Christina Y. Chan

Inverse relationship between six week postvaccination varicella antibody response to vaccine and likelihood of long term breakthrough infection

Background. We used the large clinical database that supported the development of Oka/Merck varicella vaccine to study the relationship between the primary varicella antibody response, as determined by gpELISA, an enzyme-linked immunosorbent assay that detects antibodies to varicella-zoster virus (VZV) glycoprotein, and the subsequent risk of postvaccination breakthrough varicella. Methods. We vaccinated 1164 healthy children with a single dose of varicella vaccine containing 2900 to 9000 plaque-forming units/dose. The primary immune response to vaccination was determined by gpELISA 6 weeks after vaccination. Subjects were followed annually for 7 years to ascertain cases of breakthrough varicella. Results. The estimated vaccine efficacy among children with a 6-week postvaccination antibody titer of ≥5 gpELISA units was 95.5% (95% confidence interval, 94.2%, 96.8%) compared with 83.5% (95% confidence interval, 76.9%, 89.5%) for subjects with a titer of <5 gpELISA units. Children with a 6-week postvaccination antibody titer of <5 gpELISA units were 3.5 times more likely than those with a titer of ≥5 gpELISA units to develop breakthrough varicella. Conclusions. We identified a 6-week postvaccination antibody titer of ≥5 gpELISA units as an approximate correlate of protection. In addition we established an accelerated failure time model based on log normal hazard that predicted varicella breakthrough rates based on the distribution of 6-week postvaccination varicella antibody titers.

Bowel colonization with resistant gram-negative bacilli after antimicrobial therapy of intra-abdominal infections: observations from two randomized comparative clinical trials of ertapenem therapy

The selection of resistant gram-negative bacilli by broad-spectrum antibiotic use is a major issue in infection control. The aim of this comparative study was to assess the impact of different antimicrobial regimens commonly used to treat intra-abdominal infections on the susceptibility patterns of gram-negative bowel flora after completion of therapy. In two international randomized open-label trials with laboratory blinding, adults with complicated intra-abdominal infection requiring surgery received piperacillin-tazobactam (OASIS 1) or ceftriaxone/metronidazole (OASIS II) versus ertapenem for 4–14 days. Rectal swabs were obtained at baseline, end of therapy, and 2 weeks post-therapy. Escherichia coli and Klebsiella spp. were tested for production of extended-spectrum β-lactamase (ESBL). Enterobacteriaceae resistant to the agent used were recovered from 19 of 156 (12.2%) piperacillin-tazobactam recipients at the end of therapy compared to 1 (0.6%) patient at baseline (p<0.001) in OASIS I, and from 33 of 193 (17.1%) ceftriaxone/metronidazole recipients at the end of therapy compared to 5 (2.6%) patients at baseline (p<0.001) in OASIS II. Ertapenem-resistant Enterobacteriaceae were recovered from 1 of 155 and 1 of 196 ertapenem recipients at the end of therapy versus 0 and 1 ertapenem recipients at baseline in OASIS I and II, respectively. Resistant Enterobacteriaceae emerged significantly less often during treatment with ertapenem than with the comparator in both OASIS I (p<0.001) and OASIS II (p<0.001). The prevalence of ESBL-producers increased significantly during therapy in OASIS II among 193 ceftriaxone/metronidazole recipients (from 4 [2.1%] to 18 [9.3%]) (p<0.001), whereas no ertapenem recipient was colonized with an ESBL-producer at the end of therapy in either study. Selection for imipenem-resistant Pseudomonas aeruginosa was uncommon in all treatment groups. In these studies, the frequency of bowel colonization with resistant Enterobacteriaceae substantially increased in patients treated with either piperacillin-tazobactam or ceftriaxone/metronidazole, but not in patients treated with ertapenem.

Cellular Immunity to Varicella-Zoster Virus in Patients with Major Depression

The incidence of herpes zoster increases markedly with advancing age, and this appears to be causally related to an age-dependent decline in varicella-zoster virus (VZV)-specific cellular immunity. Psychologic stress has also been linked to the occurrence of herpes zoster, but the mechanism involved has not been investigated. This study examined the relationship between major depression and VZV-specific cellular immunity by comparing VZV-specific responder cell frequency (RCF) in adults with major depression (n = 11) to that in age- and sex-matched nondepressed controls (n = 11) and in a larger group of nondepressed adults who were > or = 60 years old. VZV-specific RCF in depressed patients was markedly reduced compared with the RCF in matched controls (t = 2.7, P < .02). In fact, the levels of VZV-specific RCF in the depressed patients were comparable in magnitude to the low levels found in adults > or = 60 years of age. These data indicate that major depression is associated with a marked decline in VZV-specific cellular immunity.

A comparison of safety, tolerability and immunogenicity of Oka/Merck varicella vaccine and VARILRIX in healthy children.

This study compared safety, tolerability, and immunogenicity of the Oka/Merck varicella vaccine and VARILRIX [Oka-RIT strain SmithKline Beecham Biologicals] in healthy children 12-24 months of age. Subjects were randomized in this double blind study to receive either a single dose of Oka/Merck varicella vaccine, (approximately 50,000 plaque forming units (PFU), Group A or approximately 16,000 PFU, Group B) or 1 dose of VARILRIX, (approximately 40,000 PFU/dose, Group C). Safety profiles in each treatment group were similar. The proportions of subjects achieving a 6-week postvaccination titer> or = 5 gpELISA units in Groups A, B or C were 97.1, 95.2 and 85.6%, respectively.

Vaccination with measles, mumps and rubella vaccine and varicella vaccine: safety, tolerability, immunogenicity, persistence of antibody and duration of protection against varicella in healthy children

Background. Administration of M-M-R II (Measles, Mumps and Rubella Virus Vaccine, Live) and VARIVAX [Varicella Virus Vaccine Live (Oka/Merck)] given concomitantly at separate injection sites during the same office visit could increase vaccine compliance by reducing the number of health care visits for immunizations. We compared the safety and immunogenicity of M-M-R II and VARIVAX given concomitantly at separate sites (Group A) with administration of the two vaccines 6 weeks apart (Group B) as well as the persistence of varicella antibody and the duration of protection afforded by varicella vaccine. Methods. A total of 603 healthy children, ages 12 months to 6 years, with no history of measles, mumps, rubella, varicella and zoster or vaccination against these diseases, were randomized to either Group A or B and were followed for clinical reactions and serologic responses to all four viral components. Children were enrolled from August through December, 1993. Subjects were followed for 5 years to evaluate persistence of varicella antibody and breakthrough varicella rates. We compared breakthrough rates to expected attack rates in unvaccinated children to produce estimates of vaccine efficacy. Results. Both vaccine regimens were generally well-tolerated. There were no significant differences between the groups in the rates of fever, injection site reactions or rashes after vaccination. Seroconversion rates and geometric mean titers for measles, mumps and rubella were not significantly different between groups. The varicella seroconversion rate and percentage with glycoprotein-based ELISA titers ≥5.0 units were similar between the two groups (99.5 and 92.5%vs. 100 and 94.8% for Groups A and B, respectively), but the geometric mean titers were statistically significantly different (13.2 for Group A and 17.9 for Group B). Varicella antibody persistence rates were >98 to 100% during 6 years of follow-up in both groups. Compared with historical rates, varicella vaccine efficacy during 5 years was estimated to be 90.5% (95% confidence interval, 86.2%, 95.0%) and 88.9% (95% confidence interval, 83.7%, 93.7%) in Groups A and B, respectively. Conclusions. Administration of M-M-R II and VARIVAX concomitantly at separate injection sites or 6 weeks apart was generally well-tolerated and immunogenic in healthy children 12 months to 6 years of age. VARIVAX administered with M-M-R II induced persistent immunity and long-term protection against breakthrough varicella infection.

Efficacy and safety of ertapenem versus piperacillin-tazobactam for the treatment of intra-abdominal infections requiring surgical intervention

Complicated intra-abdominal infections usually mandate prompt surgical intervention supplemented by appropriate antimicrobial therapy. The aim of this study was to demonstrate that ertapenem was not inferior to piperacillin-tazobactam for the treatment of community-acquired intra-abdominal infections. A randomized open-label active-comparator clinical trial was conducted at 48 medical centers on four continents from December 2001 to February 2003. Adult patients with intra-abdominal infections requiring surgery were randomized to receive either ertapenem 1 g daily or piperacillin/tazobactam 13.5 g daily in 3–4 divided doses. The primary analysis of efficacy was the clinical response rate in clinically and microbiologically evaluable patients at the test-of-cure assessment 2 weeks after completion of therapy. All treated patients were included in the safety analysis. Patient demographics, disease characteristics, and treatment duration in both treatment groups were generally similar. The most commonly isolated pathogens at baseline were E coli (greater than 50% of cases in each group) and B fragilis (~9%). Favorable clinical response rates were 107/119 (90%) for ertapenem recipients and 107/114 (94%) for piperacillin/tazobactam recipients. The frequencies of drug-related adverse events, most commonly diarrhea and elevated serum alanine aminotransferase levels, were similar in both treatment groups. Six of 180 ertapenem recipients (3%) and two of 190 piperacillin/tazobactam recipients (1%) had serious drug-related adverse experiences. In this study, ertapenem and piperacillin/tazobactam were comparably safe and effective treatments for adult patients with complicated intra-abdominal infections.

Cytokine Production in Varicella-Zoster Virus—Stimulated Cultures of Human Blood Lymphocytes

Estimates of responder cell frequency (RCF) based on limiting dilution analyses are laborious, and alternative means to quantitate cell-mediated immunity to immunogens are desirable. It was shown that levels of interleukin (IL)-2 in the supernatant of varicella-zoster virus-stimulated blood lymphocytes from immune adults peaked at 48 h of culture and correlated partially with estimates of RCF (r = .74, P = .003). Levels of gamma-interferon, IL-4, and IL-10 increased through the first 4 days of culture, and gamma-interferon levels showed some correlation with peak IL-2 levels (r = .48, P = .03). Nevertheless, correlations between levels of these cytokines and RCF did not reach statistically significant levels.

Concomitant administration of a bivalent Haemophilus influenzae type b-hepatitis B vaccine, measles-mumps-rubella vaccine and varicella vaccine: safety, tolerability and immunogenicity.

Background. The study was done to verify that concomitant administration of a bivalent Haemophilus influenzae type b-hepatitis B vaccine (Comvax), measles-mumps-rubella vaccine (M-M-RII) and varicella vaccine (Varivax) would be well-tolerated and suitably immunogenic with respect to all vaccine antigens. Methods. We randomized 822 healthy 12- to 15-month-old children (1:1) to receive concomitant injections of Comvax, M-M-RII and Varivax (concomitant group) or Comvax followed 6 weeks later by injections of M-M-RII and Varivax (nonconcomitant group). Blood samples taken before and 6 weeks after vaccination were tested for antibodies to all vaccine antigens. Results. Vaccinations were generally well-tolerated. Children in the concomitant and nonconcomitant treatment groups were similar with respect to the safety endpoint of primary interest (16.1 and 19.5%, respectively, had a fever ≥103°F rectally at any time within 14 days after either of two clinic visits). Fifteen serious adverse events were reported (eight in the concomitant group and seven in the nonconcomitant group); all resolved. Elements of two serious adverse events (fever, fever and measles-like rash; both in concomitant group children) were considered possibly related to vaccination. One child was withdrawn from the study because of a nonserious adverse event subsequently judged to be unrelated to vaccination. Similar proportions of vaccinees in the concomitant and nonconcomitant groups developed satisfactory antibody responses to the H. influenzae polysaccharide, polyribosylribitol phosphate (97.8 to 98.7%), hepatitis B surface antigen (99.2 to 100%), measles virus (99.4 to 99.6%), mumps virus (98.4 to 99.2%), rubella virus (100%) and varicella virus (93.2 to 94.6%). Conclusion. Concomitant administration of Comvax, M-M-RII and VARIVAX at the 12- or 15-month clinic visit is one satisfactory way of delivering some of the multiple vaccines indicated during the second year of life.

Safety, Tolerability & Immunogenicity of Varivax® in Children with Nephrotic Syndrome: A Report of the Southwest Pediatric Nephrology Study Group

Safety, Tolerability & Immunogenicity of Varivax® in Children with Nephrotic Syndrome: A Report of the Southwest Pediatric Nephrology Study Group