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Principal Investigator: Richard Davey
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $3,718,933
Funding agency: National Institute of Allergy and Infectious Diseases
Novel means first to better characterize and then to treat infection with major respiratory pathogens using existing or newly developed strategies are a primary focus of this important project within the Clinical Research Section. In this regard, our Section has undertaken clinical research efforts to help better characterize and treat infection with both novel and seasonal subtypes of influenza. A prior treatment trial (FLU005) with hyperimmune intravenous immunoglobulin (IVIG) showed a significant treatment benefit in patients hospitalized with influenza B infection despite the lower antibody titers present in IVIG against influenza B virus. Subsequent investigation showed that IVIG produced from harvested plasma selected for enriched anti-influenza antibody titers actually has up to ten-fold higher avidity against influenza B than against influenza A. This outcome lead to the design of a new IVIG trial (FLU006) aimed at targeting a larger number of patients hospitalized with influenza B. However, the exigencies of the COVID-19 pandemic and anticipation of a mild influenza season as a result of public health measures against the former placed launching of this new trial on hold until such time as influenza B activity returns to its anticipated pre-pandemic levels.
The Special Clinical Studies Unit (SCSU) with the NIH Clinical Center remains one of a small number of special high containment patient care units within the US called upon to hospitalize patients or staff suffering high-risk exposures to highly-infectious agents who require observation and/or care under conditions of high containment. The section continues to provide direct medical oversight to the SCSU. During the recent pandemic this included hospitalizing and providing care for seriously ill patients with COVID-19 from the surrounding community who had been transferred to the NIH for access to investigational therapies. Through engagement with a large domestic and international network enterprise as coordinated through NIAIDs Division of Microbiology and Infectious Diseases (DMID), the Section enrolled patients on three of the four separate phases of the Adaptive COVID-19 Treatment Trial (ACTT) studying investigational therapeutics in COVID-19 inpatients presenting with respiratory compromise:
ACTT-1: Remdesivir for the treatment of COVID-19, which showed that patients who received remdesivir were found to be more likely than placebo recipients to have clinical improvement at day 15. While not powered to show an effect on mortality, the data also suggested that remdesivir was superior to placebo in shortening the time to recovery in hospitalized adults.
ACTT-2: Baracitinib plus remdesivir for hospitalized adults with COVID-19, which showed that baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among COVID-19 patients.
ACTT-4: Baricitinib/remdesivir vs. dexamethasone/remdesivir, which showed overall equivalence in outcomes between the two arms and hence from which it was concluded that baracitinib should be considered an acceptable alternative to dexamethasone in treating hospitalized patients with COVID-19.
In addition to the ACTT trials, the section also participated in two other COVID-19-related clinical trials: ITAC (INSIGHT 013) An International Multicenter, Adaptive, Randomized Double-Blind, Placebo-Controlled Trial of the Safety, Tolerability and Efficacy of Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin for the Treatment of Adult Hospitalized Patients at Onset of Clinical Progression of COVID-19, and a phase II double-blind, randomized, placebo-controlled trial study of the spleen tyrosine kinase inhibitor fostamatinib in hospitalized adults with Covid-19 where patients receiving remdesivir and corticosteroids were randomized to receive either fostamatinib (up to 14 days) or placebo. The results of both studies have been published.
In collaboration with the Institut National pour la Recherche Biomedicale (INRB), the WHO, and several international partners, the Section was instrumental in helping design an investigational RCT of 4 different MCMs employed during the 10th outbreak of Ebola virus infection in the Democratic Republic of the Congo (DRC) that began in August 2018. Called PALM001, 693 patients were accrued in this landmark trial that ultimately established both the safety and efficacy of two different monoclonal antibody products (REGN-EB3 and Mab-114) in treating both adult and pediatric patients with Ebola virus disease (EVD), not only proving for the first time that effective treatment of EVD was possible but also establishing that important clinical research could be safely conducted in the midst of a public health crisis. Currently we are engaged in additional analyses of an extra 363 patients enrolled in the Extension Phase of PALM001 as well as a study called PALM005 that aims to develop a means of independently validating which study participants did or did not receive prior vaccination with the rVSV-ZEBOV-GP (Merck) vaccine in order to analyze the effect of prior vaccination on disease outcome.
Launched in 2016, the Section is also completing an ongoing pre-exposure vaccination protocol called PREPARE that used the rVSV-ZEBOV-GP vaccine to immunize HCWs, BSL-4 Laboratory staff, and other at-risk personnel against Ebola virus infection. The protocol featured 1:1 randomization to a homologous booster immunization at month 18 to determine whether the booster further augments antibody levels induced by the primary immunization as assessed at month 36. Of a total of 233 participants enrolled, 92 completed all aspects of the study through Month 36 and are considered the primary analysis cohort. In striking contrast to earlier studies in which administration of a booster dose within 1-2 months of the primary generally resulted in increases in anti-GP antibody titers that were not sustained 6-12 months later, the delayed booster dose in PREPARE caused a peak antibody response up to 20-fold higher than was seen in non-boosted participates and which remained several fold above the non-boosted titers even 18 months later. These results should provide valuable insights into how booster doses can be staged more effectively as part of sustained pre-exposure prophylaxis.
Beginning in summer 2022 the Section has also been advising on the development, implementation, and conduct of a placebo-controlled RCT studying the role of the antiviral drug tecovirimat (TPoxx) in treating cases of clade 1 MPox infection at two centers in the DRC. With the concurrent outbreak of an increasing number of cases of clade IIb MPox infections in the developed world, domestically we have also been collaborating with DMID and others in the design and conduct of a dose-sparing trial of the licensed JYNNEOS Monkeypox vaccine evaluating both the immunogenicity of an intradermal route of administration as well as the safety of SC dosing in the pediatric population.
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