Enhanced immunogenicity of a respiratory syncytial virus (RSV) F subunit vaccine formulated with the adjuvant GLA-SE in cynomolgus macaques

Patton, Kathryn; Aslam, Shahin; Shambaugh, Cindy; Lin, Rui; Heeke, Darren; Frantz, Chris; Zuo, Fengrong; Esser, Mark T.; Paliard, Xavier; Lambert, Stacie

doi:10.1016/j.vaccine.2015.07.025

Cited by 30 publications

(33 citation statements)

References 28 publications

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“…In this study, the ability of a vaccine based on the F protein (in the postfusion configuration) from an RSV A strain to elicit antibodies to RSV B was demonstrated, confirming in humans what had previously been demonstrated in a nonhuman primate study ( 18 ). This generation of cross-neutralizing antibodies is expected, given the conserved nature of the F protein ( 20 ).…”

Section: Discussionsupporting

confidence: 88%

“…We present the results of the second study of a vaccine containing soluble RSV fusion protein (sF) in the postfusion configuration and a Toll-like receptor 4 (TLR-4) agonist adjuvant, glucopyranosyl lipid A (GLA), in a squalene-based stable emulsion (SE), which was designed to promote a TH1-biased immune response ( 15 – 18 ). There has been general agreement that an RSV vaccine for older adults should contain the F protein, because it induces neutralizing antibodies and is conserved across the RSV A and B subtypes and over time, so that annual reformulation would not be necessary ( 19 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

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Dose Selection for an Adjuvanted Respiratory Syncytial Virus F Protein Vaccine for Older Adults Based on Humoral and Cellular Immune Responses

Falloon¹,

Talbot

Curtis

et al. 2017

Clin Vaccine Immunol

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This is the second phase 1 study of a respiratory syncytial virus (RSV) vaccine containing RSV fusion protein (sF) adjuvanted with glucopyranosyl lipid A (GLA) in a squalene-based 2% stable emulsion (GLA-SE). In this randomized, double-blind study, 261 subjects aged ≥60 years received inactivated influenza vaccine (IIV), a vaccine containing 120 μg sF with escalating doses of GLA (1, 2.5, or 5 μg) in SE, or a vaccine containing 80 μg sF with 2.5 μg GLA in SE. Subjects receiving 120 μg sF with 2.5 or 5 μg GLA were also randomized to receive IIV or placebo. Immunity to RSV was assessed by detection of microneutralizing, anti-F immunoglobulin G, and palivizumab-competitive antibodies and F-specific gamma interferon enzyme-linked immunosorbent spot assay T-cell responses. Higher adjuvant doses increased injection site discomfort, but at the highest dose, the reactogenicity was similar to that of IIV. Significant humoral and cellular immune responses were observed. The 120 μg sF plus 5.0 μg GLA formulation resulted in the highest responses in all subjects and in older subjects. These results confirm previous observations of vaccine tolerability, safety, and immunogenicity and were used to select the 120 μg sF plus 5.0 μg GLA formulation for phase 2 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT02289820.)

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Dose Selection for an Adjuvanted Respiratory Syncytial Virus F Protein Vaccine for Older Adults Based on Humoral and Cellular Immune Responses

Falloon¹,

Talbot

Curtis

et al. 2017

Clin Vaccine Immunol

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“…However, recombinant soluble RSV post-F (produced in Chinese hamster ovary [CHO] cells), when adjuvanted with the synthetic Toll-like receptor 4 (TLR4) agonist glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE) (GLA-SE), has been shown to elicit a strong anti-RSV F immune response, a Th1-biased cellular immune response, and cytotoxic T lymphocytes, all of which led to protection from RSV challenge in BALB/c mice and cotton rats (18,19). This vaccine candidate is currently in a phase 2 clinical trial in seropositive older adults (5).…”

mentioning

confidence: 99%

Immunization with Low Doses of Recombinant Postfusion or Prefusion Respiratory Syncytial Virus F Primes for Vaccine-Enhanced Disease in the Cotton Rat Model Independently of the Presence of a Th1-Biasing (GLA-SE) or Th2-Biasing (Alum) Adjuvant

Schneider-Ohrum¹,

Cayatte²,

Bennett³

et al. 2017

J Virol

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Respiratory syncytial virus (RSV) infection of children previously immunized with a nonlive, formalin-inactivated (FI)-RSV vaccine has been associated with serious enhanced respiratory disease (ERD). Consequently, detailed studies of potential ERD are a critical step in the development of nonlive RSV vaccines targeting RSV-naive children and infants. The fusion glycoprotein (F) of RSV in either its postfusion (post-F) or prefusion (pre-F) conformation is a target for neutralizing antibodies and therefore an attractive antigen candidate for a pediatric RSV subunit vaccine. Here, we report the evaluation of RSV post-F and pre-F in combination with glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE) (GLA-SE) and alum adjuvants in the cotton rat model. Immunization with optimal doses of RSV F antigens in the presence of GLA-SE induced high titers of virus-neutralizing antibodies and conferred complete lung protection from virus challenge, with no ERD signs in the form of alveolitis. To mimic a waning immune response, and to assess priming for ERD under suboptimal conditions, an antigen dose de-escalation study was performed in the presence of either GLA-SE or alum. At low RSV F doses, alveolitis-associated histopathology was unexpectedly observed with either adjuvant at levels comparable to FI-RSV-immunized controls. This occurred despite neutralizing-antibody titers above the minimum levels required for protection and with no/low virus replication in the lungs. These results emphasize the need to investigate a pediatric RSV vaccine candidate carefully for priming of ERD over a wide dose range, even in the presence of strong neutralizing activity, Th1 bias-inducing adjuvant, and protection from virus replication in the lower respiratory tract.IMPORTANCE RSV disease is of great importance worldwide, with the highest burden of serious disease occurring upon primary infection in infants and children. FI-RSV-induced enhanced disease, observed in the 1960s, presented a major and ongoing obstacle for the development of nonlive RSV vaccine candidates. The findings presented here underscore the need to evaluate a nonlive RSV vaccine candidate during preclinical development over a wide dose range in the cotton rat RSV enhanced-disease model, as suboptimal dosing of several RSV F subunit vaccine candidates led to the priming for ERD. These observations are relevant to the validity of

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“…GLA-SE has been tested in several preclinical subunit vaccine studies targeting herpes simplex virus-2 (HSV-2), Schistosomiasis, respiratory syncytial virus and the perioperative treatment of cancers to reduce metastasis to name a few. [45][46][47][48] All of which indicate GLA is safe and a viable adjuvant that is currently on a clinical path.…”

Section: Toll-like Receptormentioning

confidence: 99%

Toll‐like receptors: the swiss army knife of immunity and vaccine development

2016

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Innate immune cells have a critical role in defense against infection and disease. Central to this is the broad specificity with which they can detect pathogen-associated patterns and danger-associated patterns via the pattern recognition receptors (PRRs) they express. Several families of PRRs have been identified including: Toll-like receptors (TLRs), C-type lectin-like receptors, retinoic acid-inducible gene-like receptors and nucleotide-binding oligomerization domain–like receptors. TLRs are one of the most largely studied families of PRRs. The binding of ligands to TLRs on antigen presenting cells (APCs), mainly dendritic cells, leads to APC maturation, induction of inflammatory cytokines and the priming of naive T cells to drive acquired immunity. Therefore, activation of TLRs promotes both innate inflammatory responses and the induction of adaptive immunity. Consequently, in the last two decades mounting evidence has inextricably linked TLR activation with the pathogenesis of immune diseases and cancer. It has become advantageous to harness these aspects of TLR signaling therapeutically to accelerate and enhance the induction of vaccine-specific responses and also target TLRs with the use of biologics and small molecule inhibitors for the treatment of disease. In these respects, TLRs may be considered a ‘Swiss Army' knife of the immune system, ready to respond in a multitude of infectious and disease states. Here we describe the latest advances in TLR-targeted therapeutics and the use of TLR ligands as vaccine adjuvants.

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Enhanced immunogenicity of a respiratory syncytial virus (RSV) F subunit vaccine formulated with the adjuvant GLA-SE in cynomolgus macaques

Cited by 30 publications

References 28 publications

Dose Selection for an Adjuvanted Respiratory Syncytial Virus F Protein Vaccine for Older Adults Based on Humoral and Cellular Immune Responses

Dose Selection for an Adjuvanted Respiratory Syncytial Virus F Protein Vaccine for Older Adults Based on Humoral and Cellular Immune Responses

Immunization with Low Doses of Recombinant Postfusion or Prefusion Respiratory Syncytial Virus F Primes for Vaccine-Enhanced Disease in the Cotton Rat Model Independently of the Presence of a Th1-Biasing (GLA-SE) or Th2-Biasing (Alum) Adjuvant

Toll‐like receptors: the swiss army knife of immunity and vaccine development

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