Type III group B Streptococcus (III-GBS) is a common cause of serious infection in neonates; resulting morbidity and mortality remain high despite the use of antimicrobials. Therefore, methods of adjuvant therapy and/or prevention must be investigated. The proposed research will evaluate 1) the possible use of human IgG for such purposes, and 2) factors involved in susceptibility of this disease. A human, polyclonal IgG preparation hyperimmune for III-GBS (HHIG), prepared following immunization of a single adult volunteer with native III-GBS polysaccharide, has been shown to be functionally active when assessed using III-GBS strain M732 in 1) a bactericidal assay utilizing complement-containing cord sera obtained following delivery of healthy, full-term infants and neutrophils isolated from healthy adults, and 2) a mucin mouse model of III-GBS disease. Pooled human IgG from multiple donors will be required for ultimate use of such immunoglobulin preparations in humans on a large scale. Such a pooled human hyperimmune globulin for III- GBS (PHHIG) will be prepared following immunization of healthy adult volunteers. The HHIG, and then the PHHIG when prepared, will be evaluated in vitro in the bactericidal assay, utilizing: 1) neutrophils isolated from cord blood following term and pre-term deliveries with and without labor, and 2) cord, or newborn sera from term and pre- term infants. The effect of these variables in the assay also will be evaluated without added IgG, thus yielding basic knowledge concerning the pathogenesis of III-GBS disease in newborns. Evaluation of the efficacy of such IgG preparations in experimental models of III-GBS disease which closely simulate conditions in the human neonate also is important. Hence, these preparations will be evaluated in a neonatal rat model of III-GBS disease. The lethal dose (LD90) of III-GBS will be determined following intraperitoneal (ip) injection. Thereafter, the protective dose (PD50) of the IgG preparations will be determined when injected ip immediately following the LD90. Both the in vitro and in vivo studies will be performed with multiple strains of III-GBS. The above experiments are important with respect to the pathogenesis of III-GBS disease as well as the use of human hyperimmune IgG preparations for the prevention and/or therapy of III-GBS disease in human neonates.
