Influenza and Emerging Infectious Diseases

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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. An initial treatment trial involving open-label administration of two units of hyperimmune plasma to 98 hospitalized patients with severe influenza suggested that investigational arm participants might have fewer days in the hospital, in the ICU, on mechanical ventilation, and may have improved disposition at Day 7. Based upon these highly suggestive trends, the CRS then launched a follow-up multicenter trial (called IRC005) enrolling patients with severe influenza A infection who were randomized in a double-blind manner to receive either high-titer (hyperimmune) plasma or a low-titer (control) plasma in addition to standard-of-care treatments. 140 subjects out of a desired goal of 150 were randomized in this trial, with the primary endpoint being an assessment of clinical status using an ordinal outcome score as measured at Day 7. The major finding of IRC005 was that the use of high-titer immune plasma did not confer a clinical benefit over non-immune plasma in patients hospitalized with influenza A, and thus this immunotherapy could not be recommended as a useful adjunctive treatment strategy for future patients. This outcome provides an important counterpoint to over 100 years of speculation and a series of anecdotal reports that convalescent plasma might be a powerful adjunct in the treatment of severe influenza A. As a separate trial launched through the INSIGHT clinical trials network, we also conducted an international multi-center randomized, double-blind, placebo-controlled study of hyperimmune intravenous immunoglobulin (IVIG) versus standard-of-care in hospitalized patients with severe influenza A or B. This clinical outcome trial was preceded by successful completion of a multi-center pilot trial in 31 patients through domestic US sites within the INSIGHT network that showed that administration of IVIG to hospitalized patients or outpatients was safe, significantly boosted HAI titers against the infecting influenza A subtypes, and could be conducted at clinical sites while maintaining the blind. By June, 2018, the trial reached and actually exceeded the accrual goal of the desired number (320) needed to power the endpoint of clinical improvement at Day 7 of illness. Similar to IRC005, however, no treatment benefit was found for IVIG in patients with influenza A. Surprisingly, however, a significant treatment benefit was found for patients hospitalized with influenza B infection despite the lower antibody titers present in IVIG against influenza B virus. In-depth antibody characterization of the IVIG product provided a potential explanation for this discrepancy by documenting the presence of up to 10-fold higher avidity antibody against both major lineages of influenza B than against the major influenza A subtypes in this plasma-derived product. The current plan is to explore this unexpected outcome through the launch of a new IVIG trial aimed at a larger number of patients hospitalized with influenza B. In addition to the completion of these interventional trials mentioned above, we continue to contribute to the management and oversight of a large international observational protocol for hospitalized patients with seasonal influenza infection, as well as a third protocol looking at the genomic host response, all administered under the auspices of the INSIGHT network. In the realm of ongoing biodefense-related initiatives, we continue to 1) monitor yearly the clinical and psychological status of a subset of patients previously exposed to anthrax as a result of the October 2001 anthrax attacks, and 2) continue to enroll and study patients on a protocol designed to permit diagnosis and in-depth characterization of individuals presenting elsewhere with unusual infectious or inflammatory conditions that have often defied diagnosis and treatment at other centers. The Special Clinical Studies Unit (SCSU) with the NIH Clinical Center is 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, such as the medically-evacuated HCWs exposed to or infected with Ebola virus in 2014-15. The section continues to provide the direct medical oversight to the SCSU. Most recently this has involved hospitalizing and providing care for patients with COVID-19 from the surrounding community who have been transferred to the NIH for access to investigational therapies. Through engagement with a large domestic and international network enterprise comprised of over 60 medical centers and coordinated through NIAIDs Division of Microbiology and Infectious Diseases (DMID), the Section has participated in three separate phases of the Adaptive COVID-19 Treatment Trial (ACTT) studying investigational therapeutics in COVID-19 inpatients presenting with respiratory compromise. The first of these trials established that the use of remdesivir results in a statistically significant reduction in the time to recovery in patients hospitalized with an oxygen requirement. The second of these trials is studying whether the addition of an immunosuppressive medication such as a JAK-Stat inhibitor (baracitinib in this case) can dampen the potentially damaging cytokine response in severe COVID-19 and thereby improve the clinical outcome relative to remdesivir alone. That second phase has completed accrual and the data for the primary and secondary endpoints are presently being analyzed. Following the Sections lead role in helping orchestrate the only multicenter randomized controlled (RCT) safety and efficacy study (PREVAIL II) of putative MCMs in the treatment of patients with confirmed Ebola infection during the 2013-16 West African crisis, the outcomes of that trial were instrumental in helping design the next investigational RCT of MCMs implemented during the 10th outbreak of Ebola virus infection in the Democratic Republic of the Congo (DRC) that began in August 2018. NIAID collaborated with the Institut National pour la Recherche Biomedicale (INRB), the WHO, and several international partners to rapidly implement an RCT of 4 different promising investigational countermeasures against Ebola in that country. 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. The phase 1 randomized, double-blind dose-escalating safety and immunogenicity trial of (VSVG-ZEBOV) vaccine against EVD that the Section completed in early 2015 was the forerunner to an ongoing pre-exposure vaccination protocol called PREPARE that is using VSVG-ZEBOV vaccine to immunize HCWs, BSL-4 Laboratory staff, and other at-risk personnel against Ebola virus infection. The protocol features 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. As of mid 2020 233 patients have been enrolled and will provide the basis for the primary endpoint determination.