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Successes and challenges in varicella vaccine Vassiliki Papaevangelou, Orestis Papaloukas and Georgia Giannouli Therapeutic Advances in Vaccines published online 6 January 2014 DOI: 10.1177/2051013613515621 The online version of this article can be found at: http://tav.sagepub.com/content/early/2013/12/20/2051013613515621
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515621 research-article2013
TAV0010.1177/2051013613515621Therapeutic Advances in VaccinesO. Papaloukas et al.O Papaloukas, G Giannouli
Therapeutic Advances in Vaccines
Review
Successes and challenges in varicella vaccine Orestis Papaloukas, Georgia Giannouli and Vassiliki Papaevangelou
Abstract: Varicella is a highly contagious disease caused by primary infection with varicella zoster virus (VZV). VZV infection, as well as varicella vaccination, induces VZV-specific antibody and T-cell-mediated immunity, essential for recovery. The immune responses developed contribute to protection following re-exposure to VZV. When cell-mediated immunity declines, as occurs with aging or immunosuppression, reactivation of VZV leads to herpes zoster (HZ). It has been almost 20 years since universal varicella vaccination has been implemented in many areas around the globe and has resulted in a significant reduction of varicella-associated disease burden. Successes are reviewed whilst emphasis is put on the challenges ahead. Most countries that have not implemented routine childhood varicella vaccination have chosen to vaccinate high-risk groups alone. The main reasons for not introducing universal vaccination are discussed, including fear of age shift of peak incidence age and of HZ incidence increase. Possible reasons for not observing the predicted increase in HZ incidence are explored. The advantages and disadvantages of universal versus targeted vaccination as well as different vaccination schedules are discussed.
Ther Adv Vaccines (2013) 0(0) 1–17 DOI: 10.1177/ 2051013613515621 © The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Keywords: Varicella vaccination, varicella zoster virus, epidemiology, herpes zoster incidence, VZV-cellular immunity
Introduction Varicella zoster virus Varicella zoster virus (VZV) is an alpha herpesvirus that infects exclusively humans [Hambleton and Gershon, 2005]. Each VZV virion consists of four parts: (1) the core (made of a linear double-stranded DNA); (2) the capsid; (3) the tegument (that surrounds the capsid); and (4) the envelope (that surrounds the tegument and incorporates the major viral glycoproteins [gps]) [Arvin, 1996]. VZV’s virion is spherical with a diameter of 180–200 nm while the core consists of a single linear double-stranded DNA 125 kb long. VZV is the smallest of the human herpes viruses and its envelope is made out of gps of about 8 nm long. During lytic infection the virus produces at least 12 gps which are expressed both on the surface of the virions and the envelope of infected human cells [Gershon and Gershon, 2010]. VZV associated diseases VZV DNA is present in respiratory secretions (upper respiratory) and fluid secretions from skin
vesicles. It is transmitted through direct contact with the skin lesions, through respiratory secretions or through inhalation of the airborne particles of the virus. Primary infection is manifested as varicella (or chickenpox) and leads to lifelong latent infection of sensory ganglion neurons. Reactivation of the latent infection causes HZ (HZ, shingles) [Hambleton and Gershon, 2005]. Varicella (or chickenpox) is a highly contagious disease in children with an estimated household secondary attack rate of 90% [Arvin, 1996; Ross, 1962]. During the incubation period (10–21 days), the virus initially replicates in the upper respiratory tract and through a primary subclinical viremia, the virus spreads to the reticuloendothelial system (liver, spleen) and other organs. Following additional viral replication, a second viremic phase ensues and prodromal clinical symptoms (fever, malaise) appear followed by the eruption of the typical rash. The rash consists of pruritic, maculopapules, vesicles and crusted lesions in varying stages of evolution. They quickly progress from one stage to
Correspondence to: Vassiliki Papaevangelou, MD, MSc, PhD Third Department of Pediatrics, University of Athens Medical School, General University Hospital ‘ATTIKON’, Rimini 1, Chaidari 124 62, Greece [email protected] Orestis Papaloukas, MD, PhD Georgia Giannouli, MD, MSc, PhD Second Department of Pediatrics, University of Athens Medical School, P&A Kyriakou Childrens’ Hospital, Greece
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Therapeutic Advances in Vaccines 0 (0) the next. In the beginning, each skin vesicle develops on an erythematous base, then progresses into a pustule and then into a crusted pustule. The distribution of the lesions is mainly central. It affects the trunk and the face and spreads rapidly to the rest of the body. New crops of vesicles are generated for 3–7 days from virus colonies in the peripheral blood mononuclear cells. The average number of lesions is 300 (10–1500). Importantly, during the late phase of the incubation period, the virus is transported to the respiratory system, spreading to susceptible contacts, before the characteristic rash appears. Although varicella is a generally benign disease, even uncomplicated cases experience significant discomfort due to itching. Complications are not uncommon and mainly involve secondary skin and soft tissue infections (streptococcal and staphylococcal) and central nervous system involvement including either viral encephalitis or post-infectious cerebellitis [Arvin, 1996]. However, it should be noted that most patients suffering from complications were previously healthy individuals. Moreover, among immunocompetent patients there are not identifiable risk factors for complications [Boelle and Hanslik, 2002; Bonhoeffer et al. 2005; Galil et al. 2002a]. Moreover, varicella infection in immunocompromised patients and healthy adults is associated with increased morbidity and mortality [Arvin, 1996]. Congenital infection can result in fetal varicella syndrome in up to 2% of cases, if the mother develops varicella during weeks 8–20 of gestation. The associated pathology may involve the skin, limbs, central nervous system and eyes. If maternal varicella onset coincides with the perinatal period, neonatal varicella follows which is very severe since no maternal antibodies are produced to be transferred vertically and to protect the newborn. If the infection left untreated, the mortality rate can be high at up to 30% [Enders et al. 1994; Paryani and Arvin, 1986]. VZV infection leads to lifetime immunity against the virus. Both cellular and humoral immunity contribute for the protection against a second infection, but cell-mediated immunity plays the predominant role. Patients with impaired cellular immunity are at greater risk of getting sick with varicella and reactivating VZV as herpes zoster (HZ) [Gershon and Gershon, 2010].
Reactivation of latent VZV infection can cause HZ also known as shingles. HZ is a unilateral vesicular lesion with dermatomal distribution. The most common dermatomes affected are thoracic and lumbar. HZ is more common in adults than children and its clinical manifestations differ between these age groups. In children, unlike adults, local pain, hyperesthesia and pruritus are not common. The lesions are mild and they appear as erythematous maculopapular lesions that rapidly evolve into vesicles. These vesicles coalesce to form bullous formations. The disease lasts up to 15 days and it might take over a month for the skin to completely heal. Common complications of HZ are post-herpetic neuralgia, iridocyclitis, secondary glaucoma, meningoencephalitis and encephalitis [Arvin, 1996]. Aim of the review The best way to prevent varicella infection and effectively decrease the disease and associated economic burden is to provide primary prevention. Following that principle, a live attenuated varicella vaccine has been developed. Universal vaccination was first introduced in the United States in 1995 [ACIP, 1996; Marin et al. 2007]. The same year, the World Health Organization (WHO) adopted the mass vaccination against varicella [WHO, 1998]. Up to now only few countries around the world have implemented universal vaccination namely Australia, Canada, Germany, Qatar, Republic of Korea, Saudi Arabia, Taiwan, Uruguay, Italy (Sicily only) and Spain (Madrid only) [Bonanni et al. 2009]. This is mainly attributable to the preference of many countries’ public health authorities to recommend targeted varicella vaccination of the highrisk population and/or different prioritization with the availability of few new vaccines over the past decade (human papillomavirus [HPV] vaccine, rotavirus vaccine, etc.). Furthermore, concerns have been raised including the fear of increase of HZ incidence, the fear of age shift of the disease towards older age groups, the possible difficulties in achieving high coverage rates and last but not least the economic burden of universal vaccination implementation [Bonanni et al. 2009]. The aim of this review is to discuss the successes achieved by universal varicella vaccination and to address challenges needed to be tackled in the future.
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O Papaloukas, G Giannouli et al. Varicella vaccine The live attenuated varicella vaccine was first developed in Japan by Takahashi [Takahashi et al. 1974]. Initially, the vaccine was solely used to protect high-risk leukemic children [Gershon et al. 1984; Takahashi et al. 1985]. In 1989, the vaccine was first introduced to healthy children in Japan and Korea and in 1995 the US Food and Drug Administration (FDA) approved the vaccine for children aged at least 12 months with a negative varicella history [Hambleton and Gershon, 2005]. There are two available live attenuated virus vaccines, Varilrix (GlaxoSmithKline Biologicals S.A., Rixensart, Belgium) and Varivax (Sanofi Pasteur Limited, Lyon, France). Both vaccines contain the Japanese varicella viral strain, Oka, and are safe and highly immunogenic [Arvin, 1996; Marin et al. 2007]. The adverse effects of the vaccine are few and are benign in nature [Arvin, 1996; Plotkin et al. 1985]. About 20% of the vaccinated population may develop mild pain, redness or swelling in the injection site, while 3–5% of the vaccinated population may present a vesicular rash either at the site of injection or more generalized. Up to 15% of recipients may suffer from fever [Arvin, 1996; Marin et al. 2007; Plotkin et al. 1985]. Serious complications of the vaccine are rarely reported (2.6/100,000 doses) [Chaves et al. 2008; Wagenpfeil et al. 2004]. Transmission of Oka strain varicella from a vaccinated child is a very rare phenomenon, since only 3 cases have been reported after 16 million doses of the vaccine had been administered [Hambleton and Gershon, 2005]. The live attenuated varicella vaccine poses a threat to immunocompromised patients. However, the vaccine can be safely administered to leukemic children under remission and HIVinfected children without severe immunodeficiency [Gershon et al. 1984, 2009]. Rarely, severe generalized varicella infection due to the Oka strain post-immunization has been reported in children vaccinated before the diagnosis of severe immunodeficiency [Chaves et al. 2008; Levin et al. 2003; Levy et al. 2003]. The Oka vaccine strain is capable of causing latent infection and it has been clearly shown that, as wild virus, it remains in the dorsal root ganglia [Chen et al. 2003; Gershon and Gershon, 2010].
Importantly, however, the risk of developing zoster among the vaccinated population is significantly lower when compared with children post-natural varicella [Baxter et al. 2013; Civen et al. 2009; Tseng et al. 2009]. It has been hypothesized that this is due to the lower viral loads induced [Gershon and Gershon, 2010]. Data from pre-licensure clinical trials have indicated that 95% of children develop protective antibodies following one dose of varicella vaccine [Provost et al. 1991]. Based on these studies one dose of varicella vaccine was initially proposed for the vaccination of healthy children 20 years had 6- and 13-fold higher risk, respectively, for hospitalization [Davis et al. 2004; Galil et al. 2002a]. Hospitalization incidence in Europe ranged from 1.3 to 4.5/100,000 varicella cases and was higher in children younger than 16 years old (12.9–28/100,000) [Bonanni et al. 2009]. The average duration of hospitalization ranges between 3 and 8 days. Morbidity and mortality The most common complications that contribute to varicella-associated mortality include pneumonia, central nervous system involvement (encephalitis, meningoencephalitis), secondary bacterial systematic infections (mainly streptococcal and staphylococcal), hemorrhagic conditions and cardiovascular involvement (myocarditis). In the USA, during a period of 25 years (1970–1994) the average number of annual deaths due to varicella was 105 (rate 0.04/100,000) [Meyer et al. 2000]. Increased mortality rates are observed in adults older than 20 years old with a 25-fold higher death risk compared with children 1–4 years old (case-fatality rate: 21.3 and 0.8/100,000
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Downloaded from tav.sagepub.com at St Petersburg State University on January 13, 2014
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O Papaloukas, G Giannouli et al. cases, respectively) [Choo et al. 1995]. In Europe, the overall annual death rate is below 0.05/100,000 cases but again adults have significant higher mortality when compared to children [Boelle and Hanslik, 2002; Bonanni et al. 2009]. In England and Wales the rate is 0.04–0.05/100,000 per year [Rawson et al. 2001], in France 0.04/100,000 per year [Deguen et al. 1998; Dubos et al. 2007], in Germany 0.08/100,000 annually [Ziebold et al. 2001]. VZV vaccine successes Varicella vaccine effectiveness in the USA In the USA, universal varicella vaccination was first implemented in 1995. Initially one dose of varicella vaccine was recommended for all toddlers 12–18 months of age, while catch-up vaccination for all susceptible children
Successes and challenges in varicella vaccine Vassiliki Papaevangelou, Orestis Papaloukas and Georgia Giannouli Therapeutic Advances in Vaccines published online 6 January 2014 DOI: 10.1177/2051013613515621 The online version of this article can be found at: http://tav.sagepub.com/content/early/2013/12/20/2051013613515621
Published by: http://www.sagepublications.com
Additional services and information for Therapeutic Advances in Vaccines can be found at: Email Alerts: http://tav.sagepub.com/cgi/alerts Subscriptions: http://tav.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Jan 6, 2014 What is This?
Downloaded from tav.sagepub.com at St Petersburg State University on January 13, 2014
515621 research-article2013
TAV0010.1177/2051013613515621Therapeutic Advances in VaccinesO. Papaloukas et al.O Papaloukas, G Giannouli
Therapeutic Advances in Vaccines
Review
Successes and challenges in varicella vaccine Orestis Papaloukas, Georgia Giannouli and Vassiliki Papaevangelou
Abstract: Varicella is a highly contagious disease caused by primary infection with varicella zoster virus (VZV). VZV infection, as well as varicella vaccination, induces VZV-specific antibody and T-cell-mediated immunity, essential for recovery. The immune responses developed contribute to protection following re-exposure to VZV. When cell-mediated immunity declines, as occurs with aging or immunosuppression, reactivation of VZV leads to herpes zoster (HZ). It has been almost 20 years since universal varicella vaccination has been implemented in many areas around the globe and has resulted in a significant reduction of varicella-associated disease burden. Successes are reviewed whilst emphasis is put on the challenges ahead. Most countries that have not implemented routine childhood varicella vaccination have chosen to vaccinate high-risk groups alone. The main reasons for not introducing universal vaccination are discussed, including fear of age shift of peak incidence age and of HZ incidence increase. Possible reasons for not observing the predicted increase in HZ incidence are explored. The advantages and disadvantages of universal versus targeted vaccination as well as different vaccination schedules are discussed.
Ther Adv Vaccines (2013) 0(0) 1–17 DOI: 10.1177/ 2051013613515621 © The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Keywords: Varicella vaccination, varicella zoster virus, epidemiology, herpes zoster incidence, VZV-cellular immunity
Introduction Varicella zoster virus Varicella zoster virus (VZV) is an alpha herpesvirus that infects exclusively humans [Hambleton and Gershon, 2005]. Each VZV virion consists of four parts: (1) the core (made of a linear double-stranded DNA); (2) the capsid; (3) the tegument (that surrounds the capsid); and (4) the envelope (that surrounds the tegument and incorporates the major viral glycoproteins [gps]) [Arvin, 1996]. VZV’s virion is spherical with a diameter of 180–200 nm while the core consists of a single linear double-stranded DNA 125 kb long. VZV is the smallest of the human herpes viruses and its envelope is made out of gps of about 8 nm long. During lytic infection the virus produces at least 12 gps which are expressed both on the surface of the virions and the envelope of infected human cells [Gershon and Gershon, 2010]. VZV associated diseases VZV DNA is present in respiratory secretions (upper respiratory) and fluid secretions from skin
vesicles. It is transmitted through direct contact with the skin lesions, through respiratory secretions or through inhalation of the airborne particles of the virus. Primary infection is manifested as varicella (or chickenpox) and leads to lifelong latent infection of sensory ganglion neurons. Reactivation of the latent infection causes HZ (HZ, shingles) [Hambleton and Gershon, 2005]. Varicella (or chickenpox) is a highly contagious disease in children with an estimated household secondary attack rate of 90% [Arvin, 1996; Ross, 1962]. During the incubation period (10–21 days), the virus initially replicates in the upper respiratory tract and through a primary subclinical viremia, the virus spreads to the reticuloendothelial system (liver, spleen) and other organs. Following additional viral replication, a second viremic phase ensues and prodromal clinical symptoms (fever, malaise) appear followed by the eruption of the typical rash. The rash consists of pruritic, maculopapules, vesicles and crusted lesions in varying stages of evolution. They quickly progress from one stage to
Correspondence to: Vassiliki Papaevangelou, MD, MSc, PhD Third Department of Pediatrics, University of Athens Medical School, General University Hospital ‘ATTIKON’, Rimini 1, Chaidari 124 62, Greece [email protected] Orestis Papaloukas, MD, PhD Georgia Giannouli, MD, MSc, PhD Second Department of Pediatrics, University of Athens Medical School, P&A Kyriakou Childrens’ Hospital, Greece
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Therapeutic Advances in Vaccines 0 (0) the next. In the beginning, each skin vesicle develops on an erythematous base, then progresses into a pustule and then into a crusted pustule. The distribution of the lesions is mainly central. It affects the trunk and the face and spreads rapidly to the rest of the body. New crops of vesicles are generated for 3–7 days from virus colonies in the peripheral blood mononuclear cells. The average number of lesions is 300 (10–1500). Importantly, during the late phase of the incubation period, the virus is transported to the respiratory system, spreading to susceptible contacts, before the characteristic rash appears. Although varicella is a generally benign disease, even uncomplicated cases experience significant discomfort due to itching. Complications are not uncommon and mainly involve secondary skin and soft tissue infections (streptococcal and staphylococcal) and central nervous system involvement including either viral encephalitis or post-infectious cerebellitis [Arvin, 1996]. However, it should be noted that most patients suffering from complications were previously healthy individuals. Moreover, among immunocompetent patients there are not identifiable risk factors for complications [Boelle and Hanslik, 2002; Bonhoeffer et al. 2005; Galil et al. 2002a]. Moreover, varicella infection in immunocompromised patients and healthy adults is associated with increased morbidity and mortality [Arvin, 1996]. Congenital infection can result in fetal varicella syndrome in up to 2% of cases, if the mother develops varicella during weeks 8–20 of gestation. The associated pathology may involve the skin, limbs, central nervous system and eyes. If maternal varicella onset coincides with the perinatal period, neonatal varicella follows which is very severe since no maternal antibodies are produced to be transferred vertically and to protect the newborn. If the infection left untreated, the mortality rate can be high at up to 30% [Enders et al. 1994; Paryani and Arvin, 1986]. VZV infection leads to lifetime immunity against the virus. Both cellular and humoral immunity contribute for the protection against a second infection, but cell-mediated immunity plays the predominant role. Patients with impaired cellular immunity are at greater risk of getting sick with varicella and reactivating VZV as herpes zoster (HZ) [Gershon and Gershon, 2010].
Reactivation of latent VZV infection can cause HZ also known as shingles. HZ is a unilateral vesicular lesion with dermatomal distribution. The most common dermatomes affected are thoracic and lumbar. HZ is more common in adults than children and its clinical manifestations differ between these age groups. In children, unlike adults, local pain, hyperesthesia and pruritus are not common. The lesions are mild and they appear as erythematous maculopapular lesions that rapidly evolve into vesicles. These vesicles coalesce to form bullous formations. The disease lasts up to 15 days and it might take over a month for the skin to completely heal. Common complications of HZ are post-herpetic neuralgia, iridocyclitis, secondary glaucoma, meningoencephalitis and encephalitis [Arvin, 1996]. Aim of the review The best way to prevent varicella infection and effectively decrease the disease and associated economic burden is to provide primary prevention. Following that principle, a live attenuated varicella vaccine has been developed. Universal vaccination was first introduced in the United States in 1995 [ACIP, 1996; Marin et al. 2007]. The same year, the World Health Organization (WHO) adopted the mass vaccination against varicella [WHO, 1998]. Up to now only few countries around the world have implemented universal vaccination namely Australia, Canada, Germany, Qatar, Republic of Korea, Saudi Arabia, Taiwan, Uruguay, Italy (Sicily only) and Spain (Madrid only) [Bonanni et al. 2009]. This is mainly attributable to the preference of many countries’ public health authorities to recommend targeted varicella vaccination of the highrisk population and/or different prioritization with the availability of few new vaccines over the past decade (human papillomavirus [HPV] vaccine, rotavirus vaccine, etc.). Furthermore, concerns have been raised including the fear of increase of HZ incidence, the fear of age shift of the disease towards older age groups, the possible difficulties in achieving high coverage rates and last but not least the economic burden of universal vaccination implementation [Bonanni et al. 2009]. The aim of this review is to discuss the successes achieved by universal varicella vaccination and to address challenges needed to be tackled in the future.
2 http://tav.sagepub.com
TAV515621.indd 2
Downloaded from tav.sagepub.com at St Petersburg State University on January 13, 2014
18/12/2013 11:13:27 AM
O Papaloukas, G Giannouli et al. Varicella vaccine The live attenuated varicella vaccine was first developed in Japan by Takahashi [Takahashi et al. 1974]. Initially, the vaccine was solely used to protect high-risk leukemic children [Gershon et al. 1984; Takahashi et al. 1985]. In 1989, the vaccine was first introduced to healthy children in Japan and Korea and in 1995 the US Food and Drug Administration (FDA) approved the vaccine for children aged at least 12 months with a negative varicella history [Hambleton and Gershon, 2005]. There are two available live attenuated virus vaccines, Varilrix (GlaxoSmithKline Biologicals S.A., Rixensart, Belgium) and Varivax (Sanofi Pasteur Limited, Lyon, France). Both vaccines contain the Japanese varicella viral strain, Oka, and are safe and highly immunogenic [Arvin, 1996; Marin et al. 2007]. The adverse effects of the vaccine are few and are benign in nature [Arvin, 1996; Plotkin et al. 1985]. About 20% of the vaccinated population may develop mild pain, redness or swelling in the injection site, while 3–5% of the vaccinated population may present a vesicular rash either at the site of injection or more generalized. Up to 15% of recipients may suffer from fever [Arvin, 1996; Marin et al. 2007; Plotkin et al. 1985]. Serious complications of the vaccine are rarely reported (2.6/100,000 doses) [Chaves et al. 2008; Wagenpfeil et al. 2004]. Transmission of Oka strain varicella from a vaccinated child is a very rare phenomenon, since only 3 cases have been reported after 16 million doses of the vaccine had been administered [Hambleton and Gershon, 2005]. The live attenuated varicella vaccine poses a threat to immunocompromised patients. However, the vaccine can be safely administered to leukemic children under remission and HIVinfected children without severe immunodeficiency [Gershon et al. 1984, 2009]. Rarely, severe generalized varicella infection due to the Oka strain post-immunization has been reported in children vaccinated before the diagnosis of severe immunodeficiency [Chaves et al. 2008; Levin et al. 2003; Levy et al. 2003]. The Oka vaccine strain is capable of causing latent infection and it has been clearly shown that, as wild virus, it remains in the dorsal root ganglia [Chen et al. 2003; Gershon and Gershon, 2010].
Importantly, however, the risk of developing zoster among the vaccinated population is significantly lower when compared with children post-natural varicella [Baxter et al. 2013; Civen et al. 2009; Tseng et al. 2009]. It has been hypothesized that this is due to the lower viral loads induced [Gershon and Gershon, 2010]. Data from pre-licensure clinical trials have indicated that 95% of children develop protective antibodies following one dose of varicella vaccine [Provost et al. 1991]. Based on these studies one dose of varicella vaccine was initially proposed for the vaccination of healthy children 20 years had 6- and 13-fold higher risk, respectively, for hospitalization [Davis et al. 2004; Galil et al. 2002a]. Hospitalization incidence in Europe ranged from 1.3 to 4.5/100,000 varicella cases and was higher in children younger than 16 years old (12.9–28/100,000) [Bonanni et al. 2009]. The average duration of hospitalization ranges between 3 and 8 days. Morbidity and mortality The most common complications that contribute to varicella-associated mortality include pneumonia, central nervous system involvement (encephalitis, meningoencephalitis), secondary bacterial systematic infections (mainly streptococcal and staphylococcal), hemorrhagic conditions and cardiovascular involvement (myocarditis). In the USA, during a period of 25 years (1970–1994) the average number of annual deaths due to varicella was 105 (rate 0.04/100,000) [Meyer et al. 2000]. Increased mortality rates are observed in adults older than 20 years old with a 25-fold higher death risk compared with children 1–4 years old (case-fatality rate: 21.3 and 0.8/100,000
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TAV515621.indd 4
Downloaded from tav.sagepub.com at St Petersburg State University on January 13, 2014
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O Papaloukas, G Giannouli et al. cases, respectively) [Choo et al. 1995]. In Europe, the overall annual death rate is below 0.05/100,000 cases but again adults have significant higher mortality when compared to children [Boelle and Hanslik, 2002; Bonanni et al. 2009]. In England and Wales the rate is 0.04–0.05/100,000 per year [Rawson et al. 2001], in France 0.04/100,000 per year [Deguen et al. 1998; Dubos et al. 2007], in Germany 0.08/100,000 annually [Ziebold et al. 2001]. VZV vaccine successes Varicella vaccine effectiveness in the USA In the USA, universal varicella vaccination was first implemented in 1995. Initially one dose of varicella vaccine was recommended for all toddlers 12–18 months of age, while catch-up vaccination for all susceptible children
