Live attenuated herpes simplex virus 2 glycoprotein E deletion mutant as a vaccine candidate defective in neuronal spread.
A herpes simplex virus 2 (HSV-2) glycoprotein E deletion mutant (gE2-del virus) was evaluated as a replication-competent, attenuated live virus vaccine candidate. The gE2-del virus is defective in epithelial cell-to-axon spread and in anterograde transport from the neuron cell body to the axon terminus. In BALB/c and SCID mice, the gE2-del virus caused no death or disease after vaginal, intravascular, or intramuscular inoculation and was 5 orders of magnitude less virulent than wild-type virus when inoculated directly into the brain. No infectious gE2-del virus was recovered from dorsal root ganglia (DRG) after multiple routes of inoculation; however, gE2-del DNA was detected by PCR in lumbosacral DRG at a low copy number in some mice. Importantly, no recurrent vaginal shedding of gE2-del DNA was detected in immunized guinea pigs. Intramuscular immunization outperformed subcutaneous immunization in all parameters evaluated, although individual differences were not significant, and two intramuscular immunizations were more protective than one. Immunized animals had reduced vaginal disease, vaginal titers, DRG infection, recurrent genital lesions, and recurrent vaginal shedding of HSV-2 DNA; however, protection was incomplete. A combined modality immunization using live virus and HSV-2 glycoprotein C and D subunit antigens in guinea pigs did not totally eliminate recurrent lesions or recurrent vaginal shedding of HSV-2 DNA. The gE2-del virus used as an immunotherapeutic vaccine in previously HSV-2-infected guinea pigs greatly reduced the frequency of recurrent genital lesions. Therefore, the gE2-del virus is safe, other than when injected at high titer into the brain, and is efficacious as a prophylactic and immunotherapeutic vaccine.
Infectious Disease Division, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. sawasthi@mail.med.upenn.edu
Sita
S
Awasthi
Elizabeth E
EE
Zumbrun
Huaxin
H
Si
Fushan
F
Wang
Carolyn E
CE
Shaw
Michael
M
Cai
John M
JM
Lubinski
Shana M
SM
Barrett
John W
JW
Balliet
Jessica A
JA
Flynn
Danilo R
DR
Casimiro
Janine T
JT
Bryan
Harvey M
HM
Friedman
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004279:DNA, Viral; D005260:Female; D005727:Ganglia, Spinal / Q000821:virology; D017353:Gene Deletion; D006168:Guinea Pigs; D006558:Herpes Genitalis / Q000401:mortality / Q000517:prevention & control / Q000628:therapy; D006561:Herpes Simplex / Q000401:mortality / Q000517:prevention & control / Q000628:therapy; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009474:Neurons / Q000821:virology*; D013116:Spinal Cord / Q000821:virology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000276:immunology*
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D004279:DNA, Viral; D022301:Herpes Simplex Virus Vaccines; D014613:Vaccines, Attenuated; D014759:Viral Envelope Proteins; C048621:glycoprotein E, herpes simplex-virus type 2