The adjuvant GLA-AF enhances human intradermal vaccine responses

Carter, Darrick; Hoeven, Neal Van; Baldwin, Susan L.; Levin, Yotam; Kochba, Efrat; Magill, Al; Charland, Nathalie; Landry, Nathalie; Nu, Khin; Frevol, Aude; Ashman, Jill A.; Sagawa, Zachary K.; Beckmann, Anna Marie; Reed, Steven G.

doi:10.1126/sciadv.aas9930

Cited by 42 publications

(46 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Humoral immune responses in guinea pigs. We assessed the immunogenicity of INO-4800 in the Hartley guinea pig model, an established model for intradermal vaccine delivery 17,18 . One hundred micrograms of pDNA was administered by Mantoux injection to the skin and followed by CELLECTRA® delivery device on day 0 as described in the methods section.…”

Section: Resultsmentioning

confidence: 99%

Immunogenicity of a DNA vaccine candidate for COVID-19

et al. 2020

View full text Add to dashboard Cite

The coronavirus family member, SARS-CoV-2 has been identified as the causal agent for the pandemic viral pneumonia disease, COVID-19. At this time, no vaccine is available to control further dissemination of the disease. We have previously engineered a synthetic DNA vaccine targeting the MERS coronavirus Spike (S) protein, the major surface antigen of coronaviruses, which is currently in clinical study. Here we build on this prior experience to generate a synthetic DNA-based vaccine candidate targeting SARS-CoV-2 S protein. The engineered construct, INO-4800, results in robust expression of the S protein in vitro. Following immunization of mice and guinea pigs with INO-4800 we measure antigen-specific T cell responses, functional antibodies which neutralize the SARS-CoV-2 infection and block Spike protein binding to the ACE2 receptor, and biodistribution of SARS-CoV-2 targeting antibodies to the lungs. This preliminary dataset identifies INO-4800 as a potential COVID-19 vaccine candidate, supporting further translational study.

show abstract

Section: Resultsmentioning

confidence: 99%

Immunogenicity of a DNA vaccine candidate for COVID-19

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Altogether, those results do not support the use of Al(OH) 3 for ID immunization. GLA-AF, an emulsion-free aqueous formulation with glucopyranosyl lipid adjuvant, a TLR-4 agonist, has been evaluated for ID immunization with an H5-VLP influenza vaccine and showed low skin reactogenicity in guinea pigs and stimulated strong anti-H5 responses in C57BL/6 mice [33].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the reactogenicity, adjuvanticity and antigenicity of LT(R192G) and LT(R192G/L211A) by intradermal immunization in mice

et al. 2019

View full text Add to dashboard Cite

The development of an effective subunit vaccine is frequently complicated by the difficulty of eliciting protective immune responses, often requiring the co-administration of an adjuvant. Heat-labile toxin (LT), an enterotoxin expressed by enterotoxigenic E. coli (ETEC) with an AB5 structure similar to cholera toxin, is a strong adjuvant. While the mucosa represents the natural route of exposure to LT and related toxins, the clinical utility of LT and similar adjuvants given by mucosal routes has been limited by toxicity, as well as the association between intranasal delivery of LT and Bell’s palsy. Single and double amino acid mutants of LT, LT(R192G)/mLT and LT(R192G/L211A)/dmLT respectively, have been proposed as alternatives to reduce the toxicity associated with the holotoxin. In the present study, we compared mLT and dmLT given via a non-mucosal route (i.e. intradermally) to investigate their adjuvanticity when co-administrated with an enterotoxigenic E. coli vaccine candidate, CfaEB. Antigenicity (i.e. ability to elicit response against LT) and reactogenicity at the injection site were also evaluated. BALB/c mice were immunized by the intradermal route with CfaEB plus increasing doses of either mLT or dmLT (0.01 to 2.5 μg). Both adjuvants induced dose-dependent skin reactogenicity, with dmLT being less reactogenic than mLT. Both adjuvants significantly boosted the anti-CfaE IgG and functional hemagglutination inhibiting (HAI) antibody responses, compared to the antigen alone. In addition to inducing anti-LT responses, even at the lowest dose tested (0.01 μg), the adjuvants also prompted in vitro cytokine responses (IFN-γ, IL-4, IL-5, IL-10 and IL-17) that followed different patterns, depending on the protein used for stimulation (CfaE or LTB) and/or the dose used for immunization. The two LT mutants evaluated here, mLT and dmLT, are potent adjuvants for intradermal immunization and should be further investigated for the intradermal delivery of subunit ETEC vaccines.

show abstract

“…Intradermal vaccine injection has been shown to elicit potent systemic and mucosal immune responses 39 , potentiate responses to co-administered antigens, as well as having antigen-sparing advantages 40 , 41 . However, in some cases, local adverse reactions seem to be more serious with intradermal than IM administration 42 , 43 . Our investigational products were administered intramuscularly to evaluate the more traditional vaccination route without need for costly devices or additional training, which would allow for more optimal transition for use in less developed countries.…”

Section: Discussionmentioning

confidence: 99%

Preclinical optimization of an enterotoxigenic Escherichia coli adjuvanted subunit vaccine using response surface design of experiments

et al. 2020

View full text Add to dashboard Cite

Enterotoxigenic E. coli (ETEC) is a leading cause of moderate-to-severe diarrhoea. ETEC colonizes the intestine through fimbrial tip adhesin colonization factors and produces heat-stable and/or heat-labile (LT) toxins, stimulating fluid and electrolyte release leading to watery diarrhoea. We reported that a vaccine containing recombinant colonization factor antigen (CfaEB) targeting fimbrial tip adhesin of the colonization factor antigen I (CFA/I) and an attenuated LT toxoid (dmLT) elicited mucosal and systemic immune responses against both targets. Additionally, the toll-like receptor 4 ligand second-generation lipid adjuvant (TLR4-SLA) induced a potent mucosal response, dependent on adjuvant formulation. However, a combination of vaccine components at their respective individual optimal doses may not achieve the optimal immune profile. We studied a subunit ETEC vaccine prototype in mice using a response surface design of experiments (DoE), consisting of 64 vaccine dose-combinations of CfaEB, dmLT and SLA in four formulations (aqueous, aluminium oxyhydroxide, squalene-in-water stable nanoemulsion [SE] or liposomes containing the saponin Quillaja saponaria-21 [LSQ]). Nine readouts focusing on antibody functionality and plasma cell response were selected to profile the immune response of parenterally administered ETEC vaccine prototype. The data were integrated in a model to identify the optimal dosage of each vaccine component and best formulation. Compared to maximal doses used in mouse models (10 µg CfaEB, 1 µg dmLT and 5 µg SLA), a reduction in the vaccine components up to 37%, 60% and 88% for CfaEB, dmLT and SLA, respectively, maintained or even maximized immune responses, with SE and LSQ the best formulations. The DoE approach can help determine the best vaccine composition with a limited number of experiments and may accelerate development of multi-antigen/component ETEC vaccines.

show abstract

The adjuvant GLA-AF enhances human intradermal vaccine responses

Abstract: We present an adjuvant for intradermal use that works in humans, enabling self-administration in case of a flu pandemic.

Cited by 42 publications

References 37 publications

Immunogenicity of a DNA vaccine candidate for COVID-19

Immunogenicity of a DNA vaccine candidate for COVID-19

Evaluation of the reactogenicity, adjuvanticity and antigenicity of LT(R192G) and LT(R192G/L211A) by intradermal immunization in mice

Preclinical optimization of an enterotoxigenic Escherichia coli adjuvanted subunit vaccine using response surface design of experiments

Contact Info

Product

Resources

About