Vaccination with a HSV-2 UL24 mutant induces a protective immune response in murine and guinea pig vaginal infection models.
The rational design and development of genetically attenuated HSV-2 mutant viruses represent an attractive approach for developing both prophylactic and therapeutic vaccines for genital herpes. Previously, HSV-2 UL24 was shown to be a virulence determinant in both murine and guinea pig vaginal infection models. An UL24-βgluc insertion mutant produced syncytial plaques and replicated to nearly wild type levels in tissue culture, but induced little or no pathological effects in recipient mice or guinea pigs following vaginal infection. Here we report that immunization of mice or guinea pigs with high or low doses of UL24-βgluc elicited a highly protective immune response. UL24-βgluc immunization via the vaginal or intramuscular routes was demonstrated to protect mice from a lethal vaginal challenge with wild type HSV-2. Moreover, antigen re-stimulated splenic lymphocytes harvested from immunized mice exhibited both HSV-2 specific CTL activity and IFN-γ expression. Humoral anti-HSV-2 responses in serum were Th1-polarized (IgG2a>IgG1) and contained high-titer anti-HSV-2 neutralizing activity. Guinea pigs vaccinated subcutaneously with UL24-βgluc or the more virulent parental strain (186) were challenged with a heterologous HSV-2 strain (MS). Acute disease scores were nearly indistinguishable in guinea pigs immunized with either virus. Recurrent disease scores were reduced in UL24-βgluc immunized animals but not to the same extent as those immunized with strain 186. In addition, challenge virus was not detected in 75% of guinea pigs subcutaneously immunized with UL24-βgluc. In conclusion, disruption of the UL24 gene is a prime target for the development of a genetically attenuated live HSV-2 vaccine.
Department of Biomedical Sciences, Mercer University School of Medicine, 4700 Waters Avenue, Savannah, GA 31404, United States. Electronic address: visalli_rj@mercer.edu.
Robert J
RJ
Visalli
Vaccine Research, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, United States.
Robert J
RJ
Natuk
Vaccine Research, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, United States.
Jacek
J
Kowalski
Vaccine Research, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, United States.
Min
M
Guo
Vaccine Research, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, United States.
Susan
S
Blakeney
Vaccine Research, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, United States.
Seema
S
Gangolli
Vaccine Research, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, United States.
David
D
Cooper
D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006558:Herpes Genitalis / Q000517:prevention & control*; D022301:Herpes Simplex Virus Vaccines / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000235:genetics* / Q000472:pathogenicity; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016254:Mutagenesis, Insertional; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology; D014621:Vagina / Q000276:immunology / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics; D014774:Virulence
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022301:Herpes Simplex Virus Vaccines; D007074:Immunoglobulin G; D014613:Vaccines, Attenuated; D014764:Viral Proteins; D007371:Interferon-gamma
Attenuated vaccine; HSV-2; UL24 mutant