Nucleoprotein Nanostructures Combined with Adjuvants Adapted to the Neonatal Immune Context: A Candidate Mucosal RSV Vaccine

Abstract

BackgroundThe human respiratory syncytial virus (hRSV) is the leading cause of severe bronchiolitis in infants worldwide. The most severe RSV diseases occur between 2 and 6 months-of-age, so pediatric vaccination will have to be started within the first weeks after birth, when the immune system is prone to Th2 responses that may turn deleterious upon exposure to the virus. So far, the high risk to prime for immunopathological responses in infants has hampered the development of vaccine. In the present study we investigated the safety and efficacy of ring-nanostructures formed by the recombinant nucleoprotein N of hRSV (NSRS) as a mucosal vaccine candidate against RSV in BALB/c neonates, which are highly sensitive to immunopathological Th2 imprinting.Methodology and Principal FindingsA single intranasal administration of NSRS with detoxified E.coli enterotoxin LT(R192G) to 5–7 day old neonates provided a significant reduction of the viral load after an RSV challenge at five weeks of age. However, neonatal vaccination also generated an enhanced lung infiltration by neutrophils and eosinophils following the RSV challenge. Analysis of antibody subclasses and cytokines produced after an RSV challenge or a boost administration of the vaccine suggested that neonatal vaccination induced a Th2 biased local immune memory. This Th2 bias and the eosinophilic reaction could be prevented by adding CpG to the vaccine formulation, which, however did not prevent pulmonary inflammation and neutrophil infiltration upon viral challenge.Conclusions/SignificanceIn conclusion, protective vaccination against RSV can be achieved in neonates but requires an appropriate combination of adjuvants to prevent harmful Th2 imprinting.

Neonatal priming and infancy boosting with a novel respiratory syncytial virus vaccine induces protective immune responses without concomitant respiratory disease upon RSV challenge

“…24 Indeed, many RSV vaccines have been tested with a neonatal mouse model. [25][26][27] We demonstrated here that after priming neonatal and boosting infant mice the G+ CsA vaccine could trigger efficient anti-RSV immunity without the ERD in the lungs.…”

Subunit and Virus-Like Particle Vaccine Approaches for Respiratory Syncytial Virus

“…In adult mice, intranasal immunization with this particle resulted in N protein specific antibody, CD4 and CD8 T cell responses, and protection from RSV replication upon challenge as determined by quantitative PCR of NP sequences in lungs (Roux et al 2008). However, in neonatal mice (Remot et al 2012), while there was some protection, there was evidence for ERD and a Th2 biased immune response upon RSV challenge. Inclusion of the adjuvant CpG only partially eliminated ERD.…”

Maternal Antibody Improves Active Neonatal Vaccination against Respiratory Syncytial Virus through Immune Complex

“…A variety of approaches has been recently explored to enhance protective Th1 biased immunity in neonates, such as antigens pre-formulated with a variety of adjuvants (Toll-like receptor agonists, CpG oligodeoxynucleotide, polyI:C, innate defense regulator peptide and polyphosphazene, etc). These adjuvants have been confirmed effective in inducing potent immune protection against RSV infection to some extent in animal models [12,[14][15][16].…”

“…However these adjuvants failed to suppress Th2 biased immune responses and lung eosinophilia. For example, intranasal immunization with recombinant RSV nuclear protein N with detoxified E. coli enterotoxin led to higher lung neutrophil and eosinophil infiltration after RSV challenge, though lung viral load was reduced [15]. Therefore it is important to develop long-lasting and Th1-biased immune responses after active vaccination in infants.…”