A phase 1a, first-in-human, randomized study of a respiratory syncytial virus F protein vaccine with and without a toll-like receptor-4 agonist and stable emulsion adjuvant

Falloon, Judith; Ji, Fei; Curtis, Craig; Bart, Stephan; Sheldon, Eric; Krieger, Diane; Dubovsky, Filip; Lambert, Stacie; Takas, Therese; Villafana, Tonya; Esser, Mark T.

doi:10.1016/j.vaccine.2016.04.002

Cited by 50 publications

(44 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RSV F in the postfusion conformation (RSV post-F) in combination with GLA-SE is currently being developed as a vaccine candidate for older adults (5). Recently, McLellan et al reported that a stabilized, soluble form of RSV F in the prefusion conformation (RSV pre-F) was able to induce higher levels of neutralizing antibodies than soluble RSV post-F in mice and nonhuman primates (NHP) and might serve as a preferred antigen for an RSV subunit vaccine (16,23).…”

Section: Resultsmentioning

confidence: 99%

“…RSV Journal of Virology post-F in combination with the synthetic TLR4 agonist GLA in a stable emulsion (GLA-SE) is currently under development as a prophylactic vaccine, preventing RSV disease in older adults (5). While the mechanism of action of RSV post-F plus GLA-SE to induce both a strong neutralizing-antibody response and a Th1-biased T cell response may be applicable for protection against RSV disease in infants, this type of adjuvanted recombinant subunit vaccine has never been tested in an RSV-seronegative pediatric population.…”

Section: Discussionmentioning

confidence: 99%

“…To date, the clinically most advanced RSV vaccines are focused on RSV-seropositive individuals, especially pregnant women and older adults (4). For these RSV-seropositive populations, clinical development is more straightforward due to a lack of safety concerns related to enhanced respiratory disease (ERD), encouraging active investigation of vaccine platforms, such as subunit vaccines (5,6). In contrast, vaccine development in seronegative pediatric populations has been primarily geared toward virally vectored or live-attenuated RSV vaccine platforms (4-7), due to the concern that immunization with nonlive vaccines, such as subunit vaccines, may prime for ERD.…”

mentioning

confidence: 99%

“…This vaccine candidate is currently in a phase 2 clinical trial in seropositive older adults (5). Because RSV post-F plus GLA-SE represents a nonlive vaccine platform, a comprehensive nonclinical assessment, including ERD studies, was conducted in the cotton rat prior to proceeding to clinical studies within pediatric populations.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

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

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

“…suggesting that it may also be effective with influenza 135,136 . Studies in children are more complex to perform, with a greater risk of unforeseen complications, but this doesn't stop …”

Section: Future Of Adjuvanted Flu Vaccinesmentioning

confidence: 99%

Adjuvanted influenza vaccines

Tregoning

Russell

Kinnear

2018

Human Vaccines & Immunotherapeutics

209

179

View full text Add to dashboard Cite

Nonclinical safety evaluation of two vaccine candidates for herpes simplex virus type 2 to support combined administration in humans

Piras

Plitnick

Berglund³

et al. 2022

J of Applied Toxicology

View full text Add to dashboard Cite

Herpes simplex virus type 2 (HSV-2) is the most common cause of genital disease worldwide. The development of an effective HSV-2 vaccine would significantly impact global health based on the psychological distress caused by genital herpes for some individuals, the risk transmitting the infection from mother to infant, and the elevated risk of acquiring HIV-1. Five nonclinical safety studies were conducted with the replication defective HSV529 vaccine, alone or adjuvanted with GLA-SE, and the G103 subunit vaccine containing GLA-SE. A biodistribution study was conducted in guinea pigs to evaluate distribution, persistence, and shedding of HSV529. A preliminary immunogenicity study was conducted in rabbits to demonstrate HSV529-specific humoral response and its enhancement by GLA-SE. Three repeated-dose toxicity studies, one in guinea pigs and two in rabbits, were conducted to assess systemic toxicity and local tolerance of HSV529, alone or adjuvanted with GLA-SE, or G103 containing GLA-SE. Data from these studies show that both vaccines are safe and well tolerated and support the ongoing HSV-2 clinical trial in which the two vaccine candidates will be given either sequentially or concomitantly to explore their potential synergistic and incremental effects.

show abstract

A phase 1a, first-in-human, randomized study of a respiratory syncytial virus F protein vaccine with and without a toll-like receptor-4 agonist and stable emulsion adjuvant

Abstract: The safety and immunogenicity results from this study support inclusion of the GLA-SE adjuvant in this RSV vaccine for older adults and also support assessment of the efficacy of the vaccine in a larger clinical trial. Clinicaltrials.gov NCT02115815.

Cited by 50 publications

References 25 publications

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

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

Adjuvanted influenza vaccines

Nonclinical safety evaluation of two vaccine candidates for herpes simplex virus type 2 to support combined administration in humans

Contact Info

Product

Resources

About