In a large Veterans Affairs cohort, heterologous boosters in adenoviral-vector–primed participants were more effective at preventing Covid-19 than homologous boosters. Among mRNA-primed participants, ...no significant differences in protection were noted between those receiving homologous or heterologous boosters.
The SARS-CoV-2 Omicron variant is thought to cause less severe disease among the general population, but disease severity among at-risk populations is unknown. We performed a retrospective analysis ...using a matched cohort of United States veterans to compare the disease severity of subjects infected during Omicron and Delta predominant periods within 14 days of initial diagnosis. We identified 22,841 matched pairs for both periods. During the Omicron period, 20,681 (90.5%) veterans had mild, 1308 (5.7%) moderate, and 852 (3.7%) severe disease. During the Delta predominant period, 19,356 (84.7%) had mild, 1467 (6.4%) moderate, and 2018 (8.8%) severe disease. Moderate or severe disease was less likely during the Omicron period and more common among older subjects and those with more comorbidities. Here we show that infection with the Omicron variant is associated with less severe disease than the Delta variant in a high-risk older veteran population, and vaccinations provide protection against severe or critical disease.
The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may be less effective against the Omicron variant than against earlier variants. With recent resurgence of SARS-CoV-2 ...cases, the role of booster doses of the vaccine needs to be highlighted.
Using a retrospective cohort study design emulating a target trial, we determined the relative vaccine effectiveness (RVE) of a homologous booster dose of a SARS-CoV-2 messenger RNA (mRNA) vaccine compared with the primary vaccine series alone in preventing infection, hospitalization, and intensive care unit admission, and death in the Department of Veterans Affairs healthcare system in the United States. Among infection-free survivors who received 2 doses of a mRNA vaccine before 30 April 2021, we identified those who received a booster between 22 September and 25 December 2021 and matched them 1:1 with individuals who did not receive a booster.
Among 2 384 272 previously uninfected persons with 2 doses of an mRNA vaccine by 30 April 2021, we identified 462 950 booster recipients between 22 September and 25 December 2021, who were matched 1:1 with non-booster recipients. The RVE (95% confidence interval) was 19% (17%-22%) for confirmed infection, 52% (46%-57%) for hospitalization, and 83% (65%-92%) for intensive care unit admission or death. Recipients of the mRNA-1273 vaccine had a lower cumulative incidence of infections and hospitalizations than recipients of the BNT162b2 vaccine (log-rank P <.001 for both comparisons).
While the RVE of SARS-CoV-2 mRNA booster vaccine dose in preventing infection against the Omicron variant is low, it is substantial in preventing hospitalization and high in preventing the most severe/critical disease.
Abstract
Background
Knowledge of the vaccine effectiveness (VE) of a third or booster vaccine dose in preventing SARS-CoV-2 infection or its consequences is critical in developing recommendations for ...their use. We determined relative VE of 3 vs 2 doses of an mRNA vaccine in preventing symptomatic SARS-CoV-2 infection, hospitalization, and severe/critical disease.
Methods
Among veterans who had received 2 doses of an mRNA vaccine by 30 April 2021, we identified those who received a third dose of the same vaccine between 22 September and 24 November 2021 and 1:1 matched controls who had not received their third dose by then. Using Cox proportional hazards model, we calculated adjusted hazards ratios for symptomatic infection, hospitalization, and intensive care unit (ICU) admission or death after SARS-CoV-2–positive test.
Results
Among 2 321 366 veterans who received 2 doses of Pfizer BNT-162b2 or Moderna mRNA-1273 vaccine by 30 April 2021, we matched 395 686 persons who received a third dose of the same vaccine between 22 September and 24 November 2021 to controls who did not receive a third dose. Adjusted HRs (95% CI) were .15 (.11–.21) for symptomatic infection and .18 (.13–.26) for hospitalizations for 3 vs 2 doses, corresponding to relative VE of 85% and 82%. Five ICU admissions or deaths were observed (4 among recipients of 2 doses). There was no difference in VE between BNT162b2 versus mRNA-1273 recipients.
Conclusions
A third dose of a SARS-CoV-2 mRNA vaccine is associated with high VE against symptomatic infection, hospitalization, and critical disease in the pre-Omicron era.
In this large national study of 395 686 Veterans who received 3 vs. 2 doses of an mRNA vaccine in the pre-Omicron era, vaccine effectiveness of 3 doses was 85% in preventing symptomatic infection and 82% in preventing acute care hospitalizations.
Abstract
Background
Persons on chronic hemodialysis have a significantly diminished humoral immune response to SARS-CoV-2 vaccines. Whether this translates to reduced vaccine effectiveness (VE) is ...unknown.
Methods
We used the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify all veterans who were tested for SARS-CoV-2 between 26 January and 31 August 2021. Using International Classification of Diseases, 10th edition, codes and attendance at a dialysis clinic/center, we identified those who were on chronic hemodialysis. We used a test-negative, case-control design using a doubly robust logistic regression model to determine the VE of the BNT-162b2 (Pfizer) or mRNA-1273 (Moderna) vaccines in preventing confirmed SARS-CoV-2 infection.
Results
Among 847 199 veterans tested for SARS-CoV-2 between 26 January and 31 August 2021, there were 6076 veterans on chronic hemodialysis. Among those, we identified 1270 cases (580 fully vaccinated) and 2959 controls (2120 fully vaccinated). The overall VE >14 days after the second dose in preventing documented infection was 68.2% (95% CI: 62.6–72.9%). VE was 68.9% (95% CI: 61.9–74.7%) for Pfizer BNT-162b2 and 66.7% (95% CI: 58.9–73.0%) for Moderna mRNA-1273 vaccine. There was no difference in VE by age (<70 vs >70 years), race, or sex. There were no events recorded in persons with a Charlson’s comorbidity index score <2.
Conclusions
VE of 2 doses of current mRNA vaccines in preventing SARS-CoV-2 infection in persons on chronic hemodialysis is lower than historic VE rates in the general population. Effects of additional doses in improving VE in this special population need further study.
Vaccine effectiveness for the currently available mRNA vaccines >14 days after the second dose was 68.2%. The effectiveness was 68.9% for the Pfizer BNT-162b2 and 66.7% for the Moderna mRNA-1273 vaccine.
Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often ...deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care.
Sepsis is life-threatening organ dysfunction due to dysregulated response to infection. Patients with sepsis exhibit wide heterogeneity stemming from genetic, molecular, and clinical factors as well ...as differences in pathogens, creating challenges for the development of effective treatments. Several gaps in knowledge also contribute: (i) biomarkers that identify patients likely to benefit from specific treatments are unknown; (ii) therapeutic dose and duration is often poorly understood; and (iii) short-term mortality, a common outcome measure, is frequently criticized for being insensitive. To date, the majority of sepsis trials use traditional design features, and have largely failed to identify new treatments with incremental benefit over standard of care. Traditional trials are also frequently conducted as part of a drug evaluation process that is segmented into several phases, each requiring separate trials, with a long time delay from inception through design and execution to incorporation of results into clinical practice. By contrast, adaptive clinical trial designs facilitate the evaluation of several candidate treatments simultaneously, learn from emergent discoveries during the course of the trial, and can be structured efficiently to lead to more timely conclusions compared to traditional trial designs. Adoption of new treatments in clinical practice can be accelerated if these trials are incorporated in electronic health records as part of a learning health system. In this review, we discuss challenges in the evaluation of treatments for sepsis, and explore potential benefits and weaknesses of recent advances in adaptive trial methodologies to address these challenges.
Abstract
Background
Clinical benefit of molnupiravir (MPV) in coronavirus disease 2019 (COVID-19)–infected subpopulations is unclear.
Methods
We used a matched cohort study design to determine the ...rate of hospitalization or death within 30 days of COVID-19 diagnosis among MPV treated and untreated controls. Participants were nonhospitalized, previously uninfected Veterans with a first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection between 1 January and 31 August 2022, who were prescribed MPV within 3 days of COVID-19 diagnosis, and matched individuals who were not prescribed MPV.
Results
Among 1459 matched pairs, the incidence of hospitalization/death was not different among MPV treated versus untreated controls (48 vs 44 cases; absolute risk difference ARD, 0.27; 95% confidence interval CI, −.94 to 1.49). No benefit was observed among those >60 or ≤60 years old (ARD, 0.27; 95% CI, −1.25 to 1.79 vs ARD, −0.29; 95% CI, −1.22 to 1.80), those with specific comorbidities, or by vaccination status. A significant benefit was observed in asymptomatic but not in symptomatic persons (ARD, −2.80; 95% CI, −4.74 to −.87 vs ARD, 1.12; 95% CI −.31 to 2.55). Kaplan-Meier curves did not show a difference in proportion of persons who were hospitalized or died among MPV treated compared with untreated controls (logrank P = .7).
Conclusions
MPV was not associated with a reduction in hospitalization or death within 30 days of COVID-19 diagnosis. A subgroup of patients presenting without symptoms experienced a benefit.
In previously uninfected, nonhospitalized, high-risk persons with COVID-19, molnupiravir use is not associated with a significant reduction in hospitalization or death within 30 days of COVID-19 diagnosis. A subgroup of patients presenting without symptoms might experience a benefit.
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