TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth
David J. Dowling, … , Pyone Pyone Aye, Ofer Levy
David J. Dowling, … , Pyone Pyone Aye, Ofer Levy
Published March 23, 2017
Citation Information: JCI Insight. 2017;2(6):e91020. https://doi.org/10.1172/jci.insight.91020.
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Research Article Vaccines

TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth

Abstract

Infection is the most common cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, newborns fail to respond optimally to most vaccines. Adjuvantation is a key approach to enhancing vaccine immunogenicity, but responses of human newborn leukocytes to most candidate adjuvants, including most TLR agonists, are functionally distinct. Herein, we demonstrate that 3M-052 is a locally acting lipidated imidazoquinoline TLR7/8 agonist adjuvant in mice, which, when properly formulated, can induce robust Th1 cytokine production by human newborn leukocytes in vitro, both alone and in synergy with the alum-adjuvanted pneumococcal conjugate vaccine 13 (PCV13). When admixed with PCV13 and administered i.m. on the first day of life to rhesus macaques, 3M-052 dramatically enhanced generation of Th1 CRM-197–specific neonatal CD4+ cells, activation of newborn and infant Streptococcus pneumoniae polysaccharide–specific (PnPS-specific) B cells as well as serotype-specific antibody titers, and opsonophagocytic killing. Remarkably, a single dose at birth of PCV13 plus 0.1 mg/kg 3M-052 induced PnPS-specific IgG responses that were approximately 10–100 times greater than a single birth dose of PCV13 alone, rapidly exceeding the serologic correlate of protection, as early as 28 days of life. This potent immunization strategy, potentially effective with one birth dose, could represent a new paradigm in early life vaccine development.

Authors

David J. Dowling, Simon D. van Haren, Annette Scheid, Ilana Bergelson, Dhohyung Kim, Christy J. Mancuso, Willemina Foppen, Al Ozonoff, Lynn Fresh, Terese B. Theriot, Andrew A. Lackner, Raina N. Fichorova, Dmitri Smirnov, John P. Vasilakos, Joe M. Beaurline, Mark A. Tomai, Cecily C. Midkiff, Xavier Alvarez, James L. Blanchard, Margaret H. Gilbert, Pyone Pyone Aye, Ofer Levy

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Figure 6

3M-052 enhances and accelerates activation of early life PnPS-specific B cells.

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3M-052 enhances and accelerates activation of early life PnPS-specific B...
(A and B) Antipneumococcal polysaccharide (PnPS) IgG/IgM-producing rhesus naive and memory B cell quantification. Higher frequencies of PnPS-specific B cells were noted in the (PCV13 + 3M-052) animals vs. the PCV13 group (n = 3–4). (C) Coadministration of 3M-052 with PCV13 to newborn rhesus macaques dramatically accelerated the transition of anti-PnPS B cells from naive to memory phenotype. Antipneumococcal polysaccharide (PnPS) IgG-producing naive (CD27–) and memory (CD27+) B cells were measured by flow cytometry. At day of life 28 (DOL28), the switch from naive to memory phenotype occurred earlier in (PCV13 + 3M-052)– vs. PCV13 only–immunized animals. Nonspecific polysaccharide in vitro activation in the control conditions (i.e., saline or 3M-052 alone) or specific CRM-197 treatment of B cells from all treatment groups never exceeded approximately 1.0%. For comparison at individual time points, the unpaired Mann-Whitney test was applied, *P < 0.05, **P < 0.01. Results represent mean ± SEM (n = 4 per group).