BARDA RESEARCH

When an immune response becomes dysregulated, host-directed therapeutics can treat resulting conditions like acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In this study, we review and discuss how clinical trials can evaluate treatments for ALI and ARDS in COVID-19 patients. We concluded that future clinical trials should use immune-based biomarkers and clinical and demographic characteristics to focus on populations most likely to benefit from the candidate therapeutic.

Viral respiratory infections predispose patients to bacterial infections and have been a major contributor to death in previous pandemics. The association of secondary bacterial infections and COVID-19 patient outcomes has not been well studied. Our study collected case data from physicians to better understand bacterial infections in hospitalized COVID-19 patients. We found that unresolved bacterial infections contributed significantly to death, thus warranting additional research to better prepare for future pandemics.

The rate of antimicrobial resistance (AMR) is increasing, particularly in pathogens for which there are few or no alternative therapeutics available. The workshop sought to understand the challenges that product developers encounter when developing vaccines for AMR pathogens. Participants from industry, government, and academia developed recommendations for overcoming these challenges, which included more funding for early- and late-stage development and refinement of target populations and indications.

After a mass casualty incident involving a nerve agent, large quantities of atropine may be needed to treat victims. Identifying contingency sources of atropine is critical when fielded atropine autoinjectors and IV doses are insufficient to treat all exposed. In this Phase I Clinical Trial, atropine eyedrops were administered sublingually and their bioavailability was compared to IV administration of atropine to evaluate the sublingual route as a viable alternative treatment route in a mass casualty incident.

In an emergency involving nerve agent exposure, immediate administration of treatment is critical to saving lives, but protecting against long-term medical sequelae can be difficult– especially if initial treatment is delayed. This study explored the therapeutic potential of adding ketamine to the current standard of care, including midazolam when treatment is delayed. Results showed that adding ketamine to the standard treatment regimen may provide protection against the long-term neurologic effects of sarin.

Ketamine is a medication that is readily available to most clinicians in emergency departments, with well-understood effects in humans. The goal of this study was to determine the pharmacokinetic (PK) profile of ketamine following single or repeated intramuscular administrations of subanesthetic levels of ketamine, with or without the nerve agent standard of care treatment. The results of this PK profile support further investigation of the efficacy of ketamine following nerve agent exposure.

Most research for medical countermeasures against nerve agent exposure assumes a military scenario, in which autoinjector-based treatment is expected to be available immediately. In a civilian setting however, treatment is delayed until the arrival of first responders, which may significantly affect treatment efficacy. The study provides a framework for evaluating the efficacy of treatment administered at a specific stage of the toxidrome (a group of injuries caused by a toxin), when immediate treatment is absent.

Vaccine-induced neutralizing antibodies (nAbs) are key biomarkers considered to be associated with determining vaccine efficacy. However, SARS-CoV-2 nAb data is collected across multiple laboratories and assay types, making it difficult to cross-validate readouts which may impede regulatory decisions on these COVID-19 vaccine candidates. This study evaluates three calibration approaches to achieve a common scale to aid data-driven decision-making on the evaluation of COVID-19 vaccines.

Does seasonal influenza vaccination save lives? Who benefits most? Among 26 million beneficiaries participating in traditional (Fee for Service) Medicare during the winter of 2017-2018, about half had accepted influenza vaccination. The greatest benefit accrued to ambulatory beneficiaries, with those accepting vaccination having a relative risk of death (all other things being equal) of 0.87, meaning a 13% reduction. A vaccination benefit extended even to aged (85+) who would have sepsis.

Now that licensed vaccines are available for disease caused by Ebola virus (Zaire species), the US Government is pivoting to vaccine programs to target Sudan ebolavirus and Marburg virus. Absent a large outbreak, licensure of such vaccines may occur via the FDA Animal Rule. Nonclinical development will be critical to the overall success of the programs, including the selection of viral isolates to be used in testing vaccines. This manuscript provides suggested isolates for use in vaccine development.

Avian flu A(H7N9) virus has been known to cause severe, often fatal, lower respiratory disease in humans. We report the findings of a clinical study evaluating the safety and immunogenicity of a new recombinant hemagglutinin H7 subtype influenza vaccine in healthy adults. The recombinant H7 vaccine was safe and well-tolerated, with a safety and immunogenicity profile comparable to that of the egg-/cell-based vaccines produced in response to the A(H7N9) viruses from the 2013 epidemic wave. The results from this study provide critical information to develop a pandemic response strategy and support regulatory requirements for vaccination under Emergency Use Authorization.

Chlorine is a toxic industrial chemical with a history of use as a chemical weapon.  Evaluation of acute chlorine exposure is complicated by the virtual lack of reliable biomarkers. Using our new chlorine exposure assay for hair and lung tissue samples and our improved chlorinated tyrosine quantitative assay, we report that chlorine exposure biomarker levels are more abundant and detectable for a greater duration in hair than in lung and blood.  

BARDA partnered with CMS to study and report on sepsis among Medicare beneficiaries. In the first of a 3-paper series, we identified more than 9.5M sepsis inpatient hospital admissions during 2012–2018. Over this interval, annual admission counts increased more than 65% to nearly 1.7M in 2018; the total 2018 cost of sepsis hospitalizations and skilled nursing facility care for beneficiaries exceeded $41.5B, excluding pre/post-stay care or any professional fees. While sepsis mortality continues to decline, it remains quite high (Fig. 3).

In paper 2 of 3, we analyzed the trajectories of individual Medicare patients during and after inpatient hospital admissions. While inpatient admission from a nursing facility (vs. from home) was more likely to be due to sepsis, patient characteristics did not otherwise predict whether admission would be due to sepsis or another reason. Sepsis patients consume an increasing fraction of inpatient days and hospital beds. Unfortunately, sepsis has significant adverse effects 6 months after inpatient admission (Fig. 6).

Paper 3 in our 3-paper series forecasted long-term costs for Medicare beneficiaries. These informed a lower-bound, rough-order-of-magnitude national cost of $62B/+ for 2019; this estimate included all Americans but excluded pre/post hospital care, professional fees, and costs of care for veterans or active duty military. We forecasted $100B/+ before 2025, noting: “ …financial forecasts are influenced strongly by catastrophic events; appearance of a global pandemic such as the 1918 “Spanish Flu” would incur costs far in excess of financial forecasts generated by the models discussed.” COVID did not yet exist.

We assessed the safety and immunogenicity of Anthrax vaccines in older adults. The results suggest that a CpG adjuvant may help to elicit a protective immune response to anthrax vaccines in those over the age of 65.

We detailed some of the lessons learned from the vaccine development perspective, from the response to Ebola (Zaire). In this manuscript, we emphasized the key gaps in product development at the outset of the West Africa epidemic of 2014-2016, and which of those gaps must be imminently filled for vaccines against Ebola (Sudan) and Marburg virus.

We provided a summary of the current status of anthrax vaccines to include those products licensed for use, as well as those currently in clinical development. The manuscript also focuses on some of the near-term research needs.