Andrea J. Swift

Safety and Immunogenicity of Heptavalent Pneumococcal Vaccine Conjugated to CRM197 Among Infants With Sickle Cell Disease

Objectives. To determine the immunogenicity and safety of heptavalent pneumococcal polysaccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated to CRM197 (7-valent conjugate pneumococcal vaccine [7VPnC]) among infants with sickle cell disease (SCD) and a comparison group of infants without SCD (non-SCD). Design. Two cohorts of infants were enrolled and received open-label doses of 7VPnC vaccine; infants enrolled before 2 months of age received 7VPnC vaccine at 2, 4, and 6 months of age followed by 23-valent pneumococcal polysaccharide vaccine (PS-23) at 24 months of age for those infants with SCD (schedule A), and infants enrolled between 2 and 12 months of age received 7VPnC at 12 months of age followed by PS-23 at 24 months of age for infants with SCD (schedule B). Safety data were collected for 3 days after each dose of vaccine. Antibody concentrations were measured to each of the 7VPnC serotypes by enzyme-linked immunosorbent assay before each vaccine dose and 1 month after the last 7VPnC dose and the PS-23 vaccine dose. Results. Forty-five infants (34 SCD and 11 non-SCD) were vaccinated according to schedule A and 16 infants (13 SCD and 3 non-SCD) according to schedule B. The 7VPnC vaccine was highly immunogenic for all serotypes among infants with and without SCD who received 3 doses of vaccine according to schedule A: depending on serotype, 89% to 100% achieved antibody concentrations above .15 μg/mL and 56% to 100% achieved antibody concentrations above 1.0 μg/mL. Among infants immunized according to schedule B, a single dose of 7VPnC vaccine resulted in antibody concentrations above .15 μg/mL in 53% to 92% by serotype and above 1.0 μg/mL in 31% to 71% by serotype. A single dose of PS-23 resulted in dramatic increases in the antibody concentrations to all serotypes regardless of 1- or 3-dose priming. There was no difference in the reactogenicity of the 7VPnC vaccine between those with and without SCD. There were no serious reactions to the 7VPnC or PS-23 vaccines, even among those with high antibody concentrations before immunization. Conclusions. Infants with SCD respond to 7VPnC vaccine with antibody concentrations that are at least as high as infants without SCD. Infants immunized with 7VPnC vaccine at 2, 4, and 6 months of age developed antibody concentrations in the same range as those achieved among infants without SCD enrolled in a large trial that demonstrated vaccine efficacy against invasive disease. Significant rises were seen in antibody concentrations to all 7VPnC serotypes after the PS-23 booster in children receiving schedule A or B.

Protective effect of residual splenic tissue after subtotal splenectomy.

Studies in animals and clinical experience in man have demonstrated that splenectomy leads to increased susceptibility to infection with encapsulated bacteria. Splenic tissue has an excellent ability to regenerate, even when implanted into subcutaneous tissue or the abdominal cavity. These implants, however, do not protect against bacterial challenge despite the fact that a number of other functions can be restored. We therefore studied the ability of residual splenic tissue to protect against challenge following subtotal splenectomy in Sprague-Dawley rats. Subtotal splenectomy was performed on 48 animals in which approximately 75% of the spleen was removed and left with a branch of its normal blood supply; 48 animals underwent total splenectomy and 48 had sham operations. Six months after surgery the groups were challenged intravenously with type 25 pneumococci to determine the LD50 for each group. Animals that had undergone subtotal splenectomy were more resistant to pneumococcal challenge than were asplenic animals, but they were not as resistant as normal animals. In addition, there was marked delay in death in the animals with subtotal splenectomy as compared with asplenic animals. Thus residual splenic tissue after subtotal splenectomy appears to confer some degree of protection against pneumococcal challenge.

Membranoproliferative glomerulonephritis in dogs with a genetically determined deficiency of the third component of complement

Renal disease is a common clinical manifestation of genetically determined deficiencies of the complement system in man. Like their human counterparts, dogs with a genetically determined complete deficiency of C3 also develop renal disease. Five of 20 C3-deficient dogs developed clinical evidence of renal failure. However, 14 of the 15 remaining dogs had histological evidence of type I membranoproliferative glomerulonephritis. The lesions were characterized by mesangial cell proliferation, an increase in the mesangial matrix, thickening of the glomerular capillary wall, electron-dense deposits in the mesangium and subendothelial space, and the presence of IgG and IgM. In order to determine the effect of treatment with C3 on the renal disease of C3-deficient dogs, two C3-deficient dogs were infused with normal canine plasma twice weekly for 3 weeks. Their urinary protein excretion rose progressively from less than 200 mg/24 hr to greater than 1000 mg/24 hr; renal function remained normal. Renal biopsies performed 1 week after the last infusion revealed more severe glomerulonephritis and the presence of C3. As controls, a C3-deficient dog was given C3-deficient canine plasma and a normal dog was given normal canine plasma; neither control animal developed proteinuria or changes in their renal biopsy. These observations suggest that renal disease may be more common in humans with complement deficiencies than would be suspected based on clinical assessment. Furthermore, these results suggest that treatment with complement-containing blood products may worsen preexisting renal disease in complement-deficient individuals.

Immunologic Effects of Hydroxyurea in Sickle Cell Anemia

BACKGROUND AND OBJECTIVE: Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea’s effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1–S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. METHODS: T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG). RESULTS: Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use. CONCLUSIONS: Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced.

Complement-mediated serum activities against genetically defined capsular transformants of Haemophilus influenzae

Although there are six different capsular serotypes of Haemophilus influenzae (a-f), only type b strains commonly cause systemic infections in man. The present study was performed to determine whether the propensity of the type b organism to cause invasive infections is due to a unique ability to evade complement-mediated host defenses. The ability of genetically defined capsular transformants (a-f) of an unencapsulated H. influenzae to resist the bactericidal and opsonic activities of serum was examined. The unencapsulated organism and the type f transformants were relatively susceptible to serum bactericidal activity in both adult and infant serum pools, the type a and e transformants were relatively resistant, and the types b, c and d transformants were intermediate. With respect to serum opsonic activity in both adult and infant serum pools, the unencapsulated organism and the type f transformant were relatively susceptible, the type a, b and e transformants were relatively resistant and the type c and d transformants were intermediate. Thus, although the type b capsule endows the organism with the ability to resist the bactericidal and opsonic effects of complement, this property is not unique to type b.

Serum Opsonic Activity in Infants with Sickle-Cell Disease Immunized with Pneumococcal Polysaccharide Protein Conjugate Vaccine

ABSTRACT Pneumococcal infections are an important cause of morbidity and mortality in children with sickle-cell disease (SCD). Pneumococcal conjugate vaccines (PCVs) are immunogenic in healthy infants <2 years of age but have not been evaluated in young children with SCD. Infants with SCD were immunized with a 7-valent PCV (Wyeth-Lederle Vaccines & Pediatrics) at 2, 4, and 6 months of age. A booster dose of 23-valent pneumococcal polysaccharide vaccine (PPV; Pnu-Immune) was administered at 24 months of age. Antipneumococcal type 6B and 14 serum opsonic activity was measured to assess the biologic function of the antibody. Following the administration of three doses of PCV, opsonic activity against serotype 6B increased from 4.8% at 2 months to 33.5% at 7 months, with a subsequent decline to 8.1% at 12 months and 7.5% at 24 months and with an increase to 30.7% at 25 months after administration of a booster dose of PPV. Similar trends were seen with serotype 14 (opsonic activities were 9.4% at 2 months, 24.9% at 7 months, 16.5% at 12 months, and 12.6% at 24 months, and the opsonic activity was 27.3% 1 month after the administration of PPV). Serum opsonic activity correlated with antibody levels for both serotypes. PCV induces serum opsonic activity in infants with SCD. Antipneumococcal serum opsonic activity correlates with antibody levels.

Defective Activation of the Third Component of Complement in the Sera of Newborn Infants

Summary: The activation of the terminal complement components, C3–9, plays an important role in the hosts defense against infection. In the present study, the ability of bacteria to activate the third component of complement (C3) in newborn serum was examined.A variety of bacteria were incubated in test sera at 37°C for 30 min and the percent of available C3 that was activated was measured. Using one strain of Escherchia coli(#3), 32% (mean) of the available C3 was activated in sera from 18 newborns, as compared to 85% in sera from their mothers and 79% in sera from 13 normal adults (P<0.005). In contrast, using another strain of E. coli (N70), the percent of C3 activated in newborn sera (83%) was the same as in sera from their mothers (81%) or in sera from normal adults (73%). The defective activation of C3 in newborn sera by E. coli was not related to the presence of the K1 antigen. Newborn sera were also challenged with other bacterial species and the activation of C3 was deficient when tested with klebsiellae, but not with staphylococci or streptococci. The defect in newborn sera appeared to be due to a deficiency of a serum factor rather than to the presence of an inhibitor.Speculation: The defective activation of C3–9 in newborn sera by some bacteria may be, in part, responsible for the neonates increased susceptibility to infection.

IMMUNOGENICITY OF A PNEUMOCOCCAL PROTEIN CONJUGATE VACCINE IN INFANTS WITH SICKLE CELL DISEASE. ▴ 946

Pneumococcal infections are an important cause of morbidity/mortality in children with sickle cell disease (SCD). Pneumococcal conjugate vaccines linked to protein carriers are immunogenic in healthy infants < 2 yrs of age, but have not been evaluated in children with SCD. Infants with SCD were immunized with a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (CRM; cross-reacting diphtheria mutant) at 2, 4, and 6 mos. Type specific antibodies were measured by ELISA after pre-absorption with C-polysaccharide. No side effects have been observed. This vaccine appears to be safe and immunogenic, and should provide protection against pneumococcal infections in infants with SCD. (Funded in part by Lederle-Praxis Biologicals.) Table

Serum Opsonic Activity for Streptococcus pneumoniae Types 6B and 14 in Infants with Sickle Cell Disease after Immunization with Pneumococcal Protein Conjugate Vaccine

Serum Opsonic Activity for Streptococcus pneumoniae Types 6B and 14 in Infants with Sickle Cell Disease after Immunization with Pneumococcal Protein Conjugate Vaccine