Increased vaccine tolerability and protection via NF-κB modulation

Abstract

Improving adjuvant responses is a promising pathway to develop vaccines against some pathogens (e.g., HIV or dengue). One challenge in adjuvant development is modulating the inflammatory response, which can cause excess side effects, while maintaining immune activation and protection. No approved adjuvants yet have the capability to independently modulate inflammation and protection. Here, we demonstrate a method to limit inflammation while retaining and often increasing the protective responses. To accomplish this goal, we combined a partial selective nuclear factor kappa B (NF-kB) inhibitor with several current adjuvants. The resulting vaccines reduce systemic inflammation and boost protective responses. In an influenza challenge model, we demonstrate that this approach enhances protection. This method was tested across a broad range of adjuvants and antigens. We anticipate these studies will lead to an alternative approach to vaccine formulation design that may prove broadly applicable to a wide range of adjuvants and vaccines.

Small Molecule NF-κB Inhibitors as Immune Potentiators for Enhancement of Vaccine Adjuvants

“…Of the molecules we tested, honokiol and capsaicin proved to be effective at both limiting inflammation and potentiating the protective response. Through knockout studies, we demonstrate that the increase in antigen specific antibodies is independent from the anti-inflammatory activity, which is congruent with our previous studies (5). To determine if these small molecules could be improved by chemical synthesis, we explored derivatives of honokiol and found several promising candidates for potential use in vaccines.…”

“…We chose to analyze systemic levels of TNF-α and IL-6 because high levels of these cytokines are pyrogenic and have been correlated with undesirable vaccine-related side effects (15)(16)(17). We previously determined that CpG-induced TNF-α and IL-6 peak at 1 h postvaccination (5). Mice vaccinated with CpG demonstrated high levels of TNF-α (1067 pg/mL) ( Figure 1B).…”

“…This disconnect is due, in part, to the challenge of balancing the proinflammatory immune response with the protective, adaptive immune response (2)(3)(4). We recently reported that vaccines could be improved through the use of a peptide NF-κB inhibitor, SN50 in combination with an immune adjuvant (5). The addition of SN50 to adjuvanted vaccines led to increased safety of the adjuvant while enhancing protection against disease.…”

Characterizing cellular and molecular variabilities of peripheral immune cells in healthy inactivated SARS-CoV-2 vaccine recipients by single-cell RNA sequencing

“…Surprisingly, we observed the down-regulation of NF-κB signal in the post-BBIBP-CorV vaccination PBMC samples. Previous study suggested that the suppression of NF-κB signal likely alleviated the vaccine adverse reaction 29,30 , which might partially explain much less adverse reaction cases was reported by the vaccine recipients of BBIBP-CorV. Even though, the antibody productions of our participants were satisfactory.…”

Toll-Like Receptor Response to Hepatitis B Virus Infection and Potential of TLR Agonists as Immunomodulators for Treating Chronic Hepatitis B: An Overview

“…In PBMCs from CHB patients, it has also been shown that anti–SIGLEC-3 mAb could reverse the effect and induce a cytokine response to the TLR-7 agonist, GS-9620 [ 128 ]. TLR agonists as vaccine adjuvants are currently under investigation for different human vaccines, including HBV vaccines, and appear promising in vaccine studies [ 129 , 130 ]. Vaccines containing particular TLR agonist(s) may activate specific TLR(s) and enhance vaccine efficacy without direct participation in protective immunity [ 131 , 132 ].…”