Administration Of Live Attenuated Vaccine Research Articles

A case series of live attenuated vaccine administration in dupilumab-treated children with atopic dermatitis.

Current regulatory labeling recommends avoiding live vaccine use in dupilumab-treated patients. Clinical data are not available to support more specific guidance for live or live attenuated vaccines administration in dupilumab-treated patients. Children (6 months-5 years old) with moderate-to-severe atopic dermatitis (AD) enrolled in a phase 2/3 clinical trial of dupilumab (LIBERTY AD PRESCHOOL Part A/B; NCT03346434) and subsequently participated in the LIBERTY AD PED-OLE (NCT02612454). During these studies, protocol deviations occurred in nine children who received measles, mumps, rubella (MMR) vaccine with or without varicella vaccine; five with a ≤12-week gap between dupilumab administration and vaccination and four with a >12-week gap after discontinuing dupilumab. Nine children (1 female; 8 male) had severe AD at baseline (8-56 months old). Of the nine children, five had a ≤12-week gap ranged 1-7 weeks between dupilumab administration and vaccination who received MMR vaccine (n = 2) or MMR and varicella vaccines (n = 3); among these, one resumed dupilumab treatment as early as 2 days and four resumed treatment 18-43 days after vaccination. No treatment-emergent adverse events, including serious adverse events and infections, were reported within the 4-week post-vaccination period in any children. In this case series of dupilumab-treated children with severe AD who received MMR vaccine with or without varicella vaccine, no adverse effects (including vaccine-related infection) were reported within 4 weeks after vaccination. Further studies are warranted to evaluate the safety, tolerability, and immune response to live attenuated vaccines in dupilumab-treated patients.

342 A case series of live attenuated vaccine administration in dupilumab-treated children with atopic dermatitis

Abstract In patients with atopic dermatitis (AD), it is unknown whether suppression of dysregulated type 2 immune cytokines, interleukin-4 and interleukin-13, with dupilumab impacts the risk of viral infections following live attenuated vaccination. Current medical consensus and regulatory labelling recommend completing age-appropriate non-live vaccinations according to immunization guidelines at least 4 weeks prior to starting dupilumab and to avoid the use of live vaccines in patients treated with dupilumab. Phase 3 dupilumab AD clinical trial protocols prohibited the administration of live attenuated vaccines within 4 weeks before the baseline visit and during treatment. For patients in the LIBERTY AD PED open-label extension (OLE; NCT02612454) who required a live attenuated vaccine, the protocol specified that the study drug be discontinued for 12 weeks prior to planned administration and could be re-initiated 4 weeks after vaccine administration. However, one patient in the 16-week LIBERTY AD PRESCHOOL (NCT03346434, part B) study received a live attenuated vaccine with a ≤ 12 weeks gap between dupilumab administration and vaccination and eight patients in the LIBERTY AD PED-OLE received a live attenuated vaccine, four patients were vaccinated with a ≤ 12 weeks gap and four patients > 12 weeks after discontinuing dupilumab. To describe the clinical course of children with moderate-to-severe AD administered a live attenuated vaccine during the LIBERTY AD PRESCHOOL or LIBERTY AD PED-OLE study. Paediatric patients with moderate-to-severe AD who had previously participated in the phase 2 open-label, multicentre, sequential study LIBERTY AD PRESCHOOL (part A; 3 or 6 mg/kg dupilumab single dose) or the randomized, double-blind placebo-controlled phase 3 study LIBERTY AD PRESCHOOL (part B; 200 mg dupilumab every 4 weeks [q4w] if baseline weight 5 to <15 kg, or 300 mg q4w if 15 to <30 kg) were subsequently enrolled into the LIBERTY AD PED-OLE study (200 mg dupilumab q4w if baseline weight 5 to <15 kg, 300 mg q4w if 15 to <30 kg, or 200 mg q2w if 30 to <60 kg). This case series includes nine patients with severe AD at the parent study baseline (Investigator’s Global Assessment score = 4) and Peak Pruritus Numerical Rating Scale (range: 0–10) scores of 5.2 (n = 1), 8 (n = 2), 9 (n = 4) or 10 (n = 2), who were administered a live attenuated vaccine, with or without pause, during dupilumab treatment in the LIBERTY AD PRESCHOOL (part B; n = 1) or LIBERTY AD PED-OLE study (n = 8). Of the nine patients in this case series, eight were male. All were first diagnosed with AD between 0 and 6 months of age and age at enrolment varied from 8 to 56 months old. Dupilumab treatment duration up to the date of vaccination with live attenuated measles, mumps, rubella (MMR) and varicella vaccines (n = 5) or MMR vaccine only (n = 4) ranged from 85 to 840 days. No adverse events (AEs), including serious AEs, treatment-emergent infections and infestations, or serious infections were observed in the 4-week window post-vaccination. In this limited prospective case series of children with moderate-to-severe AD who also received the live attenuated MMR vaccine, with or without live attenuated varicella vaccine, no serious adverse events were observed within 4 weeks or after 4 weeks post-vaccination. Additional research is needed to assess the safety of live attenuated vaccines in patients on dupilumab treatment and to investigate whether dupilumab treatment impacts vaccine efficacy.

Enhanced dengue vaccine virus replication and neutralizing antibody responses in immune primed rhesus macaques

Antibody-dependent enhancement (ADE) is suspected to influence dengue virus (DENV) infection, but the role ADE plays in vaccination strategies incorporating live attenuated virus components is less clear. Using a heterologous prime-boost strategy in rhesus macaques, we examine the effect of priming with DENV purified inactivated vaccines (PIVs) on a tetravalent live attenuated vaccine (LAV). Sera exhibited low-level neutralizing antibodies (NAb) post PIV priming, yet moderate to high in vitro ADE activity. Following LAV administration, the PIV primed groups exhibited DENV-2 LAV peak viremias up to 1,176-fold higher than the mock primed group, and peak viremia correlated with in vitro ADE. Furthermore, PIV primed groups had more balanced and higher DENV-1–4 NAb seroconversion and titers than the mock primed group following LAV administration. These results have implications for the development of effective DENV vaccine prime-boost strategies and for our understanding of the role played by ADE in modulating DENV replication.

Effect of Ponesimod Exposure on Total Lymphocyte Dynamics in Patients with Multiple Sclerosis.

The aim of this study was to characterize the relationship between ponesimod plasma concentrations and the temporal evolution of lymphocyte counts in multiple sclerosis (MS) patients. Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were developed using data from phase I, II, and III trials, and the impact of clinically relevant covariates on PK and PD parameters was assessed. Simulations were conducted to evaluate the maximal lymphocyte count reduction after ponesimod treatment, and the time required for total lymphocyte counts to return to normal values after treatment interruption. In MS patients, ponesimod PK were characterized by a low mean apparent plasma clearance (5.52L/h) and a moderate mean apparent volume of distribution at steady state (239L). The model developed indicated that none of the evaluated covariates (age, sex, formulation, food, body weight, clinical condition, and renal impairment) had a clinically relevant impact on the PK/PD parameters. In MS patients, total lymphocyte counts were characterized by a maximum reduction of 88.0% and a half maximal inhibitory concentration (IC50) of 54.9ng/mL. Simulations indicated that in patients with normal hepatic function treated with ponesimod 20mg daily, total lymphocyte counts were reduced to 41% of baseline at trough. After stopping treatment, lymphocyte counts were restored to normal levels within oneweek. The population PK/PD model well-characterized the PK of ponesimod and the time course of total lymphocyte counts in MS patients. Additionally, none of the evaluated covariates had a clinically relevant impact. This should be taken into consideration when assessing the risk of infection, administration of live-attenuated vaccines, and concomitant use of immunosuppressants.

Rotavirus Vaccination in the NICU: Where Are We? A Rapid Review of Recent Evidence

Background: Rotavirus is a leading cause of viral acute gastroenteritis (AGE) in infants. Neonates hospitalized in neonatal intensive care units (NICUs) are at risk of rotavirus infections with severe outcomes. The administration of rotavirus vaccines is only recommended, in the United States and Canada, upon discharge from the NICU despite rotavirus vaccine being proven safe and effective in these populations, due to risks of live-attenuated vaccine administration in immunocompromised patients and theoretical risks of rotavirus vaccines strains shedding and transmission. We summarized recent evidence regarding rotavirus vaccines administration in the NICU setting and safety of rotavirus vaccines in preterm infants. Methods: We conducted a rapid review of the literature from the past 10 years, searching Medline and Embase, including all study types except reviews, reporting on rotavirus vaccine 1 and rotavirus vaccine 5; NICU setting; shedding or transmission; and/or safety in preterm. One reviewer performed data extraction and quality assessment. Results: In total, 31 articles were analyzed. Vaccine-derived virus shedding following rotavirus vaccination existed for nearly all infants, mostly during the first week after dose 1, with rare transmission described only in the household setting. No case of transmission in the NICU was reported. Adverse events were mild to moderate, occurring in 10%–60% of vaccinated infants. Extreme premature infants or with underlying gastrointestinal failure requiring surgery presented more severe adverse events. Conclusions: Recommendations regarding rotavirus vaccine administration in the NICU should be reassessed in light of the relative safety and absence of transmission of rotavirus vaccine strains in the NICU.Funding: NoneDisclosures: Sicard Mélanie: I reference the use of rotavirus vaccines in the NICU setting, which is not recommended; I discuss possible reassessment of these recommendations.

Fatal outcomes following immunization errors as reported to the EudraVigilance: A case series

BackgroundSerious adverse reactions after immunization are rare but do occur. In very rare instances, cases with fatal outcome have been reported. These reports can have a huge impact and even more so when due to an immunization error. The aim of this study is to systematically review immunization errors with fatal outcomes in EudraVigilance. MethodsThis was a case-series analysis of Individual Case Safety Reports (ICSRs) reporting immunization errors and a fatal outcome. To determine the level of certainty of a causal association between the immunization errors and fatal outcomes two independent reviewers assessed all ICSRs using the WHO tool “Causality assessment of an Adverse Event Following Immunization (AEFI)”. In accordance with the tool, the ICSRs were classified as consistent, indeterminate, inconsistent/coincidental, or unclassifiable. In addition, we estimated the contribution of reported errors to the fatal outcomes as large, moderate, small, none, or unclassifiable using a classification developed for this study. ResultsA total of 154 ICSRs met the inclusion criteria. Vaccines reported most frequently were pneumococcal (33), rabies (27) and influenza vaccines (24). Most frequently reported errors were non-compliance with recommended schedules of immunization (63). The most frequently reported vaccine-error combination was rabies vaccines and non-compliance with a recommended schedule of immunization (23). Twelve cases were classified as consistent with causal association and had a large error contribution. These cases concerned a cluster of six cases reporting incorrect handling of multi-dose vials containing measles vaccine and six cases reporting administration of live-attenuated vaccines to immunocompromised patients. DiscussionIn this study, we showed that fatal outcomes following immunization errors are very rare. Four key issues were the importance of: (1) quality control of multi-dose vaccines, (2) screening patients for immunocompromising factors, (3) education on the importance of adherence, and (4) measures to improve distinction between vaccines and medicines.

Rotavirus vaccination in the neonatal intensive care units: where are we? A rapid review of recent evidence.

Rotavirus is a leading cause of viral acute gastroenteritis in infants. Neonates hospitalized in neonatal intensive care units (NICUs) are at risk of rotavirus infections with severe outcomes. The administration of rotavirus vaccines is only recommended, in the United States and Canada, upon discharge from the NICU despite rotavirus vaccines being proven well tolerated and effective in these populations, because of risks of live-attenuated vaccine administration in immunocompromised patients and theoretical risks of rotavirus vaccine strains shedding and transmission.We aimed to summarize recent evidence regarding rotavirus vaccine administration in the NICU setting and safety of rotavirus vaccines in preterm infants. We conducted a rapid review of the literature from the past 10 years, searching Medline and Embase, including all study types except reviews, reporting on rotavirus vaccines 1 and 5; NICU setting; shedding or transmission; safety in preterm. One reviewer performed data extraction and quality assessment. Thirty-one articles were analyzed. Vaccine-derived virus shedding following rotavirus vaccines existed for nearly all infants, mostly during the first week after dose 1, but with rare transmission only described in the household setting. No case of transmission in the NICU was reported. Adverse events were mild to moderate, occurring in 10-60% of vaccinated infants. Extreme premature infants or those with underlying gastrointestinal failure requiring surgery presented with more severe adverse events. Recommendations regarding rotavirus vaccine administration in the NICU should be reassessed in light of the relative safety and absence of transmission of rotavirus vaccine strains in the NICU.

Administration of live-attenuated vaccine of Vibrio harveyi to improve survival of gnotobiotic brine shrimp (Artemia salina) model against multipleVibrio infection

Administration of live-attenuated vaccine of Vibrio harveyi to improve survival of gnotobiotic brine shrimp (Artemia salina) model against multipleVibrio infection

Application of a Nonpaper Based Matrix to Preserve Chikungunya Virus Infectivity at Ambient Temperature.

For over 100 years, field studies on arboviruses and the subsequent delivery and administration of live attenuated vaccines have been complicated by the need to maintain a so-called "cold chain," which is the source to destination refrigeration of biological materials. In this study we describe the application of a nonpaper based matrix and demonstrate preservation of chikungunya virus infectivity at ambient temperature for 7 days. The technique was successfully employed using infectious cell culture medium and infected mosquito homogenate samples. This technique provides a simple solution for conducting studies in resource-limited areas, where the maintenance of a cold chain is technically challenging.

Management of Corneal Scarring Secondary to Herpes Zoster Keratitis.

To review the management of visually significant corneal scarring secondary to herpes zoster keratitis (HZK). Literature review. Management options for visually significant corneal scarring secondary to HZK include scleral contact lenses, photorefractive or phototherapeutic keratectomy, lamellar keratoplasty, penetrating keratoplasty, and keratoprosthesis. Many authors recommend tarsorrhaphy in at-risk patients at the time of corneal transplantation. Most published studies either did not mention or did not use systemic antivirals at the time of surgery. Longer quiescent periods before surgical intervention may be associated with increased rates of graft survival. Reports of HZK recurrence after live-attenuated vaccine administration suggest that risks and benefits of the vaccine should be carefully considered. Overall, the prognosis of surgical intervention for corneal scarring due to HZK relies on appropriate patient selection and measures to ensure ocular surface stability. There remains a serious risk of ocular surface instability and corneal melt in these patients. Unfortunately, there is a lack of prospective studies in this area to guide clinical management. Patients with visually significant corneal scarring secondary to HZK may have good outcomes with the appropriate medical and surgical considerations, particularly in the absence of active ocular surface disease and inflammation. Those with active disease may benefit from delaying surgical intervention until a satisfactory quiescent period has been achieved. Prospective studies, such as the proposed Zoster Eye Disease Study, are imperative for validating these principles and determining evidence-based management guidelines.

Vacinação durante a gravidez.

Vaccination of pregnant women causes concerns both for themselves and for their healthcare providers. The main concern is the possibility of transmission of the virus/bacteria to the fetus in development. Due to obvious underlying ethical questions, clinical trials in this area are scarce and of difficult accomplishment. The aim of this paper is to formulate proper guidance for vaccine Administration in pregnant women, particularly on cases of inadvertent administration, through the review of current evidence on live-attenuated vaccine administration in pregnant women. Medline, Bandolier, The Cochrane Library and National Guideline Clearinghouse were searched using the following keywords (MeSH terms): vaccination AND pregnancy. The search was limited to articles published from January 2003 to December 2008. After exclusion of articles not concordant with the objectives of the review, 12 articles were selected (four review articles, two guidelines, one dissertation, the remaining were original articles), as well as the portuguese guidelines from Direcção Geral de Saúde (DGS) in what respects to vaccine administration. The contraindication of live-attenuated vaccine administration in pregnant women is based on the hypothetical/theoretical risk of potential negative effects for the developing fetus. Physicians should consider vaccinating pregnant women on the basis of the risks of vaccination versus the benefits of protection in each particular situation. Women should be told to avoid getting pregnant in the 28 days after liveattenuated vaccination. However, the inadvertent vaccination is not considered an indication for termination of the pregnancy.

Vaccination and anesthesia: more questions than answers

SIR––We found the survey by Short et al. in the May 2006 issue of Pediatric Anesthesia (1) very interesting and believe it opened some theoretical ‘food for thought’ about the perioperative behavior of the immunized child. However the authors conclusions and recommendations that elective surgery should be postponed for one week after killed vaccine and for three weeks after live-attenuated vaccine administration is a little too strong and the findings of their study cannot support such strong recommendations. The accompanying editorial (2) tried to address some of our concerns; however there is a need to expand on some of the controversies. Vaccinations are among the most successful and costeffective public health tools. Their use has led to the global eradication of diseases such as small pox and near elimination of diseases like measles and polio in the Western hemisphere. The World Health Organization estimates that 2 million childhood deaths were prevented through vaccination in 2003 (3). While the immunoparetic role of anesthesia and surgery are theoretical possibilities, there is incontrovertible evidence that immunization saves lives and childhood mortality in the prevaccination era and in countries with poorly organized immunization programs is appalling. To ask parents to postpone elective surgical procedures for a 3 week period after immunization may not be practical. One fundamental principle of active immunization is that continued exposure to the antigen is needed for adequate immune response hence the need for periodic booster doses (4). For example the ‘triple vaccine’ Diphtheria, Tetanus toxoid and acellular pertussis (DTP) and oral or inactivated polio vaccine are administered to children at 4weekly intervals between age 2–6mo. The recommendation of Short et al. will be impractical in countries that predominantly use the oral (or live-attenuated) polio vaccine. The same arguments will apply to other liveattenuated vaccines such as measles, mumps, rubella (MMR) or Varicella. Another important consideration in live-attenuated vaccine administration is the issue of household contacts. These can easily transmit the altered virus to contacts who can become actively immunized this way and may in fact develop vaccine-related illness (5). Should we then recommend that surgery be postponed in patients with positive contact history? Clearly this recommendation will escalate the number of unnecessary cancellations and more importantly increase the number of unimmunized children. It is not clear from the literature whether the immunopertubation that results from anesthesia and surgery is a dose-effect relationship. Does long duration of surgery and anesthesia cause greater perturbation of the immune system or does short procedures like elective myringotomy, tonsillectomy or herniorrhaphy carry the same risk as say craniofacial reconstruction or open heart surgery? These are issues that need to be addressed before we can recommend postponing surgery in immunized children or postponing immunization in children with impending surgery. Olubukola O Nafiu M D F R C A Ian Lewis M D F R C A Division of Pediatric Anesthesiology, Department of Anesthesiology, University of Michigan Hospital 1500 East Medical Centre Drive, Ann Arbor, MI, USA (email: onafiu@med.umich.edu)