Orin S. Levine

Risk Factors and Opportunities for Prevention of Early-onset Neonatal Sepsis: A Multicenter Case-Control Study

Background. Early-onset group B streptococcal (GBS) prevention efforts are based on targeted use of intrapartum antibiotic prophylaxis (IAP); applicability of these prevention efforts to infections caused by other organisms is not clear. Methods. Multicenter surveillance during 1995 to 1996 for culture-confirmed, early-onset sepsis in an aggregate of 52u2009406 births; matched case-control study of risk factors for GBS and other sepsis. Results. Early-onset disease occurred in 188 infants (3.5 cases per 1000 live births). GBS (1.4 cases per 1000 births) andEscherichia coli (0.6 cases per 1000 births) caused most infections. GBS sepsis less often occurred in preterm deliveries compared with other sepsis. Compared with gestation-matched controls without documented sepsis, GBS disease was associated with intrapartum fever (matched OR, 4.1; CI, 1.2–13.4) and frequent vaginal exams (matched OR, 2.9; CI, 1.1–8.0). An obstetric risk factor—preterm delivery, intrapartum fever, or membrane rupture ≥18 hours—was found in 49% of GBS cases and 79% of other sepsis. IAP had an adjusted efficacy of 68.2% against any early-onset sepsis. Ampicillin resistance was evident in 69% of E coliinfections. No deaths occurred among susceptible E coliinfections, whereas 41% of ampicillin-resistant E coliinfections were fatal. Ninety-one percent of infants who developed ampicillin-resistant E coli infections were preterm, and 59% of these infants were born to mothers who had received IAP. Conclusions. Either prenatal GBS screening or a risk-based strategy could potentially prevent a substantial portion of GBS cases. Sepsis caused by other organisms is more often a disease of prematurity. IAP seemed efficacious against early-onset sepsis. However, the severity of ampicillin-resistant E colisepsis and its occurrence after maternal antibiotics suggest caution regarding use of ampicillin instead of penicillin for GBS prophylaxis.

Evaluation of Binax NOW, an Assay for the Detection of Pneumococcal Antigen in Urine Samples, Performed among Pediatric Patients

In our evaluation of a new assay for the detection of pneumococcal antigen in urine (Binax NOW; Binax), the test result was no more likely to be positive among 88 children with radiographically confirmed pneumonia than among 198 control subjects; however, it was significantly more likely to be positive among children who were nasopharyngeal carriers of pneumococci. This test is not likely to be useful for distinguishing children with pneumococcal pneumonia from those who are merely colonized.

Reemergence of invasive Haemophilus influenzae type b disease in a well-vaccinated population in remote Alaska.

Before vaccination, Alaska Natives experienced very high rates of invasive Haemophilus influenzae type b (Hib) disease and carriage. Vaccination with Hib conjugate vaccine PRP-OMP (polyribosylribitol phosphate Neisseria meningitidis outer membrane protein) began in 1991 and resulted in a sharp decline in cases. In 1996, after switching to a different Hib conjugate vaccine, DTP-HbOC (which combines diphtheria-tetanus-whole cell pertussis vaccines with HbOC [Hib oligosaccharide CRM197]), cases of invasive Hib disease increased, suggesting ongoing Hib transmission despite widespread vaccination. To determine the prevalence of and risk factors for carriage, a cross-sectional study of oropharyngeal Hib carriage was conducted among Alaska Native children aged 1-5 years in remote southwestern Alaska. Of 496 children with swabs taken, 46 (9.3%) were colonized with Hib. Carriage rates varied by village from 2.2% to 13.2% and by age from 6.1% in 1-year-olds to 14.7% in 5-year-olds. Crowding was associated with Hib carriage. Widespread vaccination with PRP-OMP Hib conjugate vaccine did not eliminate carriage in this population of Alaska Natives, and ongoing carriage contributed to disease resurgence.

Large scale, postlicensure, selective vaccination of Chilean infants with PRP-T conjugate vaccine: practicality and effectiveness in preventing invasive Haemophilus influenzae type b infections.

BACKGROUNDnHaemophilus influenzae type b (Hib) conjugate vaccines have demonstrated an impressive impact in diminishing Hib disease in industrialized countries. However, their high cost prompts nonindustrialized countries to corroborate their effectiveness under local conditions before considering their programmatic implementation. Such a postlicensure evaluation of vaccine effectiveness was undertaken in Chile.nnnMETHODSnAfter its licensure in Chile polyribosylribitol phosphate-tetanus toxoid protein conjugate vaccine (PRP-T), combined with diphtheria-tetanus-pertussis vaccine, was introduced into the Expanded Program on Immunization schedules in 36 health centers throughout metropolitan Santiago for 12 months, whereas 35 similar health centers administered only diphtheria-tetanus toxoid-pertussis vaccine. Bacteriologic surveillance data for invasive Hib cases collected over the ensuing 30 months were analyzed.nnnRESULTSnIn an intent-to-vaccinate (effectiveness) analysis, PRP-T provided 90.2% protection (95% confidence interval, 74.5 to 100%) against invasive Hib disease (40 vs. 4 cases, P < 0.001). Vaccine effectiveness was 91.3% against meningitis (22 vs. 2 cases) and 80% against pneumonia and empyema (10 vs. 2 cases, P = 0.039). Vaccine efficacy among infants who received all three doses of PRP-T was 91.7% (95% confidence interval, 64.8 to 100%).nnnCONCLUSIONSnProgrammatic use of Hib conjugate vaccine administered in combination with diphtheria-tetanus-pertussis vaccine constitutes a highly effective and practical intervention in Chile, a newly industrializing country.

Prevention of invasive group A streptococcal disease among household contacts of case patients and among postpartum and postsurgical patients: Recommendations from the centers for disease control and prevention

The Centers for Disease Control and Prevention hosted a workshop to formulate recommendations for the control of invasive group A streptococcal (GAS) disease among household contacts of persons with invasive GAS infections and for responding to postpartum and postsurgical invasive GAS infections. Experts reviewed data on the risk of subsequent invasive GAS infection among household contacts of case patients, the effectiveness of chemoprophylactic regimens for eradicating GAS carriage, and the epidemiology of postpartum and postsurgical GAS infection clusters. For household contacts of index patients, routine screening for and chemoprophylaxis against GAS are not recommended. Providers and public health officials may choose to offer chemoprophylaxis to household contacts who are at an increased risk of sporadic disease or mortality due to GAS. One nosocomial postpartum or postsurgical invasive GAS infection should prompt enhanced surveillance and isolate storage, whereas > or =2 cases caused by the same strain should prompt an epidemiological investigation that includes the culture of specimens from epidemiologically linked health care workers.

Introduction of Hib conjugate vaccines in the non-industrialized world: experience in four 'newly adopting' countries.

Hib conjugate vaccines are widely used in the industrialized world, but are just now beginning to be introduced into other countries. To identify factors facilitating rapid global introduction, we evaluated the decision-making process, mode of introduction, effectiveness, and impact on the immunization program of Hib conjugate vaccine introduction in four non- industrialized countries through site visits and use of a standardized questionnaire. The key promoters of Hib introduction were the pediatric community and ministries of health. Local surveillance and severity data were critical in the decision to adopt Hib vaccine. Assistance with surveillance, introduction guidelines, educational material, tenders, and funding is needed to accelerate wider adoption.

Prevention of Haemophilus influenzae Type b Colonization by Vaccination: Correlation with Serum Anti-Capsular IgG Concentration

Concentrations of serum anti-Haemophilus influenzae type b (anti-Hib) capsular polysaccharide (CPS) >/=0.15 and >/=1.0 microgram/mL are widely used as surrogates for protection against invasive Hib disease. However, the relationship between serum anti-Hib CPS following immunization and protection against colonization is not known, making it difficult to evaluate new Hib vaccines or combination vaccines. In the Dominican Republic, nasopharyngeal swabs were collected from 546 9-month-old infants who had received Hib conjugate vaccine at ages 2, 4, and 6 months and from 600 unvaccinated infants of the same age. The prevalence of Hib colonization was lower among vaccinated infants than among unvaccinated infants (0.9% vs. 2.3%). Among vaccinated infants, protection against colonization was significantly correlated with anti-Hib CPS concentrations >/=5 microgram/mL 1 month following the third dose of vaccine. These results suggest that the concentration of serum anti-Hib CPS needed for protection against colonization is greater than that needed for protection for invasive disease.

Economisation of vaccination against Haemophilus influenzae type b: a randomised trial of immunogenicity of fractional-dose and two-dose regimens

BACKGROUNDnThe cost of Haemophilus influenzae type b (Hib) conjugate vaccines has limited their use in non-industrialised countries. To identify more economical vaccination schedules, we carried out a randomised trial of the immunogenicity of alternative regimens to the standard three-dose series.nnnMETHODSn627 Chilean infants were randomly allocated to one of four regimens with either Hib polysaccharide-tetanus toxoid conjugate vaccine (PRP-T) or Hib oligosaccharide-diphtheria mutant toxoid conjugate vaccine (PRP-CRM197), for a total of eight groups. All infants receive diphtheria-tetanus-pertussis (DTP) vaccine at ages 2, 4, and 6 months. The regimens included three full doses, three fractional doses consisting of one half or one third of the full dose, and a regimen of two full doses (at age 4 and 6 months). The primary outcome was the proportion of infants with serum anti-polyribosylribitol phosphate (PRP, the type b capsular polysaccharide) concentrations of 0.15 microg/mL or more at age 8 months.nnnFINDINGSn93% (95% CI 85-98) of infants vaccinated with three full doses of PRP-T or PRP-CRM197 (95% CI 84-98) achieved anti-PRP concentrations of 0.15 microg/mL or more at age 8 months, compared with 91% (83-96) to 100% (95-100) of infants immunised with any fractional-dose regimen. Of the infants vaccinated with two doses of PRP-T or PRP-CRM197, 99% (93-100) and 87% (77-93) developed anti-PRP concentrations of 0.15 microg/mL or more, respectively.nnnINTERPRETATIONn91% (83-96) to 100% (95-100) of infants immunised with one-half or one-third of a full dose of Hib conjugate developed protective antibody concentrations. Carrier priming with DTP may make two-dose schedules an option in some places. These alternative regimens could bring the cost of Hib vaccines within reach of countries that currently cannot afford them.

Influence of disease burden, public perception, and other factors on new vaccine development, implementation, and continued use

The development, implementation, and continued use of new vaccines depends on several factors. Although disease burden seems like an obvious quantitative measure for setting priorities for new vaccine development and use, resources are not always allocated proportionately. This is particularly evident for diseases that are unique (or largely limited) to people in developing countries. Public pressure based on perceptions of the risks associated with a disease or vaccine, the cost of new vaccines, and the ability to incorporate them into existing vaccination programmes also need to be considered in the decision to introduce new vaccines. Vaccine manufacturers play an important part in development of new vaccines, and therefore, the issues that are important to them, namely, production, intellectual property rights, and product liability, must be addressed. By advocating rational decisions, supported by accurate information, scientists and public-health professionals can have an important role in transforming the potential of new vaccines into the reality of new vaccine-preventable diseases.

Functional Antibody Activity Elicited by Fractional Doses of Haemophilus influenzae Type b Conjugate Vaccine (Polyribosylribitol Phosphate-Tetanus Toxoid Conjugate)

ABSTRACT We evaluated the functional activities of antibodies, serum bactericidal activity (SBA), and immunoglobulin G (IgG) antibody avidity indices, using sodium thiocyanate (NaSCN) elution, elicited after vaccination with fractional doses of the Haemophilus influenzae type b conjugate (polyribosylribitol phosphate [PRP] conjugated to tetanus toxoid [PRP-T]) vaccine. A cohort of 600 infants from the Dominican Republic were randomized to receive one of three regimens of the PRP-T vaccine at ages 2, 4, and 6 months: full doses (10 μg of PRP antigen), one-half doses (5.0 μg), and one-third doses (3.3 μg) (J. Fernandez et al., Am. J. Trop. Med. Hyg. 62:485–490, 2000). Sixty serum samples, collected at age 7 months, with ≥2.0 μg of anti-PRP IgG per ml were randomly selected for avidity determinations. Geometric mean IgG concentrations were 13, 14, and 17 μg/ml for infants who received the full-dose (n = 19), one-half-dose (n = 19), and one-third-dose (n = 22) regimens, respectively. SBA geometric mean titers (1/dilution) were 85.0, 82.0, and 76.1 in sera from infants receiving the full-, one-half-, and one-third-dose regimens, respectively. Avidity indices (mean ± standard error weighted average of NaSCN molar concentration × serum dilution factor) were 71.9 ± 9.4, 123.6 ± 26.8, and 150.9 ± 24.9 for the full-, one-half-, and one-third-dose regimens, respectively. Upon comparison, the only significant difference (P = 0.024) found was a greater avidity index for sera from infants receiving the one-third-dose regimen than for sera from infants receiving the the full-dose regimen. We conclude that fractional doses elicit similar functional antibody activities in infants with ≥2 μg of anti-PRP IgG per ml, corresponding to 89, 90, and 97% of infants receiving three doses of either the full concentration or one-half or one-third of the labeled concentration, respectively. This approach offers an alternative strategy for the prevention of H. influenzae type b disease in countries with limited resources.