Nucleoprotein nanostructures combined with adjuvants adapted to the neonatal immune context: a candidate mucosal RSV vaccine.
BACKGROUND
The 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 (N(SRS)) as a mucosal vaccine candidate against RSV in BALB/c neonates, which are highly sensitive to immunopathological Th2 imprinting.


RESULTS
A single intranasal administration of N(SRS) 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
In conclusion, protective vaccination against RSV can be achieved in neonates but requires an appropriate combination of adjuvants to prevent harmful Th2 imprinting.
Molecular Virology and Immunology (UR892), French National Institute for Agricultural Research, Jouy-en-Josas, France.
Aude
A
Remot
Xavier
X
Roux
Catherine
C
Dubuquoy
Jenna
J
Fix
Stephan
S
Bouet
Mohammed
M
Moudjou
Jean-François
JF
Eléouët
Sabine
S
Riffault
Agnès
A
Petit-Camurdan
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000281:Administration, Intranasal; D000818:Animals; D018899:CpG Islands; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D009698:Nucleoproteins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D014764:Viral Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D009698:Nucleoproteins; D022261:Respiratory Syncytial Virus Vaccines; D014764:Viral Proteins