Assessment of pre-specified adverse events following varicella vaccine: A population-based self-controlled risk interval study.

BACKGROUND: Clinical trials and spontaneous reporting systems have revealed rare but biologically plausible adverse events following varicella immunization. Few post-marketing controlled studies have been conducted to assess the relationship between the varicella vaccine and these outcomes. OBJECTIVES: To evaluate the risk of pneumonia, idiopathic thrombocytopenic purpura (ITP), meningitis, encephalitis and ischemic stroke following varicella immunization. MATERIALS AND METHODS: This nationwide observational study was based on Taiwan National Health Insurance data and National Immunization Information System from 2004 through 2014. Primary analysis included children aged 12-35 months who received the single varicella vaccine on the date of administration. The self-controlled risk interval design compared the incidence of pre-specified outcomes during a risk interval of 1-42 days post-vaccination and a control interval of 43-84 days. The outcomes of interest were defined as admitted pneumonia, ITP, meningitis, encephalitis, and ischemic stroke, as well as fracture as a negative control. Conditional Poisson regression was used to assess the incidence rate ratio (aIRR) with adjustments for age and seasonal effects. RESULTS: Among 1,194,189 children, who receiving the varicella vaccine, there was no observed increase in the risk for ITP (aIRR 1.00; 95% CI, 0.76-1.33), meningitis (aIRR 1.21; 95% CI, 0.49-2.95), encephalitis (aIRR 1.00; 95% CI, 0.62-1.60), or ischemic stroke (aIRR 1.24; 95% CI, 0.31-4.95). A clustering feature with pneumonia occurred during days 36-42 post-vaccination (aIRR 1.10; 95% CI, 1.02-1.18). An increase in the risk for ITP was observed in children receiving the varicella and MMR vaccines concomitantly (aIRR 1.70; 95% CI, 1.19-2.43), but not among those receiving the varicella vaccine only. CONCLUSIONS: We detected a small risk of incidental pneumonia associated with varicella vaccine in the 6th week after immunization. There was no increase in the risk of other pre-specified adverse events.

[Varicella vaccination: scientific reasons for a different strategic approach]. / Vaccinazione antivaricella: argomenti scientifici per possibili strategie diverse dalle attuali.

The Italian Parliament has recently introduced 10 mandatory immunisations, including the one against varicella. For this vaccination, the obligation starts with the birth cohort of 2017, but it is offered free of charge to subjects with a negative history and not previously vaccinated. This paper presents up-to-date evidence on this issue and illustrates a number of critical arguments that may question the opportunity of this choice. Particularly, while the disease is relatively mild in children aged between 1 and 9 years, the risk of worsening its consequences is progressive with age, becoming worst in the elderly, so the vaccination of children may increase the age of the cases. Some vaccine side effects are not trivial and the duration of protection is still uncertain, as well as the cost-effectiveness of mass vaccination and its long-term effects, referring to virus reactivation and to the incidence of Herpes zoster in the general population, which could be increased and anticipated in the long run. Varicella vaccination is not included in international eradication goals and very few Europeans Countries have considered it as a public health priority. A different rational choice could have been to offer a selective vaccination only to adolescents with a negative history of chickenpox; or at least to delay the beginning of the universal campaign in the Italian regions that had not started the mass vaccination yet, evaluating the results over time. Lastly, this paper lists a number of preventive interventions of proven effectiveness and cost-effectiveness, with extraordinary margins of improvement, whose mandatory introduction in the population have never been considered, even as a matter of debate.

Varicella epidemiology in Latin America and the Caribbean.

INTRODUCTION: The Latin American Society of Pediatric Infectious Diseases (SLIPE), with the support of the Americas Health Foundation (AHF), has developed a position paper on varicella prevention in Latin America and Caribbean countries (LAC). This article summarizes the most relevant aspects of varicella in LAC, and emphasizes the need to include the varicella vaccine in the national immunization programs in the Region and evaluate its impact disease burden. AREAS COVERED: A systematic review was conducted of the medical evidence published and presented at various regional medical conferences on the disease burden in LAC, the advances made by prevention programs, the available vaccines in the Region, and their immunogenicity, efficacy, effectiveness, and safety. The different national varicella-prevention vaccination programs were reviewed, as was available information regarding the impact of these programs on the epidemiology of varicella in those countries implementing a varicella vaccine strategy. Following that initial publication, an update was conducted, including data from additional countries in the Region. EXPERT COMMENTARY: Varicella is a vaccine-preventable infectious disease, considered a 'benign disease' because of lower complication rates when compared with measles, pertussis. The incorporation of a two-dose varicella vaccine in national immunization schedules in all countries throughout LAC would be of great benefit to the health of the children.

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.

The Cost-effectiveness of Varicella Zoster Virus Vaccination Considering Late Onset Asthma.

BACKGROUND: Recent studies reported that infection by varicella zoster virus (VZV) may lead to delayed onset of asthma in children/adolescents. This information will likely alter the cost-effectiveness of the US. VZV vaccination program. We created a decision analysis model to estimate the costs and health-related effects of VZV 2-dose vaccination, assuming VZV infection delays asthma onset. METHODS: The Markov model considered a birth cohort of 3,957,577 individuals entering the population from a societal perspective. We predicted the number of asthma/VZV cases, asthma-/VZV-related mortality and costs associated with asthma/VZV. Comparison arms included (1) VZV vaccination program without delayed asthma onset, (2) VZV vaccination program with delayed asthma onset and (3) no VZV vaccination program with delayed asthma onset. We considered delayed onset ranging from 3 to 12 years. RESULTS: The vaccination program proved cost-effective without an assumed delay in asthma onset. When the vaccination and no-vaccination arms were compared assuming delayed asthma onset, vaccination remained less costly despite increased savings related to asthma without vaccination. With delayed asthma onset of 9 years post VZV infection, cost savings due to vaccination were $914.09 million, with 9984 cases of asthma averted and 9 greater overall deaths with vaccination. CONCLUSION: VZV vaccination program was less costly than the "no-vaccination" scenario, despite delayed onset of asthma post VZV infection. However, vaccination resulted in increased asthma morbidity and mortality. This adds to current evidence that VZV vaccination is cost-effective, and may alter asthma-related health-care outcomes. VZV's effect on asthma symptoms still needs further evaluation before firm conclusions can be reached.

Distribution of Health Effects and Cost-effectiveness of Varicella Vaccination are Shaped by the Impact on Herpes Zoster.

INTRODUCTION: Varicella zoster virus (VZV) is the etiological agent of varicella and herpes zoster (HZ). It has been hypothesised that immune boosting of latently infected persons by contact with varicella reduces the probability of HZ. If true, universal varicella vaccination may increase HZ incidence due to reduced VZV circulation. To inform decision-making, we conduct cost-effectiveness analyses of varicella vaccination, including effects on HZ. METHODS: Effects of varicella vaccination are simulated with a dynamic transmission model, parameterised with Dutch VZV seroprevalence and HZ incidence data, and linked to an economic model. We consider vaccination scenarios that differ by whether or not they include immune boosting, and reactivation of vaccine virus. RESULTS: Varicella incidence decreases after introduction of vaccination, while HZ incidence may increase or decrease depending on whether or not immune boosting is present. Without immune boosting, vaccination is expected to be cost-effective or even cost-saving. With immune boosting, vaccination at 95% coverage is not expected to be cost-effective, and may even cause net health losses. CONCLUSIONS: Cost-effectiveness of varicella vaccination depends strongly on the impact on HZ and the economic time horizon. Our findings reveal ethical dilemmas as varicella vaccination may result in unequal distribution of health effects between generations.

Vaccination to prevent varicella: Goldman and King's response to Myers' interpretation of Varicella Active Surveillance Project data.

BACKGROUND: There is increasing evidence that herpes zoster (HZ) incidence rates among children and adults (aged <60 years) with a history of natural varicella are influenced primarily by the frequency of exogenous exposures, while asymptomatic endogenous reactivations help to cap the rate at approximately 550 cases/100,000 person-years when exogenous boosting becomes rare. The Antelope Valley Varicella Active Surveillance Project was funded by the Centers for Disease Control and Prevention in 1995 to monitor the effects of varicella vaccination in one of the three representative regions of the United States. The stability in the data collection and number of reporting sites under varicella surveillance from 1995-2002 and HZ surveillance during 2000-2001 and 2006-2007 contributed to the robustness of the discerned trends. DISCUSSION: Varicella vaccination may be useful for leukemic children; however, the target population in the United States is all children. Since the varicella vaccine inoculates its recipients with live, attenuated varicella-zoster virus (VZV), clinical varicella cases have dramatically declined. Declining exogenous exposures (boosts) from children shedding natural VZV have caused waning cell-mediated immunity. Thus, the protection provided by varicella vaccination is neither lifelong nor complete. Moreover, dramatic increases in the incidence of adult shingles cases have been observed since HZ was added to the surveillance in 2000. In 2013, this topic is still debated and remains controversial in the United States. SUMMARY: When the costs of the booster dose for varicella and the increased shingles recurrences are included, the universal varicella vaccination program is neither effective nor cost-effective.

Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting.

BACKGROUND: A combined measles, mumps, rubella, varicella live vaccine (MMRV, Merck and Co., Inc., US) was recently licensed in the US. Pre-licensure clinical trial data showed a significant increase in fever in days 5-12 following MMRV vaccination as compared to the vaccines given separately (MMR+V). This post-licensure retrospective cohort study was undertaken to assess the incidence of febrile convulsion following MMRV. METHODS: Children ages 12-60 months who received a first dose of MMRV in February 2006-June 2007 in a managed care organization were included in the study. Subjects were optimally matched on age, sex, and calendar date of vaccination to children who received MMR+V concomitantly in November 2003-January 2006, before MMRV licensure. Potential cases of febrile convulsion were identified through administrative data and adjudicated by expert panel, according to pre-specified criteria. RESULTS: During the 30 days post-vaccination, there were 128 and 94 potential convulsion cases among the 31,298 children in the MMRV and MMR+V cohorts, respectively. After review of available medical charts and adjudication, there were 84 cases of confirmed febrile convulsion, 44 (1.41/1000) and 40 (1.28/1000) in the MMRV and MMR+V cohorts, respectively (RR=1.10, 95% CI=0.72, 1.69). In days 5-12 following vaccination, a pre-specified period of interest, the respective numbers were 22 (0.70/1000) and 10 (0.32/1000) (RR=2.20, 95% CI=1.04, 4.65). CONCLUSION: These data suggest that the risk of febrile convulsion is increased in days 5-12 following vaccination with MMRV as compared to MMR+V given separately during the same visit, when post-vaccination fever and rash are also increased in clinical trials. While there was no evidence of an increase in the overall month following vaccination, the elevated risk during this time period should be communicated and needs to be balanced with the potential benefit of a combined vaccine.

Varicella zoster vaccines.

In the past, the varicella zoster virus affected virtually the entire population and had substantial morbidity and mortality associated with both primary varicella and herpes zoster reactivation. Since the varicella vaccine was first approved in 1995, there has been a significant decline in incidence, morbidity, and mortality caused by primary varicella. Breakthrough disease with the one-dose vaccine schedule led to the recommendation in 2006 that children receive a two-dose vaccine series. Older adults have also benefited from the development of the zoster vaccine. In 2006, the Food and Drug Administration approved the zoster vaccine, a higher concentration of the same live attenuated virus used in the primary varicella vaccine, for persons 60 years of age or older. It has the potential to help millions of people avoid the pain associated with reactivation of the varicella zoster virus by reducing the incidence and severity of herpes zoster and postherpetic neuralgia.

Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP).

Two live, attenuated varicella zoster virus-containing vaccines are available in the United States for prevention of varicella: 1) a single-antigen varicella vaccine (VARIVAX, Merck & Co., Inc., Whitehouse Station, New Jersey), which was licensed in the United States in 1995 for use among healthy children aged > or = 12 months, adolescents, and adults; and 2) a combination measles, mumps, rubella, and varicella vaccine (ProQuad, Merck & Co., Inc., Whitehouse Station, New Jersey), which was licensed in the United States in 2005 for use among healthy children aged 12 months-12 years. Initial Advisory Committee on Immunization Practices (ACIP) recommendations for prevention of varicella issued in 1995 (CDC. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1996;45 [No. RR-11]) included routine vaccination of children aged 12-18 months, catch-up vaccination of susceptible children aged 19 months-12 years, and vaccination of susceptible persons who have close contact with persons at high risk for serious complications (e.g., health-care personnel and family contacts of immunocompromised persons). One dose of vaccine was recommended for children aged 12 months-12 years and 2 doses, 4-8 weeks apart, for persons aged > or = 13 years. In 1999, ACIP updated the recommendations (CDC. Prevention of varicella: updated recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1999;48 [No. RR-6]) to include establishing child care and school entry requirements, use of the vaccine following exposure and for outbreak control, use of the vaccine for certain children infected with human immunodeficiency virus, and vaccination of adolescents and adults at high risk for exposure or transmission. In June 2005 and June 2006, ACIP adopted new recommendations regarding the use of live, attenuated varicella vaccines for prevention of varicella. This report revises, updates, and replaces the 1996 and 1999 ACIP statements for prevention of varicella. The new recommendations include 1) implementation of a routine 2-dose varicella vaccination program for children, with the first dose administered at age 12-15 months and the second dose at age 4-6 years; 2) a second dose catch-up varicella vaccination for children, adolescents, and adults who previously had received 1 dose; 3) routine vaccination of all healthy persons aged > or = 13 years without evidence of immunity; 4) prenatal assessment and postpartum vaccination; 5) expanding the use of the varicella vaccine for HIV-infected children with age-specific CD4+ T lymphocyte percentages of 15%-24% and adolescents and adults with CD4+ T lymphocyte counts > or = 200 cells/microL; and 6) establishing middle school, high school, and college entry vaccination requirements. ACIP also approved criteria for evidence of immunity to varicella.

The case against universal varicella vaccination.

In 1995, the United States became the first country to implement a Universal Varicella Vaccination Program. Several questions remain: Is the varicella (chickenpox) vaccine needed? Is it cost effective as a routine immunization for all susceptible children? Or is it more beneficial for the disease to remain endemic so that adults may receive periodic exogenous exposures (boosts) that help suppress the reactivation of herpes zoster (shingles). In addition, as vaccination coverage becomes widespread, does loss of immunologic boosting cause a decline in vaccine efficacy and result in a reduced period of immunity? Scientific literature regarding safety of the varicella vaccine and its associated cost-benefit analysis have often reported optimistic evaluations based on ideal assumptions. Deleterious outcomes and their associated costs must be included when making a circumspect assessment of the Universal Varicella Vaccination Program.

Chickenpox vaccines: new drugs. A favourable risk-benefit balance in some situations.

(1) Chickenpox is generally mild. Most severe cases of chickenpox occur in immunocompromised patients, adults, and pregnant women (and their foetuses). (2) Two live attenuated chickenpox vaccines derived from the same strain of varicella virus (Oka) are marketed in France, under the trade names Varilrix and Varivax. (3) They have not been adequately evaluated in immunocompromised children. (4) The impact of routine vaccination of women of child-bearing age on complications of chickenpox during pregnancy has not been studied. (5) Immunogenicity studies in several thousand immunocompetent children aged from 1 to 12 years show that the vaccine is almost always immunogenic after a single injection. Other comparative studies in adolescents and adults show that two injections are needed, at least two months apart. (6) A double-blind placebo-controlled trial including 513 immunocompetent children showed that Varilrix prevented 88% of cases of chickenpox after a median follow-up of 29 months, but no data on severe chickenpox were reported. A study that followed up 9202 children aged 1 to 12 years for more than 13 years showed that vaccination with Varivax failed to prevent chickenpox in 12.5% of cases and that 1.7% of these cases were severe. (7) Immunocompetent children vaccinated within three days after exposure to the virus are partially protected, according to one study of Varilrix (104 children) and two small studies of Varivax (10 and 42 children). There are no equivalent studies in adults. (8) Local adverse effects such as fever and rash are common in immunocompetent vaccinees. The rash is sometimes varicella-like and is due to infection by the vaccine strain. Pharmacovigilance studies of Varivax have shown no serious adverse effects. (9) Disseminated and/or persistent infection caused by the vaccine strain has been reported in immunocompromised patients. (10) Vaccination of immunocompetent subjects does not appear to result in a risk of chickenpox transmission to subsequent contacts. There seems to be no increase in the risk of herpes zoster in vaccinated children nor is there any firm evidence that chickenpox vaccination increases the incidence of herpes zoster in the general population. (11) Little information is available on vaccination during pregnancy. As a precaution, however, pregnant women should not be vaccinated. (12) Mass vaccination does not appear to be justified: chickenpox is generally mild during childhood, and several questions concerning the effects of the vaccine remain unanswered. (13) Chickenpox vaccination should be restricted to specific groups of non immune immunocompetent adults who are in a position to transmit chickenpox to immunodeficient contacts (e.g. health care personnel and kindergarten staff); adults who have been in contact with a case of chickenpox within the past three days; and children awaiting transplantation. The potential benefits and risks of vaccinating immunocompromised patients should be assessed on a case by case basis.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Controversies in chicken-pox immunization.

Chicken-pox is one more newer vaccine in our armamentarium against infectious diseases. Due to its extremely contagious nature, varicella is experienced by almost every child or young adult in the world. Each year from 1990 to 1994, prior to availability of varicella vaccine, about 4 million cases of varicella occurred in the United States. Of these cases approximately 10,000 required hospitalization and 100 died. Although varicella is not commonly perceived as an important public health problem, the socioeconomic consequences in industrialized countries of a disease that affects practically every child and causes the carrier absence from work should not be underestimated. The varicella vaccines available in the market are safe and effective. A recent cost-benefit analysis in USA showed that routine chicken-pox vaccination is likely to save five times the investment. Even when only direct costs were considered, benefits almost balanced the costs. At present similar studies from developing countries are not available. The public health impact of varicella and zoster may be increasing in regions with high endemic rates of HIV infection. Varicella vaccine may be used either at an individual level to protect susceptible adolescents and adults, or at a population level, to cover all children as part of a national immunization programme. Vaccination of adolescents and adults will protect at-risk individuals, but will not have a significant impact on the epidemiology of the disease on a population basis. On the other hand, extensive use as a routine vaccine in children will have a significant impact on the epidemiology of the disease. If sustained high coverage can be achieved, the disease may virtually disappear. If only partial coverage can be obtained, the epidemiology may shift, leading to an increase in the number of cases in older children and adults. Hence, routine childhood varicella immunization programmes should emphasize high, sustained coverage. At present, this vaccine will have a lower priority in the National Immunization Schedule that does not have MMR and typhoid, which have a greater socioeconomic impact. Hence, at the present time WHO does not recommend the inclusion of varicella vaccination into the routine immunization programmes of developing countries.

Varicella vaccine: factors influencing uptake.

BACKGROUND: In Canada, varicella vaccine is recommended but its uptake has been low. In contrast to most other recommended paediatric vaccines, this one is not currently provided free of charge in all provinces and territories in Canada. OBJECTIVE: To evaluate the rate of health care provider offer of varicella vaccine to parents and the most important determinants of parental decision to accept the offer. METHODS: A structured questionnaire was administered by phone interview to parents of children aged 14 to 17 months in the Quebec City area where the vaccine is not publicly funded. RESULTS: Among the 477 participants, 37% had been offered the vaccine by their health care provider: 45% when the provider was a paediatrician and 29% for general practitioners or public health clinics. Only 13% of offers included information on the risk of varicella complications, the cost, efficacy and safety of the vaccine. By decreasing order of importance, the factors that positively increased parental decision to use varicella vaccine included: information on vaccine safety, a positive recommendation and a higher family income. CONCLUSION: Despite a recommendation for universal vaccination, varicella vaccine is not broadly offered and few offers contain all the information both needed to elicit proper consent and correlated with a positive uptake.

[Varicella disease and varicella vaccine. A literature review]. / Skoldkoppesygdom og -vaccine. En litteraturgennemgang.

Varicella is an infectious childhood disease. A safe and effective vaccine is accessible. The varicella disease usually takes a mild course but studies performed outside Denmark reveal a considerable occurrence of complications. There is no Danish account of morbidity and mortality following infection with varicella-zoster virus. According to experience from the USA, the introduction of routine vaccination will result in a decreasing incidence of the disease and will also reduce the frequency of complications caused by the disease. In addition, it will give indirect protection of non-vaccinated individuals (herd immunity). Introducing vaccination against varicella involves a potential risk of changing the epidemiology of the disease. Moreover, routine vaccination may affect the frequency and the severity of herpes zoster. Experience from the USA will give us a better basis of deciding whether vaccination against varicella should be implemented or not in the Danish childhood vaccination programme.

Varlirix (GlaxoSmithKline).

GlaxoSmithKline (formerly SmithKline Beecham) has developed and launched Varilrix, a preparation of live, attenuated Oka-strain varicella zoster virus, for immunization against varicella zoster infections [455138]. By the end of 1998, Varilrix was available in a few European countries and in India [284490], [455138]. By 2001, the vaccine was also available in Brazil and Hong Kong [396267].