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

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

doi:10.1172/jci.insight.91020

Cited by 90 publications

(108 citation statements)

References 60 publications

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“…Together with the increased antibody at early times post vaccination, the sustained increase strengthens the case for the use of conjugated R848 as an effective adjuvant in the context of the neonate. Additional support of the utility of TLR7/8 agonists in neonates comes from a recent study reporting the ability of a lipidated form of 3M-052 to increase antibody responses elicited in rhesus macaque neonates in the context of pneumococcal PCV13 vaccination [22]. In agreement with our study, the authors showed increases in antibody that were maintained at 150 days post vaccination [22].…”

Section: Discussionsupporting

confidence: 90%

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Holbrook

D’Agostino

Aycock

et al. 2017

Vaccine

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Generation of a potent antibody response that can be sustained over time is highly challenging in young infants. Our previous studies using a nursery-reared nonhuman primate model identified R848 conjugated to inactivated influenza virus as a highly immunogenic vaccine for neonates. Here we determined the effectiveness of this vaccine in mother-reared infants as well as its ability to promote improved responses at 6 months compared to vaccination in the absence of R848. In agreement with our nursery study, R848 conjugated to influenza virus induced a higher antibody response in neonates compared to the non-adjuvanted vaccine. Further, the increase in the response relative to that induced by the non-adjuvanted vaccine was maintained at 6 months suggesting the increased antibody secreting cells that resulted from inclusion of conjugated R848 production were capable of surviving long term. There was no significant difference in quality of antibody (i.e. neutralization or affinity), suggesting the beneficial effect of conjugated R848 during vaccination of neonates with inactivated influenza virus is likely manifest during the early generation of antibody secreting cells.

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Section: Discussionsupporting

confidence: 90%

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Holbrook

D’Agostino

Aycock

et al. 2017

Vaccine

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“…The use of in vitro systems that model soluble (plasma) and cellular age-specific human immune responses and the systems biology ("omics") approaches to biomarker and pathway discovery have enabled (i) the identification of age-specific adjuvants/adjuvant combinations to inform targeted adjuvanted vaccine development (85) and (ii) the benchmarking of new versus licensed vaccines to accelerate age-specific vaccine development. In vitro human newborn and adult monocyte studies have shown the following: (i) adjuvant, age, and kinetic concordance of monocyte secretome proteins in silico with gene expression levels in adults immunized with an monophosphoryl lipid A-adjuvanted malaria vaccine; (ii) TLR7/8-activating imidazoquinolines are more potent and efficacious than alum in inducing IL-1␤ and TNF from human neonatal and adult monocytes (86); and (iii) TLR7/8 adjuvantation dramatically accelerates and enhances neonatal immune responses to pneumococcal conjugate vaccine (PCV-13) in newborn nonhuman primates (87). Jay Evans (Missoula, MT, USA) discussed adjuvant systems as an approach to address some of the challenges in vaccine development, and he defined the role of adjuvants as being able to enhance, modulate, and direct the appropriate immune response to a vaccine Ag, promote CMI or humoral immune responses, enhance immunogenicity to weak Ags, reduce the dose of Ag required, improve efficacy in hard-to-reach populations, improve immunologic memory, and expand T and B cell repertoires in order to gain vaccine-induced long-term immunity.…”

Section: Novel Translational and Clinical Research Strategies To Provmentioning

confidence: 99%

Waning Immunity and Microbial Vaccines—Workshop of the National Institute of Allergy and Infectious Diseases

Plotkin

Edwards

et al. 2017

Clin Vaccine Immunol

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Since the middle of the 20th century, vaccines have made a significant public health impact by controlling infectious diseases globally. Although long-term protection has been achieved with some vaccines, immunity wanes over time with others, resulting in outbreaks or epidemics of infectious diseases. Long-term protection against infectious agents that have a complex life cycle and antigenic variation remains a key challenge. Novel strategies to characterize the short-and long-term immune responses to vaccines and to induce immune responses that mimic natural infection have recently emerged. New technologies and approaches in vaccinology, such as adjuvants, delivery systems, and antigen formulations, have the potential to elicit more durable protection and fewer adverse reactions; together with in vitro systems, these technologies have the capacity to model and accelerate vaccine development. The National Institute of Allergy and Infectious Diseases (NIAID) held a workshop on 19 September 2016 that focused on waning immunity to selected vaccines (for Bordetella pertussis, Salmonella enterica serovar Typhi, Neisseria meningitidis, influenza, mumps, and malaria), with an emphasis on identifying knowledge gaps, future research needs, and how this information can inform development of more effective vaccines for infectious diseases.

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“…). We and others have begun to explore this as a mechanism to overcome the immune deficits present in neonates . TLRs belong to a family of receptors that recognize molecules derived from viral, bacterial and fungal pathogens as well as endogenous molecules that signal danger .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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

Cited by 90 publications

References 60 publications

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Waning Immunity and Microbial Vaccines—Workshop of the National Institute of Allergy and Infectious Diseases

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

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