The live-attenuated yellow fever vaccine 17D induces broad and potent T cell responses against several viral proteins in Indian rhesus macaques--implications for recombinant vaccine design.
The yellow fever vaccine 17D (YF17D) is one of the most effective vaccines. Its wide use and favorable safety profile make it a prime candidate for recombinant vaccines. It is believed that neutralizing antibodies account for a large measure of the protection afforded to YF17D-vaccinated individuals, however cytotoxic T lymphocyte (CTL) responses have been described in the setting of YF17D vaccination. YF17D is an ssRNA flavivirus that is translated as a full-length polyprotein, several domains of which pass into the lumen of the endoplasmic reticulum (ER). The processing and presentation machinery for MHC class I-restricted CTL responses favor cytoplasmic peptides that are transported into the ER by the transporter associated with antigen presentation proteins. In order to inform recombinant vaccine design, we sought to determine if YF17D-induced CTL responses preferentially targeted viral domains that remain within the cytoplasm. We performed whole YF17D proteome mapping of CTL responses in six Indian rhesus macaques vaccinated with YF17D using overlapping YF17D peptides. We found that the ER luminal E protein was the most immunogenic viral protein followed closely by the cytoplasmic NS3 and NS5 proteins. These results suggest that antigen processing and presentation in this model system is not preferentially affected by the subcellular location of the viral proteins that are the source of CTL epitopes. The data also suggest potential immunogenic regions of YF17D that could serve as the focus of recombinant T cell vaccine development.
Mudd
Philip A
PA
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 555 Science Dr, Madison, WI 53711, USA.
Piaskowski
Shari M
SM
Neves
Patricia C Costa
PC
Rudersdorf
Richard
R
Kolar
Holly L
HL
Eernisse
Christopher M
CM
Weisgrau
Kim L
KL
de Santana
Marlon G Veloso
MG
Wilson
Nancy A
NA
Bonaldo
Myrna C
MC
Galler
Ricardo
R
Rakasz
Eva G
EG
Watkins
David I
DI
D000818:Animals; D015195:Drug Design; D008253:Macaca mulatta; D010446:Peptide Fragments / Q000276:immunology; D020365:RNA Helicases / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D015004:Yellow Fever / Q000276:immunology; D022341:Yellow Fever Vaccine / Q000276:immunology*; D015005:Yellow fever virus / Q000276:immunology*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D010446:Peptide Fragments; D020365:RNA Helicases; D012697:Serine Endopeptidases; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D017361:Viral Nonstructural Proteins; D022341:Yellow Fever Vaccine; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C096041:NS5 protein, flavivirus