Technologies that can change the way we measure and perceive vaccination-induced immune protection will eliminate the uncertainty and retrospective evaluation process that is the current state of affairs. By leveraging host-immune mechanisms in response to vaccination, the DARPA AIM program intends to provide the Department of Defense with the capability to predict effective vaccine duration of response prior to engaging in years-long clinical studies.
The Defense Advanced Research Projects Agency (DARPA) has selected teams of researchers to support the Assessing Immune Memory (AIM) program, which seeks to develop a research and evaluation tool that can predict early on whether a given vaccine candidate will provide long-lasting immune protection. The ability to rapidly select a future vaccine candidate that offers the longest duration of immune protection among all the potential options would greatly enhance operational readiness.
Military service members rely on effective vaccination for the prevention of communicable disease as well as to guard against biothreat exposure. Many current vaccines lack durability (i.e., do not provide effective protection over long periods of time), and there are pathogens and threats that lack prophylactic options altogether. It is currently impossible to predict vaccine durability from early response profiles, largely owing to ignorance of mechanisms underlying immune memory as well as an inability to measure the cellular contributors that invoke long-lasting immune protection. Formation of immune memory is a complex physiological process characterized by a diverse array of cellular interactions and signaling processes. AIM seeks to develop a platform capability to predict immune memory informed by a systems-level view of the host response to vaccination and its mechanisms.
“The current state of vaccine durability assessment is to take a ‘wait-and-see’ approach, largely owing to ignorance of mechanisms underlying immune memory, as well as an inability to measure the cellular contributors that invoke long-lasting immune protection,” noted Dr. Michael Feasel, AIM program manager. “AIM will take a systems-level view of the response to vaccination and explore the mechanisms that lead to long-lasting protection. The plan is that this will then be implemented as a tool to predict vaccine duration of protection without waiting years for clinical trial results.”
The selected performers include:
- Columbia University – Dr. Donna Farber, principal investigator (PI)
- Icahn School of Medicine at Mt. Sinai – Dr. Stuart Sealfon, PI
- Stanford University – Dr. Bali Pulendran, PI
- University of Maryland, Baltimore – Dr. Nevil Singh, PI
Why some vaccines provide lifetime protection and others protect for only a few months remains enigmatic and difficult to predict during vaccine product development. AIM seeks to determine early on if a vaccine candidate will later provide long-lasting immune protection in humans, a current impossibility that would benefit the warfighter and nation immensely. To accomplish this goal, AIM will take a systems-level view of the immune response to vaccination and dissect it with next-generation analytical and computational approaches to determine the host response mechanisms that lead to long-lasting protection. This systems-level understanding will then be implemented as a tool that can predict vaccine duration of protection and the associated mechanisms without waiting years for retrospective determination. Upon successful demonstration of the underlying principles of AIM, the same technology can be explored for use in a prognostic capacity to predict individual levels of immune protection.
Correlates of Protection
Duration of immune protection for new vaccines currently takes a “wait and see” approach. It is a grand challenge in vaccine development to be able to predict how long a vaccine will be protective before it is administered to humans, and more importantly, why protection is conveyed or not. Standard methods for measuring immune system response lack the ability to establish host mechanisms that contribute to [good and poor] immune protection and focus on simple markers (e.g., antibody levels, etc.) that do not capture the breadth of immune system responses possible. Rather, antibody levels and select immune cell type markers act as simple proxies that miss critical features of the immune response at a systems level, particularly the ability of the immune system to recognize a pathogen months or years after vaccination – the physiology of immune memory. AIM will uncover new biomolecular correlates using leading edge technologies from both preclinical animal models and human samples. Biomolecular correlates are defined as collections of measured responses from organisms to an immune system challenge, such as vaccination. These correlates will be assembled from quantitative features that are observed at the activity level (such as change in number or location of a given cell type) and the abundance level (such as a change in the total per-cell content of a given gene product).
Predicting Vaccine Durability
The central hypothesis of the AIM program is that immune memory can be predicted from multiple biomolecular correlates that are present earlier in the systems response to vaccination than the months-long profiles collected currently. Further, those correlates will be used to predict and understand why successful vaccines produce long-lasting protection. This approach will view the contributors to immune memory as an integrated system of cellular and molecular actors, and will determine relationships among them that are unknown, but whose presence has been appreciated in the field for decades.
Success with AIM will provide the nation with the following capabilities:
- Upfront assessments of vaccine duration of protection early in development
- Reduced need for unnecessary re-vaccination of operators upon deployment
- Progress towards individualized assessments of immune protection for a given pathogen following vaccination
AIM is a five-year program that is divided into two sequential phases. The goal of Phase 1, “Immune Memory Road Map,” is to identify cell and signaling contributors to generate a “road map” of immune memory.
During Phase 1, performers will identify critical cellular features and signaling events that will be used to build a roadmap to immune memory. To generate the data necessary for this roadmap, contributors to immune memory will be profiled with sufficient depth and temporal sampling to assemble cell features that correlate with immune memory in the chosen model systems. At the culmination of Phase 1 efforts (2 years), performers will need to validate the predictive accuracy of their road map by establishing biomolecular correlates of immune memory in their model systems.
Performers moving on to Phase 2, “Road Map Generalizability and Tool Validation,” will focus on assembling and validating an accurate assessment tool to cross-validate the immune mechanisms described. The varied approaches will utilize measurements from preclinical animal models (animal data will need to be validated for relevance in human samples, and human data will need to demonstrate that the processes are comparable in an animal models) and advanced computational techniques with a goal to establish a way to predict how long a vaccine may protect a person.
Amongst several key challenges in Phase 2 is the work of establishing the most robust and relevant biomolecular correlates representative of immune memory – across different individuals. The specific cell signaling processes that lead to the development of immune memory in one individual may not be exactly the same as in another, but there will be common features at some level that result in similar clinical end points. Deriving these types of relationships from dense, multivariate data is a perennial challenge for advanced computation in biology.
Sources: DARPA, Sam.gov