Varicella vaccine meningoencephalitis in a child receiving autologous bone marrow transplantation.

BACKGROUND: Varicella vaccine, a live-attenuated Oka-strain of varicella zoster virus (VZV), is a recommended childhood vaccine by many countries. As with wild varicella strain, after primary infection, the live-attenuated virus can establish latency in sensory ganglia and reactivate causing vaccine-strain illnesses: herpes zoster (HZ), visceral or peripheral and central nervous system dissemination. We report a case of early reactivation of live-attenuated virus-HZ and meningoencephalitis-in an immunocompromised child. METHODS: This is a retrospective descriptive report of a case, in a tertiary pediatric hospital, CHU Sainte-Justine (Montréal, Canada). RESULTS: An 18 month-year old girl diagnosed with a primitive neuro-ectodermal tumor (PNET) received the day prior to diagnosis, a first varicella vaccine (MMRV). She received chemotherapy 20 days post MMRV vaccine and autologous bone marrow transplantation 3 months post vaccination. She was considered not eligible, to acyclovir prophylaxis prior transplantation (positive for VZV IgG and negative for herpes simplex virus IgG by ELISA). At day 1 post transplantation, she developed dermatomal HZ and meningoencephalitis. Oka-strain varicella was isolated, she was treated with acyclovir and foscarnet. Neurologic status improved in 5 days. Control of VZV viral load in cerebrospinal fluid showed a slow decrease to from 5.24 log 10 copies/mL to 2.14 log 10 copies/mL in 6 weeks. No relapse was observed. She recovered without neurological sequelae. CONCLUSIONS: Our experience highlights the importance of conducting a thorough medical history regarding vaccination and serological status of newly immunocompromised patients. Intensive chemotherapy succeeding live vaccine administration <4 weeks could have influenced early and severe viral reactivation. Early initiation of prophylactic antiviral treatment is questioned in such circumstances.

Disseminated vaccine-induced varicella infection in a kidney transplant recipient.

A 33-year-old kidney transplant (KT) recipient presented with a disseminated pruritic, painful, vesicular rash and hepatitis 3 weeks after receiving a varicella vaccine (VAR). A skin lesion biopsy sent to the Centers for Disease Control and Prevention for genotyping confirmed vaccine-strain varicella-zoster virus (VZV) (Oka strain; vOka). The patient was successfully treated with intravenous acyclovir during a prolonged hospital stay. This case supports the contraindication of VAR in adult KT recipients and highlights the potential for severe illness when used in this population. Optimally, VZV-seronegative KT candidates should receive VAR before starting immunosuppressive medications. If this opportunity is missed, the recombinant varicella-zoster vaccine might be considered following transplantation as it is already recommended to prevent herpes zoster in VZV-seropositive immunocompromised adults. Further study is needed as data are limited on the safety and efficacy of recombinant varicella-zoster vaccine for primary varicella prevention in VZV-seronegative immunocompromised adults.

Efectividad preventiva de la vacuna varicela en pacientes sanos no expuestos / Preventive effectiveness of varicella vaccine in healthy unexposed patients

INTRODUCCIÓN: La varicela es una enfermedad infectocontagiosa producida por el virus varicela-zóster. Para su prevención, convencionalmente se utiliza la vacuna varicela, cuya administración busca disminuir la aparición de enfermedad y sus complicaciones. Sin embargo, aún existe controversia sobre la efectividad. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Se identificaron dos revisiones sistemáticas que en conjunto incluyeron 16 estudios primarios, de los cuales, tres corresponden a ensayos aleatorizados. Concluimos que la vacunación contra la varicela disminuye el riesgo de contraer la enfermedad a largo plazo en pacientes sanos sin exposición previa y que probablemente disminuye el riesgo de contraer la enfermedad a corto plazo. Sin embargo, aumenta la reacción local 48 horas posterior a su administración y probablemente aumenta la aparición de fiebre y varicela-like rash.

INTRODUCTION: Chickenpox is an infectious disease caused by varicella-zoster virus. Varicella vaccine is conventionally used for its prevention, and its administration seeks to reduce the onset of the disease and complications associated. However, there is still controversy about its effectiveness. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified two systematic reviews including 16 studies overall, of which three were randomized trials. We concluded that the varicella vaccine decreases the risk of contracting the disease in the long term and probably reduces the risk of developing the disease in the short term in healthy unexposed patients. Nevertheless, the vaccination increases the occurrence of local reactions 48 hours after its administration and probably increases the presence of fever and chickenpox-like rash.

Vaccines for measles, mumps, rubella, and varicella in children.

BACKGROUND: Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012. OBJECTIVES: To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019). SELECTION CRITERIA: We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE. MAIN RESULTS: We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections. AUTHORS' CONCLUSIONS: Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation.

Life-Threatening Influenza, Hemophagocytic Lymphohistiocytosis and Probable Vaccine-Strain Varicella in a Novel Case of Homozygous STAT2 Deficiency.

STAT2 is a transcription factor that plays an essential role in antiviral immunity by mediating the activity of type I and III interferons (IFN-I and IFN-III). It also has a recently established function in the negative regulation of IFN-I signaling. Homozygous STAT2 deficiency is an ultra-rare inborn error of immunity which provides unique insight into the pathologic consequence of STAT2 dysfunction. We report here a novel genetic cause of homozygous STAT2 deficiency with several notable clinical features. The proband presented aged 12 months with hemophagocytic lymphohistiocytosis (HLH) closely followed by clinical varicella, both occurring within three weeks of measles, mumps, and rubella (MMR) and varicella vaccinations. There was a history of life-threatening influenza A virus (IAV) disease 2 months previously. Genetic investigation uncovered homozygosity for a novel nonsense variant in STAT2 (c. 1999C>T, p. Arg667Ter) that abrogated STAT2 protein expression. Compatible with STAT2 deficiency, dermal fibroblasts from the child demonstrated a defect of interferon-stimulated gene expression and a failure to mount an antiviral state in response to treatment with IFN-I, a phenotype that was rescued by lentiviral complementation by wild type STAT2. This case significantly expands the phenotypic spectrum of STAT2 deficiency. The occurrence of life-threatening influenza, which has not previously been reported in this condition, adds STAT2 to the list of monogenetic causes of this phenotype and underscores the critical importance of IFN-I and IFN-III to influenza immunity. The development of probable vaccine-strain varicella is also a novel occurrence in STAT2 deficiency, implying a role for IFN-I/III immunity in control of attenuated varicella zoster virus in vivo and reinforcing the susceptibility to pathologic effects of live-attenuated viral vaccines in disorders of IFN-I immunity. Finally, the occurrence of HLH in this case reinforces emerging links to hyperinflammation in patients with STAT2 deficiency and other related defects of IFN-I signaling-highlighting an important avenue for further scientific enquiry.

Falhas vacinais: avaliando vacinas febre amarela, sarampo, varicela e caxumba / Fallos en vacunas: evaluando vacunas de fiebre amarilla, sarampión, varicela y parotiditis / Vaccine failures: assessing yellow fever, measles, varicella, and mumps vaccines

Resumo: A vacinação é uma das maiores intervenções em saúde pública pela segurança e efetividade, porém nem sempre vacinar significa imunizar. Inúmeros aspectos relacionados tanto ao indivíduo que recebe a vacina, quanto à especificidade de cada imunobiológico administrado compõem o processo para a obtenção de uma adequada imunização, sendo essencial que sejam observados para não culminar em falhas vacinais. A análise dos estudos de imunogenicidade e efetividade para as vacinas sarampo, varicela e caxumba apontam para a necessidade da incorporação de duas doses aos calendários básicos de vacinação para o controle das referidas doenças. Estudos epidemiológicos que analisaram surtos dessas doenças identificaram casos em indivíduos que receberam duas doses da vacina, o que pode apontar provável falha secundária. Para a vacina febre amarela, a discussão atual reside no número de doses ideal para a proteção individual. A Organização Mundial da Saúde recomenda dose única para toda a vida. Apesar dos poucos relatos em literatura a respeito das falhas vacinais, os estudos de imunogenicidade demonstram perda de proteção ao longo dos anos, principalmente na faixa etária pediátrica. Num cenário atual de eliminação e controle de doenças, associado à diminuição da circulação de vírus selvagens, o papel da vigilância epidemiológica é fundamental para aprofundar o conhecimento a respeito dos múltiplos fatores envolvidos, que culminam com falhas vacinais e surgimento de surtos. A ocorrência de surtos de doenças imunopreveníveis impacta negativamente a credibilidade dos programas de imunização, acarretando baixas coberturas vacinais e interferindo no êxito da vacinação.

Resumen: La vacunación es una de las mayores intervenciones en salud pública, por su seguridad y efectividad, sin embargo, no siempre vacunar significa inmunizar. Innumerables aspectos relacionados tanto con el individuo que recibe la vacuna, como con la especificidad de cada inmunobiológico administrado, componen el proceso para conseguir una adecuada inmunización, siendo esencial que sean observados para no acabar con fallos en las vacunas. El análisis de los estudios de inmunogenicidad y efectividad para las vacunas sarampión, varicela y parotiditis, apuntan hacia la necesidad de la incorporación de dos dosis a los calendarios básicos de vacunación para el control de las mencionadas enfermedades. Estudios epidemiológicos que analizaron brotes de esas enfermedades identificaron casos en individuos que recibieron dos dosis de la vacuna, lo que puede apuntar un probable fallo secundario. Para la vacuna de fiebre amarilla la discusión actual reside en el número de dosis ideal para protección individual. La Organización Mundial de la Salud recomienda una dosis única para toda la vida. A pesar de los pocos relatos en la literatura, respecto a los fallos en las vacunas, los estudios de inmunogenicidad demuestran una pérdida de protección a lo largo de los años, principalmente en la franja de etaria pediátrica. En un escenario actual de eliminación y control de enfermedades, asociado a la disminución de la circulación de virus salvajes, el papel de la vigilancia epidemiológica es fundamental para profundizar el conocimiento respecto a los múltiples factores implicados, que culminan con fallos en las vacunas y surgimiento de brotes. La ocurrencia de brotes de enfermedades inmunoprevenibles impacta negativamente en la credibilidad de los programas de inmunización, acarreando bajas coberturas de vacunación e interfiriendo en el éxito de la vacunación.

Abstract: Vaccination is one of the greatest public health interventions, based on its safety and effectiveness, but vaccination does not always mean immunization. Numerous aspects related both to the individual that receives the vaccine and the specificity of each vaccine administered are part of the process of obtaining adequate immunization, and it is essential to observe the aspects in order to avoid vaccine failures. The analysis of immunogenicity and effectiveness studies for the measles, varicella, and mumps vaccines point to the need to incorporate two doses into the basic vaccination calendars in order to control these diseases. Epidemiological studies that analyzed outbreaks of these diseases identified cases in individuals that received two doses of the vaccine, which may indicate likely secondary failure. For the yellow fever vaccine, the current discussion lies in the ideal number of doses for individual protection. The World Health Organization recommends a single dose for life. Despite the few reports in the literature concerning vaccine failures, immunogenicity studies demonstrate waning protection over the years, mainly in the pediatric age bracket. In the current scenario of elimination and control of diseases, associated with the decrease in the circulation of the wild-type viruses, the role of epidemiological surveillance is crucial for expanding knowledge on the multiple factors involved, culminating in vaccine failures and the emergence of outbreaks. Outbreaks of vaccine-preventable diseases negatively impact the credibility of immunization programs, leading to low vaccination coverage rates and interfering in vaccination's success.

Recombinant Zoster Vaccine Significantly Reduces the Impact on Quality of Life Caused by Herpes Zoster in Adult Autologous Hematopoietic Stem Cell Transplant Recipients: A Randomized Placebo-Controlled Trial (ZOE-HSCT).

Herpes zoster (HZ) can have a substantial impact on quality of life (QoL). The vaccine efficacy (VE) of a recombinant zoster vaccine (RZV) was 68.2% (95% confidence interval [CI], 55.6% to 77.5%) in a phase 3 study in adult autologous hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). Herein, we report the impact of RZV on patients' QoL. Autologous HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart. QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year postdose 2 and during suspected HZ episodes with the Zoster Brief Pain Inventory (ZBPI). The RZV impact on ZBPI burden of illness and burden of interference scores was estimated. The 2 scores were calculated from the area under the curve (days 0 to 182) of the ZBPI worst pain and ZBPI activities of daily living scores, respectively, assuming a score of 0 for patients not having a confirmed HZ episode. The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = .011). Consequently, the VE estimates for HZ burden of illness (82.5%; 95% CI, 73.6 to 91.4) and burden of interference (82.8%; 95% CI, 73.3 to 92.3) were higher than the HZ VE estimate (ie, 68.2%). RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ. In addition to reducing the risk of HZ and its complications, RZV significantly reduced the impact of HZ on patients' QoL in those who developed breakthrough disease.

Paradoxical CD4 Lymphopenia in Autoimmune Lymphoproliferative Syndrome (ALPS).

Autoimmune lymphoproliferative syndrome (ALPS) is caused by germline or somatic loss of function FAS mutations resulting in impaired apoptosis and consequent expansion of T-lymphocytes causing organomegaly and autoimmune anemia, neutropenia and thrombocytopenia. Herein, we report on a case of disseminated varicella zoster infection after post-partum vaccination in a patient found to have CD4 lymphopenia and eventually diagnosed with ALPS caused by a novel germline missense mutation in FAS death-domain. A subsequent retrospective analysis of 169 patients of the NIH ALPS-FAS cohort, revealed that CD4-T-cells lymphopenia (< 300 cells/µl) may occur in 5% of ALPS-FAS patients irrespectively of the underlying genetic defect, organomegaly or immunosuppressive treatment. Although immunophenotyping did not show depletion of specific CD4-T-cells subpopulations, CD4-lymphopenic ALPS-FAS subjects had an expansion of a subset of circulating T-follicular-helper (cTfh) cells, associated with autoantibody production (CCR7lowPD-1high). Furthermore, autoantibodies binding on CD4-T-cells were detected in 50% of the CD4-lymphopenic ALPS-FAS patients and caused cytotoxicity in a natural killer (NK)-mediated antibody-dependent-cellular cytotoxicity assay. Such autoantibodies can therefore be associated with CD4-T-cell death, impaired activation induced proliferation or impaired trafficking. The expansion of autoreactive T-cells in ALPS-FAS is known to be associated with autoimmune clinical manifestations, however our study reveals that ALPS-FAS can also be associated with a paradoxical depletion of CD4-T-cells due to the presence of autoantibodies on the surface of CD4-T-cells which can in turn result in increased susceptibility to opportunistic infections. These novel findings have implications for the diagnosis, clinical monitoring, and management of patients with ALPS-FAS.

Optimal approach to assessing T-cell function in haematopoietic cell transplant recipients.

Standardised approaches to functional immune assessment after haematopoietic cell transplantation (HCT) are lacking. A 12-year-old girl with relapsed acute myelogenous leukaemia, 2 years post-unrelated HCT, underwent immunological evaluation prior to receiving live vaccinations. Assessment of standard immune parameters and T-cell proliferation to phytohaemagglutinin was reassuring. She was given Varicella vaccination based on usual post-transplant protocols but was hospitalised 10 days later with localised Varicella infection (vaccine strain). Following recovery, she underwent further assessment that showed reduced T-cell proliferation to an anti-CD3 stimulation panel (anti-CD3 alone, soluble anti-CD3+ anti-CD28 and soluble anti-CD3+ plus exogenous IL-2). On reassessment, 7 months later, T-cell responses to anti-CD3 stimulation were normal and she was revaccinated without further incident. Measurement of T-cell proliferation to anti-CD3 stimulants likely yields more useful information about global T-cell function and should be strongly considered prior to live vaccine administration post-allogeneic haematopoietic transplant.

Vaccine Adverse Events: Separating Myth from Reality.

Vaccines are one of the most successful medical advances in modern times. Most vaccine-preventable illnesses are unfamiliar to modern parents. Because of this, parents are increasingly questioning the necessity of immunizing their children, especially because no vaccine is completely free of adverse effects or the risk of complications. Family physicians should be aware of the risks and benefits of recommended immunizations. Thimerosal is currently used only in multidose vials of influenza vaccine, and exposure through vaccines is not associated with adverse neurologic outcomes. The measles, mumps, and rubella vaccine is not associated with autism. Vaccines are associated with local reactions, such as pain and erythema. The rotavirus vaccine minimally increases the rate of intussusception, whereas other vaccines minimally increase the risk of syncope. Although immunization with the human papillomavirus vaccine is recommended for all boys and girls, vaccination rates remain low. Physicians should guide parents to credible resources if they are considering vaccine refusal. If a recommended vaccine is refused, proper documentation is essential. The Vaccine Adverse Event Reporting System and National Vaccine Injury Compensation Program track adverse events and allow compensation for documented harms from vaccinations.

Challenges in conducting post-authorisation safety studies (PASS): A vaccine manufacturer's view.

Post-authorisation safety studies (PASS) of vaccines assess or quantify the risk of adverse events following immunisation that were not identified or could not be estimated pre-licensure. The aim of this perspective paper is to describe the authors' experience in the design and conduct of twelve PASS that contributed to the evaluation of the benefit-risk of vaccines in real-world settings. We describe challenges and learnings from selected PASS of rotavirus, malaria, influenza, human papillomavirus and measles-mumps-rubella-varicella vaccines that assessed or identified potential or theoretical risks, which may lead to changes to risk management plans and/or to label updates. Study settings include the use of large healthcare databases and de novo data collection. PASS methodology is influenced by the background incidence of the outcome of interest, vaccine uptake, availability and quality of data sources, identification of the at-risk population and of suitable comparators, availability of validated case definitions, and the frequent need for case ascertainment in large databases. Challenges include the requirement for valid exposure and outcome data, identification of, and access to, adequate data sources, and mitigating limitations including bias and confounding. Assessing feasibility is becoming a key step to confirm that study objectives can be met in a timely manner. PASS provide critical information for regulators, public health agencies, vaccine manufacturers and ultimately, individuals. Collaborative approaches and synergistic efforts between vaccine manufacturers and key stakeholders, such as regulatory and public health agencies, are needed to facilitate access to data, and to drive optimal study design and implementation, with the aim of generating robust evidence.

Safety and immunogenicity of inactivated varicella-zoster virus vaccine in adults with hematologic malignancies receiving treatment with anti-CD20 monoclonal antibodies.

BACKGROUND: Immunocompromised patients can experience significant morbidity and occasional mortality from complications associated with herpes zoster (HZ), but live attenuated HZ vaccine is contraindicated for these patients. Inactivated zoster vaccine (ZVIN) is in development for prevention of HZ in immunocompromised patients. However, there are limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies on vaccine-related cell-mediated immune response. This study evaluated safety and immunogenicity of ZVIN in patients with hematologic malignancies (HM) receiving anti-CD20 monoclonal antibodies (alone or in combination chemotherapy regimens) and not likely to undergo hematopoietic cell transplant (HCT) (n=80). METHODS: This was an open-label, single-arm, multicenter Phase I study (NCT01460719) of a 4-dose ZVIN regimen (∼30days between doses) in patients ⩾18years old. Blood samples were collected prior to dose 1 and 28days Postdose 4 to measure varicella zoster virus (VZV)-specific T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses at ∼28days Postdose 4, with a geometric fold rise (GMFR) >1.0. All vaccinated patients were evaluated for adverse events (AE) through 28days Postdose 4. RESULTS: ZVIN elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28days Postdose 4 (GMFR=4.34 [90% CI:3.01, 6.24], p-value<0.001), meeting the pre-specified success criterion. Overall, 85% (68/80) of patients reported ⩾1 AE, 44% (35/80) reported ⩾1 injection-site AE, and 74% (59/80) reported ⩾1 systemic AE. The majority of systemic AEs were non-serious and considered unrelated to vaccination by the investigator. Frequencies of AEs did not increase with subsequent doses of vaccine. No recipient of ZVIN had rash polymerase chain reaction (PCR) positive for VZV vaccine strain. CONCLUSIONS: In adults with HM receiving anti-CD20 monoclonal antibodies, ZVIN was well-tolerated and elicited statistically significant VZV-specific T-cell responses ∼28days Postdose 4. CLINICALTRIALS.GOV identifier: NCT01460719.

Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation - A systematic review of randomized trials, observational studies and case reports.

BACKGROUND: Live vaccines are generally contraindicated on immunosuppressive therapy due to safety concerns. However, data are limited to corroborate this practice. OBJECTIVES: To estimate the safety of live vaccinations in patients with immune-mediated inflammatory diseases (IMID) or solid organ transplantation (SOT) on immunosuppressive treatment and in patients after bone-marrow transplantation (BMT). DATA SOURCES: A search was conducted in electronic databases (Cochrane, Pubmed, Embase) and additional literature was identified by targeted searches. ELIGIBILITY CRITERIA: Randomized trials, observational studies and case reports. POPULATION: Patients with IMID or SOT on immunosuppressive treatment and BMT patients <2years after transplantation. INTERVENTION/VACCINATIONS LOOKED AT: Live vaccinations: mumps, measles, rubella (MMR), yellow fever (YF), varicella vaccine (VV), herpes zoster (HZ), oral typhoid, oral polio, rotavirus, Bacillus Calmette-Guérin (BCG), smallpox. DATA EXTRACTION: One author performed the data extraction using predefined data fields. It was cross-checked by two other authors. RESULTS: 7305 articles were identified and 64 articles were included: 40 on IMID, 16 on SOT and 8 on BMT patients. In most studies, the administration of live vaccines was safe. However, some serious vaccine-related adverse events occurred. 32 participants developed an infection with the vaccine strain; in most cases the infection was mild. However, in two patients fatal infections were reported: a patient with RA/SLE overlap who started MTX/dexamethasone treatment four days after the YFV developed a yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and died. The particular vaccine lot was found to be associated with a more than 20 times risk of YEL-AVD. One infant whose mother was under infliximab treatment during pregnancy received the BCG vaccine at the age of three months and developed disseminated BCG infection and died. An immunogenicity assessment was performed in 43 studies. In most cases the patients developed satisfactory seroprotection rates. In the IMID group, YFV and VV demonstrated high seroconversion rates. MTX and tumor necrosis factor inhibitory therapy appeared to reduce immune responses to VV and HZ vaccine, but not to MMR and YF-revaccination. Seroconversion in SOT and BMT patients showed mostly higher rates for rubella than for measles, mumps and varicella. LIMITATIONS: Risk of bias was high in the majority of studies since 39 of them were observational and 17 were case series/case reports. Only eight studies were randomized trials. BMT patient numbers included in this review were low. CONCLUSIONS: Although live vaccinations were safe and sufficiently immunogenic in most studies, some serious reactions and vaccine-related infections were reported in immunosuppressed IMID and SOT patients. Apart from mild vaccine-related infections MMR and VV vaccines were safe when administered less than two years after BMT. IMPLICATIONS OF KEY FINDINGS: Until further data are available, live vaccinations under most immunosuppressive treatments should only be administered after a careful risk benefit assessment of medications and dosages. FUNDING: None.

Varicella Vaccination of Children With Leukemia Without Interruption of Maintenance Therapy: A Danish Experience.

BACKGROUND: Varicella-zoster virus (VZV) can be fatal or cause severe complications in children with acute lymphoblastic leukemia (ALL). This analysis set out to investigate the morbidity and mortality of VZV vaccination without interruption of maintenance therapy in children with ALL. METHODS: Files of 73 seronegative children with ALL were examined for data regarding VZV vaccination and infection, and long-term seroconversion was measured. Criteria before VZV vaccination were (1) seronegative, (2) in complete remission, (3) age ≥ 1.0 year, (4) lymphocyte count ≥ 0.6 × 10/L at time of vaccination and (5) receiving maintenance therapy. RESULTS: Forty-five children were vaccinated. No child died or experienced serious adverse events due to VZV vaccination. Nine children developed late chickenpox despite vaccination. Long-term protection was found in 86% of children not receiving acyclovir and 78% of the entire population. Long-term seroconversion was found in 52% of the children. There were no severe cases of varicella infection. Acyclovir prophylaxis postvaccination was associated with an increased risk of late chickenpox [hazard ratio = 5.40 (1.43, 20.41), P = 0.01]. In contrast, a vaccine-induced rash reduced the risk of late chickenpox [hazard ratio = 0.08 (0.01, 0.66), P = 0.02]. No child had interruption of maintenance therapy at the time of vaccination, but 33% experienced discontinuation of therapy due to vaccine-induced rash. Dexamethasone was associated with an increased risk of vaccine-induced rash [hazard ratio = 2.9 (1.21, 6.90), P = 0.02]. CONCLUSIONS: This analysis indicates that VZV vaccination is feasible and justified in seronegative children with ALL, in countries where VZV vaccination is not part of the national vaccination program.

Acute Demyelinating Events Following Vaccines: A Case-Centered Analysis.

BACKGROUND: Case reports have suggested that vaccines may trigger transverse myelitis (TM) or acute disseminated encephalomyelitis (ADEM), but the evidence for a causal association is inconclusive. We analyzed the association of immunization and subsequent development of TM or ADEM. METHODS: We identified all cases of TM and ADEM in the Vaccine Safety Datalink population. Using a case-centered method, we compared vaccination of each case to vaccination of all matched persons in the study population, who received the same type of vaccine, with respect to whether or not their vaccination occurred during a predetermined exposure interval. We calculated a risk difference (excess risk) of TM and ADEM for each vaccine. RESULTS: Following nearly 64 million vaccine doses, only 7 cases of TM and 8 cases of ADEM were vaccinated during the primary exposure window 5-28 days prior to onset. For TM, there was no statistically significant increased risk of immunization. For ADEM, there was no statistically significant increased risk following any vaccine except for Tdap (adolescent and adult tetanus, reduced diphtheria, acellular pertussis) vaccine. Based on 2 exposed cases, the odds ratio for Tdap exposure 5-28 days prior to ADEM onset was 15.8 (95% confidence interval [CI], 1.2-471.6; P = .04), and the estimated excess risk was 0.385 (95% CI, -.04 to 1.16) cases per million doses. CONCLUSIONS: We found no association between TM and prior immunization. There was a possible association of ADEM with Tdap vaccine, but the excess risk is not likely to be more than 1.16 cases of ADEM per million vaccines administered.

Disseminated Varicella-Zoster Virus After Vaccination in an Immunocompetent Patient.

Severe adverse events associated with varicella-zoster virus (VZV) vaccination are rare. The authors describe a 53-year-old woman with no known immunodeficiency who presented with diffuse pruritic rash 17 days after receiving the varicella virus vaccine live. She had a low level of white blood cells and received a diagnosis of thrombocytopenia with elevated aminotransferase levels. Punch biopsy demonstrated positive VZV immunostaining and viral culture positive for VZV. After treatment with acyclovir, her rash improved and her white blood cell and platelet counts returned to normal. Mild reactions to vaccines including localized rash are well recognized. Disseminated infections have been reported in patients with congenital and acquired immunodeficiency, but systemic postvaccination infections are rare in immunocompetent adults. This case highlights the importance of recognizing adverse events associated with vaccination.

A double blind, randomized, active controlled study to assess the safety, tolerability and immunogenicity of measles, mumps rubella, and varicella vaccine (MMRV) manufactured using an alternative process.

Vaccination against measles, mumps, rubella, and varicella is recommended for all children in the US. Limitations manufacturing Oka/Merck strain varicella-zoster virus have hampered the availability of the combination vaccine (MMRV) against these 4 viruses, which drove the need to investigate an alternative manufacturing process. Healthy children 12-to-23 months of age at 71 US sites were randomized (1:1) to receive MMRV manufactured using an alternative process (MMRVAMP) or the currently licensed MMRV. Subjects received 2 0.5 mL doses 3 months apart. Sera were collected before and 6 weeks after Dose-1. Adverse experiences (AEs) were collected for 42 d after each dose and serious AEs and events of special interest for 180 d after Dose-2. Overall, 706 subjects were randomized to MMRVAMP and 706 to MMRV and 698 and 702 received at least 1 dose of study vaccine, respectively. The risk difference in response rates and geometric mean concentrations of antibody to measles, mumps, rubella, and varicella viruses 6 weeks after Dose-1 met non-inferiority criteria for MMRVAMP versus, MMRV. Response rates met acceptability criteria for each virus, and the seroconversion rate to varicella-zoster virus was 99.5% in both groups. Vaccine-related AEs were mostly mild-to-moderate in intensity and somewhat more common after MMRVAMP. Febrile seizures occurred at similar rates in both groups during the first 42 d after each vaccine dose. MMRVAMP is non-inferior to MMRV and represents an important advancement in maintaining an adequate supply of vaccines against these diseases.

Projecting adverse event incidence rates using empirical Bayes methodology.

Although there is considerable interest in adverse events observed in clinical trials, projecting adverse event incidence rates in an extended period can be of interest when the trial duration is limited compared to clinical practice. A naïve method for making projections might involve modeling the observed rates into the future for each adverse event. However, such an approach overlooks the information that can be borrowed across all the adverse event data. We propose a method that weights each projection using a shrinkage factor; the adverse event-specific shrinkage is a probability, based on empirical Bayes methodology, estimated from all the adverse event data, reflecting evidence in support of the null or non-null hypotheses. Also proposed is a technique to estimate the proportion of true nulls, called the common area under the density curves, which is a critical step in arriving at the shrinkage factor. The performance of the method is evaluated by projecting from interim data and then comparing the projected results with observed results. The method is illustrated on two data sets.

Disseminated, persistent, and fatal infection due to the vaccine strain of varicella-zoster virus in an adult following stem cell transplantation.

Live attenuated varicella vaccine is recommended for healthy individuals who are susceptible to varicella. Although the vaccine is safe, effective, and used worldwide, serious adverse events have been reported, mainly in immunocompromised patients who subsequently recovered. Here, we describe the fatality of an immunocompromised patient who received the varicella vaccine. His medical history provides a cautionary lens through which to view the decision of when vaccination is appropriate. A middle-aged man with non-Hodgkin lymphoma received chemotherapy and a stem cell transplant. He was vaccinated 4 years post-transplantation, despite diagnosis of a new low-grade lymphoma confined to the lymph nodes. Within 3 months of vaccination, he developed recurrent rashes with fever, malaise, weakness, hepatitis, weight loss, and renal failure. The syndrome was eventually determined to be associated with persistent disseminated zoster caused by the vaccine virus. This case illustrates a circumstance when a live viral vaccine should not be used.