Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.

BACKGROUND AND OBJECTIVES: The 9-valent human papillomavirus (9vHPV) vaccine Phase III immunogenicity study in 9- to 15-year-old boys and girls was extended to assess immunogenicity and effectiveness through 10 years after the last vaccine dose (NCT00943722). METHODS: Boys (n = 301) and girls (n = 971) who received three 9vHPV vaccine doses in the base study (day 1, months 2 and 6) enrolled in the extension. Serum was collected through month 126 for antibody assessments by competitive Luminex immunoassay and immunoglobulin G-Luminex immunoassay. For effectiveness analysis starting at age 16 years, genital swabs were collected (to assess HPV DNA by polymerase chain reaction) and external genital examinations conducted every 6 months. Primary analyses were conducted in per-protocol populations. RESULTS: Geometric mean antibody titers peaked around month 7, decreased sharply between months 7 and 12, then gradually through month 126. Seropositivity rates remained ≥81% by competitive Luminex immunoassay and ≥95% by immunoglobin G-Luminex immunoassay at month 126 for each 9vHPV vaccine type. After up to 11.0 (median 10.0) years of follow-up postdose 3, there were no cases of HPV6/11/16/18/31/33/45/52/58-related high-grade intraepithelial neoplasia or condyloma in males or females. Incidence rates of HPV6/11/16/18/31/33/45/52/58-related 6-month persistent infection in males and females were low (54.6 and 52.4 per 10000 person-years, respectively) and within ranges expected in vaccinated cohorts, based on previous human papillomavirus vaccine efficacy trials. CONCLUSIONS: The 9vHPV vaccine demonstrated sustained immunogenicity and effectiveness through ∼10 years post 3 doses of 9vHPV vaccination of boys and girls aged 9 to 15 years.

4-Valent Human Papillomavirus (4vHPV) Vaccine in Preadolescents and Adolescents After 10 Years.

OBJECTIVES: We describe the final 10-year data for the long-term follow-up study of the 4-valent human papillomavirus (4vHPV) vaccine in preadolescents and adolescents. METHODS: In the base study (V501-018), 1661 sexually inactive boys and girls received the 4vHPV vaccine (early vaccination group [EVG], managed for 9.9 years) or a placebo at day 1, month 2, and month 6. Thereafter, at month 30, the placebo group (catch-up vaccination group [CVG], managed for 7.4 years) received the 4vHPV vaccine by using the same dosing schedule. Long-term anti-HPV type 6, 11, 16, and 18 immune responses were assessed. Effectiveness was estimated by calculating the incidence rate of the primary endpoints (HPV types 6, 11, 16, and 18-related disease or persistent infection). RESULTS: For HPV types 6, 11, and 16, 89% to 96% of subjects remained seropositive through 10-years postvaccination. The preadolescents had 38% to 65% higher geometric mean titers at month 7, which remained 16% to 42% higher at 10 years compared with adolescents. No cases of HPV type 6, 11, 16, and 18-related diseases were observed. Ten subjects had a persistent infection of ≥6 months duration with vaccine-type HPV and 2 subjects had persistent infection for ≥12 months. No new serious adverse events were reported through 10 years. CONCLUSIONS: A 3-dose regimen of the 4vHPV vaccine was immunogenic, clinically effective, and generally well tolerated in preadolescents and adolescents during 10 years of follow-up. These long-term findings support efforts to vaccinate this population against HPV before exposure.

Long-Term Safety and Immunogenicity of a Tetravalent Live-Attenuated Dengue Vaccine and Evaluation of a Booster Dose Administered to Healthy Thai Children.

We evaluated the safety and immunogenicity of two doses of a live-attenuated, tetravalent dengue virus vaccine (F17/Pre formulation) and a booster dose in a dengue endemic setting in two studies. Seven children (7- to 8-year-olds) were followed for 1 year after dose 2 and then given a booster dose (F17/Pre formulation), and followed for four more years (Child study). In the Infant study, 49 2-year-olds, vaccinated as infants, were followed for approximately 3.5 years after dose 2 and then given a booster dose (F17) and followed for one additional year. Two clinically notable events were observed, both in dengue vaccine recipients in the Infant study: 1 case of dengue approximately 2.7 years after dose 2 and 1 case of suspected dengue after booster vaccinations. The booster vaccinations had a favorable safety profile in terms of reactogenicity and adverse events reported during the 1-month follow-up periods. No vaccine-related serious adverse events were reported during the studies. Neutralizing antibodies against dengue viruses 1-4 waned during the 1-3 years before boosting, which elicited a short-lived booster response but did not provide a long-lived, multivalent antibody response in most subjects. Overall, this candidate vaccine did not elicit a durable humoral immune response.

Phase III, randomized controlled trial in girls 9-15 years old to evaluate lot consistency of a novel nine-valent human papillomavirus L1 virus-like particle vaccine.

A 9-valent human papillomavirus (6/11/16/18/31/33/45/52/58) VLP (9vHPV) vaccine has recently been proven highly efficacious in preventing disease associated with vaccine HPV types in a pivotal Phase III study. The demonstration of lot-to-lot consistency to confirm the reliability of the manufacturing process is a regulatory requirement for vaccine licensure in the United States. A randomized trial was conducted to demonstrate that three lots of 9vHPV vaccine elicit equivalent antibody response for all 9 vaccine types. The study required thorough planning because it required success on 27 separate statistical comparisons. An innovative statistical approach was used taking into account between-lot variance for more conservative power calculations. The study demonstrated equivalence of three lots of 9vHPV vaccine for all 9 vaccine types.

Long-term study of a quadrivalent human papillomavirus vaccine.

BACKGROUND: We present a long-term safety, immunogenicity, and effectiveness study of a quadrivalent human papillomavirus (HPV4) vaccine. METHODS: Sexually naive boys and girls aged 9 to 15 years (N = 1781) were assigned (2:1) to receive HPV4 vaccine or saline placebo at day 1 and months 2 and 6. At month 30, the placebo group (n = 482) received HPV4 vaccine following the same regimen and both cohorts were followed through month 96. Subjects ≥ 16 years were eligible for effectiveness evaluations. The primary objective was to evaluate the long-term anti-HPV6/11/16/18 serological levels. The secondary objective was to estimate vaccine effectiveness against HPV6/11/16/18-related persistent infection or disease. RESULTS: For each of the HPV4 vaccine types, vaccination-induced anti-HPV response persisted through month 96. Among 429 subjects who received HPV4 vaccine at a mean age of 12, none developed HPV6/11/16/18-related disease or persistent infection of ≥ 12 months' duration. Acquisition of new sexual partners (among those ≥ 16 years) was ∼1 per year. Subjects receiving HPV4 vaccine at month 30 (mean age 15 years) had a similar baseline rate of seropositivity to ≥ 1 of the 4 HPV types to those vaccinated at day 1 (mean age 12 years; 1.9% [9 of 474] vs 1.7% [20 of 1157]); however, 4 of the 9 subjects vaccinated at the later age were seropositive to 3 vaccine types, indicating previous HPV exposure. No new significant serious adverse events were observed for 8 years postvaccination in both genders. CONCLUSIONS: When administered to adolescents, the HPV4 vaccine demonstrated durability in clinically effective protection and sustained antibody titers over 8 years.

Safety and immunogenicity of a tetravalent live-attenuated dengue vaccine in flavivirus-naive infants.

A Phase I/II observer-blind, randomized, controlled trial evaluated the safety and immunogenicity of a dengue virus (DENV) vaccine candidate in healthy Thai infants (aged 12-15 months) without measurable pre-vaccination neutralizing antibodies to DENV and Japanese encephalitis virus. Fifty-one subjects received two doses of either DENV (N = 34; four received 1/10th dose) or control vaccine (N = 17; dose 1, live varicella; dose 2, Haemophilus influenzae type b). After each vaccine dose, adverse events (AEs) were solicited for 21 days, and non-serious AEs were solicited for 30 days; serious AEs (SAEs) were recorded throughout the study. Laboratory safety assessments were performed at 10 and 30 days; neutralizing antibodies were measured at 30 days. The DENV vaccine was well-tolerated without any related SAEs. After the second dose, 85.7% of full-dose DENV vaccinees developed at least trivalent and 53.6% developed tetravalent neutralizing antibodies ≥ 1:10 to DENV (control group = 0%). This vaccine candidate, therefore, warrants continued development in this age group (NCT00322049; clinicaltrials.gov).

Invasive pneumococcal disease in Phramongkutklao Hospital 2004-2008: clinical data, serotype distribution and antimicrobial resistance patterns.

OBJECTIVE: To describe the clinical course, serotype distribution and antimicrobial resistance patterns of invasive pneumococcal disease (IPD) cases in a public hospital. MATERIAL AND METHOD: Retrospective review of IPD cases occurring from January 2004 through December 2008 was performed. Antibiotic susceptibility testing and serotyping were performed for available isolates. RESULTS: Fifty one IPD cases occurred during the study period, of which 47 had medical records available for review. The majority of cases occurred among children under 5 years of age (23.4%) and adults over 60 years of age (36.1%). Underlying diseases were identified in 72.3% of patients. Fifty-three percent of cases were associated with pneumonia, while 17% had meningitis, and 15% had isolated bacteremia. Serotype could be determined for 15 (31.9%) isolates, and 6B was most common. Based on current antibiotic susceptibility breakpoints for meningitis, 4 of the 7 available isolates from meningitis cases were penicillin resistant and one had reduced susceptibility to cefotaxime. Among non-meningitis isolates, 96.7% were penicillin susceptible and 3.3% had intermediate susceptibility to penicillin. Overall case fatality proportion was 19%. CONCLUSION: At this tertiary care hospital in Bangkok, IPD has disproportionately affected young children and the elderly. High rates of penicillin resistance among meningitis cases, the most severe form of IPD, underscore the need of appropriate treatment strategies and vaccine usage.

Cerebrospinal fluid lymphocytosis in an infant with acute Streptococcus pnuemoniae meningitis: a case report.

A 10 month-old female infant presented with one day of high fever with drowsiness and seizures. Physical examination showed meningeal irritation and mild cyanosis. The cerebrospinal fluid (CSF) profile revealed opening pressure of 27 cmH2O, closing pressure of 17 cmH2O, red blood cells 310 cells/microL, white blood cells 100 cells/microL of which 90 percents were lymphocytes, protein 391 mg/dl, sugar 0 mg/dL and blood sugar 74 mg/dl. Numerous gram positive diplococci were found on CSF Gram-stained smear. Bacterial meningitis was diagnosed and cefotaxime 300 mg/kg/day plus vancomycin 60 mg/kg/ day were given empirically. The patient developed hypotension, poor tissue perfusion, dyspnea and disseminated intravascular coagulopathy (DIC). She expired 10 hours after hospitalization. The CSF and blood culture grew out Streptococcus pneumoniae serotype 6B with the minimal inhibitory concentration (MIC) of 0.5 and 1.5 microg/mL for penicillin and cefotaxime respectively. Atypical characteristics of CSF in bacterial meningitis may cause delay in empirical antimicrobial therapy. Gram-stained smear of CSF is helpful for rapid diagnosis and proper management.

Epidemiological characteristics of Acinetobacter baumannii infections at Phramongkutklao Hospital.

OBJECTIVE: To describe epidemiological characteristics of Acinetobacter baumannii infections and identify molecular patterns of A. baumannii isolated from the patients admitted in Phramongkutklao Hospital. MATERIAL AND METHOD: A retrospective study on previously isolated A. baumannii from the clinical specimens submitted to the microbiology laboratory of Phramongkutklao Hospital from January to March 2008 were carried out together with molecular typing using PCR-based method. Clinical data were obtained from IC surveillance and patients' records. RESULTS: 114 A. baumannii were isolated from 80 patients. A. baumannii was a cause of healthcare-associated infection (90%, 72 of 80 cases), colonization (7.5%), and community-acquired infection (2.5%) with mortality rate of 50%. Majority of the patients from which A. baumannii were isolated were male (58.8%), age over 60 years (56.3%), diagnosed with lower respiratory diseases (26.3%), had A. baumannii ventilator-associated pneumonia (66.7%), and admitted in medical department (57.5%) with median length of hospital stay 35 days. PDR- and MDR- A. baumannii were accounted for 67.5% and 21.1%, respectively. All isolates showed sensitive to tigecycline and colistin. Using PCR-based typing was able to distinguish 6 molecular types among 114 A. baumannii isolates. Molecular type 2 was the most common type (47.4%) and widely spread in 14 wards. Spread of clonally related isolates was found in 14 cases admitted in 8 medical wards and ICUs. CONCLUSION: Multiple clones of PDR- and MDR- A. baumannii were widely spread in the hospital. Clonally related A. baumannii infected 14 cases in 8 wards.

Bed rails and endotracheal tube connectors as possible sources for spreading Acinetobacter baumannii in ventilator-associated pneumonia patients.

This study aimed to determine molecular patterns of Acinetobacter baumannii using a PCR-based technique with REP-1, REP-2 and M13 primers to distinguish the patients' strains and the environmental strains (condensate, endotracheal tube connector, bed rail and nurses hands). There were 67 cases of ventilator-associated pneumonia (VAP) among 600 patients using mechanical ventilators in 10 wards from March to July 2006. The incidence of VAP was 11.2% or 8.9/1,000 ventilator days with a 54.5% fatality rate. Among 19 of 22 A. baumannii VAP patients, 68.4% (13/19) had their environmental samples contaminated with A. baumannii and the most common contaminated sites were bed rails and endotracheal tube connectors (36.8% each). Multidrug resistant (MDR) A. baumannii were involved in 77.3% of A. baumannii VAP. Molecular typing of 96 A. baumannii isolates was able to differentiate A. baumannii isolates into 7 types. Type 2 was the most common and found in 77.3% (17/22) of A. baumannii VAP patients admitted in 6 of 7 wards. Identical fingerprints were found in clinical isolates and their bed rails, endotracheal tube connectors and condensates of 5 patients. The results demonstrate that multiple clones of MDR A. baumannii were widely spread in the hospital. Bed rails and contaminated endotracheal tube connectors could be potential sources of A. baumannii spread.

Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia.

BACKGROUND: This study was designed to evaluate the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) against culture-confirmed influenza in children 12 to <36 months of age during 2 consecutive influenza seasons at multiple sites in Asia. METHODS: In year 1, 3174 children 12 to <36 months of age were randomized to receive 2 doses of CAIV-T (n = 1900) or placebo (n = 1274) intranasally > or =28 days apart. In year 2, 2947 subjects were rerandomized to receive 1 dose of CAIV-T or placebo. RESULTS: Mean age at enrollment was 23.5 +/- 7.4 months. In year 1, efficacy of CAIV-T compared with placebo was 72.9% [95% confidence interval (CI): 62.8-80.5%] against antigenically similar influenza subtypes, and 70.1% (95% CI: 60.9-77.3%) against any strain. In year 2, revaccination with CAIV-T demonstrated significant efficacy against antigenically similar (84.3%; 95% CI: 70.1-92.4%) and any (64.2%; 95% CI: 44.2-77.3%) influenza strains. In year 1, fever, runny nose/nasal congestion, decreased activity and appetite, and use of fever medication were more frequent with CAIV-T after dose 1. Runny nose/nasal congestion after dose 2 (year 1) and dose 3 (year 2) and use of fever medication after dose 3 (year 2) were the only other events reported significantly more frequently in CAIV-T recipients. CONCLUSIONS: CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia.

Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial.

OBJECTIVE: Administration of a quadrivalent HPV-6/ 1/16/18 vaccine to 16- to 26-year-old women was highly effective in preventing HPV-6/ 1/16/18-related cervical/vulvar/vaginal precancerous lesions and genital warts. As the risk of acquiring HPV significantly rises after sexual debut, HPV vaccines should have the greatest benefit in sexually naive adolescents. We evaluated the tolerability and immunogenicity of quadrivalent vaccine in males and females 9 to 15 years of age through 18 months postenrollment. METHODS: In this randomized, double-blind trial, 1781 sexually naive children were assigned (2:1) to quadrivalent HPV-6/11/16/18 vaccine or saline placebo administered at day 1 and months 2 and 6. Serum neutralizing anti-HPV-6/11/16/18 responses were summarized as geometric mean titers (GMTs) and seroconversion rates. Primary analyses were done per-protocol (subjects received 3 doses, had no major protocol violations and were HPV type-specific seronegative at day 1). Adverse experiences were collected by diary card. RESULTS: At month 7, seroconversion rates were > or =99.5% for the 4 vaccine-HPV-types. GMTs and seroconversion rates in boys were noninferior to those in girls (P < 0.001). At month 18, > or =91.5% of vaccine recipients were seropositive, regardless of gender. A higher proportion of vaccine recipients (75.3%) than placebo recipients (50.0%) reported one or more injection-site adverse experiences following any vaccination. Rates of fever were similar between vaccination groups. No serious vaccine-related adverse experiences were reported. CONCLUSIONS: In 9- to 15-year-old adolescents, the quadrivalent vaccine was generally well tolerated and induced persistent anti-HPV serologic responses in the majority of subjects for at least 12 months following completion of a three-dose regimen. The vaccine durability supports universal HPV vaccination programs in adolescents to reduce the burden of clinical HPV disease, particularly cervical cancer and precancers.

Seroprevalence of hepatitis A in thai army medical cadets and nursing students: a reflection of regional risk differences.

A cross-sectional study of 432 army college students comprising 278 medical cadets and 154 nursing students, ages ranging from 15 to 26 years, was conducted in 2001 to determine the seroprevalence of hepatitis A virus (HAV) antibody. Serum specimens were tested for HAV antibody by a commercial enzyme immunoassay method. Anti-HAV was detected in 14.0%, 17.5%, and 15.3% of medical cadets, nursing students, and the total cohort, respectively. There was no statistically significant difference in seroprevalence between medical cadets and nursing students. Increasing prevalence of HAV correlated with increasing age. Significantly higher seroprevalence was detected in students from provinces outside of Bangkok compared to those who were from Bangkok (18.7% vs. 9.8%). The highest HAV seroprevalence was observed in subjects from the northeastern region of Thailand, suggesting that this region may be associated with greater risk for infection and should be the focus of preventive health strategies.

Quantification of HIV-1 RNA load by one-tube-one-step RT PCR and real time PCR assay with TaqMan probe.

OBJECTIVES: To develop a less expensive assay to calculate HIV-1 viral load for use in resource-limited countries. MATERIAL AND METHOD: An In-house One-tube-one-step Viral Load Assay (IOVA) was developed by using real-time PCR-based with TaqMan probe. Primers and probe were designed from the conserved region of sequences from all HIV subtypes. A standard curve was generated from reference virus in various dilutions. IOVA was applied on 105 HIV-positive and 25 HIV-negative samples and compared with the results from ROCHE AMPLICLOR. RESULTS: IOVA measured HIV RNA in the samples ranging from 125 to 2 x 10(6) copies/mL. The coefficient of variation of intra- and inter-assay ranged from 0.68% to 7.89%. The sensitivity, specificity, positive and negative predictive values were 92%, 100%, 100% and 79.5% respectively. The parallel quantitative analysis showed high correlation (r=0.95) between IOVA and AMPLICOR. CONCLUSION: A new HIV-1 viral load assay was developed and validated. It was reliable and less expensive.

Transplacentally transferred maternal-infant antibodies to dengue virus.

Antibodies of all four dengue virus serotypes were detected by hemagglutination inhibition (HI) in 97% of 2,000 infants' cord sera at the time of delivery. In comparison with 250 mother-infant's paired sera, we found that 53% of the infants' serum HI titers were higher than those of the mother's. The mother/infant IgG subclasses 1, 2, 3, and 4 titers were 53.1/87.0, 8.4/11.7, 0.14/0.11, and 1.1/1.0 mg/dL, respectively. In 18 months of follow-up of 100 infants studied, we observed that antibody to dengue virus disappeared in 3% by two months of age, in 19% by four months of age, in 72% by six months of age, in 99% by nine months of age, and in 100% by 12 months of age, with a half-life of 41 days. We conclude that the antibodies to dengue virus disappeared in the first year of life. We suggest that the most appropriate age for vaccination with a live-attenuated dengue vaccine in an endemic area is one year of age.