title: Neither antibody to a group B streptococcal conjugate vaccine nor the vaccine itself is teratogenic in rabbits.
abstract: Group B Streptococcus (GBS) is a leading cause of human neonatal bacterial disease, resulting in pneumonia, sepsis, meningitis and sometimes, death. Supportive preclinical studies of GBS capsular polysaccharide (CPS)-protein conjugate vaccines have led to several phase 1 and phase 2 trials in healthy, non-pregnant adults, which demonstrated that the vaccines, produced at the Channing Laboratory, were safe and immunogenic. However, evaluation of the safety and immunogenicity of a GBS conjugate vaccine administered to pregnant women demanded that it be manufactured under current good manufacturing practices (cGMP) and that it undergo developmental toxicity evaluation. In this report, we describe a GBS type III CPS-tetanus toxoid (III-TT) vaccine lot 3-1-96 manufactured and vialed under cGMP and our evaluation of the effect of this vaccine and of GBS type III CPS-specific antibody on conception and early- and late-stage fetal development in rabbits. III-TT lot 3-1-96 was compositionally similar to prototype III-TT lot 91-1, produced under non-GMP, and was potent in a mouse maternal vaccination-neonatal pup challenge model of GBS disease. Four groups of 30 female rabbits each were randomized to receive III-TT lot 3-1-96 vaccine, saline-alum, or combinations of these treatments before and after insemination. The dose of conjugated CPS on a weight basis was 1 microg/kg, mimicking the anticipated actual human dose. Based on the weight of the rabbits, this was 20- to 100-fold greater than the expected human dose. Does were pre-assigned to deliver litters naturally or have their kits delivered by Caesarean-section at gestation day 29, to assess late fetal development. Sera from does and kits were collected, and the presence of type III CPS-specific IgG was confirmed by quantitative ELISA. Based on all assessments, GBS type III-TT lot 3-1-96, nor antibody to it did not affect embryo fetal viability, sex ratio, growth or cause malformations (i.e., it was non-teratogenic). In addition, that III-TT lot 3-1-96 was found to be safe and immunogenic in two clinical studies involving healthy non-pregnant adults supports a clinical evaluation of this vaccine in pregnant women.
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. lpaoletti@rics.bwh.harvard.edu
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Paoletti
authors.forename: Hilde-Kari
authors.initials: HK
authors.lastname: Guttormsen
authors.forename: Mildred S
authors.initials: MS
authors.lastname: Christian
authors.forename: Alan M
authors.initials: AM
authors.lastname: Hoberman
authors.forename: Pamela
authors.initials: P
authors.lastname: McInnes
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000009:adverse effects* / Q000097:blood; D016667:Bacterial Capsules / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D000013:Congenital Abnormalities; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D051379:Mice; D011247:Pregnancy; D011270:Pregnancy, Animal; D011817:Rabbits; D011897:Random Allocation; D012744:Sex Ratio; D022541:Streptococcal Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D016019:Survival Analysis
chemical_list: D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D022541:Streptococcal Vaccines; C105866:group B streptococcal type III capsular polysaccharide-tetanus toxoid vaccine