Light reflection models for computer graphics.

During the past 20 years, computer graphic techniques for simulating the reflection of light have progressed so that today images of photorealistic quality can be produced. Early algorithms considered direct lighting only, but global illumination phenomena with indirect lighting, surface interreflections, and shadows can now be modeled with ray tracing, radiosity, and Monte Carlo simulations. This article describes the historical development of computer graphic algorithms for light reflection and pictorially illustrates what will be commonly available in the near future.

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55years of age. The aim of this study was to assess the safety of MenACWY-D administered as part of routine clinical care to patients at Kaiser Permanente Northern California (KPNC). METHODS: This was an observational, retrospective study that included all KPNC members who received MenACWY-D during the study period. We monitored all vaccine recipients for non-elective hospitalizations, emergency department visits, and selected outcomes captured in the clinic setting (Bell's palsy, seizures, neuritis, Guillain-Barré syndrome, encephalopathy, encephalitis, epilepsy, transverse myelitis, multiple sclerosis, hypersensitivity reactions, idiopathic thrombocytopenic purpura, diabetes, arthritis, hemolytic anemia, collagen-vascular disease) through 6months after vaccination. Using vaccine recipients as their own controls, we calculated incidence rate ratios (IRRs) of outcomes during the post-vaccination risk interval and compared these with rates during a comparison interval more remote from vaccination. We also compared rates of outcomes in MenACWY-D recipients with those in matched controls who received selected vaccines in the prior year. We reviewed medical records for selected outcomes. RESULTS: From April 2005 through April 2006, 31,561 KPNC patients (>99% of whom were 11-55years of age) received MenACWY-D. Overall, there were 21 outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs did not suggest any relationship with MenACWY-D. Two serious adverse events were considered possibly related to vaccination by the study investigator. CONCLUSIONS: This study did not detect any safety concerns following MenACWY-D and provides reassurance that MenACWY-D administered as part of routine care was not associated with unexpected safety risks. ClinicalTrials.gov Identifier is NCT00254995.

Effectiveness and safety of an Haemophilus influenzae type b conjugate vaccine (PRP-T) in young infants. Kaiser-UCLA Vaccine Study Group.

OBJECTIVE: To study the safety, immunogenicity, and protective efficacy of the Haemophilus influenzae capsular polysaccharide tetanus conjugate vaccine (PRP-T). DESIGN: Randomized, double-blind, controlled clinical trial. SETTING: Southern California Kaiser-Permanente Health Plan. PARTICIPANTS: 10,317 infants 6 to 15 weeks of age, with no known immune dysfunction, exposure to hepatitis B, or contraindication to diphtheria-tetanus-pertussis (DTP) vaccination were enrolled between August 1989 and September 1990. INTERVENTION: Infants were randomized to receive either PRP-T or a recombinant hepatitis B control vaccine (in addition to DTP) at approximately 2, 4, and 6 months of age. OUTCOME MEASURES: Adverse reactions occurring during the first 72 hours and between doses (including hospitalizations and outpatient visits) were measured using parental reporting/interviews and review of records. Invasive disease caused by H influenzae was ascertained from the time of enrollment until December 31, 1990. RESULTS: In October 1990, the study was prematurely terminated because of licensure of other H influenzae vaccines recommended for routine infant use. The rates of systemic and local reactions occurring within 72 hours of each vaccine dose were generally similar for infants given PRP-T and hepatitis B, but some reaction rates (local reactions, fever > or = 102 degrees F, irritability, crying) were significantly higher in the PRP-T group. In the month following receipt of vaccine, PRP-T-vaccinated infants experienced five definite seizures compared with three in the hepatitis B control group. Within 48 hours of vaccination, three seizures (two definite and one possible), which were thought to be related to vaccination, occurred in the PRP-T group, compared with none in the control group (P < .13). Overall morbidity, mortality, and hospitalization rates were similar in the two vaccine groups. Three cases of invasive disease caused by H influenzae occurred in the control group; none occurred in the PRP-T group. CONCLUSIONS: The PRP-T vaccine is safe and appears to be effective in preventing invasive disease caused by H influenzae type b.

Pediatric experience with recombinant hepatitis B vaccines and relevant safety and immunogenicity studies.

Yeast-derived recombinant hepatitis B vaccines have replaced plasma-derived vaccines in the United States and have now been given to millions of infants and children throughout the world. Routine immunization of infants in the United States with hepatitis B vaccine has been endorsed as the optimal means to prevent infection. The recombinant vaccines have an excellent safety record; most children have no adverse reactions whereas a few experience only minor local and systemic reactions that resolve within a short time. Both of the vaccines licensed in the United States are highly immunogenic in infants and children who complete a three dose vaccination sequence. Approximately 95 to 100% achieve protective levels of antibody to hepatitis B surface antigen (> or = 10 mIU/ml) after three doses. Immunization may begin at birth or at 1 to 2 months of age, and hepatitis B vaccine may be given simultaneously with other routine childhood vaccines. Antibody levels to hepatitis B surface antigen gradually wane over time, and the duration of maintaining protective levels correlates strongly with the peak level achieved. The protective efficacy against perinatal transmission from mothers who are positive for hepatitis B surface antigen and e antigen is 90 to 100% when the first dose of vaccine is administered at birth with hepatitis B immunoglobulin. In highly endemic populations immunization in infancy also protects against horizontal transmission from chronically infected family members. Studies currently in progress will determine the duration of protection, the potential need for booster doses and the feasibility of combining antigens in multivalent vaccines.

Considerations for hepatitis B as part of a combination vaccine.

BACKGROUND: In 1991 the Advisory Committee on Immunization Practices (ACIP) developed a comprehensive strategy to eliminate the transmission of hepatitis B virus in the United States, which includes immunization of all infants. Today, as the number of recommended childhood vaccinations increases, combination vaccines are needed to simplify the immunization schedule and improve coverage levels. METHODS: A review of the literature was performed to determine the considerations that should be taken when hepatitis B virus vaccine (HepB) is included as part of a combination vaccine. RESULTS: A combination vaccine that incorporates HepB and other routine infant vaccine antigens has been developed for administration at 2, 4 and 6 months of age. Clinical studies have demonstrated that administration of HepB, either as a monovalent or combination vaccine at 2, 4 and 6 months of age, induces a seroprotective immune response similar to that achieved with monovalent HepB administered at 0, 1 and 6 months of age. In addition the combination vaccine results in similar or fewer adverse reactions compared with separate administration of its components. Infants given a dose of monovalent HepB at birth will receive a total of four doses of HepB when the combination is used. The extra dose of HepB has not led to increased adverse reactions. CONCLUSIONS: A HepB-containing combination vaccine administered at 2, 4 and 6 months of age is as safe and immunogenic as separate administration of its components and will help simplify the childhood immunization schedule.

Safety evaluation of PRP-D Haemophilus influenzae type b conjugate vaccine in children immunized at 18 months of age and older: follow-up study of 30,000 children.

We evaluated the safety of the PRP-D conjugate Hib vaccine (ProHIBit, Connaught) in 29,309 children vaccinated at 18-60 months of age in the Southern California Kaiser Permanente medical clinics during the period April 1, 1988, to July 31, 1989. Surveillance for potential reactions involved postcard questionnaires, telephone surveys, reports of Kaiser staff and review of hospitalizations and covered two periods following immunization: (1) the first 48 hours and (2) days 2 through 30. Surveillance for invasive Hib disease involved the above methods in addition to systematic reviews of laboratory and hospital records through January 31, 1990. Rates of local and systemic reactions within 48 hours of vaccination with PRP-D alone were low (less than or equal to 2% for fever greater than 102 degrees F, local redness or swelling) and similar to those previously reported after vaccination with PRP. Hospitalization and seizures (0.15% and 0.09% of vaccinated children, respectively) occurring within 1 month of immunization appeared to be unrelated to vaccination. One 29-month-old child had onset of a fatal episode of Hib sepsis/meningitis within 48 hours of vaccination. Also, a 30-month-old child developed Hib meningitis 10 months after PRP-D vaccination. We conclude that PRP-D is safe when given alone or in combination with other childhood vaccines between 18 and 60 months of age.

Factors influencing immunogenicity and safety of two Haemophilus influenzae type b polysaccharide vaccines in children 18 and 24 months of age.

The purpose of this study was to evaluate differences in the safety and immunogenicity of Haemophilus influenzae type b (Hib) capsular polysaccharide vaccine produced by two manufacturers (Connaught and Praxis) in children 18 and 24 months of age. Eighty-five children were evaluated in a prospective, double-blind, randomized fashion. Postvaccination antibody concentrations (measured by radioimmunoassay) and response rates were not significantly different between the two manufacturers' vaccines but immunogenicity was significantly less in 18-month-old children (antibody concentration, 0.149 microgram/ml) compared with 24-month-old children (0.838 microgram/ml) (P = 0.001). No significant differences were noted in the safety of the two vaccines. This study suggests that previously observed differences of immunogenicity data between various type b capsular polysaccharide vaccines are due to differences in antibody assays, not in vaccines. Eighteen-month-old children appear to have a relatively poor immune response to type b capsular polysaccharide. Therefore to optimize the benefits of immunization, we suggest children receive this vaccine at 24 months of age.

Protection provided by Haemophilus influenzae type b conjugate vaccines in Los Angeles County: a case-control study.

The objective was to assess the degree of disease control and to evaluate the protective efficacy of licensed Haemophilus influenzae type b (Hib) conjugate vaccines (HbOC, PRP-OMP, PRP-D) used routinely in children 2 to 35 months of age. We conducted a case-control study in Los Angeles County between January 1, 1991, and December 31, 1992, and a cohort analysis of Hib cases between 1983 and 1992. For the case-control study 105 cases of invasive Hib disease were identified and 767 geographically and age-matched controls were selected by random digit telephone dialing. Sixteen HbOC vaccine failures occurred > 14 days after a single dose of vaccine, 6 vaccine failures after 2 doses and 3 failures after 3 doses; 2 cases occurred 6 and 12 days, respectively, after an initial dose of HbOC. The protective efficacy of a single HbOC vaccine dose was 71.1% (95% confidence interval (CI), 37.5 to 87.2%). After 2 doses the efficacy was 88.8% (95% CI, 59.5 to 96.9%) and after 3 doses it was 94.4% (95% CI, 68.0% to 99.0%). Similar 95% CIs were seen for 1 and 2 doses of PRP-OMP vaccine. Adjustment of efficacy estimates for potential confounding variables did not significantly alter the results. Despite relatively low rates of immunization (20 to 60%) the rates of Hib disease decreased strikingly between 1990 and 1992 (from 24.2 to 4.4/100,000 children < 5 years of age). The HbOC conjugate vaccine, used predominantly but incompletely during this period, provided substantial protection against invasive Hib disease in children immunized between 2 and 35 months of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunogenicity of a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine when mixed with a diphtheria-tetanus-acellular pertussis-hepatitis B combination vaccine.

BACKGROUND: Combination vaccines are urgently needed to reduce the number of injections given to young children. The aim of the study was to evaluate the safety and immunogenicity of a combination vaccine that contains diphtheria and tetanus toxoids and acellular pertussis antigens (DTaP), recombinant hepatitis B surface antigen (HepB) and Haemophilus influenzae type b (Hib) polysaccharide conjugated to tetanus toxoid (PRP-T). METHODS: Four hundred five infants were randomized equally to three groups and immunized at 2, 4 and 6 months of age with: (1) DTaP/HepB vaccine used to reconstitute lyophilized PRP-T vaccine and administered as a single injection; (2) DTaP/HepB vaccine and PRP-T vaccine administered as two separate injections; or (3) DTaP, HepB and PRP-T vaccines administered as three separate injections. Safety was closely monitored, and blood specimens were obtained to assess antibody responses to each vaccine antigen. RESULTS: All study vaccines were well-tolerated, and the rates of systemic and injection site reactions were similar between groups. After the third dose the geometric mean antibody concentrations to Hib were significantly lower in subjects in Group 1 (1.63 microg/ml) compared with subjects in Groups 2 and 3 (6.26 and 6.15 microg/ml, respectively; P < 0.0001). Subjects with antibody concentrations <1.0 microg/ml after the third dose responded well to a booster dose of Hib conjugate vaccine given at 11 to 15 months of age (41 of 44 with anti-PRP > or = 1.0 microg/ml). Differences between groups for antibody responses to the other vaccine components were not clinically significant. CONCLUSIONS: Infants given a combined DTaP/ HepB/PRP-T vaccine experienced a significantly lower antibody response to the PRP-T component than infants given PRP-T vaccine as a separate injection. However, the immune response to a booster dose of Hib conjugate vaccine indicated the presence of immunologic memory.

Comparative safety and immunogenicity of two recombinant hepatitis B vaccines given to infants at two, four and six months of age.

OBJECTIVES: To evaluate the relative safety and immunogenicity of the two recombinant hepatitis B vaccines licensed in the United States with doses recommended for routine immunization of low risk infants and a schedule that corresponds with routine pediatric visits. METHODS: Healthy infants were immunized at 2, 4 and 6 months of age with hepatitis B vaccine manufactured by either SmithKline Beecham (Engerix-B, 10 micrograms/dose, n = 228) or Merck and Co. (Recombivax HB, 2.5 micrograms/dose, n = 200). Adverse reactions were ascertained by parental reports and interviews and by review of medical records. Antibody concentrations to hepatitis B surface antigen (anti-HBs) were measured in sequential serum specimens by enzyme immunoassay. RESULTS: Adverse reactions were mild and the rates were not significantly different between the two groups. After the first and second doses the rates of seropositivity (> or = 10 mIU/ml) and seroprotection (> or = 10 mIU/ml) were significantly higher in infants given SmithKline Beecham vaccine (P < 0.01). After the second and third doses infants given SmithKline Beecham vaccine also had significantly higher geometric mean anti-HBs concentrations compared with those given Merck vaccine (348.0 mIU/ml vs. 66.9 and 1914.8 mIU/ml vs. 514.8 mIU/ml, respectively, P < 0.001). Nevertheless after the third dose 99% of infants in both vaccine groups achieved seroprotective antibody concentrations. CONCLUSIONS: Both recombinant hepatitis B vaccines were safe and immunogenic when administered concurrently with other pediatric vaccines at 2, 4 and 6 months of age, but earlier protective responses were observed with the SmithKline Beecham vaccine than with the Merck vaccine.

Eradication of Haemophilus influenzae type b disease in southern California. Kaiser-UCLA Vaccine Study Group.

OBJECTIVE: To assess the effects of Haemophilus influenzae vaccination of infants. RESEARCH DESIGN: We evaluated H influenzae type b (Hib) disease rates in Los Angeles County, California (population, 9 million; 1983 through 1992), and in the Southern California Kaiser Health Plan (2.5 million enrollees; 1988 through 1992) during the past decade. Cases were obtained through active and passive disease surveillance in the two populations. The following vaccines were used during the study period (1983 through 1992): (1) Hib polysaccharide vaccine (polyribosyl ribitol phosphate) (used from 1985 through 1987 for children 24 through 60 months of age); (2) Hib polysaccharide-diphtheria toxoid conjugate, Hib polysaccharide CRM197 mutant diphtheria toxoid conjugate vaccine, and Hib polysaccharide outer-membrane protein of group B meningococcus conjugate vaccine in older children (1988 through 1990; ages 15 through 60 months); and (3) Hib polysaccharide CRM197 mutant diphtheria toxoid conjugate vaccine and Hib polysaccharide outer-membrane protein of group B meningococcus conjugate vaccine used in infants (1991 through 1992). MEASUREMENTS AND RESULTS: Between 1983 and 1988, the Hib disease incidence in Los Angeles County was unchanged (32.7 to 42.5/100,000 person-years in children younger than 5 years). In 1989 through 1990, before Hib conjugate licensure for infant use, Hib disease rates in all age groups declined. After licensure of Hib vaccines for infants in 1990, there was a further fivefold decrease in infants. More dramatic decreases occurred in the better-immunized Kaiser Health Plan children aged 0 through 60 months (53 cases in 1989, only two cases in 1992). CONCLUSIONS: The Hib disease has been nearly eradicated in a fully immunized population (Kaiser Health Plan), and significant reductions have also occurred in Los Angeles County.

Prevention of bacterial meningitis. Vaccines and chemoprophylaxis.

The morbidity and mortality caused by bacterial meningitis remains significant despite advances in antimicrobial therapy and supportive care. Prevention of meningitis by routine immunization of infants, who are at greatest risk, offers the only practical way of reducing the incidence of this disease. Widespread use of the recently developed protein conjugate vaccines against Haemophilus influenzae type b by itself could reduce the incidence of bacterial meningitis in the U.S. by more than half. To prevent disease caused by the other pathogens, an effective vaccine against the group B meningococcus must be developed, and the immunogenicity of the pneumococcal and quadrivalent meningococcal vaccines should be improved. Until such time that universal immunization of infants with highly immunogenic vaccines is possible, continued efforts must focus on targeting immunization at high-risk individuals and using chemoprophylaxis to prevent secondary disease where indicated. Addendum: On October 4, 1990, the U.S. Food and Drug Administration licensed the praxis Haemophilus influenzae type b-protein conjugate vaccine (Hboc) for use in infants at 2, 4, and 6 months of age with a booster dose at 15-18 months. Physicians are directed to statements by the Immunizations Practices Advisory Committee and the American Academy of Pediatrics for official recommendations concerning its use.

Clinician satisfaction with vaccination visits and the role of multiple injections, results from the COVISE Study (Combination Vaccines Impact on Satisfaction and Epidemiology).

Because little is known about clinician satisfaction with infant vaccination visits, we measured satistaction and the effects of the number of injections on satisfaction. Clinicians from 35 pediatric centers self-administered a questionnaire using visual analog scales augmented by a Likert scale. All 95 pediatricians and 137 nonphysician vaccinators responded. In both populations, increased injections predicted decreased overall satisfaction, and decreased satisfaction with obtaining consent, time to prepare/administer, getting upset during administration, and time to update records (each p<0.01). Satisfaction decreased markedly, on each measure, at 4-injection visits, 5-injection visits, or both.

Update on the development and use of viral and bacterial vaccines for the prevention of acute otitis media.

Acute otitis media (AOM) is the most frequent diagnosis in physician offices among children 1-4 years of age. Viruses that cause upper respiratory tract infections (i.e., respiratory syncytial virus [RSV], influenza virus, parainfluenza virus [PIV], and others) play an important role in the development of AOM. Prevention of infections with these viral pathogens likely would reduce the incidence of AOM. In three previous studies, influenza virus vaccines showed 30-36% efficacy against the development of AOM. Vaccines to prevent infections with RSV and PIV type 3 are undergoing clinical testing at this time. The three major bacterial pathogens causing AOM are Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis. Pneumococcal conjugate vaccine, licensed in the United States in 2000, was shown in two pivotal trials to reduce the incidence of all causes of AOM by 6%, pneumococcal AOM by 34%, and pneumococcal AOM caused by serotypes contained in the vaccine by 57%. Currently, vaccines against NTHi and M. catarrhalis are under development.

Vaccine prevention of acute otitis media.

The incidence of acute otitis media (AOM) in infants and young children has increased dramatically in recent years in the United States. AOM often follows upper respiratory tract infections due to pathogens such as respiratory syncytial virus (RSV), influenza virus, and parainfluenza virus (PIV). These viruses cause eustachian tube dysfunction that is critical to the pathogenesis of AOM. Vaccines against these viruses would likely reduce the incidence of AOM. In three previous studies, influenza virus vaccines reduced the incidence of AOM by 30% to 36%. Vaccines to prevent infections with RSV and PIV type 3 are undergoing clinical testing at this time. Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi), and Moraxella catarrhalis are the three most common AOM pathogens. Heptavalent pneumococcal conjugate vaccine is effective in preventing invasive disease and AOM caused by serotypes contained in the vaccine. Vaccine candidates for NTHi and M. catarrhalis are under development.

Correlates of therapeutic efficacy in experimental methicillin-resistant Staphylococcus aureus endocarditis.

Seventy animals with experimental aortic valve endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) were randomized to receive: no therapy; pefloxacin 40 or 80 mg/kg/day i.v.; or vancomycin 30 mg/kg/day i.v. Vancomycin caused a more rapid decrease in intravegetation MRSA counts than pefloxacin at 40 or 80 mg/kg/day (p less than 0.001, p less than 0.05, respectively, therapy day 3). The major correlate of therapeutic efficacy in this study was the significantly higher mean intravegetation levels achieved by vancomycin (16.8 +/- 6.1 micrograms/g) versus those attained by pefloxacin therapy at either 40 (1.6 +/- 0.13 micrograms/g) or 80 mg/kg/day (2.8 +/- 0.53 micrograms/g, p less than 0.005, p less than 0.025, respectively).

Influence of Staphylococcus aureus antibody on experimental endocarditis in rabbits.

To evaluate the potential protective benefit of antibody to whole cells of Staphylococcal aureus for the prevention of endocarditis, the rabbit endocarditis model was used. Methicillin-sensitive (17A) and methicillin-resistant (173) S. aureus strains were evaluated in rabbits with or without indwelling intracardiac catheters. All immunized rabbits developed significant homologous agglutinating antibody titers (the mean reciprocal titers were 15,300 to strain 17A and 1,150 to strain 173). After challenge, virtually no significant differences were observed between immunized and unimmunized animals with respect to (i) incidence of endocarditis, (ii) concentration of bacteria in infected vegetations, (iii) incidence of metastatic renal abscesses, or (iv) concentrations of bacteria in infected kidneys. The clearance of homologous S. aureus strains from blood cultures was similar for immunized and unimmunized animals at 10 to 90 min after intravenous challenge. In vivo adherence of homologous S. aureus strains to aortic valves and vegetations was similar in immunized and unimmunized animals when evaluated at 30 and 90 min postchallenge. Even without catheterization, the incidence of bacteremia and renal abscesses was the same in immunized and unimmunized rabbits. Whole-cell-induced S. aureus antibody did not prevent or modify any stage in the development of endocarditis in rabbits.

Antibody responses to protein A in patients with Staphylococcus aureus bacteremia and endocarditis.

To assess the significance of antibody to Staphylococcus aureus protein A (SpA) in human sera, we developed a modified enzyme-linked immunosorbent assay (ELISA). SpA antibody levels in 23 patients with S. aureus endocarditis (IE), 21 patients with non-IE S. aureus bacteremia, and 33 controls were measured. Geometric mean levels of antibody to SpA were significantly higher in S. aureus IE patients (134 ELISA units [EU]) than in uninfected controls (52 EU; P less than 0.01). Also, a significantly greater proportion of S. aureus IE patients (12 of 23) and S. aureus non-IE bacteremia patients (11 of 21) had antibody levels greater than an arbitrary threshold of 100 EU compared with uninfected controls (0 of 23; P less than or equal to 0.001). However, no significant differences in geometric mean SpA antibody levels between the bacteremic patients with and without IE were noted. The sensitivity and specificity of this ELISA to distinguish patients with S. aureus IE from those with non-IE bacteremia were low (52 and 48%, respectively). There was a significant association between SpA antibody levels and either immunoglobulin G or immunoglobulin M teichoic acid antibody levels (r = 0.406, P less than 0.05; r = 0.571, P = 0.002, respectively). For patients from whom multiple sera were available (13 IE and 5 non-IE patients), SpA antibody levels were measured over time and showed a wide temporal variation of immune responses. We conclude that antibody responses to SpA can be measured in many patients with invasive S. aureus disease but that the levels are of insufficient sensitivity or specificity to be of clinical use as a diagnostic or prognostic test.