Stephen B. Lambert

Immunogenicity of a Monovalent 2009 Influenza A(H1N1) Vaccine in Infants and Children: A Randomized Trial

CONTEXT In the ongoing influenza pandemic, a safe and effective vaccine against 2009 influenza A(H1N1) is needed for infants and children. OBJECTIVE To assess the immunogenicity and safety of a 2009 influenza A(H1N1) vaccine in children. DESIGN, SETTING, AND PARTICIPANTS Randomized, observer-blind, age-stratified, parallel group study assessing 2 doses of an inactivated, split-virus 2009 influenza A(H1N1) vaccine in 370 healthy infants and children aged 6 months to less than 9 years living in Australia. INTERVENTION Intramuscular injection of 15 microg or 30 microg of hemagglutinin antigen dose of monovalent, unadjuvanted 2009 influenza A(H1N1) vaccine in a 2-dose regimen, administered 21 days apart. MAIN OUTCOME MEASURES Hemagglutination inhibition assay to estimate the proportion of participants with antibody titers of 1:40 or greater, seroconversion, or a significant antibody titer increase, and factor increase in geometric mean titer. Assessments of solicited adverse events during 7 days and unsolicited adverse events for 21 days after each vaccination. RESULTS Following the first dose of vaccine, antibody titers of 1:40 or greater were observed in 161 of 174 infants and children in the 15-microg group (92.5%; 95% confidence interval [CI], 87.6%-95.6%) and in 168 of 172 infants and children in the 30-microg group (97.7%; 95% CI, 94.2%-99.1%). Corresponding seroconversion rates were 86.8% (95% CI, 80.9%-91.0%) and 94.2% (95% CI, 89.6%-96.8%), and factor increases in geometric mean titer were 13.6 (95% CI, 11.8-15.6) and 18.3 (95% CI, 15.7-21.4). All participants demonstrated antibody titers of 1:40 or greater after the second vaccine dose. Immune responses were robust regardless of age, baseline serostatus, or seasonal influenza vaccination status. The majority of adverse events were mild to moderate in severity. CONCLUSION One 15-microg dose of vaccine was immunogenic in infants and children starting at 6 months of age and vaccine-associated reactions were mild to moderate in severity. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00940108.

Characterisation of a newly identified human rhinovirus, HRV-QPM, discovered in infants with bronchiolitis

Abstract Background Human rhinoviruses (HRVs) are some of the earliest identified and most commonly detected viruses associated with acute respiratory tract infections (ARTIs) and yet the molecular epidemiology and genomic variation of individual serotypes remains undefined. Objectives To molecularly characterise a novel HRV and determine its prevalence and clinical impact on a predominantly paediatric population. Study design Nucleotide sequencing was employed to determine the complete HRV-QPM coding sequence. Two novel real-time RT-PCR diagnostic assays were designed and employed to retrospectively screen a well-defined population of 1244 specimen extracts to identify the prevalence of HRV-QPM during 2003. Results Phylogenetic studies of complete coding sequences defined HRV-QPM as a novel member the genus Rhinovirus residing within the previously described HRV-A2 sub-lineage. Investigation of the relatively short VP1 sequence suggest that the virus is resistant to Pleconaril, setting it apart from the HRV A species. Sixteen additional HRV-QPM strains were detected (1.4% of specimens) often as the sole micro-organism present among infants with suspected bronchiolitis. HRV-QPM was also detected in Europe during 2006, and a closely related virus circulated in the United States during 2004. Conclusions We present the molecular characterisation and preliminary clinical impact of a newly identified HRV along with sequences representing additional new HRVs.

Number and Order of Whole Cell Pertussis Vaccines in Infancy and Disease Protection

lowing negative studies. Despite studies showing that echinacea does not treat cold symptoms, it is one of the best selling supplements in the United States with estimated sales exceeding

Reduction in Rotavirus-associated Acute Gastroenteritis Following Introduction of Rotavirus Vaccine Into Australia's National Childhood Vaccine Schedule

300 million per year. Dr Leach claims that I supported my position “through the selective reporting of a few clinical studies.” However, all studies are not equal. The studies I selected regarding gingko, chondroitin sulfate, glucosamine, garlic, St John’s wort, milk thistle, and echinacea were the best controlled, most rigorous, and most internally consistent. Indeed, most of these excellent studies were supported by NCCAM. Briggs and Killen and Leach argue that refraining from studying alternative medicine would deny the public muchneeded clinical data to make informed health care decisions. In a better world, of course, this discussion would not be happening. In a better world, dietary supplements and alternative therapies would be subject to testing before claims were allowed, as is required by the US Food and Drug Administration (FDA) for licensure of drugs, biologicals, and medical devices. Now patients are stuck with a system in which some alternative medicines might be tested after claims have been made and after nutraceutical companies have spent millions of dollars “educating” the public. At best, NCCAM functions as a post-hoc FDA, except without the FDA’s regulatory authority and without the communication skills or dollars to confront a well-heeled nutraceutical industry. Sadly, until the 1994 Dietary Supplement and Health Education Act—which essentially freed the nutraceutical industry from FDA oversight—is repealed, consumers will continue to receive bad information that could lead to bad medical decisions, NCCAM or no NCCAM.

Incidence of Hepatitis B Virus Infection in the United States, 1976–1994: Estimates from the National Health and Nutrition Examination Surveys

Introduction: Rotavirus vaccines were introduced into the funded Australian National Immunization Program (NIP) in July 2007. Due to purchasing arrangements, individual states and territories chose either a 2-dose RV1 (Rotarix, GSK) regimen or 3-dose RV5 (Rotateq, Merck/CSL) regimen. This allowed comparison of both vaccines in similar populations with high infant vaccination coverage. Methods: Admission and rotavirus identification data from the major pediatric hospitals in 3 states (2 using RV5, 1 RV1), together with state-based hospitalization and vaccination data from Queensland (RV5) were analyzed for the years before, and up to 30 months following rotavirus vaccine introduction. Emergency encounters and short-stay unit admissions for gastroenteritis are also described. Results: Rotavirus vaccine coverage in Australia is high, with 87% of infants receiving at least 1 dose. Hospital admissions for both rotavirus gastroenteritis and nonrotavirus-coded gastroenteritis were reduced following vaccine introduction in all states, not only for the age group eligible for NIP rotavirus vaccination, but also for children born prior. RV5 vaccine efficacy in Queensland has been estimated at 89.3%. Marked reductions in acute gastroenteritis emergency presentations and short-stay unit admissions have also been observed. Conclusions: Early evidence from the NIP in Australia has demonstrated high rotavirus coverage with both RV1 and RV5. The introduction of both vaccines has been associated with a marked reduction in gastroenteritis admissions, supportive of both direct vaccine protection, as well as with indirect herd protection.

Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case-control study nested within a population based screening programme in Australia.

Precise estimates of the incidence of hepatitis B virus (HBV) infection are required to assess the impact of immunization and other prevention strategies in the United States. Race- and age-specific prevalence data obtained from the second and third National Health and Nutrition Examination Surveys (NHANES II, 1976-1980, and NHANES III, 1988-1994) were used to estimate the annual incidence of HBV infection by catalytic modeling. During the period covered by NHANES II, an estimated 323,462 persons were infected annually, and 334,863 were infected annually during the period covered by NHANES III. No statistically significant declines in prevalence of HBV infection occurred between the two surveys, a period during which hepatitis B vaccination targeted only limited numbers of high-risk adults.

Distinguishing molecular features and clinical characteristics of a putative new rhinovirus species, human rhinovirus C (HRV C).

Objective To measure the effectiveness of the quadrivalent human papillomavirus (HPV) vaccine against cervical abnormalities four years after implementation of a nationally funded vaccination programme in Queensland, Australia. Design Case-control analysis of linked administrative health datasets. Setting Queensland, Australia. Participants Women eligible for free vaccination (aged 12-26 years in 2007) and attending for their first cervical smear test between April 2007 and March 2011. High grade cases were women with histologically confirmed high grade cervical abnormalities (n=1062) and “other cases” were women with any other abnormality at cytology or histology (n=10 887). Controls were women with normal cytology (n=96 404). Main outcome measures Exposure odds ratio (ratio of odds of antecedent vaccination (one, two, or three vaccine doses compared with no doses) among cases compared with controls), vaccine effectiveness ((1−adjusted odds ratio)×100), and number needed to vaccinate to prevent one cervical abnormality at first screening round. We stratified by four age groups adjusted for follow-up time, year of birth, and measures of socioeconomic status and remoteness. The primary analysis concerned women whose first ever smear test defined their status as a case or a control. Results The adjusted odds ratio for exposure to three doses of HPV vaccine compared with no vaccine was 0.54 (95% confidence interval 0.43 to 0.67) for high grade cases and 0.66 (0.62 to 0.70) for other cases compared with controls with normal cytology, equating to vaccine effectiveness of 46% and 34%, respectively. The adjusted numbers needed to vaccinate were 125 (95% confidence interval 97 to 174) and 22 (19 to 25), respectively. The adjusted exposure odds ratios for two vaccine doses were 0.79 (95% confidence interval 0.64 to 0.98) for high grade cases and 0.79 (0.74 to 0.85) for other cases, equating to vaccine effectiveness of 21%. Conclusion The quadrivalent HPV vaccine conferred statistically significant protection against cervical abnormalities in young women who had not started screening before the implementation of the vaccination programme in Queensland, Australia.

Comparing Nose-Throat Swabs and Nasopharyngeal Aspirates Collected From Children With Symptoms for Respiratory Virus Identification Using Real-Time Polymerase Chain Reaction

Background Human rhinoviruses (HRVs) are the most frequently detected pathogens in acute respiratory tract infections (ARTIs) and yet little is known about the prevalence, recurrence, structure and clinical impact of individual members. During 2007, the complete coding sequences of six previously unknown and highly divergent HRV strains were reported. To catalogue the molecular and clinical features distinguishing the divergent HRV strains, we undertook, for the first time, in silico analyses of all available polyprotein sequences and performed retrospective reviews of the medical records of cases in which variants of the prototype strain, HRV-QPM, had been detected. Methodology/Principle Findings Genomic analyses revealed that the six divergent strains, residing within a clade we previously called HRV A2, had the shortest polyprotein of all picornaviruses investigated. Structure-based amino acid alignments identified conserved motifs shared among members of the genus Rhinovirus as well as substantive deletions and insertions unique to the divergent strains. Deletions mostly affected regions encoding proteins traditionally involved in antigenicity and serving as HRV and HEV receptor footprints. Because the HRV A2 strains cannot yet be cultured, we created homology models of predicted HRV-QPM structural proteins. In silico comparisons confirmed that HRV-QPM was most closely related to the major group HRVs. HRV-QPM was most frequently detected in infants with expiratory wheezing or persistent cough who had been admitted to hospital and required supplemental oxygen. It was the only virus detected in 65% of positive individuals. These observations contributed to an objective clinical impact ranging from mild to severe. Conclusions The divergent strains did not meet classification requirements for any existing species of the genus Rhinovirus or Enterovirus. HRV A2 strains should be partitioned into at least one new species, putatively called Human rhinovirus C, populated by members detected with high frequency, from individuals with respiratory symptoms requiring hospital admission.

Community epidemiology of human metapneumovirus, human coronavirus NL63, and other respiratory viruses in healthy preschool-aged children using parent-collected specimens.

OBJECTIVES. The objective of this study was to calculate sensitivity values for the detection of major respiratory viruses of childhood by using combined nose-throat swabs and nasopharyngeal aspirates. METHODS. Children who had symptoms and presented to a pediatric teaching hospital and had a diagnostic respiratory specimen collected were enrolled, and paired nose-throat swab and nasopharyngeal aspirate specimens were collected. Parents were asked to collect the nose-throat swab specimen in the first instance but could defer to a health care worker if unwilling. Nose-throat swab collectors were asked to rate perceived quality of collection. All nasopharyngeal aspirates were collected by a health care worker by using a standard protocol. Real-time polymerase chain reaction for 8 respiratory viruses was performed in our hospitals diagnostic laboratory. RESULTS. Paired nose-throat swab/nasopharyngeal aspirate specimens were collected during 303 illnesses, with at least 1 respiratory virus identified in 186 (61%). For the major pathogens of childhood, influenza A virus and respiratory syncytial virus, collection by using the nose-throat swab had a sensitivity of 91.9% and 93.1%, respectively. A health care worker collected 219 (72%) of the nose-throat swab specimens; concordance with the nasopharyngeal aspirate was not related to health care worker collection or perceived quality of collection. CONCLUSIONS. Nose-throat swab specimens, in combination with sensitive molecular testing, are a less invasive diagnostic respiratory specimen with adequate sensitivity for use in the clinic and hospital outpatient settings and large-scale community studies through parent collection. For children who present to a hospital in which an avian or pandemic strain of influenza virus is reasonably part of the differential diagnosis, nasopharyngeal aspirates or a similar collection technique (eg, nasal washes) should continue to be used.

Pentavalent rotavirus vaccine and prevention of gastroenteritis hospitalizations in Australia.

OBJECTIVES. The purpose of this work was to assess the impact of recently described human metapneumovirus and human coronavirus NL63 compared with other respiratory viruses by using sensitive molecular techniques in a cohort of healthy preschool-aged children. We also aimed to assess the use of parent collection to obtain an adequate respiratory specimen from acutely unwell children in the community. PATIENTS AND METHODS. The community epidemiology and burden of human metapneumovirus and other respiratory viruses (influenza A, influenza B, respiratory syncytial virus, parainfluenza viruses, adenoviruses, and picornaviruses) were examined in a cohort of 234 preschool-aged children from Melbourne, Australia, over a 12-month period by using polymerase chain reaction testing. Parents collected a daily symptom diary for the duration of the study and were taught to collect a combined nose-throat swab and complete an impact diary when the study child had an acute respiratory illness. RESULTS. The average incidence of acute respiratory illness was 0.48 per child-month for the duration of the study, with a winter peak. Of 543 illnesses with ≥1 specimen returned, 33 were positive for human metapneumovirus (6.1%) and 18 for human coronavirus NL63 (3.3%). Of all of the viruses for which we tested, human metapneumovirus and human coronavirus NL63 were most strongly linked to child care attendance, occurring in 82% and 78% of infected children, respectively. Picornaviruses were the most commonly identified virus group (269 [49.5%]). Influenza virus and adenovirus illnesses had the greatest impact, with fever in more than three quarters and requiring, on average, >1 local doctor visit per illness. CONCLUSIONS. Recently identified human metapneumovirus and human coronavirus NL63 are important pathogens in community-based illness in children, particularly in those who attend child care. Picornaviruses were detected in half of the nose-throat swabs collected during acute respiratory illness in children but resulted in milder illnesses; influenza and adenovirus caused the highest-impact illnesses. The use of parent-collected specimens should be considered for additional community-based epidemiologic studies and vaccine trials.