1, 2021 and January 31, 2022. We found that vaccination, especially with recent boosting, was more effective than prior infection and monoclonal antibody therapy against both the delta and omicron variants. Vaccination and prior infection were much less effective against infection with the omicron variant than with the delta variant, but the opposite was true of death after infection. Boosting greatly increased the effectiveness of the two mRNA vaccines against both infection and death, although its effects waned markedly after 6 months. In addition, monoclonal antibody therapy was notably less effective at preventing death from the omicron variant than from the delta variant. Finally, the relatively low mortality of the omicron variant was due to both the reduced lethality of this variant and the increased population immunity acquired from booster vaccination and previous infection.

Reliably Assessing Duration of Protection for COVID-19 Vaccines

Decision-making about booster dosing for COVID-19 vaccine recipients hinges on reliable methods for evaluating the longevity of vaccine protection. We show that modeling of protection as a piecewise linear function of time since vaccination for the log hazard ratio of the vaccine effect provides more reliable estimates of vaccine effectiveness at the end of an observation period and also more reliably detects plateaus in protective effectiveness as compared with the traditional method of estimating a constant vaccine effect over each time period. This approach will be useful for analyzing data pertaining to COVID-19 vaccines and other vaccines where rapid and reliable understanding of vaccine effectiveness over time is desired.

Effectiveness of Covid-19 Vaccines in the United States Over 9 Months: Surveillance Data from the State of North Carolina

BackgroundThe duration of protection afforded by Covid-19 vaccines in the United States is unclear. Whether the recent increase of breakthrough infections was caused by waning immunity to the primary vaccination or by emergence of new variants that are more highly transmissible is also unknown. MethodsWe extracted data on vaccination histories and clinical outcomes (Covid-19, hospitalization, death) for the period from December 13, 2020 through September 8, 2021 by linking data from the North Carolina COVID-19 Surveillance System and COVID-19 Vaccine Management System covering [~]10.6 million residents statewide. We used the Kaplan-Meier method to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Janssen) vaccines in reducing the incidence of Covid-19 over successive post-vaccination time periods, producing separate estimates for individuals vaccinated during different calendar periods. In addition, we used Cox regression with time-dependent vaccination status and time-varying hazard ratios to estimate the effectiveness of the three vaccines in reducing the hazard rates or current risks of Covid-19, hospitalization, and death, as a function of time elapsed since the first dose. ResultsFor the Pfizer two-dose regimen, vaccine effectiveness in reducing the current risk of Covid-19 ramps to a peak level of 94.9% (95% confidence interval [CI], 94.5 to 95.2) at 2 months (post the first dose) and drops to 70.1% (95% CI, 68.9 to 71.2) after 7 months; effectiveness in reducing the current risk of hospitalization ramps to a peak level of 96.4% (95% CI, 94.7 to 97.5) at 2 months and remains at 87.7% (95% CI, 84.3 to 90.4) at 7 months; effectiveness in reducing the current risk of death ramps to 95.9% (95% CI, 92.9 to 97.6) at 2 months and is maintained at 88.4% (95% CI, 83.0 to 92.1) at 7 months. For the Moderna two-dose regimen, vaccine effectiveness in reducing the current risk of Covid-19 ramps to a peak level of 96.0% (95% CI, 95.6 to 96.4) at 2 months and drops to 81.9% (95% CI, 81.0 to 82.7) after 7 months; effectiveness in reducing the current risk of hospitalization ramps to a peak level of 97.5% (95% CI, 96.3 to 98.3) at 2 months and remains at 92.3% (95% CI, 89.7 to 94.3) at 7 months; effectiveness in reducing the current risk of death ramps to 96.0% (95% CI, 91.9 to 98.0) at 3 months and remains at 93.7% (95% CI, 90.2 to 95.9) at 7 months. For the Janssen one-dose regimen, effectiveness in reducing the current risk of Covid-19 ramps to a peak level of 79.0% (95% CI, 77.1 to 80.7) at 1 month and drops to 64.3% (95% CI, 62.3 to 66.1) after 5 months; effectiveness in reducing the current risk of hospitalization ramps to a peak level of 89.8% (95% CI, 78.8 to 95.1) at 2 months and stays above 80% through 5 months; effectiveness in reducing the current risk of death ramps to 89.4% (95% CI, 52.3 to 97.6) at 3 months and stays above 80% through 5 months. For all three vaccines, the ramping and waning patterns are similar for individuals who were vaccinated at different dates, and across various demographic subgroups (age, sex, race/ethnicity, geographic region, county-level vaccination rate). ConclusionsThe two mRNA vaccines are remarkably effective and durable in reducing the risks of hospitalization and death. The Janssen vaccine also offers a high level of protection against hospitalization and death. The Moderna vaccine is significantly more durable than the Pfizer vaccine in reducing the risk of Covid-19. Waning vaccine effectiveness is caused primarily by declining immunity rather than emergence of new variants. It would be worthwhile to investigate the effectiveness of the Janssen vaccine as a two-dose regimen, with the second dose given approximately 1-2 months after the first dose.

Evaluating Vaccine Efficacy Against SARS-CoV-2 Infection

Although interim results from several large placebo-controlled phase 3 trials demonstrated high vaccine efficacy (VE) against symptomatic COVID-19, it is unknown how effective the vaccines are in preventing people from becoming asymptomatically infected and potentially spreading the virus unwittingly. It is more difficult to evaluate VE against SARS-CoV-2 infection than against symptomatic COVID-19 because infection is not observed directly but rather is known to occur between two antibody or RT-PCR tests. Additional challenges arise as community transmission changes over time and as participants are vaccinated on different dates because of staggered enrollment or crossover before the end of the study. Here, we provide valid and efficient statistical methods for estimating potentially waning VE against SARS-CoV-2 infection with blood or nasal samples under time-varying community transmission, staggered enrollment, and blinded or unblinded crossover. We demonstrate the usefulness of the proposed methods through numerical studies mimicking the BNT162b2 phase 3 trial and the Prevent COVID U study. In addition, we assess how crossover and the frequency of diagnostic tests affect the precision of VE estimates. SummaryWe show how to estimate potentially waning efficacy of COVID-19 vaccines against SARS-CoV-2 infection using blood or nasal samples collected periodically from clinical trials with staggered enrollment of participants and crossover of placebo recipients.

Evaluating the Long-Term Efficacy of COVID-19 Vaccines

Large-scale deployment of safe and durably effective vaccines can curtail the COVID-19 pandemic.1-3 However, the high vaccine efficacy (VE) reported by ongoing phase 3 placebo-controlled clinical trials is based on a median follow-up time of only about two months4-5 and thus does not pertain to long-term efficacy. To evaluate the duration of protection while allowing trial participants timely access to efficacious vaccine, investigators can sequentially cross participants over from the placebo arm to the vaccine arm according to priority groups. Here, we show how to estimate potentially time-varying placebo-controlled VE in this type of staggered vaccination of participants. In addition, we compare the performance of blinded and unblinded crossover designs in estimating long-term VE. Authors InformationDan-Yu Lin, Ph.D., is Dennis Gillings Distinguished Professor of Biostatistics, and Donglin Zeng, Ph.D., is Professor of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599-7420, USA. Peter B. Gilbert, Ph.D., is Member, Vaccine and Infectious Disease Division, Fred Hutch, Seattle, WA 98109-1024, USA. SummaryWe show how to estimate the potentially waning long-term efficacy of COVID-19 vaccines using data from randomized, placebo-controlled clinical trials with staggered enrollment of participants and sequential crossover of placebo recipients.

α-Synuclein induced mitochondrial dysfunction via cytochrome c oxidase subunit 2 in SH-SY5Y cells.

The transfer of misfolded α-Synuclein (α-Syn) from cell to cell as a prion protein is important in α-Synucleinopathies. Extraneous α-Syn induces apoptosis of dopaminergic neurons by causing mitochondrial dysfunction. However, the mechanism by which α-Syn disrupts the mitochondrial function is still unclear. In the present study, we used a gene microarray and western blotting analysis to show that the expression of mitochondrially encoded cytochrome c oxidase subunit 2 (MT-CO2, COXII) increased significantly in SH-SY5Y cells stimulated by α-Syn for 24 h. Furthermore, the decline in ATP levels, the decreased mitochondrial membrane potential, and the enhanced reactive oxygen species in cells treated by α-Syn was reversed by inhibiting MT-CO2 gene expression. Subsequently, we observed that upregulation of MT-CO2 contributed to the release of cytochrome c and altered the levels of certain mitochondria-localized proteins, such as BCL2 family proteins. Therefore, we hypothesized that after being transferred into dopaminergic neurons, α-Syn injures mitochondria via activating MT-CO2. Our results suggested the initial step of the process by which α-Syn injures dopaminergic neurons and provides new therapeutic targets for α-Syn associated neurodegenerative disorders.

The rehabilitation effects of Si tactic of breathing exercises for stable patients with chronic obstructive pulmonary disease / 中国实用护理杂志

Objective To discuss Si tactic of breathing exercises on the rehabilitation of lung function, dyspnea, distance of 6-minute walk distance (6MWD), respiratory muscle endurance and quality of life in stable patients with chronic obstructive pulmonary disease (COPD). Methods 63 patients with COPD were divided into experimental group with 31 cases and control group with 32 cases according to random digital table method. The experimental group were given routine treatment and nursing care, take Si tactic of breathing exercises. The control group were given routine treatment and nursing care only. Both groups were given treatment for 4 months. The indexes of lung function (FEV1, FEV1%, FEV1/FVC), scores of the Modified Medical Research Council Scale (MMRC), 6MWD, scores of Saint-George′s Respiratory Questionnaire (SGRQ), maximal voluntary ventilation (MVV) changes before and after the therapy were measured. Results After intervention, the lung function as measured by FEV1, MVV, 6MWD showed a significant improvement in the experimental group, and was higher than that in the control group[(1.42±0.43) L vs.(1.22±0.32) L and(1.21±0.45) L,(52.39±14.21) L vs.(47.20±14.59) L and (43.65±11.89) L, (288.36±71.70) m vs.(244.42±71.50) m and (250.56 ±79.25) m, P<0.05]; MMRC scores, SGRQ scores, activities and daily life part score were lower after intervention and was lower than that in the control group [(2.63 ±1.00) points vs. (3.21 ±0.92) points and (3.14±1.12) points, (44.38±5.23) points vs. (54.74±5.73) points and (52.87±5.49) points, (41.25± 6.03) pints vs.(66.48±6.38) points and (64.13±5.34) points, (28.00±7.34) points vs. (44.87±4.86) points and (42.31 ±9.12) points, P<0.05]. Conclusions For COPD patients in stable stage, Si tactic of breathing exercises can improve the pulmonary function and alleviate dyspnea, enhance exercise endurance and respiratory endurance, thereby improve the quality of life of patients, so this is one of the method for comprehensive pulmonary rehabilitation in the future.