Influenza response planning for the centers of excellence for influenza research and surveillance: Science preparedness for enhancing global health security

Abstract Background The Centers of Excellence for Influenza Research and Surveillance (CEIRS) network, funded by the US National Institutes of Health, has been operational since 2007 and is tasked with conducting research to improve understanding of influenza viruses. Recently, CEIRS developed an Influenza Response Plan (IRP) to improve science preparedness for the network. Methods Development of the IRP involved a collaborative process between project staff, CEIRS center directors or their designees, and NIAID CEIRS leadership (referred to as the Pandemic Planning Advisory Committee [PPAC]). Project staff identified and summarized the response capabilities of each center and then worked with the PPAC to identify and rank research priorities for an emergency response using a modified Delphi method. Results Key elements of the response plan include tables of response capabilities for each CEIRS center, a framework that outlines and ranks research priorities for CEIRS during an emergency situation, and an operational strategy for executing the research priorities. Conclusions The CEIRS IRP highlights the importance of enhancing science preparedness in advance of an influenza pandemic or other influenza‐related zoonotic incident to ensure that research can be carried out expeditiously and effectively in emergency situations and to improve global health security.


| BACKG ROU N D
Over the past 20 years, the world has witnessed a number of global or regional infectious disease emergencies, including the outbreak of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV)  (HHS), science preparedness "is a collaborative effort to establish and sustain a scientific research framework that can enable emergency planners, responders, and the whole community to better prepare for, respond to, and recover from major public health emergencies and disasters." 8 Furthermore, in a public health emergency, scientists may need to "operate within a finite window of opportunity to identify, collect, and analyze critical and time-sensitive data that may be available only during the immediacy of the event or incident," which highlights the importance of preparedness efforts. 8 Recent publications on science preparedness have focused on the need to develop plans (eg, protocols and approvals from Institutional Review Boards) for initiating clinical research during public health emergencies, particularly regarding the inclusion of pregnant women and children in clinical trials of candidate medical countermeasures during outbreaks. 9,10 A need also exists, however, to ensure rapid initiation of basic science research during outbreaks of novel or emerging pathogens, particularly with regard to developing new medical countermeasures.
Because of the constant and unpredictable threat of an influenza pandemic, preparedness to conduct research during situations involving pandemic influenza or emergence of novel influenza viruses with pandemic potential remains an important priority for enhancing overall science preparedness and global health security. While not caused by a novel influenza virus, the current COVID-19 outbreak has many parallels to pandemic influenza and clearly demonstrates the importance of rapid mobilization of critical scientific research as part of the overall response. To strengthen capabilities for scientific research on influenza, in 2007 the US National Institutes of Health (NIH) established the Centers of Excellence for Influenza Research and Surveillance (CEIRS) network. Since the program was initiated, NIH has funded six multidisciplinary research centers across the United States, with a number of associated international partners.
Currently, five centers are funded through CEIRS. 11 By conducting animal and human influenza surveillance and influenza pathogenesis and host response research, the CEIRS network is expected to fill key knowledge gaps, enabling accelerated development of new and improved control measures against influenza. In addition, the CEIRS centers are expected to serve as resources for the scientific community and to provide a research response (including production of essential reagents) in the event of an emergency influenza situation.
Finally, the CEIRS network also has critical research capabilities that can be leveraged for responding to outbreaks involving other novel respiratory pathogens, which was done with MERS in 2012 and is now ongoing with COVID-19.
The CEIRS network has been highly successful in advancing the field of influenza research, as evidenced by the extensive number of publications produced by CEIRS investigators over the past 13 years (more than 1700 publications between 2007 and early 2018). 11 In addition, the CEIRS network has demonstrated its ability to rapidly redirect research in response to emergency situations, as shown during the 2009-2010 H1N1 pandemic, which is a strong testament to the value of having a coordinated research infrastructure and flexible funding mechanism in place before the onset of a public health emergency. While the CEIRS network made significant scientific contributions during the 2009-2010 pandemic, several organizational improvements were later identified that could enhance the CEIRS response in future. One key issue was the need to have a mechanism in place to provide an up-to-date assessment of the technical response capabilities of each CEIRS center, which could serve as an easy reference during emergency situations. A second issue was the need for a more standardized approach to coordinating the research of CEIRS investigators during emergencies, using a pre-defined research prioritization scheme. A third was the need to more clearly define the role of the NIAID CEIRS project officer (also referred to as the director of operations) during an emergency response. To address these concerns, the CEIRS centers worked collaboratively to develop the CEIRS Influenza Response Plan (IRP). This report briefly outlines the steps in that process and highlights the unique elements of the CEIRS IRP that focus on successfully executing the scientific mission of the CEIRS network during an emergency situation.

| ME THODS
The first step in this project was to create the CEIRS Pandemic Planning Advisory Committee (PPAC), which included center directors and/or at least one senior researcher from each center, NIAID CEIRS leadership personnel, and project staff (contracted from the Center for Infectious Disease Policy and Research [CIDRAP] at the University of Minnesota). The committee's charge was to provide critical feedback and guidance regarding the process and outcome of CEIRS pandemic research planning, including review of interim and final products. During the course of the planning process, the PPAC met regularly to discuss various aspects of CEIRS influenza response planning and to provide critical input on overarching planning issues.
The second step involved collecting background information from each CEIRS center on its research capabilities and areas of expertise relevant to rapid initiation of pandemic research and response. Project staff reviewed the work of each center, including publications, project plans, and other available written information, and identified overarching themes for capabilities in two areas. The first-capability to provide technical resources-included the following themes: enhancing situational awareness of novel viruses, reagent production and distribution, ability to perform high-quality analytics, availability of biocontainment facilities, ability to perform human cell culture, public communication, availability of clinical protocols, tools for information sharing, and other capabilities not identified elsewhere. The secondrapid initiation of pandemic research-included the following themes: Each center director verified the information to ensure its accuracy. These tables were initially compiled in 2017 and have been updated annually since; they provide an easy up-to-date mechanism to quickly identify center capabilities. The next step involved developing a framework for prioritizing research activities during future pandemic incidents or situations involving the emergence of novel influenza viruses with pandemic potential. This framework identifies the key research questions for CEIRS to address during a pandemic or pre-pandemic situation and prioritizes the associated research activities. Project staff developed a draft framework of research questions and activities and convened an in-person meeting of the PPAC to review and prioritize them. The prioritization process involved a modified Delphi method, whereby PPAC members were asked to individually rank activities as high or medium priority and as readily feasible (ie, the activity can be completed in a timely fashion and will not require additional resources) or not readily feasible (ie, the activity will take longer, will require additional resources, or may not be feasible). The prioritization rankings were then added to the framework to reflect the input of PPAC members. A revised version of the framework was resubmitted to PPAC members for a second review and then was discussed in detail during another in-person PPAC meeting to develop consensus among the group.

| RE SULTS: KE Y ELEMENTS OF THE CEIR S IRP
The CEIRS IRP includes several elements unique to the scientific mission of CEIRS; the full version of the plan is available on the CEIRS website. 12 First, the CEIRS IRP provides detailed information on the research capabilities of each of the CEIRS centers with regard to the ability to rapidly provide technical resources and the expertise necessary to quickly initiate new influenza research studies. This information is summarized in the tables described above, so that response coordinators can easily assess and review the capabilities of each center.
Second, the plan includes a response framework (Table 1)    Once research priorities appropriate to the situation have been established by NIAID CEIRS leadership, with technical input from the PRAC, they will be communicated to the CEIRS centers. Each center will then be asked to provide a specific research plan that aligns with the defined research priorities that have been approved by NIAID leadership. These research plans will be reviewed by NIAID to ensure that: the plans are consistent with the role of CEIRS in a research response, they align with the research priorities specific to the incident, and the level of redundancy across centers is appropriate. NIAID will determine which plans or aspects of the plans will be funded (through existing or new contracts) in order to fulfill NIAID's expectations for the role of the CEIRS centers during the particular emergency situation. This approach NIH roles and responsibilities for pandemic response a

Primary research activities for the CEIRS network that apply to the research questions
Study the evolution and emergence of influenza viruses, including the identification of factors that affect influenza host range and virulence • What is the likely origin (species, geographic location) of the virus? • What is the relatedness of the pandemic virus to seasonal influenza viruses? • What is the potential for reassortment of the pandemic virus with seasonal viruses? HP: Provides critical scientific information or a critical service for the USG response to either an influenza pandemic or a pre-pandemic situation and the information/service is urgently needed.
MP: Provides critical scientific information that will be useful for pandemic/pre-pandemic response but the information is not urgently needed.
RF: Readily feasible; NRF: Not readily feasible or feasibility may not be clear.

RF:
The activity can be completed in a timely fashion and will not require additional resources.

NRF:
The activity will take longer, will require additional resources, or may not be feasible. These goals are specifically intended for response to an influenza pandemic, but are also applicable to emergence of a novel influenza strain with pandemic potential.

TA B L E 1 (Continued)
offers an efficient mechanism to rapidly identify and move forward with a carefully determined set of critical research priorities. It also allows the CEIRS centers to provide their expertise in defining the priorities, but leaves the ultimate decision-making to NIAID leadership, in accordance with the contractual agreements between the US government and the CEIRS centers.

| D ISCUSS I ON
According to ASPR, science preparedness involves five key elements: coordination and integration, scientific research, research infrastructure, public health practice, and emergency management. 8 Several of these elements apply to the CEIRS role in responding to a public health emergency involving a novel or emerging influenza virus (or potentially other respiratory virus of concern, such as While the CEIRS IRP is an important step in promoting science preparedness for the CEIRS network, it does not address a number of other key needs, such as having clinical trial protocols in place in advance of an emergency, rapid access to viral samples, generation of interagency agreements, or challenges with international memoranda of understanding (MOUs) and approvals. These issues were determined to be outside the scope of the current plan, but are essential to optimal scientific preparedness for the CEIRS network.
CEIRS leadership (NIAID personnel and the CEIRS center directors or their designees) need to continue to identify remaining gaps and specific steps to address them, and create an overall strategy to ensure that they are addressed to the degree feasible.
The 2017 update to the HHS Pandemic Influenza Plan identifies science infrastructure and preparedness as one of the seven key domains for improving pandemic response capacity between 2017 and 2027. 16 The update specifically mentions the valuable role of the CEIRS network in influenza research. According to the update, "HHS's fundamental investments in science infrastructure and preparedness have delivered critical knowledge to understand both seasonal influenza viruses and those with pandemic potential.
Establishing and sustaining scientific research frameworks, addressing the full spectrum from basic discovery through patient intervention, will dramatically improve comprehensive pandemic outbreak preparedness, response, and recovery." From 2017 to 2027, HHS intends to enhance science preparedness by achieving the following three goals. 16 The first is to support scientific infrastructure preparedness, including ensuring the capacity to conduct clinical, behavioral, and epidemiologic research. This also includes issues such as safety oversight and steps to simplify collaboration, ethical practices, and evaluation activities. The second is to support basic and translational research to improve medical countermeasures and strategies to prevent, diagnose, treat, and respond to pandemic influenza. The third is to establish and sustain a scientific preparedness framework that can align and integrate public health practice and scientific research during an influenza pandemic. Research conducted by the CEIRS network is applicable to all three of these science preparedness goals, and the CEIRS IRP is an important step in ensuring that research is prioritized quickly and an overarching research approach is established early in any pandemic or potential pre-pandemic situation, with appropriate oversight and coordination of activities by NIAID leadership.