Experimental congenital disease with simian cytomegalovirus in rhesus monkeys.

Cytomegalovirus (CMV) infections occur worldwide and are responsible for severe damage to the child in from one to five newborns per 20,000 births. Animal models of congenital CMV infection resulting in disease have been developed in mice and guinea pigs. We report here the development of ventricular dilatation and leptomeningitis in rhesus monkeys, Macaca mulatta, following intrauterine infection with rhesus cytomegalovirus (RCMV). Central nervous system (CNS) lesions were associated with low cytomegalovirus fluorescent antibody titers in affected fetuses. In several infected animals, RCMV was isolated at necropsy from neural and nonneural tissues taken shortly after birth. This model allows investigators to study the pathogenesis and prevention of CNS changes following RCMV infection.

Coxsackie virus B4 produces transient diabetes in nonhuman primates.

Cynomolgus, rhesus, and Cebus monkeys failed to show glucose tolerance or insulin secretion abnormalities after infection with encephalomyocarditis virus or Coxsackie virus B4. Patas monkeys also showed no abnormalities after infection with encephalomyocarditis virus. However, patas monkeys infected with Coxsackie virus B4 or treated first with a subdiabetogenic dose of streptozocin and then infected sequentially with Coxsackie viruses B4 and B3 showed transient elevation of glucose tolerance tests, depressed insulin secretion, and glucose in the urine. Our experiments in nonhuman primates support earlier studies in mice and humans that under certain circumstances, Coxsackie viruses can cause abnormalities in glucose homeostasis.

Intravenous immunoglobulin in neonatal group B streptococcal disease. Pharmacokinetic and safety studies in monkeys and humans.

Numerous studies have suggested that opsonic antibody is important in neonatal immunity to group B streptococci. Immunoglobulin G is primarily transferred from the mother to the fetus across the placenta in the last few weeks of pregnancy. Premature babies may, therefore, not acquire sufficient opsonic antibody to protect them from infection with group B streptococci. Although maternal immunization may provide adequate maternal opsonic antibody, premature infants with antibody deficiency may remain susceptible to infection. Intravenous immunoglobulin administered to term pregnant rhesus monkeys did not provide reliable levels of serum opsonic activity to group B streptococci in their offspring. Pharmacokinetic and safety studies were also performed in human neonates. Significant elevations in group B streptococcal-specific IgG did occur in human neonates given 500 mg/kg intravenous immunoglobulin and the infusions appeared safe and well tolerated. The availability of intravenous immunoglobulin with functional activity against group B streptococci may provide a rapid and effective method of delivering opsonic antibody to neonates.

Antibody to type III group B Streptococcus in the rhesus monkey.

Susceptibility to infection due to intra-amniotic type III group B streptococcal infection was studied in 27 rhesus monkeys. Sera from mothers and their offspring were tested to determine the concentration of antibody to the native type III group B Streptococcus antigen. Among 17 controls there was a statistically significant association between the concentration of maternal antibody prior to infection and both the neonatal survival rate and survival time (P less than 0.05). Neonatal survival was decreased to less than or equal to 6 hours (P = 0.005) if the maternal antibody concentration was less than 0.5 micrograms/ml. Modified immune serum globulin was given intravenously to the mothers prior to intra-amniotic infection with (five animals) or without (five animals) neonatal modified immune serum globulin. Neither of the modified immune serum globulin groups demonstrated a significant reduction in the neonatal mortality rate; however, the addition of the modified immune serum globulin provided protection against rapid neonatal death among those animals born to mothers which had low or no detectable antibody. All maternal groups developed a significant increase in the concentration of antibody in postpartum sera. These results indicate that both naturally acquired and passive (modified immune serum globulin) antibodies to type III group B Streptococcus antigen are partially protective against intra-amniotic infection.

Detection of group B streptococcal antigens in amniotic fluid of rhesus monkeys.

To simulate group B streptococci (GBS) amniotic fluid infections common in humans and to examine bacterial growth and the appearance of GBS antigens in vivo, GBS were injected into the amniotic cavity of 19 near-term rhesus monkeys. Transabdominal aspirates of amniotic fluid were obtained before bacterial challenge, after 2 and 6 h, and during cesarean section delivery (24 h). Each fluid was quantitatively cultured for GBS. Specimens of amniotic fluid and gastric aspirate from each infant were tested for the presence of GBS antigens with a commercial latex particle agglutination test (Wellcogen Strep B; Wellcome Diagnostics, Dartford, England). To eliminate nonspecific latex particle agglutination reactivity, presumably caused by proteins, a processing procedure was required. Despite active proliferation of bacteria, only 12% of the 2-h amniotic specimens were latex particle agglutination positive. In contrast, 94% of th3 6-h and 100% of the 24-h specimens had detectable antigens, as did 89% of the gastric fluid specimens aspirated from the 19 newborns. Latex particle agglutination tests, after proper processing, will readily detect GBS antigens in amniotic or gastric aspirate fluid from experimentally infected rhesus monkeys.

Teratological effects of western equine encephalitis virus on the fetal nervous system of Macaca mulatta.

Fetal rhesus monkeys were inoculated intracerebrally with an attenuated strain of western equine encephalitis virus. All animals developed microcephaly. Twelve of sixteen monkeys developed ex vacuo hydrocephalus. All virus inoculated fetuses developed WEE virus antibody. Virus could not be recovered at the time of delivery. Monkeys with the highest WEE antibody titers showed the greatest degree of hydrocephalus.

Intraamniotic infection due to group G streptococcus: treatment and antibody response.

Penicillin treatment and antibody response were studied using a rhesus monkey model for intraamniotic infection with type III group B streptococci (T3GBS). Acute and convalescent phase sera from mothers and their offspring were tested with a radioactive antigen-binding assay to determine the concentration of antibody to the capsular T3GBS antigen. The frequency of placentitis was significantly lower in penicillin-treated animals (3 of 8) than in controls (10 of 10; P less than .01). The penicillin group also had a significantly lower neonatal mortality (1 of 9) than controls (6 of 10; P less than .05). Both groups of rhesus mothers developed a significant increase in concentration of antibody to T3GBS, but the antibody response was of lesser magnitude in the penicillin-treated group. This experimental model appears to be useful for studying both therapy for intraamniotic infection and the humoral immune response to infection with T3GBS.

Penicillin treatment for group B streptococcal meningitis in the rhesus monkey.

Penicillin therapy for experimentally produced neonatal meningitis due to intracerebral inoculation of group B streptococci (GBS) was studied in 25 rhesus monkeys. Penicillin was administered either therapeutically to the newborns 3 hours after GBS inoculation or prophylactically as a bolus to the pregnant females 2 hours before delivery. The neonatal mortality in the newborn treatment groups was 40% (6 of 15) compared to 100% (5 of 5) in the maternal prophylaxis group, and 0% (0 of 5) among uninfected and untreated controls. It was concluded that although penicillin can be used successfully to treat neonates with meningitis after intracerebral inoculation of GBS, penicillin given antepartum as bolus prophylaxis to the mother monkey was ineffective.

Experimental group B streptococcal infection in the rhesus monkey. I. Disease production in the neonate.

Group B streptococci (GBS) are responsible for serious infections of newborn infants. An experimental model for GBS infection was developed in the newborn rhesus monkey in order to obtain more information concerning the pathogenesis of such infections. A series of 29 newborn monkeys were inoculated with either type Ic or type III GBS or sterile broth. Fatal neonatal meningitis without associated pneumonia was produced consistently following intracerebral inoculation with either type Ic or type III; intracerebral inoculation with sterile broth produced no apparent disease. Variable disease production followed intravenous or intra-amniotic GBS inoculation, and clinical manifestations ranged from no apparent disease to fatal meningitis and pneumonia. This monkey model may be useful for further investigation of treatment and prevention of neonatal GBS infection.