Postlicensure Period Research Articles

Identification of prior dengue-naïve Dengvaxia recipients with an increased risk for symptomatic dengue during fever surveillance in the Philippines.

Dengue virus (DENV) is the leading cause of mosquito-borne viral diseases in humans. Dengvaxia, the first licensed dengue vaccine, is recommended for DENV-seropositive individuals aged 9-45 years. In the Philippines, Dengvaxia was administered to more than 830,000 children without prior serological testing in 2016-2017. Subsequently, it was revealed that DENV-seronegative children who received Dengvaxia developed severe disease following breakthrough DENV infection. As a result, thousands of children participating in the mass vaccination campaign were at higher risk of severe dengue disease. It is vital that an assay that identifies baseline DENV-naïve Dengvaxia recipients be developed and validated. This would permit more frequent and extensive assessments and timely treatment of breakthrough DENV infections. We evaluated the performance of a candidate assay, the DENV1-4 nonstructural protein 1 (NS1) IgG enzyme-linked immunosorbent assay (ELISA), developed by the University of Hawaii (UH), using well-documented serum/plasma samples including those >20 years post-DENV infection, and tested samples from 199 study participants including 100 Dengvaxia recipients from the fever surveillance programs in the Philippines. The sensitivity and specificity of the assay were 96.6% and 99.4%, respectively, which are higher than those reported for pre-vaccination screening. A significantly higher rate of symptomatic breakthrough DENV infection was found among children that were DENV-naïve (10/23) than among those that were DENV-immune (7/53) when vaccinated with Dengvaxia (p=0.004, Fisher's exact test), demonstrating the feasibility of the assay and algorithms in clinical practice. The UH DENV1-4 NS1 IgG ELISA can determine baseline DENV serostatus among Dengvaxia recipients not only during non-acute dengue but also during breakthrough DENV infection, and has implications for assessing the long-term safety and effectiveness of Dengvaxia in the post-licensure period.

Trajectories of self-regulatory driving practices: Role of learner phase practice

IntroductionPrevious research suggests that driving practice in diverse contexts may contribute to earlier licensure and improve driving skills among teen drivers. However, few studies have examined the role of practice diversity in driving outcomes post-licensure. Specifically, examining self-regulatory driving practices post-licensure may provide insight into the extent to which teens choose to avoid driving various environments. The current study examined the relationship between learner phase driving practice diversity and teen self-regulatory driving practices over the first six months of licensure. MethodsFifty-six newly licensed 16-year-olds reported pre-licensure practice diversity, driving exposure and, self-regulatory driving practices at three timepoints (within 2 weeks of licensure and at 3 and 6 months post-licensure). ResultsMulti-level models revealed self-regulatory driving practices significantly decreased over the first six months of independent driving. Practice in complex environments (e.g., on a commercial road, on a highway, etc.) was associated with fewer self-regulatory driving practices at baseline. Practice in simple environments (e.g., in a residential area, in a parking lot) was associated with more self-regulatory driving practices at baseline. Practice driving at night and in bad weather conditions predicted greater post-licensure self-regulation of driving in those specific environments. ConclusionThis study reinforces the importance of practice diversity for teens before independent driving, as early practice can have implications for self-regulatory driving practices immediately upon licensure. Future research examining this topic may inform parent-based interventions to maximize teen driver safety during the critical post-licensure period.

Insights on the Impact of External and Internal Boosting on Varicella-Zoster Virus Reactivation Based on Evidence From the First Decade of the United States Universal Varicella Vaccination Program.

Since the licensure of the varicella vaccine in the United States in 1995 and the implementation of the universal varicella vaccination program, varicella infection rates, and associated morbidity and mortality rates have decreased. However, controversy exists over whether universal vaccination has resulted in an increased incidence of herpes zoster (HZ). In 1965, Dr. Hope-Simpson hypothesized that exogenous exposures to the wild-type varicella-zoster virus (wt-VZV) provide immune boosts that inhibit HZ; therefore, reducing the amount of circulating wt-VZV may have the negative effect of increasing the incidence of HZ. A historical review of data from the Centers for Disease Control and Prevention-sponsored Antelope Valley Varicella Active Surveillance Project, along with other studies, is provided to investigate the exogenous boosting hypothesis in the first decade post-vaccine licensure. These data indicated that adoption of universal varicella vaccination led to (1) significant HZ incidence rate increases among children, adolescents, and adults with a history of wild-type varicella and (2) decline in varicella vaccine efficacy after the initial post-licensure period. These effects were likely due to reduced exogenous exposures from children shedding wt-VZV. Appropriate methodologies for ongoing research are also discussed, both in studies during the first decade post-licensure and more recent work.

A dynamical systems perspective on driver behavior

Dynamical systems (DS) theoretical and methodological approaches have furthered our understanding of human development and behavior across many different domains, but have not yet been applied to driver behavior. Using a DS lens, a new theory of driver behavior is proposed, the phase transition framework (PTF), and then applied to understanding how novice drivers develop. The PTF can facilitate new lines of research by providing an individual-level explanatory account that yields the widely observed and poorly understood aggregate declines in novice drivers’ crash rates in the early months of licensure. For the purpose of the PTF, learning to drive is defined as changes in the psychological system integral to the acquisition, refinement, automation, and maintenance of competencies necessary for safe driving. In the PTF, the greatest reductions in population-level collision rates observed in the early months of the post-licensure period are hypothesized to be due to qualitative cognitive reorganizations (e.g., adoption of strategies that reduce risk) that cause abrupt shifts in crash risk trajectories into lower risk strata followed by refinement of strategy use and deployment through real-world experience. Critically, the PTF differs from other theories of driver behavior in that it holds that drivers’ behavioral development is self-organizing and emergent.

Efficacy of Human Botulism Immune Globulin for the Treatment of Infant Botulism: The First 12 Years Post Licensure

To report the efficacy of Human Botulism Immune Globulin Intravenous (BIG-IV) in the first 12 years following its licensure in 2003 and to characterize its use nationwide in treating patients with infant botulism. Medical records and billing information were collected for US patients treated with BIG-IV from 2003 to 2015. Length of hospital stay (LOS) and hospital charge information for treated patients were compared with the BIG-IV Pivotal Clinical Trial Placebo Group to quantify decreases in LOS and hospital charges. The use of BIG-IV reduced mean LOS from 5.7 to 2.2 weeks. This shortened hospital stay resulted in a mean decrease in hospital charges of $88 900 per patient. For all US patients 2003-2015, total decreases in LOS and hospital charges were 66.9 years and $86.2 million, respectively. The decrease in mean LOS was time dependent: BIG-IV treatment on hospital days 0-3 reduced mean LOS by 3.7 weeks (P <.001 vs the BIG-IV Pivotal Clinical Trial Placebo Group), on hospital days 4-7 by 2.6 weeks (P <.001 vs the BIG-IV Pivotal Clinical Trial Placebo Group) and on hospital days 8-10 by just 1 week (P = NS). Since licensure, 1192 patients in 48 states and Washington, DC, have been treated with BIG-IV. The use of BIG-IV since its licensure in 2003 treated approximately 93% of US patients with laboratory-confirmed infant botulism, and prevented >65 years in hospital stay and >$85 million in hospital charges from occurring. The greatest LOS reduction was achieved when BIG-IV was administered soon after hospital admission. Effective and appropriate use of BIG-IV in the US has continued in the postlicensure period.

From the licensure of vaccines to the recommendation of the Standing Committee on Vaccination in Germany : criteria for the assessment of benefits and risks

Vaccines are among the most effective preventive measures in modern medicine and have led to a dramatic decline and-for a few diseases-even to the elimination of severely infectious diseases. There are some particularities of the risk-benefit assessment of vaccines compared with that of therapeutic drugs. These include the fact that vaccines are applied to healthy individuals with the aim of preventing an infectious disease, while therapeutic drugs are administered to sick people to cure them of an already acquired disease. The acceptable level of risk associated with the application of a vaccine is therefore much lower. In addition, high vaccination coverage can lead to population-level effects (e.g., the indirect protection of unvaccinated individuals) that can confer additional benefits to the population overall. When a marketing authorization application (MAA) for a novel vaccine is evaluated, conclusions are made regarding its quality, safety, and efficacy, and a benefit-risk assessment is carried out accordingly. In contrast, when deciding on the introduction of a new vaccine into a national immunization program or on a recommendation for a specific risk-group, the focus is shifted to considerations of how a licensed vaccine can be best used in a population (e.g., which immunization strategy is most effective in preventing deaths or hospitalizations, or in reducing treatment costs for the health care system). Stringent assessment criteria have been developed that require a robust safety analysis before a new vaccine is administered to humans for the first time in pre-licensure studies. Similarly, criteria are applied for calculating the benefit-risk ratio at the time of the licensure of a new vaccine in addition to during the entire post-licensure period. However, when deciding if and how a licensed vaccine can best be integrated into an existing immunization program, additional criteria are applied that are different, yet complementary to those applied for granting a marketing authorization. These decisions require-in addition to considerations of vaccine quality, vaccine efficacy and safety-conclusions regarding population-level effects combined with an integrative analysis of the local context (e.g., local epidemiology, cost-effectiveness, and acceptance by the population). To serve these objectives, national authorities such as the Standing Committee on Vaccination in Germany (STIKO) have been established to integrate globally developed vaccines into the national context of immunization strategies.

Decline in Gastroenteritis-Related Triage Calls After Rotavirus Vaccine Licensure

We sought to determine the impact of rotavirus vaccine implementation on gastroenteritis (GE)-related calls to a large telephone triage service in Tennessee. Total and GE-related calls received by the Vanderbilt Telephone Triage Program for children <5 years of age were examined from May 1, 2004 to April 30, 2010. Time series adapted Poisson regression models were used to compare weekly GE-related call proportions between the prevaccine (May 2004 to April 2007) and postlicensure (May 2007 to April 2010) periods. Separate models compared GE-related call proportions in the historical rotavirus (February to April) and nonrotavirus (May to January) seasons. Associations between call data and laboratory-confirmed rotavirus detections and regionally reported norovirus activity were also assessed. There were 156362 total calls and 19731 GE-related calls. Annual GE-related call proportions declined by 8% (95% confidence interval, 3%-12%) in the postlicensure period; declines ranging from 23% to 31% occurred during the historical rotavirus season in all 3 postlicensure years. No declines occurred in the nonrotavirus season. After vaccine licensure, reductions in laboratory-confirmed rotavirus activity were associated with declines in GE-related call proportions. Peak GE-related call proportions in the postlicensure period occurred earlier than in prevaccine years and were not strongly associated with laboratory-confirmed rotavirus but instead showed good correlation with norovirus outbreaks. A decline in GE-related call proportions among young children after rotavirus vaccine licensure was documented by using a novel surveillance platform that captures mild GE not detected in other surveillance systems. Since rotavirus vaccine licensure, peak call proportions correlate with regional norovirus activity, highlighting the role of that pathogen in community GE.

Rotarix®: vaccine performance 6 years postlicensure

Rotarix® was first licensed in 2004 and rapidly introduced into private and public markets worldwide. In a previous 2009 article, we reviewed the impact of rotavirus-associated disease, the rationale for different vaccines, prelicensure efficacy studies and cost–effectiveness studies for Rotarix. As of September 2011, Rotarix had been licensed in 123 countries in the Americas, Europe, Australia, Africa and Asia, of which 27 have incorporated the vaccine into national or regional immunization programs. The current review intends to provide the reader with further insight into this vaccine, focusing mainly on the new information obtained after a 6-year postlicensure period. This review will provide only a brief summary of prelicensure studies extensively discussed in the previous publication and refer, in more depth, to the worldwide experience with the vaccine, vaccine impact, and safety observed in effectiveness and observational studies, including a particular analysis on protection against rotavirus G2P[4].

Decline in Varicella-Related Ambulatory Visits and Hospitalizations in the United States Since Routine Immunization Against Varicella

Widespread varicella vaccination has led to substantial decreases in varicella-related mortality and hospitalizations. The effect of the vaccine on ambulatory care utilization is poorly defined. To determine trends in varicella-related ambulatory care and hospital discharges before and after vaccine licensure. Estimates of varicella-related ambulatory and hospital discharges were calculated for the pre- (1993-1995) and post- (1996-2004) vaccine licensure periods using the National Ambulatory Medical Care Survey, National Hospital Ambulatory Medical Care Survey, and National Hospital Discharge Survey. Ambulatory and hospital discharge rates for varicella. The rate of varicella-related ambulatory discharges decreased by 66% from 106.6 per 100,000 (95% confidence interval [CI]: 80.5-132.6) in the prelicensure period to 36.4 per 100,000 population (95% CI: 29.3-43.5) in the post-licensure period (P < 0.001). The decrease was significant across all age groups <45 years, with the greatest reduction (98%) occurring among patients 0 to 4 years of age. The incidence of varicella-related hospital discharges decreased by 53% from 30.9 per 100,000 (95% CI: 24.4-37.3) to 14.5 per 100,000 population (95% CI: 12.1-16.8; P < 0.001). This difference was significant among patients <14 years of age. Rates of varicella-related ambulatory discharges decreased significantly for both whites and non-whites in the postlicensure period, but postlicensure ambulatory discharge rates remained higher for non-whites than for whites. Decreases in varicella-related hospital discharges were statistically significant for whites and non-whites. Racial differences in the incidence of varicella-related hospital discharges also persisted following vaccine licensure. Varicella-related ambulatory visits and hospitalizations have decreased significantly in the period after licensure of the varicella vaccine.

Assessing the Effectiveness and Public Health Impact of Rotavirus Vaccines after Introduction in Immunization Programs

Two new vaccines against severe rotavirus gastroenteritis that have high efficacy in middle- and high-income countries have recently been licensed in many countries worldwide. Clinical trials in low-income countries in Africa and Asia are ongoing. Experience gained through studies of natural rotavirus infection and the clinical trials for the current and previous rotavirus vaccines indicate that, as countries begin to introduce these newly approved vaccines into routine childhood immunization programs, monitoring their performance in real world settings should be a high priority. Key epidemiological considerations in the postlicensure period include (1) how the vaccine will perform against severe rotavirus disease under routine public health use; (2) how routine vaccination will impact the epidemiology of disease with regard to the burden of severe disease and death, age distribution of cases, seasonality, and serotype distribution; (3) whether vaccination will have a sufficient impact on transmission to reduce disease burden in unvaccinated age groups; and (4) whether vaccine will confer protection through the first 3 years of life, when most severe disease and mortality associated with rotavirus occur. Monitoring of impact with focus on these public health considerations will allow parents, health care providers, and decision makers to appreciate the health benefits of vaccination in reducing the burden of severe rotavirus disease. It will also allow assessment of the effectiveness of rotavirus vaccines in programmatic use and the need for modifying vaccination schedules or vaccine formulations to enhance the performance of immunization. In this article, we review data for the protective efficacy of the 2 new rotavirus vaccines, with emphasis on issues particularly important for consideration as these vaccines are introduced in routine infant immunization programs.

Surveillance for Invasive Pneumococcal Disease During 2000–2005 in a Population of Children Who Received 7-Valent Pneumococcal Conjugate Vaccine

To assess the incidence of invasive pneumococcal disease (IPD) in all children younger than 5 years of age in the Northern California Kaiser Permanente (NCKP) health care system during a 5-year surveillance period (2000-2005) after the introduction in April 2000 of routine use of 7-valent pneumococcal conjugate vaccine (PCV7). This was a laboratory-based surveillance study of all children younger than 5 years of age in the NCKP health care system from April 2000 to March 2005. The comparison group was all children younger than 5 years of age in the NCKP health care system from April 1996 to March 2000. Data obtained from clinical databases included microbiologic identification and susceptibility testing; serotyping of isolates; immunization records; and IPD diagnoses for inpatients and outpatients. IPD was defined as a positive culture of Streptococcus pneumoniae from a normally sterile body site. For all serotypes, the mean annual incidence of IPD during the postlicensure surveillance period was 15.3 cases/100,000 person-years (10(5) p-y) compared with 62.5 cases/10(5) p-y in the prelicensure years of 1996-2000. The average incidence of IPD caused by vaccine serotypes was reduced from 50.1 cases/10(5) p-y during the prelicensure years to 4.9 cases/10(5) p-y during the postlicensure period. The average incidences of IPD caused by cross-reactive and by nonvaccine serotypes were 5.8 and 5.3 cases/10(5) p-y, respectively, during the prelicensure years and 2.5 and 6.2 cases/10(5) p-y, respectively, during the postlicensure period. Of the 131 IPD cases observed during the postlicensure surveillance period, bacteremia (50.4%) and pneumonia (31.3%) were the most common diagnoses. During the 5-year postlicensure surveillance period, only 3 subjects who were identified to be fully vaccinated for age with PCV7 (3 doses by 7 months of age or 4 doses by 18 months of age) developed vaccine-serotype IPD. The incidence of IPD has significantly decreased in a large population of children after the introduction of PCV7. Vaccine-type IPD was rare in patients who received full 4-dose immunization with PCV7. There is no clear evidence of a significant increase in nonvaccine-serotype IPD. Introduction of a 4-dose infant schedule of PCV7 into this population has resulted in a marked and sustained reduction of IPD in children.

Emergence of Vaccine-Related Pneumococcal Serotypes as a Cause of Bacteremia

The heptavalent pneumococcal conjugate vaccine (PCV7) has decreased the incidence of invasive pneumococcal disease among children in the United States. In the postlicensure period, the impact of non-PCV7 serotypes against pediatric pneumococcal bacteremia is unknown. Episodes of bacteremia due to Streptococcus pneumoniae and other respiratory pathogens (ORP), namely Neisseria meningitidis, Haemophilus influenzae, and Moraxella catarrhalis, were identified in children <18 years old at the Children's Hospital of Philadelphia from January 1999 to May 2005. For pneumococci, serotype distribution and antibiotic resistance were compared. A total of 188 episodes of pneumococcal bacteremia and 55 episodes of ORP bacteremia were identified. By comparing data from 1999-2000 with data from 2001 to May 2005, we found that the incidence of pneumococcal bacteremia decreased by 57%. The incidence of bacteremia caused by ORPs was unchanged; 1.43 episodes (95% confidence interval [CI], 0.84-2.29 episodes) to 1.25 (95% CI, 0.88-1.71) per 10,000 emergency department visits. Vaccine serotypes caused 85% of episodes of bacteremia in 1999-2000, compared with 34% of episodes of bacteremia in 2001 to May 2005 (P<.01). The percentage of isolates nonsusceptible to penicillin increased from 25% to 39% (P<.05). The percentage of episodes of pneumococcal bacteremia caused by vaccine-related serotypes--those of the same serogroup but not of the same serotype as PCV7--increased from 6% of episodes in the prelicensure period to 35% of episodes in the postlicensure period (P<.01). Rates of serotype pneumococcal bacteremia caused by nonvaccine serotypes were not statistically different between the 2 periods. The overall incidence of pneumococcal bacteremia decreased by 57% after the introduction of PCV7. During the postlicensure period, there were significant decreases in the incidence of pneumococcal bacteremia caused by vaccine serotypes; however, rates of penicillin resistance and bacteremia due to vaccine-related serotypes increased.

Trends in Invasive Pneumococcal Disease—Associated Hospitalizations

The heptavalent pneumococcal conjugate vaccine was licensed in the United States in 2000 for use in infants and children. Postlicensure surveillance revealed substantial regional and national decreases in invasive pneumococcal disease. It is not known whether widespread vaccine use has led to a concomitant decrease in invasive pneumococcal disease-associated hospitalization rates. We examined national trends in rates of hospitalization among both children and adults with invasive pneumococcal disease. Data from the 1998-2003 National Hospital Discharge Survey and population estimates from the National Center for Health Statistics were used to calculate rates of hospital discharge for patients admitted with invasive pneumococcal disease, defined as meningitis or bacteremia caused by Streptococcus pneumoniae. Rates of hospital discharge for patients admitted with invasive pneumococcal disease decreased during the study period from a peak of 12.03 discharges per 100,000 population in 1999 to 5.60 discharges per 100,000 population in 2003 (P < .001). Rates of hospital discharge for persons admitted with pneumococcal meningitis decreased from 1.60 discharges per 100,000 person-years in the prelicensure period to 0.53 discharges per 100,000 person-years in the postlicensure period. For persons > or = 65 years of age but not for those < 4 years of age, the rates of hospital discharge for those admitted with pneumococcal bacteremia were significantly lower during the postlicensure period, compared with the prelicensure period. Hospital discharge rates for persons admitted with invasive pneumococcal disease, including meningitis, have decreased since introduction of the heptavalent pneumococcal conjugate vaccine. The decrease was driven in part by the reduction of invasive pneumococcal disease-associated hospitalizations in the subgroup aged > or = 65 years.

Changing epidemiology of intussusception in Australia

Oral rotavirus vaccines are expected to become available in Australia within the next 2 years. In light of evidence for an association between a rotavirus vaccine and intussusception, it is important to define the baseline epidemiology of intussusception in Australia and establish a system for intussusception surveillance in the immediate post-licensure period. This study reports on incidence and epidemiology of intussusception in Australia. Data were obtained from the Australian Institute of Health and Welfare on all patients with a discharge diagnosis of intussusception from public and private hospitals in each state and territory of Australia from 1994 to 2000. We examined age at presentation, sex, month and year of presentation, indigenous status and clinical outcomes. The incidence of intussusception was calculated and annual trends examined. Surveillance data on rotavirus gastroenteritis hospitalizations over the same time period were also obtained to compare seasonal patterns. From 1994 to 2000, a 39% reduction in intussusception incidence in infants aged <1 year was observed in Australia (13.1/10,000 to 8.1/10,000; P < 0.001). The incidence of intussusception was lower in indigenous infants (3.3/10,000 <1 year) compared to non-indigenous infants (10.4/10,000 <1 year; P < 0.001). There was no association between the seasonality of rotavirus infection and intussusception. Only one of 12 deaths due to intussusception was reported in an infant <1 year. This study documents the epidemiology of intussusception in Australia from 1994 to 2000 and provides important baseline information for future rotavirus vaccines. A lower risk of intussusception was identified in indigenous compared to non-indigenous infants.

Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate): a prospective pharmacovigilance study.

Clinical trials to date have not been adequately powered to assess comparatively infrequent events such as inhibitor development in previously treated patients (PTPs). Comprehensive large-scale pharmacovigilance studies can be useful for this purpose. We prospectively collected inhibitor development reports worldwide among recipients of Recombinate rAHF recombinant factor VIII (rFVIII), also formerly distributed under the product name Bioclate, for the entire postlicensure period from 1993 through 2002. To determine level of exposure to rFVIII we also compiled the Recombinate rAHF/Bioclate International Units (IU) distributed annually. To estimate inhibitor incidence separately for previously untreated or minimally treated patients (PUPs) with 1-50 exposure days and PTPs with >50 exposure days, we used haemophilia A incidence and prevalence data and pooled mean annual rFVIII consumption per PUP and PTP from international multicentre prospective clinical trials. Documented inhibitor cases totalled 89, and the total quantity of Recombinate rAHF/Bioclate rFVIII distributed was 6.48 x10(9) IU. No lot association or other clustering of inhibitor events was evident in PTPs. The incidence of all reported inhibitors, expressed as a percentage of patients treated, was 11.9% (CI: 5.05-28.0%) for PUPs when compared with 0.123% (CI: 0.030-0.512%) for PTPs. The rates for high-titre inhibitors (>5 BU) only were 5.96% (CI: 3.00-11.8%) for PUPs and 0.0554% (CI: 0.0113-0.271%) for PTPs. Thus, incidence rates for both all inhibitors and high-titre inhibitors in PTPs were 1% of the corresponding rates in PUPs. Data from prospective PUP clinical trials involving intensive active monitoring suggest that true inhibitor incidence may be approximately twice that estimated in this pharmacovigilance study. Nevertheless, inhibitor development in PTPs receiving Recombinate rAHF/Bioclate is infrequent.

High incidence of shingles among children with prior chickenpox: an inadvertent consequence of the universal varicella vaccination program?

Medical Veritas is the pre-eminent journal for those interested in balanced information regarding vaccine-associated as well as vaccine preventable disease. It serves as an interface between academics, those in Research and Development, and concerned patients and parents.