Immunogenicity and efficacy of intramuscular replication-defective and subunit vaccines against herpes simplex virus type 2 in the mouse genital model.
Herpes simplex virus type 2 (HSV-2) is a sexually transmitted virus that is highly prevalent worldwide, causing a range of symptoms that result in significant healthcare costs and human suffering. ACAM529 is a replication-defective vaccine candidate prepared by growing the previously described dl5-29 on a cell line appropriate for GMP manufacturing. This vaccine, when administered subcutaneously, was previously shown to protect mice from a lethal vaginal HSV-2 challenge and to afford better protection than adjuvanted glycoprotein D (gD) in guinea pigs. Here we show that ACAM529 given via the intramuscular route affords significantly greater immunogenicity and protection in comparison with subcutaneous administration in the mouse vaginal HSV-2 challenge model. Further, we describe a side-by-side comparison of intramuscular ACAM529 with a gD vaccine across a range of challenge virus doses. While differences in protection against death are not significant, ACAM529 protects significantly better against mucosal infection, reducing peak challenge virus shedding at the highest challenge dose by over 500-fold versus 5-fold for gD. Over 27% (11/40) of ACAM529-immunized animals were protected from viral shedding while 2.5% (1/40) were protected by the gD vaccine. Similarly, 35% (7/20) of mice vaccinated with ACAM529 were protected from infection of their dorsal root ganglia while none of the gD-vaccinated mice were protected. These results indicate that measuring infection of the vaginal mucosa and of dorsal root ganglia over a range of challenge doses is more sensitive than evaluating survival at a single challenge dose as a means of directly comparing vaccine efficacy in the mouse vaginal challenge model. The data also support further investigation of ACAM529 for prophylaxis in human subjects.
Sanofi Pasteur, Discovery North America, Cambridge, Massachusetts, United States of America. simon.delagrave@sanofipasteur.com
Simon
S
Delagrave
Hector
H
Hernandez
Changhong
C
Zhou
John F
JF
Hamberger
Sophia T
ST
Mundle
John
J
Catalan
Simge
S
Baloglu
Stephen F
SF
Anderson
Joshua M
JM
DiNapoli
Patricia
P
Londoño-Hayes
Mark
M
Parrington
Jeffrey
J
Almond
Harry
H
Kleanthous
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000821:virology; D006558:Herpes Genitalis / Q000276:immunology / Q000517:prevention & control*; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage* / Q000276:immunology; D018258:Herpesvirus 2, Human / Q000276:immunology*; D006801:Humans; D007273:Injections, Intramuscular; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology; D014621:Vagina / Q000821:virology; D014759:Viral Envelope Proteins / Q000008:administration & dosage / Q000276:immunology
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C423449:CpG ODN 1826; D022301:Herpes Simplex Virus Vaccines; D009838:Oligodeoxyribonucleotides; D014613:Vaccines, Attenuated; D022223:Vaccines, Subunit; D014759:Viral Envelope Proteins; C040570:glycoprotein D-herpes simplex virus type 2; C041524:aluminum sulfate