Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55years of age. The aim of this study was to assess the safety of MenACWY-D administered as part of routine clinical care to patients at Kaiser Permanente Northern California (KPNC). METHODS: This was an observational, retrospective study that included all KPNC members who received MenACWY-D during the study period. We monitored all vaccine recipients for non-elective hospitalizations, emergency department visits, and selected outcomes captured in the clinic setting (Bell's palsy, seizures, neuritis, Guillain-Barré syndrome, encephalopathy, encephalitis, epilepsy, transverse myelitis, multiple sclerosis, hypersensitivity reactions, idiopathic thrombocytopenic purpura, diabetes, arthritis, hemolytic anemia, collagen-vascular disease) through 6months after vaccination. Using vaccine recipients as their own controls, we calculated incidence rate ratios (IRRs) of outcomes during the post-vaccination risk interval and compared these with rates during a comparison interval more remote from vaccination. We also compared rates of outcomes in MenACWY-D recipients with those in matched controls who received selected vaccines in the prior year. We reviewed medical records for selected outcomes. RESULTS: From April 2005 through April 2006, 31,561 KPNC patients (>99% of whom were 11-55years of age) received MenACWY-D. Overall, there were 21 outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs did not suggest any relationship with MenACWY-D. Two serious adverse events were considered possibly related to vaccination by the study investigator. CONCLUSIONS: This study did not detect any safety concerns following MenACWY-D and provides reassurance that MenACWY-D administered as part of routine care was not associated with unexpected safety risks. ClinicalTrials.gov Identifier is NCT00254995.

Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine.

OBJECTIVE: An observational safety study of the quadrivalent human papillomavirus vaccine (HPV4) in women was conducted. This report presents findings from autoimmune surveillance. Design. Subjects were followed for 180days after each HPV4 dose for new diagnoses of 16 prespecified autoimmune conditions. SETTING: Two managed care organizations in California. Subjects. Number of 189,629 women who received ≥1 dose of HPV4 between 08/2006 and 03/2008. OUTCOME: Potential new-onset autoimmune condition cases amongst HPV4 recipients were identified by electronic medical records. Medical records of those with ≥12-month health plan membership prior to vaccination were reviewed by clinicians to confirm the diagnosis and determine the date of disease onset. The incidence of each autoimmune condition was estimated for unvaccinated women at one study site using multiple imputations and compared with that observed in vaccinated women. Incidence rate ratios (IRR) were calculated. Findings were reviewed by an independent Safety Review Committee (SRC). RESULTS: Overall, 1014 potential new-onset cases were electronically identified; 719 were eligible for case review; 31-40% were confirmed as new onset. Of these, no cluster of disease onset in relation to vaccination timing, dose sequence or age was found for any autoimmune condition. None of the estimated IRR was significantly elevated except Hashimoto's disease [IRR=1.29, 95% confidence interval: 1.08-1.56]. Further investigation of temporal relationship and biological plausibility revealed no consistent evidence for a safety signal for autoimmune thyroid conditions. The SRC and the investigators identified no autoimmune safety concerns in this study. CONCLUSIONS: No autoimmune safety signal was found in women vaccinated with HPV4.

Underimmunization at discharge from the neonatal intensive care unit.

OBJECTIVE: The objectives of this study are to determine immunization rates at discharge from the neonatal intensive care unit (NICU) among infants 2 months of age and above and to evaluate risk factors for underimmunization. STUDY DESIGN: A retrospective cohort study was performed for infants in six NICUs in the Northern California Kaiser Permanente Medical Care Program. Immunization status at discharge was determined for all infants discharged on or after age 60 days. Logistic regression was used to identify risk factors for underimmunization at the time of discharge. RESULT: Of 668 infants discharged on or after age 60 days from the NICU, 51% were up-to-date for routine immunizations. Twenty-seven percent of infants had received no vaccines. Factors associated with higher immunization rates at discharge include history of mechanical ventilation, congenital heart disease and a diagnosis of apnea or bronchopulmonary dysplasia during the NICU stay, whereas surgery was associated with lower immunization rates. CONCLUSION: A significant proportion of infants discharged on or after 2 months of age in the NICU in this health system was unimmunized or underimmunized at discharge. Further efforts should be made to improve immunization rates prior to discharge.

Risk of fever and sepsis evaluations after routine immunizations in the neonatal intensive care unit.

OBJECTIVE: Premature infants can experience cardiorespiratory events such as apnea after immunization in the neonatal intensive care unit (NICU). These changes in clinical status may precipitate sepsis evaluations. This study evaluated whether sepsis evaluations are increased after immunizations in the NICU. STUDY DESIGN: We conducted a retrospective cohort study of infants older than 53 days who were vaccinated in the NICU at the KPMCP (Kaiser Permanente Medical Care Program). Chart reviews were carried out before and after all immunizations were administered and for all sepsis evaluations after age 53 days. The clinical characteristics of infants on the day before receiving a sepsis evaluation were compared between children undergoing post-immunization sepsis evaluations and children undergoing sepsis evaluation at other times. The incidence rate of sepsis evaluations in the post-immunization period was compared with the rate in a control time period not following immunization using Poisson regression. RESULT: A total of 490 infants met the inclusion criteria. The rate of fever was increased in the 24 h period after vaccination (2.3%, P<0.05). The incidence rate of sepsis evaluations was 40% lower after immunization than during the control period, although this was not statistically significant (P=0.09). Infants undergoing a sepsis evaluation after immunization were more likely to have an apneic, bradycardic or moderate-to-severe cardiorespiratory event in the day before the evaluation than were infants undergoing sepsis evaluations at other times (P<0.05). CONCLUSION: Despite an increase in fever and cardiorespiratory events after immunization in the NICU, routine vaccination was not associated with increased risk of receiving sepsis evaluations. Providers may be deferring immunizations until infants are clinically stable, or may have a higher threshold for initiating sepsis evaluations after immunization than at other times.

Immunogenicity and tolerability of a quadrivalent meningococcal glycoconjugate vaccine in children 2-10 years of age.

Meningococcal disease incidence is highest in infants, but a significant burden of disease also occurs in children. In this Phase II, single-centre US study, 619 healthy children (2-10 years of age) received one dose of an investigational quadrivalent meningococcal CRM(197)-conjugated vaccine (MenACWY-CRM) or a licensed quadrivalent meningococcal polysaccharide vaccine (MPSV4). Immunogenicity was assessed using the serum bactericidal assay with human complement (hSBA) at 1 and 12 months post-vaccination. Local and systemic reactions were recorded for 7 days, all adverse events (AEs) for 1 month, and medically significant and serious AEs (SAEs) for 12 months post-vaccination. For all four serogroups, more MenACWY-CRM recipients achieved an hSBA titre >or=1:4 at 1 month post-vaccination (A: 82%; C: 83%; W-135: 95%; Y: 91%) compared with the group that received MPSV4 (A: 45%; C: 66%; W-135: 71%; Y: 61%); this difference persisted through to 12 months post-vaccination. Both vaccines were well tolerated. In children 2-10 years of age, MenACWY-CRM induced a higher immune response than that of MPSV4, and was well tolerated.

Src kinases involved in hepatitis B virus replication.

Chronic infection by hepatitis B virus is a leading cause of human liver cancer and liver disease. The hepatitis B virus HBx protein is a regulatory factor that is essential for virus infection in mammals and is implicated in development of liver cancer and liver disease. Among the reported activities of HBx is the ability to stimulate Src tyrosine kinases, Ras-GTPases and transcriptional activation. We now demonstrate that HBx activation of Src tyrosine kinases, but not Ras, promotes a high level of viral replication in cell culture. HBx is shown to stimulate reverse transcription of the viral pregenomic mRNA into genomic DNA through a Src-mediated pathway in tissue culture cells. Targeted inhibition of Src tyrosine kinase activity, mutational inactivation of the HBx gene or retargeting of HBx to the nucleus to abolish cytoplasmic signal transduction activity, are shown to impair viral reverse transcription strongly. These studies implicate HBx stimulation of the Src family of tyrosine kinases in stimulation of viral polymerase activity.

Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras.

The HBx protein of hepatitis B virus (HBV) is a small transcriptional transactivator that is essential for infection by the mammalian hepadnaviruses and is thought to be a cofactor in HBV-mediated liver cancer. HBx stimulates signal transduction pathways by acting in the cytoplasm, which accounts for many but not all of its transcriptional activities. Studies have shown that HBx protein activates Ras and downstream Ras signaling pathways including Raf, mitogen-activated protein (MAP) kinase kinase kinase (MEK), and MAP kinases. In this study, we investigated the mechanism of activation of Ras by HBx because it has been found to be central to the ability of HBx protein to stimulate transcription and to release growth arrest in quiescent cells. In contrast to the transient but strong stimulation of Ras typical of autocrine factors, activation of Ras by HBx protein was found to be constitutive but moderate. HBx induced the association of Ras upstream activating proteins Shc, Grb2, and Sos and stimulated GTP loading onto Ras, but without directly participating in complex formation. Instead, HBx is shown to stimulate Ras-activating proteins by functioning as an intracellular cytoplasmic activator of the Src family of tyrosine kinases, which can signal to Ras. HBx protein stimulated c-Src and Fyn kinases for a prolonged time. Activation of Src is shown to be indispensable for a number of HBx activities, including activation of Ras and the Ras-Raf-MAP kinase pathway and stimulation of transcription mediated by transcription factor AP-1. Importantly, HBx protein expressed in cultured cells during HBV replication is shown to activate the Ras signaling pathway. Mechanisms by which HBx protein might activate Src kinases are discussed.

trans-dominant inhibition of human immunodeficiency virus type 1 Rev occurs through formation of inactive protein complexes.

The human immunodeficiency virus type 1 Rev protein controls expression of certain viral RNAs by binding to these RNAs in the nucleus. To investigate how dominant negative Rev mutants inhibit Rev function, we fused such mutants to hormone-dependent localization signals from the glucocorticoid receptor. Each was found to have fully potent inhibitory activity whether expressed in the nucleus or in the cytoplasm. Wild-type Rev colocalized with an inhibitory fusion protein, implying that the two proteins interact. The resulting complexes accumulated within nuclei in response to steroids but had no effect on expression of Rev-responsive mRNAs. A mutation known to block in vitro oligomerization of Rev abolished both complex formation and inhibitory activity of the mutant fusion proteins. Thus, trans-dominant inhibition of Rev does not require competition for nuclear substrates but may instead reflect the ability of a mutant to form nonfunctional complexes with the wild-type protein in vivo.

Effector domains of human immunodeficiency virus type 1 Rev and human T-cell leukemia virus type I Rex are functionally interchangeable and share an essential peptide motif.

The human immunodeficiency virus type 1 Rev and human T-cell leukemia virus type I Rex transactivators are posttranscriptional regulatory proteins that promote retroviral gene expression by interacting with specific viral mRNAs. Rev and Rex have markedly dissimilar amino acid sequences and RNA target specificities but are thought to act through the same cellular pathway. In this report, we demonstrate that short peptide domains which are required for effector activity in Rev and Rex are functionally interchangeable. Activity of these effector domains depends upon a previously unrecognized tetrapeptide motif that is present in both Rev and Rex and also in analogous proteins from other complex retroviruses. The conserved effector motif may mediate essential interactions of Rev, Rex, and other transactivators of this type with a common cellular cofactor.