SARS-CoV-2 RNA and nucleocapsid antigen are blood biomarkers associated with severe disease outcomes that improve in response to remdesivir.

BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter ACTT-1 clinical trial that randomized patients to remdesivir or placebo. METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 COVID-19 patients were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95%CI 1.40-2.71) for levels >245 pg/ml vs 1.04 (95%CI 0.76-1.42) for levels < 245 pg/ml. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive. CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.

Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology.

BACKGROUND: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification. METHODS: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research. RESULTS: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1-10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets. CONCLUSION: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue.

Development of standard clinical endpoints for use in dengue interventional trials.

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials.

Development of standard clinical endpoints for use in dengue interventional trials

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials.

Immunology of protection from Ebola virus infection.

A December 2014 meeting reviewed Ebola virus immunology relevant to vaccine development, including Ebola prevention, immunity, assay standardization, and regulatory considerations. Vaccinated humans appear to achieve immune responses comparable in magnitude with those associated with protection in nonhuman primates, suggesting that immunological data could be used to demonstrate vaccine efficacy.

Safety and immunogenicity of a candidate parvovirus B19 vaccine.

Parvovirus B19 is an important human pathogen causing erythema infectiosum, transient aplastic crisis in individuals with underlying hemolytic disorders and hydropsfetalis. We therefore evaluated a parvovirus B19 virus like particle (VLP) vaccine. The safety and immunogenicity of a 25 µg dose of parvovirus B19 recombinant capsid; 2.5 and 25 µg doses of the recombinant capsid given with MF59; and saline placebo were assessed in healthy adults. Because of 3 unexplained cutaneous events the study was halted after enrollment of 43 subjects and before any subject received their third scheduled dose. The rashes developed 5-9 days after the first or second injection and were seen in one placebo recipient (without an injection site lesion) and two vaccine recipients (with injection site reactions). No clear cause was established. Other safety evaluations revealed mostly injection site reactions that were mild to moderate with an increase in pain in subjects receiving vaccine and MF59. After dose 2 the majority of vaccine recipients developed ELISA and neutralizing antibody to parvovirus B19. Given the possible severe consequences of parvovirus B19 infection, further development of a safe and effective vaccine continues to be important.