A Novel Respiratory Syncytial Virus (RSV) F Subunit Vaccine Adjuvanted with GLA-SE Elicits Robust Protective TH1-Type Humoral and Cellular Immunity In Rodent Models

Lambert, Stacie; Aslam, Shahin; Stillman, Elizabeth A.; MacPhail, Mia; Nelson, Christine L.; Ro, Bodrey W.; Sweetwood, Rosemary; Lei, Yuk Man; Woo, Jennifer; Tang, Roderick S.

doi:10.1371/journal.pone.0119509

Cited by 52 publications

(40 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When formulated in an oil-in-water stable emulsion (SE), GLA induces in vivo innate immune responses as well as Th1-skewed cellular immunity to coadministered vaccine antigens (27,28). GLA adjuvant formulations have been used with experimental vaccines for influenza, HIV (29), respiratory syncytial virus (RSV) (30), leishmaniasis (31), malaria (32), and leprosy (33) in addition to TB (34,35). Many of these vaccines using GLA formulations have also resulted in protection in preclinical animal models, including mice (34)(35)(36), ferrets (37,38), guinea pigs (34,35,39), cotton rats (30), and hamsters (40), against infectious challenge.…”

Section: Et Al Have Shown a Transient Increase In Ifn-␥ From Cd4mentioning

confidence: 99%

Protection and Long-Lived Immunity Induced by the ID93/GLA-SE Vaccine Candidate against a Clinical Mycobacterium tuberculosis Isolate

Baldwin

Reese

Huang

et al. 2016

Clin Vaccine Immunol

View full text Add to dashboard Cite

dMycobacterium tuberculosis HN878 represents a virulent clinical strain from the W-Beijing family, which has been tested in small animal models in order to study its virulence and its induction of host immune responses following infection. This isolate causes death and extensive lung pathology in infected C57BL/6 mice, whereas lab-adapted strains, such as M. tuberculosis H37Rv, do not. The use of this clinically relevant isolate of M. tuberculosis increases the possibilities of assessing the long-lived efficacy of tuberculosis vaccines in a relatively inexpensive small animal model. This model will also allow for the use of knockout mouse strains to critically examine key immunological factors responsible for long-lived, vaccine-induced immunity in addition to vaccine-mediated prevention of pulmonary immunopathology. In this study, we show that the ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE) tuberculosis vaccine candidate, currently in human clinical trials, is able to elicit protection against M. tuberculosis HN878 by reducing the bacterial burden in the lung and spleen and by preventing the extensive lung pathology induced by this pathogen in C57BL/6 mice.T he development of an effective Mycobacterium tuberculosis vaccine, and increased availability of novel drugs targeting drug-resistant strains, would significantly contribute to decreasing the continuing spread of this global disease. Nine million people were estimated to have contracted tuberculosis (TB) in 2013, with 1.5 million deaths occurring annually (1). Overall, 3.5% of new cases and 20.5% of previously treated cases are multidrugresistant (MDR) TB (1), although this can be as high as 35% and 75%, respectively, in central Asian countries. The Beijing lineage of TB has been associated with a number of MDR TB outbreaks (2-6) and accounts for approximately 13% of isolates worldwide (7). The Beijing lineage itself has expanded more rapidly than other lineages (8); this may be due to the higher virulence of modern strains compared with phylogenetically older sublineages (9-11). The clinical isolate, HN878, is a representative strain from the W-Beijing lineage. The HN878 isolate has been studied in mice to characterize the infectivity and pathogenicity of this virulent clinical strain of M. tuberculosis (12)(13)(14). These same studies have provided insight into the role of the immune response generated to this pathogen in animals and humans and how the immune response to HN878 contributes to the pathology induced following infection with this isolate. Mice infected with the hypervirulent HN878 strain have increased type I interferon (IFN) expression in the lung and decreased Th1 immunity (12), and HN878 infection in IFN-␣/␤R-deficient mice results in decreased bacterial growth (13). In humans, a type I IFN-␣ molecular signature, expressed by a population of isolated neutrophils, was observed in patients with active TB (15). More recently, analysis using a whole-genome microarray approach showed a similar type I interferon molecular signa...

show abstract

Section: Et Al Have Shown a Transient Increase In Ifn-␥ From Cd4mentioning

confidence: 99%

Protection and Long-Lived Immunity Induced by the ID93/GLA-SE Vaccine Candidate against a Clinical Mycobacterium tuberculosis Isolate

Baldwin

Reese

Huang

et al. 2016

Clin Vaccine Immunol

View full text Add to dashboard Cite

show abstract

“…Replication-defective gene-based single-cycle vectors (15,16), subunit vaccines adjuvanted with various Toll-like receptor (TLR) agonists (17), viruslike particles (VLPs) with protective antigens (18)(19)(20), and new formulations with the prefusion conformation of RSV F (21-25) defy our traditional understanding of replicating and nonreplicating vaccines, posing new questions for the field and for human studies. This challenge is particularly significant for RSV because a vaccine designed to protect infants and toddlers against RSV in the 1960s primed for a severe form of respiratory illness upon RSV infection, known as enhanced RSV disease (ERD).…”

mentioning

confidence: 99%

Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease

Acosta

Caballero

Polack

2016

Clin Vaccine Immunol

199

173

View full text Add to dashboard Cite

In 1967, infants and toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (RSV) experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. The enhanced disease was initially characterized as a "peribronchiolar monocytic infiltration with some excess in eosinophils." Decades of research defined enhanced RSV disease (ERD) as the result of immunization with antigens not processed in the cytoplasm, resulting in a nonprotective antibody response and CD4؉ T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection. In recent years, the field of RSV experienced significant changes. Numerous vaccine candidates with novel designs and formulations are approaching clinical trials, defying our previous understanding of favorable parameters for ERD. This review provides a succinct analysis of these parameters and explores criteria for assessing the risk of ERD in new vaccine candidates. R espiratory syncytial virus (RSV) is the leading respiratory cause of hospitalization in infants and young children in the United States and in the world (1, 2). Most severe infections occur in young infants, with the peak incidence of lower respiratory tract illness (LRTI) occurring between 2 and 4 months of age (3-5). In the United States, hospitalization rates have risen during the last decades (6), and while premature babies and infants with chronic lung disease and/or congenital heart disease are at increased risk for severe presentations, the majority of hospitalizations occur in previously healthy infants. Recent estimates of global mortality suggest that between 66,000 and 234,000 infants and young children die every year due to RSV (1, 2). Ninety-nine percent of deaths occur in the developing world (2). A significant proportion of these fatalities are thought to occur in the community. The need for preventive interventions against the virus is indisputable.The virus. RSV is a member of the pneumovirus genus of the family Paramyxoviridae. The virus is a negative-sense RNA virus with a nonsegmented encapsidated genome and a lipid envelope (7). The envelope is a host plasma membrane-derived lipid bilayer containing three virally encoded transmembrane glycoproteins: the fusion (F) protein, the attachment (G) protein, and the small hydrophobic (SH) protein. RSV F is the main neutralizing antigen, highly conserved and essential for virus viability (7). The secondary protective antigen eliciting neutralizing antibodies is the RSV G protein. Both neutralizing antigens are the main candidates for novel vaccines and targets for monoclonal antibodies.A new scenario. The world of RSV vaccines is experiencing important changes. In recent years, epidemiologic...

show abstract

“…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

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

A Novel Respiratory Syncytial Virus (RSV) F Subunit Vaccine Adjuvanted with GLA-SE Elicits Robust Protective TH1-Type Humoral and Cellular Immunity In Rodent Models

Cited by 52 publications

References 58 publications

Protection and Long-Lived Immunity Induced by the ID93/GLA-SE Vaccine Candidate against a Clinical Mycobacterium tuberculosis Isolate

Protection and Long-Lived Immunity Induced by the ID93/GLA-SE Vaccine Candidate against a Clinical Mycobacterium tuberculosis Isolate

Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease

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

Contact Info

Product

Resources

About