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      Toward precision adjuvants: optimizing science and safety

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          Abstract

          Purpose of review

          The gradual replacement of inactivated whole cell and live attenuated vaccines with subunit vaccines has generally reduced reactogenicity but in many cases also immunogenicity. Although only used when necessary, adjuvants can be key to vaccine dose/antigen-sparing, broadening immune responses to variable antigens, and enhancing immunogenicity in vulnerable populations with distinct immunity. Licensed vaccines contain an increasing variety of adjuvants, with a growing pipeline of adjuvanted vaccines under development.

          Recent findings

          Most adjuvants, including Alum, Toll-like receptor agonists and oil-in-water emulsions, activate innate immunity thereby altering the quantity and quality of an adaptive immune response. Adjuvants activate leukocytes, and induce mediators (e.g., cytokines, chemokines, and prostaglandin-E 2) some of which are biomarkers for reactogenicity, that is, induction of local/systemic side effects. Although there have been safety concerns regarding a hypothetical risk of adjuvants inducing auto-immunity, such associations have not been established. As immune responses vary by population (e.g., age and sex), adjuvant research now incorporates principles of precision medicine. Innovations in adjuvant research include use of human in vitro models, immuno-engineering, novel delivery systems, and systems biology to identify biomarkers of safety and adjuvanticity.

          Summary

          Adjuvants enhance vaccine immunogenicity and can be associated with reactogenicity. Novel multidisciplinary approaches hold promise to accelerate and de-risk targeted adjuvant discovery and development.

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          Most cited references114

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          A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants.

          The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).
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            Towards an understanding of the adjuvant action of aluminium.

            The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work.
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              Vaccine Adjuvants: from 1920 to 2015 and Beyond

              The concept of stimulating the body’s immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines.
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                Author and article information

                Journal
                Curr Opin Pediatr
                Curr. Opin. Pediatr
                COPED
                Current Opinion in Pediatrics
                Lippincott Williams and Wilkins
                1040-8703
                1531-698X
                February 2020
                06 January 2020
                : 32
                : 1
                : 125-138
                Affiliations
                [a ] Precision Vaccines Program
                [b ]Division of Infectious Diseases, Boston Children's Hospital
                [c ]Harvard Medical School, Boston
                [d ]Broad Institute of MIT & Harvard, Cambridge, Massachusetts, USA
                Author notes
                Correspondence to Ofer Levy, MD, PhD, Staff Physician & Principal Investigator, Director, Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital; Professor, Harvard Medical School; Associate Member, Broad Institute, Harvard Institutes of Medicine, Rm 837A, Boston, MA 02115, USA. Tel: +1 617 919 2904; e-mail: ofer.levy@ 123456childrens.harvard.edu , Twitter:@ 123456PrecVaccines
                Article
                MOP320124 00018
                10.1097/MOP.0000000000000868
                6970548
                31904601
                cf68797b-2fb4-4c13-bab8-2773f9bd7cd3
                Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                Categories
                INFECTIOUS DISEASES AND IMMUNIZATION: Edited by Grace Lee
                Custom metadata
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                adjuvant,biomarker,reactogenicity,safety,vaccine
                adjuvant, biomarker, reactogenicity, safety, vaccine

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