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3.
JAMA ; 282(4): 331-40, 1999 Jul 28.
Article in English | MEDLINE | ID: mdl-10432030

ABSTRACT

CONTEXT: In the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic. OBJECTIVE: To evaluate the efficacy of a vaccine for prevention of HSV-2 infection. DESIGN: Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 microg each of 2 major HSV-2 surface glycoproteins (gB2 and gD2) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization. SETTING AND PARTICIPANTS: We enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2-seronegative partners of HSV-2-infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine. MAIN OUTCOME MEASURE: Time to acquisition of HSV-2 infection, defined by seroconversion or isolation of HSV-2 in culture during the study period by randomization group. RESULTS: Time-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, overall vaccine efficacy was 9% (95% confidence interval, -29% to 36%). Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P =.58). Follow-up of vaccine recipients acquiring HSV-2 infection showed vaccination had no significant influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P>.10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placebo, 0.3; P>.10). The vaccine induced high levels of HSV-2-specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes. CONCLUSIONS: Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study.


Subject(s)
Herpes Genitalis/prevention & control , Herpesvirus 2, Human/immunology , Vaccines, Synthetic , Viral Envelope Proteins/immunology , Viral Vaccines , Adolescent , Adult , Aged , Antibodies, Viral/biosynthesis , Case-Control Studies , Double-Blind Method , Female , Herpes Genitalis/immunology , Humans , Male , Middle Aged , Neutralization Tests , Proportional Hazards Models , Vaccination , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology , Viral Vaccines/administration & dosage , Viral Vaccines/immunology
4.
Ann Intern Med ; 122(12): 889-98, 1995 Jun 15.
Article in English | MEDLINE | ID: mdl-7755223

ABSTRACT

OBJECTIVE: To evaluate the safety and immunogenicity of a recombinant glycoprotein vaccine for herpes simplex virus type 2 (HSV-2), which contains glycoproteins gD2 and gB2 combined with the novel MF59 adjuvant emulsion, in HSV-2-seronegative persons. DESIGN: Integrated summary of two phase I and two phase II studies. SETTING: University and private outpatient clinics. PATIENTS: 137 persons seronegative for HSV-2 antibodies as determined by HSV Western blot assay. INTERVENTION: Open-label vaccine administration with a dose-escalating design (phase I) was followed by randomized vaccine administration (phase II). Vaccine was administered intramuscularly into the deltoid at 0, 1, and 6 months. MEASUREMENTS: Neutralizing, HSV-2-binding antibodies and HSV-2-stimulated proliferative responses were measured before and after immunization. RESULTS: Among HSV-seronegative patients, the gD2 and gB2 enzyme-linked immunosorbent assay (ELISA) and HSV-2-neutralizing antibody titers increased to levels equal to or higher than those seen in naturally acquired HSV-2 infection after the full three-dose immunization schedule. Among HSV-1-seropositive patients, one immunization produced increases in gD2 and gB2 ELISA antibody titers and HSV-2-neutralizing antibody titers that were 3 to 5 times greater than those in persons with naturally acquired HSV-2 infection. Among HSV-seronegative patients, frequency analysis assays showed a marked increase in the precursor frequency of gD2- and gB2-specific T cells after vaccination: T-cell responses after two immunizations were equal to the responses of HSV-2-seropositive patients and were sustained at day 180. The vaccine was well tolerated. CONCLUSIONS: This subunit vaccine induces both humoral and cellular responses to HSV-2 that are equal to or greater than those of persons with naturally acquired HSV-2 infection. Studies to evaluate this vaccine for the prevention of genital herpes appear warranted.


Subject(s)
Glycoproteins/therapeutic use , Herpes Genitalis/prevention & control , Herpesvirus 2, Human , Viral Vaccines/therapeutic use , Adjuvants, Immunologic/therapeutic use , Adolescent , Adult , Aged , Antibody Formation , Glycoproteins/adverse effects , Glycoproteins/immunology , Humans , Immunologic Memory , Middle Aged , Polysorbates/therapeutic use , Recombinant Proteins/therapeutic use , Squalene/therapeutic use , T-Lymphocytes/immunology , Viral Vaccines/adverse effects , Viral Vaccines/immunology
5.
J Infect Dis ; 170(5): 1288-91, 1994 Nov.
Article in English | MEDLINE | ID: mdl-7963729

ABSTRACT

A phase 1 study of 42 non-human immunodeficiency virus type 1 (HIV)-infected volunteers was initiated to determine the safety and immunogenicity of an HIV subunit vaccine consisting of recombinant envelope gp120 derived from HIVSF2 (rgp120SF2) combined with a novel adjuvant, MF59, with or without the immunomodulator muramyl tripeptide dipalmitoyl phosphatidylethanolamine (MTP-PE). All injections contained adjuvant MF59, and subjects were grouped according to MTP-PE dose. Injections were given on days 0, 30, 180, and 365. The vaccine was well tolerated with limited local and systemic reactions. These immunizations induced rgp120SF2-specific binding antibodies that persisted > or = 24 weeks. After three immunizations, all subjects receiving the antigen developed neutralizing antibodies to HIVSF2, and serum from 67% of these subjects also cross-neutralized HIVMN. ELISA-reactive antibodies to the HIVSF2 V3 region and strong lymphoproliferative responses to HIVSF2 envelope proteins were detected in all rgp120SF2-immunized subjects.


Subject(s)
AIDS Vaccines/immunology , Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Adjuvants, Immunologic/administration & dosage , HIV Envelope Protein gp120/immunology , Phosphatidylethanolamines/administration & dosage , Polysorbates/administration & dosage , Squalene/administration & dosage , Vaccines, Synthetic/immunology , AIDS Vaccines/administration & dosage , Acetylmuramyl-Alanyl-Isoglutamine/administration & dosage , Adolescent , Adult , Double-Blind Method , Female , HIV Antibodies/blood , Humans , Immunization , Male , Middle Aged , Vaccines, Synthetic/administration & dosage
9.
Am J Dis Child ; 144(8): 899-904, 1990 Aug.
Article in English | MEDLINE | ID: mdl-2378338

ABSTRACT

The clinical efficacy of an acellular pertussis vaccine containing lymphocytosis-promoting factor, filamentous hemagglutinin, agglutinogens, and the 69-kd outer membrane protein, combined with diphtheria and tetanus toxoids and adsorbed onto an aluminum salt, was assessed in a household contact study. The occurrence of pertussis 7 to 30 days following home exposure among 62 previously vaccinated children was compared with that among 62 unvaccinated children similarly exposed. Classic whooping cough was diagnosed in 43 unimmunized children, and 1 vaccinated child experienced a 5-week illness that was probably pertussis (efficacy, 98%; 95% confidence interval, 84% to 99%). A few children in each group incurred respiratory illnesses that may have represented mild, atypical pertussis; including these as probable pertussis, vaccine efficacy was 81% (95% confidence interval, 64% to 90%). It is concluded that prior immunization with this four-component pertussis vaccine combined with diphtheria and tetanus toxoids is highly efficacious in preventing pertussis.


Subject(s)
Diphtheria-Tetanus-Pertussis Vaccine/standards , Whooping Cough/prevention & control , Bias , Child , Child, Preschool , Diphtheria-Tetanus-Pertussis Vaccine/administration & dosage , Diphtheria-Tetanus-Pertussis Vaccine/pharmacology , Humans , Infant , Japan , Whooping Cough/diagnosis , Whooping Cough/epidemiology
10.
J Pediatr ; 117(1 Pt 1): 46-51, 1990 Jul.
Article in English | MEDLINE | ID: mdl-2196360

ABSTRACT

Healthy 17- to 24-month-old children, previously immunized with three doses of whole-cell diphtheria-tetanus-pertussis (DTP) vaccine, were enrolled in a multi-center double-blind, randomized study comparing a DTP vaccine with an acellular pertussis-component (APDT) and a conventional whole-cell pertussis-component DTP vaccine. Thirty-eight children received APDT vaccine, and 37 children received DTP vaccine. APDT vaccine recipients had significantly less local pain and warmth than DTP vaccine recipients. Antibody responses to lymphocytosis-promoting factor were similar in the two groups. The APDT vaccine recipients had a higher IgG antibody response to filamentous hemagglutinin than the DTP vaccinees had. Equivalent agglutinin responses were seen in the two groups. The APDT vaccine recipients had a significantly better antibody re-enzyme-linked immunosorbent assay, than DTP vaccinees had 1 month and 1 year after immunization. This APDT vaccine was immunogenic and caused fewer local reactions than conventional DTP vaccine when administered as a fourth dose to 17- to 24-month-old children.


Subject(s)
Antibodies, Bacterial/analysis , Diphtheria-Tetanus-Pertussis Vaccine/immunology , Agglutinins/immunology , Bacterial Proteins/immunology , Bordetella pertussis/immunology , Diphtheria-Tetanus-Pertussis Vaccine/administration & dosage , Double-Blind Method , Enzyme-Linked Immunosorbent Assay , Hemagglutinins/immunology , Humans , Immunoglobulin G/analysis , Infant , Interleukins/immunology , Lymphokines/immunology , Membrane Proteins/immunology , Multicenter Studies as Topic , Pertussis Vaccine/administration & dosage , Pertussis Vaccine/immunology , Random Allocation
11.
Am J Dis Child ; 144(1): 41-5, 1990 Jan.
Article in English | MEDLINE | ID: mdl-2403747

ABSTRACT

An acellular pertussis-component combined diphtheria and tetanus toxoids, and pertussis (APDT) vaccine adsorbed was compared with a licensed whole-cell pertussis-component combined diphtheria and tetanus toxoids, and pertussis (DTP) vaccine adsorbed for reactogenicity and immunogenicity when given as the fifth DTP immunization to eighty-two 4- to 6-year-old children. The reaction rates with both vaccines were low; APDT vaccine recipients had significantly less pain and warmth at the injection site than did DTP vaccine recipients. Antibody responses to pertussis antigens (lymphocytosis-promoting factor, filamentous hemagglutinin, and agglutinogens) and to diphtheria and tetanus toxoids were all brisk. The APDT vaccine recipients had a more marked response in antibodies to filamentous hemagglutinin and a less marked response in agglutinins than whole-cell vaccine recipients. On the day after immunization, both APDT and DTP vaccine recipients had an increase in mean leukocyte and neutrophil counts. This APDT vaccine is immunogenic and less reactogenic than a DTP vaccine with a whole-cell pertussis component when administered as a booster to 4- to 6-year-old children.


Subject(s)
Antibodies, Bacterial/biosynthesis , Bordetella pertussis/immunology , Diphtheria-Tetanus-Pertussis Vaccine/immunology , Immunization, Secondary , Agglutinins/immunology , Antigens, Bacterial/immunology , Child , Child, Preschool , Diphtheria Toxoid/immunology , Diphtheria-Tetanus-Pertussis Vaccine/adverse effects , Double-Blind Method , Enzyme-Linked Immunosorbent Assay , Hemagglutinins/immunology , Humans , Multicenter Studies as Topic , Random Allocation , Tetanus Toxoid/immunology
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