TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth
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
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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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 2

3M-052 synergistically enhances type 1 immunity from newborn leukocytes when combined with pneumococcal conjugate vaccine in vitro.

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3M-052 synergistically enhances type 1 immunity from newborn leukocytes ...
Human neonatal and adult blood cultured in vitro for 6 hours with buffer control (RPMI), oil-in-water (O/W) vehicle, PCV13 alone (1:5.7 to 1:57,000 v/v), 3M-052 alone (0.01, 0.1, 1, 10, 100 μM), or combinations of each. The dashed line indicates the vehicle control. Supernatants were collected for ELISA and multiplex assay, TNF (A and B, n = 12) and IFN-γ (C and D, n = 10). For comparisons between overall groups [e.g., (PCV13 + 3M-052) vs. PCV13], 2-way repeated-measures ANOVA for nonparametric sample populations were applied, ++P < 0.01, +++P < 0.001. For comparison at individual concentrations, unpaired Mann-Whitney test was applied at each time point, *P < 0.05, **P < 0.01, ***P < 0.001. Results represent mean ± SEM. Level of synergy was calculated using an adapted Loewe definition of additivity (D > 1: antagonism, D = 1: additivity, D < 1: synergy).