Safety and Cross‐Reactive Immunogenicity of Candidate AS03‐Adjuvanted Prepandemic H5N1 Influenza Vaccines: A Randomized Controlled Phase 1/2 Trial in Adults

Langley, Joanne M.; Frenette, Louise; Ferguson, Linda; Riff, Dennis; Sheldon, Eric; Risi, George; Johnson, Casey; Li, Ping; Kenney, Richard T.; Innis, Bruce L.; Fries, Louis

doi:10.1086/652701

Cited by 85 publications

(56 citation statements)

References 25 publications

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“…The AS03 adjuvant system is specifically designed to increase innate immune responses by enhancing migration of monocytes and macrophages and by increasing localized production of a range of cytokines and chemokines intramuscularly at the site of injection and in the draining lymph nodes. Thus, the higher local reactogenicity observed in the HiP-AS group than in the HiP group may be secondary to these enhanced innate immune responses elicited at the site of injection and therefore is not unexpected (32,33). This was consistently observed in studies evaluating AS03-adjuvanted influenza vaccines, in which higher local reactogenicity was observed with adjuvanted versus nonadjuvanted vaccines (34,35).…”

Section: Discussionmentioning

confidence: 72%

Safety, Immunogenicity, and Antibody Persistence following an Investigational Streptococcus pneumoniae and Haemophilus influenzae Triple-Protein Vaccine in a Phase 1 Randomized Controlled Study in Healthy Adults

Berglund

Vink

Silva

et al. 2014

Clin Vaccine Immunol

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cWe investigated a protein-based nontypeable Haemophilus influenzae (NTHi) and pneumococcal (HiP) vaccine containing pneumococcal histidine triad D (PhtD), detoxified pneumolysin (dPly), and NTHi protein D (PD) in adults. In a phase I study, 40 healthy 18-to 40-year-old subjects were randomized (2:2:1) to receive two HiP doses administered 60 days apart, with or without AS03 adjuvant (HiP-AS and HiP groups, respectively), or Engerix B (GlaxoSmithKline, Belgium) as a control. Safety, antibodies, and antigen-specific CD4؉ T-cell immune responses were assessed before and until 480 days after vaccination. No serious adverse events were reported, and no subject withdrew due to an adverse event. Local and systemic symptoms were reported more frequently in the HiP-AS group than in the other two groups. The frequency and intensity of local and systemic symptoms appeared to increase after the second dose of HiP-AS or HiP but not Engerix B. Antibody geometric mean concentrations (GMCs) for PhtD, dPly, and PD increased after each dose of HiP-AS or HiP, with higher GMCs being observed in the HiP-AS group (statistically significant for anti-PD after dose 1 and anti-Ply after dose 2). GMCs remained higher at day 420 than prior to vaccination in both the HiP-AS and HiP groups. Antigen-specific CD4 ؉ T cells increased after each dose but were unmeasurable by day 480. Two doses of an investigational PhtD-dPly-PD protein vaccine induced humoral immunity and antigenspecific CD4؉ T-cell responses after each dose, with generally higher responses when the vaccine was administered with AS03. HiP combined with AS03 appeared to be more reactogenic than the antigens alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT00814489.)

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Section: Discussionmentioning

confidence: 72%

Safety, Immunogenicity, and Antibody Persistence following an Investigational Streptococcus pneumoniae and Haemophilus influenzae Triple-Protein Vaccine in a Phase 1 Randomized Controlled Study in Healthy Adults

Berglund

Vink

Silva

et al. 2014

Clin Vaccine Immunol

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“…Two different doses of AS03 (AS03A, containing the full dose of 2.5% squalene and 2.5% ␣-tocopherol, versus AS03B, containing a half dose) were evaluated in another influenza vaccine clinical trial, where it was concluded that while initial immune responses elicited by the two different adjuvant doses were equivalent, the durability of the response measured at 182 days postvaccination was somewhat better with the higher adjuvant dose (21). Furthermore, the 41-to 64-year-old age group showed significantly reduced antibody responses at the lower adjuvant dose.…”

Section: Figmentioning

confidence: 99%

“…Both of these adjuvants contain squalene at ϳ2.5% (vol/vol) in the final vaccine formulation (13). However, until recently, only a few reports regarding the motivation for selecting this squalene concentration were published (9,21,25). Moreover, a recent study showed that dilution of MF59 did not compromise the immune response in a pandemic influenza vaccine clinical trial (20).…”

mentioning

confidence: 99%

Effects on Immunogenicity by Formulations of Emulsion-Based Adjuvants for Malaria Vaccines

Fox¹,

Baldwin²,

Vedvick³

et al. 2012

Clin. Vaccine Immunol.

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bNew malaria vaccines are urgently needed to improve vaccine protective efficacy. PfCelTOS is a recombinant malaria vaccine antigen that has shown protective efficacy in a small-animal challenge model when combined with a water-in-oil emulsion adjuvant (Montanide ISA 720). In this report, we show that PfCelTOS vaccines containing GLA-SE (a stable oil-in-water emulsion combined with a Toll-like receptor 4 [TLR4] agonist) elicit strong Th1-type immune responses in BALB/c mice. These responses include higher antigen-specific IgG2a antibody titers and more gamma interferon (IFN-␥) production than those seen with a PfCelTOS vaccine containing Montanide ISA 720. Furthermore, reducing the emulsion dose from 2% to 1% or 0.5% (vol/vol) squalene in GLA-SE did not compromise immunogenicity. Emulsion dose titration in the absence of formulated GLA caused some reduction in humoral and cellular immune responses compared to those with the 2% squalene emulsion dose. Oil-in-water (o/w) emulsions have been used safely and successfully as adjuvants in modern vaccines. The most notable o/w emulsions are MF59 and AS03, which are produced by Novartis and GSK Biologicals, respectively. Both of these adjuvants contain squalene at ϳ2.5% (vol/vol) in the final vaccine formulation (13). However, until recently, only a few reports regarding the motivation for selecting this squalene concentration were published (9,21,25). Moreover, a recent study showed that dilution of MF59 did not compromise the immune response in a pandemic influenza vaccine clinical trial (20). If adjuvant activity can be maintained with a reduction of the squalene dose, then the local reactogenicity of o/w emulsions can potentially be reduced. Furthermore, the vaccine cost could decrease while the available adjuvant supply would increase, thus making vaccine and adjuvant production in resource-poor countries more achievable.The recombinant malaria antigen PfCelTOS (Plasmodium falciparum cell traversal protein for ookinetes and sporozoites) combined with an emulsion adjuvant (Montanide ISA 720) protected 60% of mice in a heterologous challenge model (8). PfCelTOS inhibits sporozoite motility and hepatocyte infectivity and could be an important component of new malaria vaccines. Both cellular and humoral immune responses are important for protective efficacy directed against this antigen (7,8).In this work, we evaluated squalene-based stable emulsion (SE) adjuvant dose effects on humoral and cellular immune responses to PfCelTOS. Moreover, we investigated the effect of including a formulated synthetic Toll-like receptor 4 (TLR4) agonist, glucopyranosyl lipid adjuvant (GLA), in the vaccine formulation. We show that squalene concentrations of Ͻ2% (vol/vol) in GLA-SE may induce adjuvant responses equivalent to those seen with a 2% (vol/vol) squalene concentration. This finding has important implications for vaccine adjuvant production and dosing as well as for novel routes of administration (such as intradermal routes), which may be more sensitive to oil concentrations. Mo...

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“…[41][42][43][44] A recently published phase 2 open-label study that includes adults older than 61 y assessed the immune response elicited after two single or two double doses of ASO3 adjuvanted H5N1 vaccine administered 21 d apart compared with unadjuvanted influenza vaccine. Two injections of a single dose of 3.75mg H5N1 ASO3 adjuvanted vaccine were shown to elicit high levels of HA and neutralizing antibodies and cell mediated immunity was maintained for six months after vaccination.…”

Section: New Vaccinesmentioning

confidence: 99%

Influenza vaccination for older adults

Talbot

Libster

Edwards

2012

Human Vaccines & Immunotherapeutics

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Safety and Cross‐Reactive Immunogenicity of Candidate AS03‐Adjuvanted Prepandemic H5N1 Influenza Vaccines: A Randomized Controlled Phase 1/2 Trial in Adults

Abstract: Humoral responses against the adjuvanted 3.75-microg hemagglutinin antigen vaccines from both manufacturing sites fulfilled European and US licensure criteria for immunogenicity for influenza vaccines.

Cited by 85 publications

References 25 publications

Safety, Immunogenicity, and Antibody Persistence following an Investigational Streptococcus pneumoniae and Haemophilus influenzae Triple-Protein Vaccine in a Phase 1 Randomized Controlled Study in Healthy Adults

Safety, Immunogenicity, and Antibody Persistence following an Investigational Streptococcus pneumoniae and Haemophilus influenzae Triple-Protein Vaccine in a Phase 1 Randomized Controlled Study in Healthy Adults

Effects on Immunogenicity by Formulations of Emulsion-Based Adjuvants for Malaria Vaccines

Influenza vaccination for older adults

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