Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes

Calabrό, Samuele; Tortoli, Marco; Baudner, Barbara C.; Pacitto, Alessandra; Cortese, Mario; O’Hagan, Derek T.; Gregorio, Ennio De; Seubert, Anja; Wack, Andreas

doi:10.1016/j.vaccine.2010.12.090

Cited by 371 publications

(366 citation statements)

References 32 publications

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“…Oil-in-water emulsions, comprised of squalene nanodroplets (∼160 nM), successfully augment influenza vaccines in humans (5,6,15). These adjuvants stimulate local inflammatory responses at the injection site, which lead to leukocyte recruitment, antigen transport to draining lymph nodes, and APC activation (17). In preclinical models, adjuvants like MF59 appear to stimulate lymphocyte priming through a TLR-independent MyD88-dependent pathway (18) and subsequent Th2-mediated antibody responses (19), whereas the majority of helper CD4 T cells induced in people are biased to a Th0/Th1 phenotype (20,21).…”

Section: Discussionmentioning

confidence: 99%

Adjuvant solution for pandemic influenza vaccine production

Clegg

Roque

Hoeven

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Extensive preparation is underway to mitigate the next pandemic influenza outbreak. New vaccine technologies intended to supplant egg-based production methods are being developed, with recombinant hemagglutinin (rHA) as the most advanced program for preventing seasonal and avian H5N1 Influenza. Increased efforts are being focused on adjuvants that can broaden vaccine immunogenicity against emerging viruses and maximize vaccine supply on a worldwide scale. Here, we test protection against avian flu by using H5N1-derived rHA and GLA-SE, a two-part adjuvant system containing glucopyranosyl lipid adjuvant (GLA), a formulated synthetic Toll-like receptor 4 agonist, and a stable emulsion (SE) of oil in water, which is similar to the best-in-class adjuvants being developed for pandemic flu. Notably, a single submicrogram dose of rH5 adjuvanted with GLA-SE protects mice and ferrets against a high titer challenge with H5N1 virus. GLA-SE, relative to emulsion alone, accelerated induction of the primary immune response and broadened its durability against heterosubtypic H5N1 virus challenge. Mechanistically, GLA-SE augments protection via induction of a Th1-mediated antibody response. Innate signaling pathways that amplify priming of Th1 CD4 T cells will likely improve vaccine performance against future outbreaks of lethal pandemic flu.

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Section: Discussionmentioning

confidence: 99%

Adjuvant solution for pandemic influenza vaccine production

Clegg

Roque

Hoeven

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…MF59 was prepared as described (20). Desiccated Mycobacterium tuberculosis H37 Ra (Difco) was dissolved in PBS and used with Freund's Incomplete Adjuvant to give CFA.…”

Section: Methodsmentioning

confidence: 99%

“…peripheral blood mononuclear cells (7,18). In addition to antigen delivery functions, MF59 induces the local up-regulation of cytokines, chemokines, and other innate immunity genes in the muscle (19), which promote the recruitment of immune cells like monocytes, DCs, and granulocytes (20). The innate immune pathways required for MF59 adjuvanticity are unknown.…”

mentioning

confidence: 99%

Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

Seubert

Calabrό

Santini

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Oil-in-water emulsions have been successfully used to increase the efficacy, immunogenicity, and cross-protection of human vaccines; however, their mechanism of action is still largely unknown. Nlrp3 inflammasome has been previously associated to the activity of alum, another adjuvant broadly used in human vaccines, and MyD88 adaptor protein is required for the adjuvanticity of most Toll-like receptor agonists. We compared the contribution of Nlrp3 and MyD88 to the adjuvanticity of alum, the oil-in-water emulsion MF59, and complete Freund's adjuvant in mice using a threecomponent vaccine against serogroup B Neisseria meningitidis (rMenB). Although the basal antibody responses to the nonadjuvanted rMenB vaccine were largely dependent on Nlrp3, the highlevel antibody responses induced by alum, MF59, or complete Freund's adjuvant did not require Nlrp3. Surprisingly, we found that MF59 requires MyD88 to enhance bactericidal antibody responses to the rMenB vaccine. Because MF59 did not activate any of the Tolllike receptors in vitro, we propose that MF59 requires MyD88 for a Toll-like receptor-independent signaling pathway.

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“…However, it was subsequently shown that adsorbed antigens are released within first few hours after the injection [26]. It has been shown that aluminum adjutants induce strong innate immune responses that consist of an influx of neutrophils, eosinophils, NK cells, CD11b+ monocytes and dendritic cells (DCs) to the site of injection [27][28][29][30]. The cellular signaling pathways triggered by aluminum that activate DCs and macrophages and direct toward Th2 immune responses and effective humoral immunity against antigens have only recently been addressed.…”

Section: Discussionmentioning

confidence: 99%

Preliminary Assessment of Safety and Immunogenicity of an Inactivated Whole-Virion Vaccine against Influenza А (H1N1) Pdm09 Containing Aluminum Hydroxide Adjuvant: A Randomized, Blinded Phase I Clinical Study

Tabynov¹,

Khairullin²,

Kydyrbayev³

et al. 2013

J Vaccines Vaccin

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We performed a randomized, blinded, dose-dependent placebo-controlled phase I clinical study of single administration of Refluvac®, a monovalent inactivated whole-virion vaccine against pandemic influenza А (Н1N1) pdm09 containing aluminum adjuvant, in healthy volunteers aged 18-60. Single intramuscular injection at doses of 3.75, 7.5, or 15.0 µg hemagglutinin (НА) identified no safety issues in adult volunteers (n=12 per group); no severe or serious vaccination-related adverse events were observed. Only mild/moderate local adverse events (n= 3/12, 25% in 7.5 µg НА arm,) and one moderate systemic reaction (n=1/12, 8.3% in 15.0 µg НА arm) were observed. In volunteers vaccinated at 3.75 µg HA, the proportion of subjects with 4-fold seroconversion was 75%, the level of seroprotection was also 75%, the antibody titer increase was 10.7-fold, and the geometric mean titer (GMT) of antibodies to А/H1N1p-dm09 was 53.4; for the 7.5 µg HA dose, the proportion of 4-fold seroconversion was 75%, the antibody titer increase was 32.0-fold, the GMT was 160.0, and the level of seroprotection was 75%. When administered at a higher dose (15 µg HA), the proportion of subjects with protective antibody titers increased from 75% to 83%; however, the GMT and antibody titer increase were not significantly different (P>0.05) to the group vaccinated at 7.5 µg HA. Phase II clinical studies of the 3.75 and 7.5 µg HA doses of Refluvac® vaccine should be performed in a larger cohort of healthy volunteers aged 18-60. The effective immunogenicity of low doses of Refluvac® vaccine may enable increased production of pandemic influenza vaccines, and thus provide more people with a safe, effective vaccine. Citation: Tabynov K, Khairullin B, Kydyrbayev Z, Sandybayev N, Stukova M, et al. (2013) [16]. Notably, the lowest НА content required to induce a sufficient immune response was seen when whole-virion or adjuvant-containing vaccines were used. The НА content is the most important limiting factor when developing a pandemic vaccine, as existing production capacities for seasonal influenza vaccines are rather limited and are unable to meet the worldwide demand for a pandemic vaccine. Thus, a higher number of doses of vaccines with low antigenic loads can be manufactured. Journal of Vaccines & VaccinationOn this basis, in order to create a pandemic vaccine to protect the population of Kazakhstan and neighbouring Central Asian countries, an inactivated whole-virion vaccine (Refluvac®) against Н1N1pdm09 containing aluminum hydroxide adjuvant was developed at the Research Institute for Biological Safety Problems (Kazakhstan). We previously demonstrated the safety and immunogenicity of this vaccine in preclinical studies conducted at research centers in Russia (The Research Institute of Influenza, Institute of Toxicology, Chemical and Pharmaceutical Academy) and Kazakhstan (The National Center for Expertise on Drugs) [17,18]. On the basis of these preclinical studies, Refluvac® vaccine was recommended for a phase I clinical study of single intra...

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Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes

Cited by 371 publications

References 32 publications

Adjuvant solution for pandemic influenza vaccine production

Adjuvant solution for pandemic influenza vaccine production

Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

Preliminary Assessment of Safety and Immunogenicity of an Inactivated Whole-Virion Vaccine against Influenza А (H1N1) Pdm09 Containing Aluminum Hydroxide Adjuvant: A Randomized, Blinded Phase I Clinical Study

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