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Principal Investigator: Richard Davey
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $4,224,059
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. 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 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 launching of this new trial remains on hold until such time as influenza B activity returns to its anticipated pre-pandemic levels. As of mid 2024 the Victoria lineage of influenza B has started to resurface but the Yamagata lineage has not.
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 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
ACTT-2: Baracitinib plus remdesivir for hospitalized adults with COVID-19
ACTT-4: Baricitinib/remdesivir vs. dexamethasone/remdesivir
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 or placebo. The results of both studies have been published.
The past year has also been marked by active engagement with, and a much stronger collaboration between, the leadership of the SCSU and the 13 federally-funded Regional Emerging Special Pathogen Treatment Centers (RESPTC) that are part of the National Special Pathogen System of Care (NSPS) overseen by the National Emerging Special Pathogens Training and Education Center (NETEC) at the University of Nebraska This has occurred through our active involvement in the regularly scheduled meetings of the RESPTC, attendance at NETEC-sponsored symposia on topics related to high containment issues, lecturing at NETEC-sponsored training sessions, and co-authorship on publications related to select agents and the medical countermeasures available to treat them.
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 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 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. This validation method has now been confirmed as accurate and reliable and will shortly be applied to the testing of PALM001 samples as planned. Most recently, a protocol to treat HCWs infected with Ebola Sudan with the investigational monoclonal MBP134 has been implemented.
The Section has also recently completed a 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 20-fold higher than was seen in non-boosted participates and which remained several fold above the non-boosted titers even 18 months later. Specialized studies of the B cell response to the booster dose have also been undertaken and results are anticipated shortly. Altogether, this protocol has provided valuable insights into how booster doses can be staged more effectively as part of sustained pre-exposure prophylaxis against Ebola.
With the concurrent outbreak of an increasing number of cases of clade IIb MPox infections in the developed world, domestically we have also collaborated 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.
Beginning in summer 2022 the Section also began 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. This study is fully enrolled and the preliminary study results are being unblinded in August 2024.
Finally, the Section has also been part of the new Strategies and Treatments for Respiratory Infections and Viral Emergencies (STRIVE) network funded by NIAID that has implemented two international interventional treatment trials for patients hospitalized with COVID-19 and is now in process of launching a large observational platform trial of patients hospitalized with other serious infections.
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