Gunasekaran Ramakrishnan

Decennial Administration of a Reduced Antigen Content Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine in Young Adults

BACKGROUND Booster vaccination against tetanus and diphtheria at 10-year intervals is commonly recommended. Reduced antigen content diphtheria and tetanus toxoids and acellular pertussis (dTpa) vaccines developed for booster vaccination of preschool children, adolescents, and adults are licensed for once-in-a-lifetime use in most countries. Objective. To evaluate decennial administration of a dTpa vaccine. Methods. Young adults vaccinated with dTpa or diphtheria and tetanus toxoids followed by acellular pertussis (DT+ap) 1 month later in a clinical trial 10 years previously received 1 dTpa dose. Blood samples were taken before and 1 month after vaccination. Antibody concentrations against vaccine antigens were measured by enzyme-linked immunosorbent assay. Solicited and unsolicited symptoms and serious adverse events were recorded. RESULTS Eighty-two individuals were enrolled in the study. In the 75 individuals who had received the dTpa vaccine 10 years previously, prevaccination seroprotection or seropositivity rates were 98.8% (diphtheria), 97.5% (tetanus), 64.6% (pertussis toxoid), 100% (filamentous hemagglutinin), and 96.3% (pertactin). One month after the second booster, all study participants were seroprotected or seropositive against all vaccine antigens. Antibody concentrations increased by a similar magnitude as 10 years previously. During the 4-day follow-up, 9.9% of participants recorded grade 3 pain; 17.3% and 18.5% recorded redness and swelling of 50 mm or larger, respectively; and 8.6% recorded fever (temperature, 37.5 degrees C). No serious adverse events were considered causally related to the vaccine. CONCLUSIONS A second dTpa booster was highly immunogenic and well tolerated in this population of young adults. This study supports the use of this vaccine as a decennial booster. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00610168 .

A decennial booster dose of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine (Boostrix™) is immunogenic and well tolerated in adults

Reduced-antigen-content diphtheria-tetanus-acellular-pertussis (dTpa) vaccines are predominantly recommended for once-in-a-lifetime use. A second dTpa (Boostrix™, GlaxoSmithKline Biologicals) administration in 164 adults previously vaccinated with dTpa 10 years previously was evaluated. Before the decennial booster, 89.4% and 94.8% subjects were seroprotected (antibodies ≥0.1 IU/mL) for diphtheria and tetanus, respectively. One-month post-booster, all subjects were seroprotected/seropositive against all vaccine antigens. Robust GMC increases indicated a booster response similar to the first booster. The decennial booster was well tolerated without serious adverse events, consistent with product experience. This study supports replacing traditional Td boosters with dTpa, and use of Boostrix™ as a decennial booster. This study is registered at www.clinicaltrials.com NCT00548171.

Lasting immune memory against hepatitis B in children after primary immunization with 4 doses of DTPa-HBV-IPV/Hib in the first and 2nd year of life.

BackgroundFew studies have assessed long term persisting immunity against hepatitis B virus (HBV) in children vaccinated during infancy with combined vaccines containing recombinant HBV surface antigen (HBs). We assessed antibody persistence and immune memory in children 4-5 years of age, previously vaccinated with four doses of combined hexavalent DTPa-HBV-IPV/Hib vaccine (Infanrix hexa™).MethodsImmune memory was assessed in 301 children through administration of a challenge dose of monovalent HBV vaccine.ResultsAt 4-5 years of age, 85.3% of subjects had persisting anti-HBs antibody concentrations ≥ 10 mIU/mL, rising to 98.6% after the HBV challenge dose. All but 12 subjects (95.8%) achieved post-challenge anti-HBs concentrations ≥ 100 mIU/mL. The post-challenge anti-HBs GMC rose by 100-fold compared to pre-challenge concentrations. An anamnestic response to the HBV vaccine challenge was observed in 96.8% of subjects, including 17/21 (81.0%) of children with initially undetectable antibodies (<3.3 mIU/mL). All but 4 of 42 subjects (90.5%) with anti-HBs antibodies <10 mIU/mL prior to the challenge dose, achieved seroprotective levels afterwards. A 4-fold rise in antibody concentration after the challenge dose was observed in 259/264 (98.1%) of initially seropositive subjects. The magnitude of the post-challenge responses was proportional to pre-challenge anti-HBs levels. No serious adverse events were reported during the study.ConclusionThe combined DTPa-HBV-IPV/Hib vaccine induced lasting immune memory against hepatitis B. Long term protection afforded by DTPa-HBV-IPV/Hib is likely to be similar to that observed following priming with monovalent HBV vaccines.Trial registrationhttp://www.clinicaltrials.gov 106789 NCT00411697

Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical intraepithelial neoplasia across 5 countries in Asia.

Objective Independent, prospective, multicenter, hospital-based cross-sectional studies were conducted across 5 countries in Asia, namely, Malaysia, Vietnam, Singapore, South Korea, and the Philippines. The objectives of these studies were to evaluate the prevalence of human papillomavirus (HPV) types (high risk and others including coinfections) in women with invasive cervical cancer (ICC) and high-grade precancerous lesions. Methods Women older than 21 years with a histologic diagnosis of ICC and cervical intraepithelial neoplasia [CIN 2 or 3 and adenocarcinoma in situ (AIS)] were enrolled. Cervical specimens were reviewed by histopathologists to confirm the presence of ICC or CIN 2/3/AIS lesion and tested with short PCR fragment10-DNA enzyme immunoassay-line probe assay for 14 oncogenic HPV types and 11 non-oncogenic HPV types. The prevalence of HPV 16, HPV 18, and other high-risk HPV types in ICC [including squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (ADC/ASC)] and CIN 2/3/AIS was estimated. Results In the 5 Asian countries, diagnosis of ICC was confirmed in 500 women [SCC (n = 392) and ADC/ASC (n = 108)], and CIN 2/3/AIS, in 411 women. Human papillomavirus DNA was detected in 93.8% to 97.0% (84.5% for the Philippines) of confirmed ICC cases [94.0%–98.7% of SCC; 87.0%–94.3% (50.0% for the Philippines) of ADC/ASC] and in 93.7% to 100.0% of CIN 2/3/AIS. The most common types observed among ICC cases were HPV 16 (36.8%–61.3%), HPV 18 (12.9%–35.4%), HPV 52 (5.4%–10.3%), and HPV 45 (1.5%–17.2%), whereas among CIN 2/3/AIS cases, HPV 16 (29.7%–46.6%) was the most commonly observed type followed by HPV 52 (17.0%–66.7%) and HPV 58 (8.6%–16.0%). Conclusions This article presents the data on the HPV prevalence, HPV type distribution, and their role in cervical carcinogenesis in 5 Asian countries. These data are of relevance to public health authorities for evaluating the existing and future cervical cancer prevention strategies including HPV-DNA testing–based screening and HPV vaccination in these Asian populations.

Repeated administration of a reduced-antigen-content diphtheria-tetanus-acellular pertussis and poliomyelitis vaccine (dTpa-IPV; Boostrix™ IPV).

Background: The rising incidence of pertussis amongst adults and adolescents in industrialised countries could be reduced by replacing tetanus and diphtheria (Td) boosters with reduced-antigen-content dT-acellular pertussis (dTpa) vaccines. Repeated administration of a dTpa-IPV (dTpa-inactivated poliomyelitis; Boostrix™ Polio, GlaxoSmithKline) booster to adolescents, 5 years after their previous dose was evaluated. Methods: 415 subjects (mean age 11.4 years) who had received either dTpa-IPV or dTpa + IPV at age 4-8 years, all received one dose of dTpa-IPV in this open, phase IV trial. Blood samples were taken before and one-month post-vaccination. Antibody concentrations against D, T, pertussis toxoid (PT), filamentous haemagglutinin (FHA), pertactin (PRN) and polio antigens were determined. Reactogenicity and safety was assessed. Results: Before the second dTpa-IPV booster, the percentage of subjects who were seroprotected/seropositive was: 98.2% (D); 98.5% (T); 40.6% (PT); 99.7% (FHA); 97.0% (PRN); 98.8% (anti-polio 1); 99.7% (anti-polio 2); 97.0% (anti-polio 3). One-month after the second dTpa-IPV dose, all subjects were seroprotected against D, T and polio and anti-pertussis booster responses (seroconversion or ≥2-fold increase) were seen in 93.3% (PT), 93.4% (FHA) and 95.2% (PRN) of subjects. During 4-day follow-up, 4.1% subjects recorded grade 3 pain; 4.6% and 3.6% recorded redness or swelling >50mm, respectively. No serious adverse events were recorded. The incidence of symptoms was not higher than after the previous booster. Conclusions: A second dTpa-IPV booster was highly immunogenic and well tolerated in this population of adolescents, supporting the repeated administration of Boostrix™ Polio. This study is registered at www.clinicaltrials.gov NCT00635128.

Impact of rotavirus vaccination in Australian children below 5 years of age: A database study

This study was conducted to assess the impact of administration of two-dose rotavirus (RV) vaccine (RIX4414; GlaxoSmithKline Vaccines) among children aged less than 5 y in three states/territories of Australia. Aggregated and de-identified data on rotavirus gastroenteritis (RVGE) and all-cause gastroenteritis (AGE) from July 1998–June 2009 were obtained from the Australian Institute of Health and Welfare database. The baseline incidence (July 1998–June 2006) of RVGE hospitalizations before RV vaccine introduction in New South Wales (NSW), the Australian Capital Territory (ACT) and the Northern Territory (NT) were 33.75, 42.93 and 288.67 per 10 000 child-years, respectively among children aged 0–11 mo. Following RV vaccine introduction in NSW, the ACT and the NT, incidence of RVGE hospitalizations reduced to 13.06, 17.35 and 47.52 per 10 000 child-years, respectively, during July 2007–June 2008 and 3.87, 8.40 and 122.79 per 10,000 child-years, respectively, during July 2008–June 2009 among children aged 0–11 mo. Reductions in RVGE and AGE were also observed in all children below 5 y of age in NSW and the ACT. Overall reduction in hospitalizations due to RVGE and AGE was observed following RV vaccine introduction into the NIP in Australia.

Prevalence and type distribution of human papillomavirus in cervical adenocarcinoma in Korean women.

BACKGROUND An increase in incidence of cervical adenocarcinoma (CADC) has been reported in many countries, including Korea. However, few studies describe human papillomavirus (HPV) type distribution among CADC in Asia. OBJECTIVE AND METHODS This was a retrospective, hospital-based observational study between 2005 and 2010 to estimate the overall prevalence and distribution of HPV types among CDAC in Korean women. The study used hematoxylin & eosin and immunohistochemical staining (for the two biomarkers p16 and progesterone receptor [PR]) to diagnose and subtype CADC samples. HPV DNA was amplified by polymerase chain reaction (PCR) and HPV genotypes were identified using reverse hybridization. RESULTS Of 196 cases submitted, 89.3% of the cases were confirmed as CADC. The mean age at diagnosis was 47.1 (standard deviation [SD] 11.9) years. No statistically significant differences in mean age at diagnosis by histological subtype were found. HPV DNA was detected in 90.3% (177/196) of CADC. HPV-18 was the most prevalent type (54.2%), followed by HPV-16 (44.1%) and HPV-45 (3.4%). Infection with any high-risk HPV type was identified in 97.7% of HPV-DNA-positive CADC. The biomarker p16 was positive in 92% of CADC cases and PR was positive in 19.6% of CADC. CONCLUSION HPV DNA was found in the large majority of CADC in Korean women, with HPV-18 being the most common type followed by HPV-16 and HPV-45. This study is among the first in Asia to specifically report HPV type distribution in CADC. This information will help inform policy decisions concerning HPV vaccination for the prevention of CADC.

The burden of rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis among children aged less than 6 years in Japan: a retrospective, multicenter epidemiological survey

BackgroundRotavirus is a leading worldwide cause of acute gastroenteritis in young children. This retrospective hospital-based study assessed the burden of rotavirus gastroenteritis in children younger than 6 years in Japan.MethodsChildren admitted to eight hospitals for acute gastroenteritis between 2008 and 2009 were identified from hospital admission databases. Diagnosis of acute gastroenteritis/rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis was confirmed based on either the International Classification of Diseases and Related Health Problems 10th revision (ICD10) codes (intestinal infectious diseases [AA00-AA09] and rotavirus gastroenteritis [A08.0]) or from rapid rotavirus diagnostic test results.ResultsOf 13,767 hospitalized children, 11.9% (1,644), 4.8% (665) and 0.6% (81) were diagnosed with acute gastroenteritis, rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis, respectively. Among acute gastroenteritis hospitalizations, 40.5% (665/1,644; ICD10 and rapid test) and 57.7% (645/1,118; rapid test only) were confirmed as rotavirus positive. Of 1,563 children with community-acquired acute gastroenteritis, 584 (37.4%) cases were confirmed as rotavirus positive. The median durations of hospitalization for all and community-acquired rotavirus gastroenteritis were 5.0 days (range: 2.0−133.0 days) and 5.0 days (range: 2.0-34.0 days), respectively. Among rotavirus gastroenteritis hospitalizations, 12.2% (81/665) of cases were hospital-acquired and the median duration of hospitalization was 10.0 days (range: 2.0-133.0 days). The median duration of additional hospitalization due to hospital-acquired rotavirus gastroenteritis was 3.0 days (range: 0–14 days). The overall incidence rate of hospital-acquired rotavirus gastroenteritis was 1.0 per 1,000 children hospital-days. The number of rotavirus gastroenteritis cases peaked between February and May in both 2008 and 2009, and the highest number of cases was reported in March 2008 (21.8%; 145/665). The highest number of rotavirus gastroenteritis hospitalizations (24.1%; 160/665) was observed in children aged 12–18 months. The proportion of hospital-acquired rotavirus gastroenteritis was higher in children aged below 18 months as compared to children at least 18 months of age (0.94 [95% CI: 0.71-1.21] vs. 0.39 [95% CI: 0.25-0.58]) and for children hospitalized for at least 5 days compared to those hospitalized for less than 5 days (0.91 [95% CI: 0.72-1.14] vs. 0.15 [95% CI: 0.05-0.32]).ConclusionsBoth community- and hospital-acquired rotavirus gastroenteritis are significant public health problems in Japan. Data from this study justify the need for the introduction and implementation of rotavirus vaccination in the Japanese national immunization program.Trial registrationClinicalTrials.gov, NCT01202201

Booster vaccination against pertussis in Chinese children at six years of age using reduced antigen content diphtheria-tetanus-acellular pertussis vaccine (Boostrix™)

Pertussis continues to circulate in Chinese communities and older children, adolescents and adults are sources of infection for unprotected infants. Two studies conducted in Jiangsu Province in the People’s Republic of China assessed the immunogenicity, reactogenicity and safety of Boostrix™, a combined reduced antigen content diphtheria-tetanus-acellular pertussis vaccine (dTpa) when administered as a booster dose to children 6−8 years of age. Immunogenicity was assessed before and one month after vaccination in a subset. Reactogenicity was assessed over a 4-day follow-up using diary cards. A total of 690 Chinese subjects were enrolled. Boostrix™ was well tolerated. One month after the booster dose, 100% of dTpa recipients had seroprotective antibody concentrations against diphtheria and tetanus. The percentage of subjects with a response against pertussis antigens (using locally defined cut-offs) was 91.9% for pertussis toxoid, 98.8% for filamentous hemagglutinin, and 100% for pertactin. The exploratory analysis showed no statistically significant differences between dTpa or diphtheria-tetanus vaccine in terms of the percentage of subjects with seroprotective antibodies against diphtheria or tetanus. These studies demonstrate that Boostrix™ is well tolerated and immunogenic when administered as a booster dose to 6−8 year old Chinese children previously immunized with a combined diphtheria-tetanus-pertussis vaccine. Introduction of dTpa into the routine Chinese immunization schedule would provide booster vaccination against pertussis without the addition of further injections into the Chinese vaccination schedule and is likely to promote improved pertussis control in older children.

Immunogenicity, reactogenicity and safety of three-dose primary and booster vaccination with combined diphtheria-tetanus-whole-cell pertussis-hepatitis B-reduced antigen content Haemophilus influenzae type b vaccine in Filipino children

Objectives: To evaluate the immunogenicity, reactogenicity and safety of primary and booster vaccination with DTPw-HBVLT/Hib2.5 vaccine containing low thiomersal and reduced quantities of Hib polysaccharide (PRP). Background: Combined DTP vaccines have high global coverage. Thus, the addition of new antigens to existing DTP vaccines is the most effective way to ensure high coverage. Methods: 192 healthy infants were randomized to receive the investigational DTPw-HBVLT/Hib2.5 vaccine or licensed DTPw-HBV/Hib10 at 6,10,14 weeks. Immune memory to the Hib antigen was assessed through administration of plain PRP challenge at 10 months in 50% of subjects. Challenged and unchallenged subjects respectively received a DTP-HBV or DTPa-HBV/Hib booster at 15–18 months of age. Antibody responses were measured using enzyme-linked immunosorbent assay (ELISA) and reactogenicity was assessed using diary cards. Results: One month post-primary vaccination, 100% and ≥93.7% of subjects in both groups had anti-PRP antibody concentrations ≥0.15μg/mL and ≥1.0μg/mL, respectively. Robust responses to PRP were observed after the 10 month plain PRP challenge and booster responses were observed in unchallenged subjects after the booster dose at 15–18 months of age. Post-primary and post-booster responses to the other vaccine antigens were at least as high in the DTPw-HBVLT/Hib2.5 group versus the DTPw-HBV/Hib10 group. The reactogenicity profile of the DTPw-HBVLT/Hib2.5 vaccine was acceptable. Conclusion: The DTPw-HBVLT/Hib2.5 combination vaccine with reduced thiomersal and Hib content had equivalent immunogenicity and tolerability versus the full standard DTPw-HBV/Hib10 vaccine. DTPw-HBVLT/Hib2.5 or DTPw-HBV/Hib10 vaccines can contribute to reducing childhood diseases through ensuring high vaccine coverage in mass vaccination programs. ClinicalTrials.gov identifiers: NCT 01061541, NCT00158808.