An R848 adjuvanted influenza vaccine promotes early activation of B cells in the draining lymph nodes of non‐human primate neonates

Abstract

Impaired immune responsiveness is a significant barrier to vaccination of neonates. By way of example, the low seroconversion observed following influenza vaccination has led to restriction of its use to infants over 6 months of age, leaving younger infants vulnerable to infection. Our previous studies using a non-human primate neonate model demonstrated that the immune response elicited following vaccination with inactivated influenza virus could be robustly increased by inclusion of the Toll-like receptor agonist flagellin or R848, either delivered individually or in combination. When delivered individually, R848 was found to be the more effective of the two. To gain insights into the mechanism through which these adjuvants functioned in vivo, we assessed the initiation of the immune response, i.e. at 24 hr, in the draining lymph node of neonate non-human primates. Significant up-regulation of co-stimulatory molecules on dendritic cells could be detected, but only when both adjuvants were present. In contrast, R848 alone could increase the number of cells in the lymph node, presumably through enhanced recruitment, as well as B-cell activation at this early time-point. These changes were not observed with flagellin and the dual adjuvanted vaccine did not promote increases beyond those observed with R848 alone. In vitro studies showed that R848 could promote B-cell activation, supporting a model wherein a direct effect on neonate B-cell activation is an important component of the in vivo potency of R848 in neonates.

Adjuvant-Dependent Enhancement of HIV Env-Specific Antibody Responses in Infant Rhesus Macaques

“…We chose the TLR7/8 agonist 3M-052 because TLR7/8 agonists are uniquely able to activate neonatal and infant APCs (2,9). Indeed, our results demonstrated that the highest breadth and functionality were observed when infant macaques were vaccinated with the 3M-052-SE-adjuvanted Env protein (38,39). Our finding that 3M-052-SE outperformed GLA-SE is consistent with previous studies documenting the potency of TLR7/8-based adjuvants for pediatric vaccines.…”

“…Our finding that 3M-052-SE outperformed GLA-SE is consistent with previous studies documenting the potency of TLR7/8-based adjuvants for pediatric vaccines. This includes the aforementioned vaccination of neonatal macaques with PCV in the absence and presence of 3M-052 (15) and a study in which infant macaques vaccinated with an inactivated influenza vaccine conjugated to the TLR7/8 agonist R848 developed enhanced and sustained antibody responses compared to responses of infants receiving unadjuvanted vaccine (38,39). In contrast to alum or oil-in-water emulsions like MF59, adjuvants based on or incorporating TLR ligands can directly activate innate responses and thereby improve priming and the induction of adaptive immune responses by vaccination.…”

Distinguishing naive‐ from memory‐derived human B cells during acute responses

“…Similarly, Kwissa et al found that CD14 + CD16 + monocytes, which are induced by dengue virus infection, and by R848 but not CpG, enhance B‐cell differentiation, providing another possible explanation for the differential role of monocytes in R848‐ versus CpG‐stimulated B‐cell differentiation. The capacity of TLR7/8 agonists to induce B‐cell differentiation is also apparent in vivo whereby adjuvanting inactivated influenza vaccine with a TLR7 agonist accelerates B‐cell differentiation and antibody secretion in mice and non‐human primate neonates . Analogously, inactivated whole‐virion influenza vaccine, as opposed to subunit or split virion vaccines, induces TLR7‐mediated B‐cell activation and increased antibody production in mice .…”

“…The capacity of TLR7/8 agonists to induce B-cell differentiation is also apparent in vivo whereby adjuvanting inactivated influenza vaccine with a TLR7 agonist accelerates B-cell differentiation and antibody secretion in mice 39 and non-human primate neonates. 40 Analogously, inactivated wholevirion influenza vaccine, as opposed to subunit or split virion vaccines, induces TLR7-mediated B-cell activation and increased antibody production in mice. 41 IFN-a is also secreted by monocytes and is essential for inducing TLR7 expression by B cells, 12,42,43 but was not detected via CBA in any of our B-cell culture supernatants (data not shown).…”

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

“…The effects of vita‐PAMPs as signature of microbial viability in live vaccination can be substituted by synthetic TLR8 agonists, such as CL075, which could overcome the safety concerns of live vaccines . The efficacy of TLR7/8 ligands as potent adjuvants was already confirmed in different experimental setups including nonhuman primates . Interestingly, the archaeon M. stadtmanae is recognized by the innate immune system solely dependent on TLR8 and TLR7 and apparently without the involvement of any other innate immune receptors .…”