A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for ...about 390 million infections annually. Protective efficacy results for the most advanced dengue vaccine candidate (CYD) were disappointing despite its ability to induce neutralizing antibodies against all four dengue virus (DENV) serotypes. TV003 is a live attenuated tetravalent DENV vaccine currently in phase 2 evaluation. To better assess the protective efficacy of TV003, a randomized double-blind, placebo-controlled trial in which recipients of TV003 or placebo were challenged 6 months later with a DENV-2 strain, rDEN2Δ30, was conducted. The primary endpoint of the trial was protection against dengue infection, defined as rDEN2Δ30 viremia. Secondary endpoints were protection against rash and neutropenia. All 21 recipients of TV003 who were challenged with rDEN2Δ30 were protected from infection with rDEN2Δ30. None developed viremia, rash, or neutropenia after challenge. In contrast, 100% of the 20 placebo recipients who were challenged with rDEN2Δ30 developed viremia, 80% developed rash, and 20% developed neutropenia. TV003 induced complete protection against challenge with rDEN2Δ30 administered 6 months after vaccination. TV003 will be further evaluated in dengue-endemic areas. The controlled dengue human challenge model can accelerate vaccine development by evaluating the protection afforded by the vaccine, thereby eliminating poor candidates from further consideration before the initiation of large efficacy trials.
In response to the Ebola outbreak of 2014-2016, the US Office of the Assistant Secretary for Preparedness and Response (ASPR) established 10 regional treatment centers, called biocontainment units ...(BCUs), to prepare and provide care for patients infected with high-consequence pathogens. Many of these BCUs were among the first units to activate for coronavirus disease 2019 (COVID-19) patient care. The activities of the Johns Hopkins BCU helped prepare the Johns Hopkins Health System for COVID-19 in the 3 domains of containment care: (1) preparedness planning, education and training, (2) patient care and unit operations, and (3) research and innovation. Here, we describe the role of the JH BCU in the Hopkins COVID-19 response to illustrate the value of BCUs in the current pandemic and their potential role in preparing healthcare facilities and health systems for future infectious disease threats.
Background. Dengue virus (DENV) causes hundreds of millions of infections annually. Four dengue serotypes exist, and previous infection with one serotype increases the likelihood of severe disease ...with a second, heterotypic DENV infection. Methods. In a randomized, placebo-controlled study, the safety and immunogenicity of 4 different admixtures of a live attenuated tetravalent (LATV) dengue vaccine were evaluated in 113 flavivirus-naive adults. Serum neutralizing antibody levels to all 4 dengue viruses were measured on days 0, 28, 42, and 180. Results. A single dose of each LATV admixture induced a trivalent or better neutralizing antibody response in 75%—90% of vaccinees. There was no significant difference in the incidence of adverse events between vaccinees and placebo-recipients other than rash. A trivalent or better response correlated with rash and with non-black race (P < .0001). Black race was significantly associated with a reduced incidence of vaccine viremia. Conclusions. TV003 induced a trivalent or greater antibody response in 90% of flavivirus-naive vaccinees and is a promising candidate for the prevention of dengue. Race was identified as a factor influencing the infectivity of the LATV viruses, reflecting observations of the effect of race on disease severity in natural dengue infection. Clinical Trials Registration. NCT01072786.
Zika virus has spread rapidly in the Americas and has been imported into many nonendemic countries by travelers.
To describe clinical manifestations and epidemiology of Zika virus disease in ...travelers exposed in the Americas.
Descriptive, using GeoSentinel records.
63 travel and tropical medicine clinics in 30 countries.
Ill returned travelers with a confirmed, probable, or clinically suspected diagnosis of Zika virus disease seen between January 2013 and 29 February 2016.
Frequencies of demographic, trip, and clinical characteristics and complications.
Starting in May 2015, 93 cases of Zika virus disease were reported. Common symptoms included exanthema (88%), fever (76%), and arthralgia (72%). Fifty-nine percent of patients were exposed in South America; 71% were diagnosed in Europe. Case status was established most commonly by polymerase chain reaction (PCR) testing of blood and less often by PCR testing of other body fluids or serology and plaque-reduction neutralization testing. Two patients developed Guillain-Barré syndrome, and 3 of 4 pregnancies had adverse outcomes (microcephaly, major fetal neurologic abnormalities, and intrauterine fetal death).
Surveillance data collected by specialized clinics may not be representative of all ill returned travelers, and denominator data are unavailable.
These surveillance data help characterize the clinical manifestations and adverse outcomes of Zika virus disease among travelers infected in the Americas and show a need for global standardization of diagnostic testing. The serious fetal complications observed in this study highlight the importance of travel advisories and prevention measures for pregnant women and their partners. Travelers are sentinels for global Zika virus circulation and may facilitate further transmission.
Centers for Disease Control and Prevention, International Society of Travel Medicine, and Public Health Agency of Canada.
The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low ...absolute lymphocyte count ALC, high absolute neutrophil count ANC, and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib.
To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile.
Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579).
Sixty-seven trial sites in 8 countries.
Adults hospitalized with COVID-19 (
= 999; 85% U.S. participants).
Baricitinib+remdesivir versus placebo+remdesivir.
Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories.
In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio HR, 0.38 95% CI, 0.16 to 0.86;
= 0.020), decreased progression to IMV or death (HR, 0.57 CI, 0.35 to 0.93;
= 0.024), and improved recovery rate (HR, 1.53 CI, 1.16 to 2.02;
= 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile.
Secondary analysis of data collected before circulation of current SARS-CoV-2 variants.
The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19.
National Institute of Allergy and Infectious Diseases.
Abstract
This post hoc analysis of the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) shows a treatment effect of remdesivir (RDV) on progression to invasive mechanical ...ventilation (IMV) or death. Additionally, we create a risk profile that better predicts progression than baseline oxygen requirement alone. The highest risk group derives the greatest treatment effect from RDV.
To the Editor:
We share the concern of Chastain and colleagues (Aug. 27 issue)
1
that racial and ethnic minorities affected by social and structural health disparities in the United States should ...have equitable access to Covid-19 trials. However, we disagree with their conclusion about the SIMPLE-Severe (GS-U.S.-540-5773)
2
and SIMPLE-Moderate (GS-U.S.-540-5774)
3
trials of remdesivir, since their comparison of overall race and ethnicity data from these trials involving patients from 12 countries with those of a nonrepresentative sample of the U.S. population is misleading. The SIMPLE trials completed enrollment for their primary analysis populations by mid-April 2020, and between them they included . . .
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