Neither antibody to a group B streptococcal conjugate vaccine nor the vaccine itself is teratogenic in rabbits

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Human vaccines (Impact Factor: 3.64). 05/2008; 4(6):435-43. DOI: 10.4161/hv.4.6.6178
Source: PubMed


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.

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Available from: Alan Hoberman, Apr 13, 2015
    • "One option that has been utilized is to increase the group size to 25 and then allow (per statement in the protocol) only the first 20 mated females to continue on study. Although this report has focused on small-molecule pharmaceuticals, it should be mentioned that the combined female fertility and developmental toxicity study has been successfully employed for biopharmaceuticals such as vaccines (Paoletti et al., 2008; Wise et al., 2008). Interested readers may consult the FDA guidance document on developmental toxicity studies for preventive and therapeutic vaccines (FDA, 2006). "
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    ABSTRACT: Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the International Conference on Harmonization (ICH) S5(R2) document (available at The studies that assess developmental hazard are generally conducted in rodents and rabbits. Based on the authors' collective experience, adequate designs (including range-finding studies) and the presentation of data for these studies are described in detail. In addition, the suggested initiation and then total duration of these studies in relation to clinical studies that enroll women of childbearing potential are described. Optional parameters that may be included in the studies are discussed, as are study designs that combine assessments of fertility and developmental toxicity. New methods that may replace or enhance current procedures are outlined. The details described herein will assist all laboratories performing these studies, individuals who need to plan for the studies, and regulatory agencies that ultimately review these studies.
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    ABSTRACT: Invasive disease due to group B Streptococcus (GBS) has been recognized as a threat to the health of pregnant women and their infants for almost half a century. Development of GBS vaccine candidates has progressed at an exemplary pace given lack of sponsorship by manufacturers. A trivalent or pentavalent vaccine will be required, and decisions must be made as to the criteria by which efficacy will be determined and the population in whom efficacy will be assessed. Concerns regarding durability of conjugate vaccine-derived immunity, pregnant women as a possible target group and regulatory issues required for licensing must be resolved if the prospect of impacting GBS disease burden through immunization is to become a reality.
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    ABSTRACT: Bacterial infections remain a significant threat to the health of newborns and adults. Group B Streptococci (GBS) are Gram-positive bacteria that are common asymptomatic colonizers of healthy adults. However, this opportunistic organism can also subvert suboptimal host defenses to cause severe invasive disease and tissue damage. The increasing emergence of antibiotic-resistant GBS raises more concerns for sustained measures in treatment of the disease. A number of factors that are important for virulence of GBS have been identified. This review summarizes the functions of some well-characterized virulence factors, with an emphasis on how GBS regulates their expression. Regulatory and signaling molecules are attractive drug targets in the treatment of bacterial infections. Consequently, understanding signaling responses of GBS is essential for elucidation of pathogenesis of GBS infection and for the identification of novel therapeutic agents.
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