Mechanisms underlying combination adjuvant-driven improvement of influenza vaccine responses

The National Institute of Allergy and Infectious Diseases awarded Duke University $695,041 on August 3, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate mechanisms underlying combination adjuvant-driven improvement of influenza vaccine responses.

The research defines the innate immune signatures and adaptive immune responses elicited by existing and novel combination adjuvants as they relate to driving immune responses directed against influenza virus hemagglutinin. Individual adjuvants each elicit different immune responses that are typically not perfectly aligned with the immunity desired for specific applications; the project seeks to develop a rational basis for generating novel adjuvant combinations that can tailor immune responses for maximum disease protection. The work uses influenza virus hemagglutinin protein as a model antigen and includes characterization of commercially available adjuvants and development of new adjuvant combinations with compatible innate immune signatures and desired aspects of immunity.

Performance occurs in Durham, North Carolina, with a period of performance from the award date through July 31, 2031. This is a project grant, the standard assistance type for investigator-initiated research under NIAID's Allergy and Infectious Diseases Research program.

Abstract

The use of adjuvants has been demonstrated to be highly effective in shaping the magnitude and composition of the immune responses generated during vaccination. As the use of each adjuvant elicits a different response that is typically not perfectly aligned with the immunity desired for a specific application, there has long been interest in using combinations of adjuvants. Theoretically, specific adjuvant mixtures could be used to tailor immune responses for maximum disease protection in different scenarios. The ability to realize this goal, however, has been limited by a lack of ability to predict the aggregate effects of combination adjuvant use. Indeed, while multiple combination adjuvants have been developed, and some show enhanced adjuvanting ability, the ability to drive specific desired responses with specific adjuvant mixtures remains elusive. We hypothesized that with an in-depth understanding of the responses induced by some of the most advanced commercially available adjuvants (some of which are already combinations themselves), we could develop a rational basis for generating novel combinations of adjuvants. Using an influenza virus hemagglutinin (HA) protein as a model antigen, we performed these studies and found that while none of the adjuvants alone elicited an ideal response profile, many had compatible innate immune signatures and drove desired aspects of immunity that would be highly advantageous when combined. The major goal of this application is to define the outcomes, and underlying mechanisms, of the use of existing and novel combination adjuvants as IT relates to driving immune responses directed against the influenza virus HA. In aim 1, we will precisely define the innate immune signatures and the adaptive immune responses elicited by existing and new combination adjuvants. This work will allow not only for characterization of the outcomes of their adjuvanting activities, but also a test of our framework for selecting adjuvants for novel combinatorial use. In aim 2, we will define the roles of type i, II, and III interferon signaling in the context of combination adjuvanted vaccines. These experiments will allow for an understanding of key mechanisms driving the improved responses seen after combination adjuvant use. Finally, in aim 3, we will test how combination adjuvants function across genetically divergent immune systems with different propensities to generate desired immune responses. These studies will be critical to predict how genetically heterologous individuals will respond to specific adjuvant formulations. Together, completion of these studies will not only increase our basic understanding of how the immune system responds to combination adjuvants but also provide a basis for future practical development of adjuvant combinations.