Most COVID-19 vaccines require two doses, however with limited vaccine supply, policymakers are considering single-dose vaccination as an alternative strategy. Using a mathematical model combined ...with optimization algorithms, we determined optimal allocation strategies with one and two doses of vaccine under various degrees of viral transmission. Under low transmission, we show that the optimal allocation of vaccine vitally depends on the single-dose efficacy. With high single-dose efficacy, single-dose vaccination is optimal, preventing up to 22% more deaths than a strategy prioritizing two-dose vaccination for older adults. With low or moderate single-dose efficacy, mixed vaccination campaigns with complete coverage of older adults are optimal. However, with modest or high transmission, vaccinating older adults first with two doses is best, preventing up to 41% more deaths than a single-dose vaccination given across all adult populations. Our work suggests that it is imperative to determine the efficacy and durability of single-dose vaccines, as mixed or single-dose vaccination campaigns may have the potential to contain the pandemic much more quickly.
The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the ...United States, Chile, and Peru has not been known.
In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru.
A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval CI, 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose.
AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).
Malaria is a potentially life-threatening disease caused by Plasmodium protozoa transmitted by infected Anopheles mosquitoes. Controlled human malaria infection (CHMI) trials are used to assess the ...efficacy of interventions for malaria elimination. The operating characteristics of statistical methods for assessing the ability of interventions to protect individuals from malaria is uncertain in small CHMI studies. This paper presents simulation studies comparing the performance of a variety of statistical methods for assessing efficacy of intervention in CHMI trials.
Two types of CHMI designs were investigated: the commonly used single high-dose design (SHD) and the repeated low-dose design (RLD), motivated by simian immunodeficiency virus (SIV) challenge studies. In the context of SHD, the primary efficacy endpoint is typically time to infection. Using a continuous time survival model, five statistical tests for assessing the extent to which an intervention confers partial or full protection under single dose CHMI designs were evaluated. For RLD, the primary efficacy endpoint is typically the binary infection status after a specific number of challenges. A discrete time survival model was used to study the characteristics of RLD versus SHD challenge studies.
In a SHD study with the continuous time survival model, log-rank test and t-test are the most powerful and provide more interpretable results than Wilcoxon rank-sum tests and Lachenbruch tests, while the likelihood ratio test is uniformly most powerful but requires knowledge of the underlying probability model. In the discrete time survival model setting, SHDs are more powerful for assessing the efficacy of an intervention to prevent infection than RLDs. However, additional information can be inferred from RLD challenge designs, particularly using a likelihood ratio test.
Different statistical methods can be used to analyze controlled human malaria infection (CHMI) experiments, and the choice of method depends on the specific characteristics of the experiment, such as the sample size allocation between the control and intervention groups, and the nature of the intervention. The simulation results provide guidance for the trade off in statistical power when choosing between different statistical methods and study designs.
Immunoassays for determining past SARS-CoV-2 infection have not been systematically evaluated in vaccinated persons in comparison with unvaccinated persons.
To evaluate antinucleocapsid antibody ...(anti-N Ab) seropositivity in mRNA-1273 (Moderna) vaccinees with breakthrough SARS-CoV-2 infection.
Nested substudy of a phase 3 randomized, double-blind, placebo-controlled vaccine efficacy trial. (ClinicalTrials.gov: NCT04470427).
99 sites in the United States, July 2020 through March 2021.
Participants were aged 18 years or older, had no known history of SARS-CoV-2 infection, and were at risk for SARS-CoV-2 infection or severe COVID-19. Substudy participants were diagnosed with SARS-CoV-2 infection during the trial's blinded phase.
2 mRNA-1273 or placebo injections 28 days apart.
Nasopharyngeal swabs from days 1 and 29 (vaccination days) and from symptom-prompted illness visits were tested for SARS-CoV-2 via polymerase chain reaction (PCR). Serum samples from days 1, 29, and 57 and the participant decision visit (PDV, when participants were informed of treatment assignment; median day 149) were tested for anti-N Abs by the Elecsys immunoassay.
Among 812 participants with PCR-confirmed COVID-19 illness during the blinded phase of the trial (through March 2021), seroconversion to anti-N Abs (median of 53 days after diagnosis) occurred in 21 of 52 mRNA-1273 vaccinees (40% 95% CI, 27% to 54%) versus 605 of 648 placebo recipients (93% CI, 92% to 95%). Each 1-log increase in SARS-CoV-2 viral copies at diagnosis was associated with 90% higher odds of anti-N Ab seroconversion (odds ratio, 1.90 CI, 1.59 to 2.28).
The scope was restricted to mRNA-1273 vaccinees and the Elecsys assay, the sample size was small, data on Delta and Omicron infections were lacking, and the analysis did not address a prespecified objective of the trial.
Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing.
National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
Abstract
Coronavirus disease 2019 (COVID-19) vaccines are highly efficacious at preventing symptomatic infection, severe disease, and death. Most of the evidence that COVID-19 vaccines also reduce ...transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is based on retrospective, observational studies. Specifically, an increasing number of studies are evaluating vaccine effectiveness against the secondary attack rate of SARS-CoV-2 using data available in existing health-care databases or contact-tracing databases. Since these types of databases were designed for clinical diagnosis or management of COVID-19, they are limited in their ability to provide accurate information on infection, infection timing, and transmission events. We highlight challenges with using existing databases to identify transmission units and confirm potential SARS-CoV-2 transmission events. We discuss the impact of common diagnostic testing strategies, including event-prompted and infrequent testing, and illustrate their potential biases in estimating vaccine effectiveness against the secondary attack rate of SARS-CoV-2. We articulate the need for prospective observational studies of vaccine effectiveness against the SARS-CoV-2 secondary attack rate, and we provide design and reporting considerations for studies using retrospective databases.
Research methods for biomarker evaluation lag behind those for evaluating therapeutic treatments. Although a phased approach to development of biomarkers exists and guidelines are available for ...reporting study results, a coherent and comprehensive set of guidelines for study design has not been delineated. We describe a nested case–control study design that involves prospective collection of specimens before outcome ascertainment from a study cohort that is relevant to the clinical application. The biomarker is assayed in a blinded fashion on specimens from randomly selected case patients and control subjects in the study cohort. We separately describe aspects of the design that relate to the clinical context, biomarker performance criteria, the biomarker test, and study size. The design can be applied to studies of biomarkers intended for use in disease diagnosis, screening, or prognosis. Common biases that pervade the biomarker research literature would be eliminated if these rigorous standards were followed.
Several vaccine candidates to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19) have entered or will soon enter ...large-scale, phase 3, placebo-controlled randomized clinical trials. To facilitate harmonized evaluation and comparison of the efficacy of these vaccines, a general set of clinical endpoints is proposed, along with considerations to guide the selection of the primary endpoints on the basis of clinical and statistical reasoning. The plausibility that vaccine protection against symptomatic COVID-19 could be accompanied by a shift toward more SARS-CoV-2 infections that are asymptomatic is highlighted, as well as the potential implications of such a shift.
The recent epidemiologic and clinical literature is filled with studies evaluating statistical models for predicting disease or some other adverse event. Risk stratification tables are a new way to ...evaluate the benefit of adding a new risk marker to a risk prediction model that includes an established set of markers. This approach involves cross-tabulating risk predictions from models with and without the new marker. In this article, the authors use examples to show how risk stratification tables can be used to compare 3 important measures of model performance between the models with and those without the new marker: the extent to which the risks calculated from the models reflect the actual fraction of persons in the population with events (calibration); the proportions in which the population is stratified into clinically relevant risk categories (stratification capacity); and the extent to which participants with events are assigned to high-risk categories and those without events are assigned to low-risk categories (classification accuracy). They detail common misinterpretations and misuses of the risk stratification method and conclude that the information that can be extracted from risk stratification tables is an enormous improvement over commonly reported measures of risk prediction model performance (for example, c-statistics and Hosmer-Lemeshow tests) because it describes the value of the models for guiding medical decisions.
Trial results for two COVID-19 vaccines suggest at least 90% efficacy against symptomatic disease (VE
). It remains unknown whether this efficacy is mediated by lowering SARS-CoV-2 infection ...susceptibility (VE
) or development of symptoms after infection (VE
). We aim to assess and compare the population impact of vaccines with different efficacy profiles (VE
and VE
) satisfying licensure criteria. We developed a mathematical model of SARS-CoV-2 transmission, calibrated to data from King County, Washington. Rollout scenarios starting December 2020 were simulated with combinations of VE
and VE
resulting in up to 100% VE
. We assumed no reduction of infectivity upon infection conditional on presence of symptoms. Proportions of cumulative infections, hospitalizations and deaths prevented over 1 year from vaccination start are reported. Rollouts of 1 M vaccinations (5000 daily) using vaccines with 50% VE
are projected to prevent 23-46% of infections and 31-46% of deaths over 1 year. In comparison, vaccines with 90% VE
are projected to prevent 37-64% of infections and 46-64% of deaths over 1 year. In both cases, there is a greater reduction if VE
is mediated mostly by VE
. The use of a "symptom reducing" vaccine will require twice as many people vaccinated than a "susceptibility reducing" vaccine with the same 90% VE
to prevent 50% of the infections and death over 1 year. Delaying the start of the vaccination by 3 months decreases the expected population impact by more than 50%. Vaccines which prevent COVID-19 disease but not SARS-CoV-2 infection, and thereby shift symptomatic infections to asymptomatic infections, will prevent fewer infections and require larger and faster vaccination rollouts to have population impact, compared to vaccines that reduce susceptibility to infection. If uncontrolled transmission across the U.S. continues, then expected vaccination in Spring 2021 will provide only limited benefit.
Markers that predict treatment effect have the potential to improve patient outcomes. For example, the OncotypeDX® RecurrenceScore® has some ability to predict the benefit of adjuvant chemotherapy ...over and above hormone therapy for the treatment of estrogen‐receptor‐positive breast cancer, facilitating the provision of chemotherapy to women most likely to benefit from it. Given that the score was originally developed for predicting outcome given hormone therapy alone, it is of interest to develop alternative combinations of the genes comprising the score that are optimized for treatment selection. However, most methodology for combining markers is useful when predicting outcome under a single treatment. We propose a method for combining markers for treatment selection which requires modeling the treatment effect as a function of markers. Multiple models of treatment effect are fit iteratively by upweighting or “boosting” subjects potentially misclassified according to treatment benefit at the previous stage. The boosting approach is compared to existing methods in a simulation study based on the change in expected outcome under marker‐based treatment. The approach improves upon methods in some settings and has comparable performance in others. Our simulation study also provides insights as to the relative merits of the existing methods. Application of the boosting approach to the breast cancer data, using scaled versions of the original markers, produces marker combinations that may have improved performance for treatment selection.
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