- Email: [email protected]
New vaccines for children
Symposium: immunity and infection
New vaccines for children
doses of meningococcus group C vaccine followed by a second year combined conjugate booster vaccine (Menitorix) for Haemophilus influenzae type b (Hib) and meningococcus group C, a three dose schedule (two priming, one second year booster) of the pneumococcal conjugate vaccine (Prevenar) was added in September 2006. A ‘catch-up programme’ was also launched in September 2007 whereby a Hib booster is offered to young children who have not previously received one, so that these children are protected in line with older and younger children. These additions highlight the importance of surveillance of vaccine effectiveness following implementation as they were prompted by evidence that immunity conferred by immunisation in early infancy waned by the second year of life1,2 and in response to an observed rise in the number of cases of invasive Hib disease. Such changes contribute to the increasing complexity of the standard schedule; an extra visit is required at age 12 months, the vaccines administered are no longer the same at each of the first three visits and the infant receives three simultaneous injections at the third visit. Although most parents ensure that their children are fully immunised according to current recommendations, anxieties provoked by scare stories about specific vaccines or immunisation in general can be important since even modest reductions in uptake may impact on ‘herd immunity’.
Hannah G Cottis Adam Finn
Abstract Significant changes have recently been made to the UK childhood immunisation schedule to introduce protection against pneumococcal disease and improve protection against Haemophilus influenzae type b and meningococcus group C. From September 2008, a new primary immunisation programme against cervical cancer will be introduced for adolescent girls. In the future, we may see the introduction of licensed rotavirus vaccines against infant gastroenteritis and broader use of varicella, influenza and hepatitis B vaccines. Higher valency meningococcal conjugate vaccines, vaccines against meningococcus group B disease and vaccines against respiratory viruses are available, approaching licensure or in clinical trials in children in the UK.
New vaccines
Keywords hepatitis B; human papillomavirus; immunisation schedule;
Human papillomavirus Cervical cancer is one of the leading causes of cancer mortality in women worldwide and is virtually always caused by persistent infection with oncogenic human papillomaviruses (HPVs).3 This causal role has driven research into primary prevention by vaccination, initially against the two HPV types, 16 and 18, which are most commonly associated with the disease (around 70% of cases).4 Vaccines against types 6 and 11, which cause 90% of anogenital warts,5 have also been developed. The vaccines consist of self-assembling virus-like particles made of recombinant major capsid protein L1. Adjuvanted preparations of these ‘empty’ viral capsids are highly immunogenic when administered intramuscularly. Virus-like particle vaccines based on HPV-16 alone,6 HPV-16/187 and HPV-6/11/16/188 have been shown in phase II trials to prevent greater than 90% (and in some case approaching 100%) of incident and persistent infections and their associated precursors of cancer. No serious adverse outcomes following immunisation have been attributed to the vaccines. Phase III trials have demonstrated the efficacy of vaccination in preventing HPV-16 and HPV-18 related cervical intraepithelial neoplasia grade 2 or 3,9,10 used as a surrogate marker for cervical cancer. There are two vaccines currently licensed and on the market in Europe. Cervarix, a bivalent vaccine targeting only those strains of HPV (16 and 18) associated with the development of cervical cancer; and Gardasil, a quadravalent vaccine active against HPV-6, 11, 16 and 18 (therefore, providing additional protection against anogenital warts). Both require three intramuscular doses to be given over the course of a 6-month period. An independent cost-benefit review conducted by the UK Department of Health has led to the implementation of a schools-based vaccination programme from September 2008 using Cervarix. Preliminary results11 showed that routine vaccination of girls with
influenza; meningococcal conjugate vaccines; rotavirus vaccine; varicella zoster
Introduction Vaccines have been widely hailed as one of the most important developments in medicine in the 20th century. In many cases they are either the most or the only effective way of controlling infectious diseases. Efforts are being focused on novel and less invasive approaches to delivery and at minimising any adverse effects – a requirement rendered more urgent by rising public concern about vaccine safety in the context of a growing number of vaccines under development. Today, the process of introducing a new vaccine involves enormous effort in assembling adequate evidence of safety and efficacy, detailed investigation into cost benefit and a clear case to be communicated to parents or recipients that they should accept it for their children or themselves.
Recent changes to the UK childhood immunisation schedule The UK childhood immunisation schedule has seen a number of recent modifications. Along with a reduction to two priming
Hannah G Cottis BSc(Hons) BMBCh MRCPCH is a Specialist Registrar in Paediatrics at the Bristol Royal Hospital for Children, Bristol, UK. Adam Finn PhD FRCP FRCPCH is a David Baum Professor of Paediatrics, University of Bristol, Dept Clinical Science at South Bristol, UHBNFT Education Centre, Bristol, UK.
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Symposium: immunity and infection
In 1998, the first vaccine against rotavirus, RotaShield, was promptly introduced for routine childhood immunisation in the United States. Progress was halted and the vaccine withdrawn when unexpectedly high numbers of cases of intussusception following immunisation were reported. After this set back, research efforts were renewed and large phase III trials (powered to detect small numbers of cases of intussusception if they occurred) of two new rotavirus vaccines, Rotateq (Merck) and Rotarix (GlaxoSmithKline) were published in 2006.18,19 Both are intended for administration to infants with other primary schedule vaccines but were developed using very different approaches. Rotarix is a monovalent vaccine derived from the most common human strain, P[8]G1, attenuated in cell culture and relies on shared epitopes with other strains to induce cross-protective immunity. Rotateq is a pentavalent vaccine derived from bovine strains that induce immunity to the most common human antigenic types. Discriminating between the two vaccines is difficult as they have not been compared directly and different populations were studied. However, both have demonstrated reductions in the number of cases of symptomatic rotavirus diarrhoea (most marked for more severe illness) and related hospitalisations18,19 and have good safety profiles to date. Recruiting more than 60,000 infants each, neither trial identified different rates of intussusception between vaccine and placebo recipients. Although the vaccines are already in widespread use in Latin America (Rotarix) and the US (Rotateq), there are additional clinical and financial issues to be addressed before rotavirus vaccination can be introduced globally. The greater diversity of viral strains combined with differing host factors (particularly human immunodeficiency virus infection) in some developing countries may affect vaccine efficacy. Trials of rotavirus vaccine have commenced in South Africa and Malawi to address these issues.20
a HPV vaccine before the age of 14 years would be cost-effective at 80% vaccine coverage and assuming the average duration of vaccine protection is at least 10 years. It was also cost-effective to vaccinate girls as part of a catch-up programme up to their 18th birthday. An effective programme will need to consider the age at which the vaccine is to be given and the cultural and social issues that may arise concerning informed consent from both girls and parents for a vaccine that protects against a sexually transmitted infection. Many further issues need to be resolved following the introduction of immunisation against HPV.12 The duration of protection provided by the vaccines is not known as published studies have followed women for only around 5 years to date. Booster doses may yet be required and the present vaccines are not expected to be effective in women already persistently infected with vaccine virus types. Continued compliance with the highly effective UK national cervical screening programme is vital for the foreseeable future as the immunisation programme will take some time to have any impact and will provide, at best, modest cross-protection against virus types not contained in the vaccine. In countries like the UK where screening has been done effectively, the scenario could exist in which, if immunisation creates false complacency or diversion of funding and undermines secondary prevention, the net effect could be a rise in cervical cancer deaths in coming years unless the two programmes are effectively managed in concert. Rotavirus Rotavirus is the most common cause of severe diarrhoea in children worldwide and infects nearly all children in the UK by the age of 5 years. The winter epidemic of rotavirus experienced in countries with temperate climates places a heavy burden on primary and secondary care.13 Globally, the World Health Organization (WHO) estimates that rotavirus remains responsible for approximately 520,000 deaths in children under 5 years of age annually.14 The development and swift introduction of effective immunisation against rotavirus into global immunisation programmes has, therefore, held a high priority with international health agencies including WHO. Rotaviruses are double-stranded RNA viruses. Their core of 11 segments of RNA is covered by an inner and outer capsid. Two of the proteins found on the outer capsid – VP-7 (a glycoprotein) and VP-4 (a protease cleaved protein) – are used to classify different strains by their P and G genotypes respectively. Both possess antigenic regions that stimulate both serotype-specific and cross-reactive antibodies and can contribute to naturally and vaccine-induced protective immunity. Eleven P genotypes and 10 G genotypes have been implicated in human gastroenteritis. The five most common strains detected (P[8]G1, P[4]G2, P[8]G3, P[8]G4 and P[8]G9) have become the main targets for vaccine development.15 Studies following the natural history of rotavirus infections have demonstrated protective immunity induced by infection early in life. A single rotavirus infection protects 38% of children against further infection and 87% against severe disease.16 The precise mechanism of immune protection remains unclear although local mucosal immunity is thought to be key.17 Three distinct oral live-attenuated vaccines have been developed that confer protection by mimicking early infection and naturally acquired immunity.
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Varicella zoster Chickenpox (varicella) is caused by the herpes virus, varicella zoster. In temperate climates, the disease incidence is approximately 13–16 cases per 1000 people per year and 90% of people have chicken pox before adolescence.21 The illness is now most common in children aged 1–4 years of age, a downward shift that is thought to be due to increased attendance at preschool groups.22 Although an uncomplicated illness in many, chickenpox can carry significant morbidity, with higher risk among those who are immunocompromised, pregnant, newborn or those who have their primary infection as adults. However, recent literature has documented prospectively the complications of varicella in hospitalised children in the UK over a 13-month period.23 Most cases of fatal and severe varicella were in immunocompetent children over the age of 12 months. Such cases could not, therefore, have been prevented by selective immunisation but only by a universal immunisation programme. Two preparations of a live attenuated varicella vaccine strain (‘OKA’) are licensed and available in the UK (Varivax and Valirix). They are currently only recommended24 for use in ‘atrisk’ groups such as non-immune healthcare workers. This selective approach contrasts with that of the US, Canada, Australia and Germany where universal childhood immunisation has been recommended. Post-licensure surveillance in the US25 showed a decline in cases by between 71% and 84% with the greatest 492
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Symposium: immunity and infection
include A, Y, W-135, 29E and Z.24 Initial vaccines, based on capsular polysaccharide, were developed in response to disease outbreaks. They provided only short-term protection to older children and adults but not infants. In 1999, universal infant MenC conjugate immunisation was introduced in the UK. Additionally, all children and young people up to the age of 23 years were offered conjugate vaccine in a large catch-up programme over a 2-year period. Surveillance data following this campaign has demonstrated successful control of the disease,2 not only through direct protection but also as a result of substantial herd immunity,35 achieved through reduction in carriage rates of serogroup C meningococci.36 Evidence demonstrating that protection induced by immunisation in infancy does not extend beyond the first year of life2 led to the modification of the schedule to include a booster dose at 12 months of age. Development of multivalent meningococcal vaccines is the next logical step. Menactra – a tetravalent conjugate vaccine composed of the capsular polysaccharides of groups A, C, Y, and W-135 – was licensed in the US in 2005 and is recommended there for use in teenagers. Endemic disease rates are lower in the US but a higher proportion is caused by group Y. However, the vaccine is poorly immunogenic in infants, the age in which meningococcal disease is most common. Another tetravalent (Novartis) A, C, Y, W-135, CRM 197 conjugate vaccine, which appears to be immunogenic in younger children,37 is approaching licensure in Europe. Given that nearly all residual meningococcal disease in the UK is caused by group B, the role for these vaccines within the UK schedule may only be for travellers and high-risk individuals.
decline seen in children aged 1–4 years. The fall in disease burden in both children and (unvaccinated) adults indicates a reduction in transmission and that substantial herd immunity has been achieved. Rates of hospital admission have also declined and age-adjusted mortality rates have fallen by 66%.26 Again, the greatest reduction in mortality (92%) was among children aged 1–4 years. Reactivation of the varicella zoster virus causes herpes zoster (shingles) – a painful vesicular rash. A vaccine programme has the potential to change the epidemiology of herpes zoster as well as varicella. In the longer term, the incidence should fall in an immunised population. Initially, however, there are theoretical concerns that the fall in exposure of adults to chickenpox would prevent boosting of virus-specific cell-mediated immune responses, resulting in an increase in the incidence of shingles. This has not been observed consistently in recent US literature,27 although it could be too soon to observe any such rise. In any case, universal vaccination of the over 60s against herpes zoster was recommended in the US in 2006.28 Two combination vaccines against measles, mumps, rubella and varicella (MMRV) have recently been licensed. ProQuad (Merck) was granted a license in the US in 2005 and in the European Union in April 2006. The vaccine contains a higher titre of attenuated varicella zoster virus than the single antigen preparations and the same amount of measles, mumps and rubella vaccine viruses as the MMR.21 A second MMRV vaccine – Priorix-Tetra (Glaxo) – was licensed in Germany and Australia in 2006. For both vaccines, seroconversion rates are 98% for their components after two doses of MMRV.29,30 A recent observation of higher incidence of uncomplicated febrile convulsions following MMRV vaccination has led to a US policy change so that there is no longer an expressed preference for MMRV over vaccination with MMR and single antigen varicella.31 Introduction of universal varicella immunisation is currently under consideration in the UK. A combination MMRV vaccine might simplify the implementation and increase the cost benefit of a childhood varicella vaccination programme but public acceptability may be an issue in the context of residual anxieties following the unfounded MMR-autism scare. While the process of rebuilding public confidence goes on, a temporary strategy could be implemented, extending selective immunisation to susceptible teenagers to prevent cases of severe disease in adults and generate positive publicity for primary prevention of varicella infection.32
Vaccines in the wings Influenza vaccine Annual epidemics of influenza virus infection occur each winter. Infection produces a varying clinical picture – from a mild respiratory tract illness to a severe bronchiolitis. Morbidity is highest in the elderly, those with chronic disease and in young children. Hence the current rationale for offering annual targeted paediatric immunisation with trivalent inactivated vaccine in the UK,24 although there is a general lack of direct evidence that this results in significant prevention. This contrasts with US recommendations to immunise all healthy children aged 6 months to 18 years.38 Although safety in children aged 6–23 months was recently confirmed in a large retrospective study,39 the efficacy of the vaccine in under 2-yearolds is uncertain.40 A live attenuated intranasal vaccine – ‘Flumist’ – is also widely used in the US programme in children aged 2 years and older38 and has been shown to have higher efficacy.41 It is possible that immunisation of young children could result in significant herd immunity and indirect protection of elderly people in whom mortality is highest.42 Definitive controlled studies demonstrating the efficacy of available influenza vaccines in young children are urgently needed to provide a sound evidence base for future recommendations. In addition, effective affordable strategies for reliable annual delivery of vaccine to this age group would need to be developed for any such programme to work.
Meningococcus groups A, C, Y and W-135 conjugate vaccines Neisseria meningitidis remains one of the leading causes of meningitis and septicaemia. The incidence of meningococcal disease is highest in children aged 0–9 years and overall mortality remains around 10% in the UK.33 The longer term morbidity is also high with 10–20% of survivors suffering complications, such as limb amputation, hearing loss and neurological damage.34 Although morbidity and mortality statistics have been improved by advances in treatment and education campaigns, the only way to eliminate the disease completely is by primary prevention through immunisation. N. meningitidis has at least 13 different serogroups, of which B and C were the most common in the UK prior to universal immunisation against group C. Other less frequent subgroups
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concerned with the health of children so that the choices made are the right ones. ◆
Hepatitis B Hepatitis B (HBV) is largely sexually transmitted. New infection and acute disease rates are highest in adults. Chronic infection is more likely in those infected either as infants or children and it is these patients that act as the main reservoir for continued HBV transmission and are at risk of hepatocellular carcinoma and cirrhosis. The current UK policy for selective hepatitis B immunisation contrasts with the WHO recommendation for universal vaccine use and has given rise to considerable recent debate.43,44 Combined DTaP/IPV/Hib/HepB vaccine is licensed and in use in other European countries and could, in principle, replace the ‘5-in-1’ vaccine currently used in the infant programme, although selective immunisation of perinatally exposed infants at birth would continue to be necessary. Adolescent immunisation, possibly in conjunction with the forthcoming programme for HPV, could also be considered either as an alternative or as a measure to accelerate the impact of a new programme during the 15 years between introduction and when immunised infants would reach the age at which transmission becomes a significant risk.
References 1 Trotter CL, Ramsay ME, Slack MPE. Rising incidence of Haemophillus influenzae type b disease in England and Wales indicates a need for a second catch-up vaccination campaign. Commun Dis Public Health 6: 517–519. 2 Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay M. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 2004; 364: 365–367. 3 Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, WHO International Agency for Research on Cancer. Carcinogenicity of human papillomaviruses. Lancet Oncol 2005; 6: 204. 4 Nubia Muñoz MD, Xavier Bosch F, Silvia de Sanjosé MD, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348: 518–527. 5 Von Krogh G. Management of anogenital warts. Eur J Dermatol 2001; 11: 598–604. 6 Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002; 347: 1645–51. 7 Harper DM, Franco EL, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004; 364: 1757–1765. 8 Villa LL, Costa R, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005; 6: 271–278. 9 The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356: 1915–1927. 10 Paavonen J, Jenkins D, Bosch X, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007; 369: 2161–2171. 11 Joint Committee on Vaccination and Immunisation. Influenza subgroup. Minutes of the Meeting held on Wednesday 17 October 2007. Available from: http://www.advisorybodies.doh.gov.uk/jcvi/ mins17Oct07.htm, (accessed 28.07.08). 12 Raffle EA. Challenges of implementing human papillomavirus (HPV) vaccination policy. BMJ 2007; 335: 375–377. 13 Soriano-Gabarro M, Mrukowicz J, Vesikari T, Verstraeten T. Burden of rotavirus disease in European Union countries. Pediatr Infect Dis J 2006; 25(Suppl): 7–11. 14 World Health Organization. Estimated rotavirus deaths for children under 5 years of age. Available from: http://www.who.int/ immunization_monitoring/burden/rotavirus_estimates/en/index.htm, 2004 (accessed: 28.07.08). 15 Santos N, Hoshino Y. Global distribution of rotavirus serotypes/ genotypes and its implication for the development and implementation of an effective rotavirus vaccine. Rev Med Virol 2005; 15: 29–56. 16 Velazquez FR, Matson DO, Calva JJ, et al. Rotavirus infection in infants as protection against subsequent infections. N Engl J Med 1996; 335: 1022–1028.
Respiratory syncytial virus Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and children worldwide but development of a successful vaccine has so far been elusive for three main reasons.45 Natural infection with RSV does not appear to produce immunity to re-infection, a phenomenon that remains poorly understood. RSV infection in children immunised with an early candidate (formalin-inactivated) vaccine induced enhanced disease, which was accompanied by a damaging inflammatory response. Finally, the optimum time to immunise would be in early infancy but maternal antibodies may interfere with the generation of a lasting immune response. Efforts to establish a successful vaccine will rely on tackling these issues. Meningococcus B Several vaccine candidates for prevention of meningococcus group B disease, against which the conjugated polysaccharide vaccine approach is thought by most authorities to be inappropriate, are under investigation. It is hard to predict how soon one or other of these will become available for use and it seems possible that many of the candidates may deliver, at best, protection against some but not all group B strains. Promising early results from one vaccine were recently presented46 and this vaccine is currently entering larger phase II studies in infants.
Conclusion Paediatric immunisation is developing and changing at an accelerating rate. As opportunities for primary prevention of disease grow, the field becomes more complex and the information and choices confronting policy makers, health professionals and parents become more bewildering. Future challenges will include maintaining a manageable schedule through development of easily administered combined formulations and ensuring that clear and accurate information is effectively communicated to all those
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32 Sengupta N, Booy R, Schmitt HJ, et al. Varicella vaccination in Europe: are we ready for a universal childhood program? Eur J Pediatr 2008; 167: 47–55. 33 Goldacre MJ, Roberts SE, Yeates D. Case fatality rates for meningococcal disease in an English population, 1963–98: database study. BMJ 2003; 327: 596–597. 34 Erickson L, De Wals P. Complications and sequelae of meningococcal disease in Quebec, Canada, 1990–1994. Clin Infect Dis 1998; 26: 1159–1164. 35 Ramsay M, Andrews NJ, Trotter CL, Kaczmarski EB, Miller E. Herd immunity from meningococcal serogroup C conjugate vaccination in England: database analysis. BMJ 2003; 326: 365–366. 36 Maiden MCJ, Stuart JM. Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination. Lancet 2002; 359: 1829–1831. 37 Snape M, Perrett KP, Ford K, et al. Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants. J Am Med Assoc 2008; 299: 173–184. 38 Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2008. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/ rr57e717a1.htm?s_cid=rr57e717a1_e (accessed 28.07.08). 39 Hambridge S, Glanz J, France E, et al. Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old. J Am Med Assoc 2006; 296: 1990–1997. 40 Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2008(2): CD004879. 41 Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007; 356: 729–731. 42 Heikkinen T, Booy R, Campins M, et al. Should healthy children be vaccinated against influenza? A consensus report of the Summits of Independent European Vaccination Experts.Eur J Pediatr 2006; 165: 223–228. 43 English P. Should universal hepatitis B immunisation be introduced in the UK? Arch Dis Child 2006; 91: 286–289. 44 Pollard AJ. Hepatitis B vaccination. BMJ 2007; 335: 950. 45 Bush A, Thomson AH. Acute bronchiolitis. BMJ 2007; 335: 1037–1041. 46 Borrrow R. Advances in the MenB vaccine development: an update. Novartis vaccine. 26th Annual Meeting of the European Society of Paediatric Infectious Diseases. Graz, Austria. 13–17 May 2008. Available from: http://www.kenes.com/espid2008/program_symposia/.
17 Glass R, Parashar UD, Bresee JS, et al. Rotavirus vaccines: current prospects and future challenges. Lancet 2006; 368: 323–333. 18 Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortment rotavirus vaccine. N Engl J Med 2006; 354: 23–34. 19 Ruiz-Palacios G, Pérez-Schael I, Raúl Velázquez F, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354: 11–22. 20 Glass R, Parashar U. The promise of new rotavirus vaccines. N Engl J Med 2006; 354: 75–77. 21 Heininger U, Seward JF. Varicella. Lancet 2006; 368: 1365–1376. 22 Bramley JC, Jones IG. Epidemiology of chickenpox in Scotland 1981–1998. Commun Dis Public Health 2001; 3: 282–287. 23 Cameron JC, Allan G, Johnston F, Finn A, Heath PT, Booy R. Severe complications of chickenpox in hospitalised children in the UK and Ireland. Arch Dis Child 2007; 92: 1062–1066. 24 Salisbury D, Ramsay M, Noakes K. Immunisation against infectious disease ‘The Green Book’, London: Department of Health, 2006. 25 Seward JF, Watson BM, Peterson CL, et al. Varicella disease after introduction of varicella vaccine in the United States, 1995–2000. J Am Med Assoc 2002; 287: 606–611. 26 Nguyen HQ, Jumaan AO, Seward JF. Decline in mortality due to varicella after implementation of varicella vaccination in the United States. N Engl J Med 2005; 352: 450. 27 Jumaan AO, Yu O, Jackson LA, Bohlke K, Galil K, Seward JF. Incidence of herpes zoster, before and after varicella-vaccination-associated incidence decreases in the incidence of varicella, 1992–2002. J Infect Dis 2005; 191: 2002–2007. 28 Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2008. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/ rr57e0515a1.htm (accessed 28.07.08). 29 Shinefield H, Black S, Digilio L, et al. Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr Infect Dis J 2005; 24: 665–669. 30 Knuf M, Habermehl P, Zepp F, et al. Immunogenicity and safety of two doses of tetravalent measles-mumps-rubella-varicella vaccine in healthy children. Pediatr Infect Dis J 2006; 25: 12–18. 31 Dickinson C. ACIP approves MMRV vaccine revision. Possible increased risk for febrile seizures found among children aged 12 to 23 months after receipt of MMRV vaccine. Infectious Diseases in Children April 2008. Available from: http://idinchildren.com/200804/ mmrv.asp (accessed 28.07.08).
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doses of meningococcus group C vaccine followed by a second year combined conjugate booster vaccine (Menitorix) for Haemophilus influenzae type b (Hib) and meningococcus group C, a three dose schedule (two priming, one second year booster) of the pneumococcal conjugate vaccine (Prevenar) was added in September 2006. A ‘catch-up programme’ was also launched in September 2007 whereby a Hib booster is offered to young children who have not previously received one, so that these children are protected in line with older and younger children. These additions highlight the importance of surveillance of vaccine effectiveness following implementation as they were prompted by evidence that immunity conferred by immunisation in early infancy waned by the second year of life1,2 and in response to an observed rise in the number of cases of invasive Hib disease. Such changes contribute to the increasing complexity of the standard schedule; an extra visit is required at age 12 months, the vaccines administered are no longer the same at each of the first three visits and the infant receives three simultaneous injections at the third visit. Although most parents ensure that their children are fully immunised according to current recommendations, anxieties provoked by scare stories about specific vaccines or immunisation in general can be important since even modest reductions in uptake may impact on ‘herd immunity’.
Hannah G Cottis Adam Finn
Abstract Significant changes have recently been made to the UK childhood immunisation schedule to introduce protection against pneumococcal disease and improve protection against Haemophilus influenzae type b and meningococcus group C. From September 2008, a new primary immunisation programme against cervical cancer will be introduced for adolescent girls. In the future, we may see the introduction of licensed rotavirus vaccines against infant gastroenteritis and broader use of varicella, influenza and hepatitis B vaccines. Higher valency meningococcal conjugate vaccines, vaccines against meningococcus group B disease and vaccines against respiratory viruses are available, approaching licensure or in clinical trials in children in the UK.
New vaccines
Keywords hepatitis B; human papillomavirus; immunisation schedule;
Human papillomavirus Cervical cancer is one of the leading causes of cancer mortality in women worldwide and is virtually always caused by persistent infection with oncogenic human papillomaviruses (HPVs).3 This causal role has driven research into primary prevention by vaccination, initially against the two HPV types, 16 and 18, which are most commonly associated with the disease (around 70% of cases).4 Vaccines against types 6 and 11, which cause 90% of anogenital warts,5 have also been developed. The vaccines consist of self-assembling virus-like particles made of recombinant major capsid protein L1. Adjuvanted preparations of these ‘empty’ viral capsids are highly immunogenic when administered intramuscularly. Virus-like particle vaccines based on HPV-16 alone,6 HPV-16/187 and HPV-6/11/16/188 have been shown in phase II trials to prevent greater than 90% (and in some case approaching 100%) of incident and persistent infections and their associated precursors of cancer. No serious adverse outcomes following immunisation have been attributed to the vaccines. Phase III trials have demonstrated the efficacy of vaccination in preventing HPV-16 and HPV-18 related cervical intraepithelial neoplasia grade 2 or 3,9,10 used as a surrogate marker for cervical cancer. There are two vaccines currently licensed and on the market in Europe. Cervarix, a bivalent vaccine targeting only those strains of HPV (16 and 18) associated with the development of cervical cancer; and Gardasil, a quadravalent vaccine active against HPV-6, 11, 16 and 18 (therefore, providing additional protection against anogenital warts). Both require three intramuscular doses to be given over the course of a 6-month period. An independent cost-benefit review conducted by the UK Department of Health has led to the implementation of a schools-based vaccination programme from September 2008 using Cervarix. Preliminary results11 showed that routine vaccination of girls with
influenza; meningococcal conjugate vaccines; rotavirus vaccine; varicella zoster
Introduction Vaccines have been widely hailed as one of the most important developments in medicine in the 20th century. In many cases they are either the most or the only effective way of controlling infectious diseases. Efforts are being focused on novel and less invasive approaches to delivery and at minimising any adverse effects – a requirement rendered more urgent by rising public concern about vaccine safety in the context of a growing number of vaccines under development. Today, the process of introducing a new vaccine involves enormous effort in assembling adequate evidence of safety and efficacy, detailed investigation into cost benefit and a clear case to be communicated to parents or recipients that they should accept it for their children or themselves.
Recent changes to the UK childhood immunisation schedule The UK childhood immunisation schedule has seen a number of recent modifications. Along with a reduction to two priming
Hannah G Cottis BSc(Hons) BMBCh MRCPCH is a Specialist Registrar in Paediatrics at the Bristol Royal Hospital for Children, Bristol, UK. Adam Finn PhD FRCP FRCPCH is a David Baum Professor of Paediatrics, University of Bristol, Dept Clinical Science at South Bristol, UHBNFT Education Centre, Bristol, UK.
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Symposium: immunity and infection
In 1998, the first vaccine against rotavirus, RotaShield, was promptly introduced for routine childhood immunisation in the United States. Progress was halted and the vaccine withdrawn when unexpectedly high numbers of cases of intussusception following immunisation were reported. After this set back, research efforts were renewed and large phase III trials (powered to detect small numbers of cases of intussusception if they occurred) of two new rotavirus vaccines, Rotateq (Merck) and Rotarix (GlaxoSmithKline) were published in 2006.18,19 Both are intended for administration to infants with other primary schedule vaccines but were developed using very different approaches. Rotarix is a monovalent vaccine derived from the most common human strain, P[8]G1, attenuated in cell culture and relies on shared epitopes with other strains to induce cross-protective immunity. Rotateq is a pentavalent vaccine derived from bovine strains that induce immunity to the most common human antigenic types. Discriminating between the two vaccines is difficult as they have not been compared directly and different populations were studied. However, both have demonstrated reductions in the number of cases of symptomatic rotavirus diarrhoea (most marked for more severe illness) and related hospitalisations18,19 and have good safety profiles to date. Recruiting more than 60,000 infants each, neither trial identified different rates of intussusception between vaccine and placebo recipients. Although the vaccines are already in widespread use in Latin America (Rotarix) and the US (Rotateq), there are additional clinical and financial issues to be addressed before rotavirus vaccination can be introduced globally. The greater diversity of viral strains combined with differing host factors (particularly human immunodeficiency virus infection) in some developing countries may affect vaccine efficacy. Trials of rotavirus vaccine have commenced in South Africa and Malawi to address these issues.20
a HPV vaccine before the age of 14 years would be cost-effective at 80% vaccine coverage and assuming the average duration of vaccine protection is at least 10 years. It was also cost-effective to vaccinate girls as part of a catch-up programme up to their 18th birthday. An effective programme will need to consider the age at which the vaccine is to be given and the cultural and social issues that may arise concerning informed consent from both girls and parents for a vaccine that protects against a sexually transmitted infection. Many further issues need to be resolved following the introduction of immunisation against HPV.12 The duration of protection provided by the vaccines is not known as published studies have followed women for only around 5 years to date. Booster doses may yet be required and the present vaccines are not expected to be effective in women already persistently infected with vaccine virus types. Continued compliance with the highly effective UK national cervical screening programme is vital for the foreseeable future as the immunisation programme will take some time to have any impact and will provide, at best, modest cross-protection against virus types not contained in the vaccine. In countries like the UK where screening has been done effectively, the scenario could exist in which, if immunisation creates false complacency or diversion of funding and undermines secondary prevention, the net effect could be a rise in cervical cancer deaths in coming years unless the two programmes are effectively managed in concert. Rotavirus Rotavirus is the most common cause of severe diarrhoea in children worldwide and infects nearly all children in the UK by the age of 5 years. The winter epidemic of rotavirus experienced in countries with temperate climates places a heavy burden on primary and secondary care.13 Globally, the World Health Organization (WHO) estimates that rotavirus remains responsible for approximately 520,000 deaths in children under 5 years of age annually.14 The development and swift introduction of effective immunisation against rotavirus into global immunisation programmes has, therefore, held a high priority with international health agencies including WHO. Rotaviruses are double-stranded RNA viruses. Their core of 11 segments of RNA is covered by an inner and outer capsid. Two of the proteins found on the outer capsid – VP-7 (a glycoprotein) and VP-4 (a protease cleaved protein) – are used to classify different strains by their P and G genotypes respectively. Both possess antigenic regions that stimulate both serotype-specific and cross-reactive antibodies and can contribute to naturally and vaccine-induced protective immunity. Eleven P genotypes and 10 G genotypes have been implicated in human gastroenteritis. The five most common strains detected (P[8]G1, P[4]G2, P[8]G3, P[8]G4 and P[8]G9) have become the main targets for vaccine development.15 Studies following the natural history of rotavirus infections have demonstrated protective immunity induced by infection early in life. A single rotavirus infection protects 38% of children against further infection and 87% against severe disease.16 The precise mechanism of immune protection remains unclear although local mucosal immunity is thought to be key.17 Three distinct oral live-attenuated vaccines have been developed that confer protection by mimicking early infection and naturally acquired immunity.
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Varicella zoster Chickenpox (varicella) is caused by the herpes virus, varicella zoster. In temperate climates, the disease incidence is approximately 13–16 cases per 1000 people per year and 90% of people have chicken pox before adolescence.21 The illness is now most common in children aged 1–4 years of age, a downward shift that is thought to be due to increased attendance at preschool groups.22 Although an uncomplicated illness in many, chickenpox can carry significant morbidity, with higher risk among those who are immunocompromised, pregnant, newborn or those who have their primary infection as adults. However, recent literature has documented prospectively the complications of varicella in hospitalised children in the UK over a 13-month period.23 Most cases of fatal and severe varicella were in immunocompetent children over the age of 12 months. Such cases could not, therefore, have been prevented by selective immunisation but only by a universal immunisation programme. Two preparations of a live attenuated varicella vaccine strain (‘OKA’) are licensed and available in the UK (Varivax and Valirix). They are currently only recommended24 for use in ‘atrisk’ groups such as non-immune healthcare workers. This selective approach contrasts with that of the US, Canada, Australia and Germany where universal childhood immunisation has been recommended. Post-licensure surveillance in the US25 showed a decline in cases by between 71% and 84% with the greatest 492
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Symposium: immunity and infection
include A, Y, W-135, 29E and Z.24 Initial vaccines, based on capsular polysaccharide, were developed in response to disease outbreaks. They provided only short-term protection to older children and adults but not infants. In 1999, universal infant MenC conjugate immunisation was introduced in the UK. Additionally, all children and young people up to the age of 23 years were offered conjugate vaccine in a large catch-up programme over a 2-year period. Surveillance data following this campaign has demonstrated successful control of the disease,2 not only through direct protection but also as a result of substantial herd immunity,35 achieved through reduction in carriage rates of serogroup C meningococci.36 Evidence demonstrating that protection induced by immunisation in infancy does not extend beyond the first year of life2 led to the modification of the schedule to include a booster dose at 12 months of age. Development of multivalent meningococcal vaccines is the next logical step. Menactra – a tetravalent conjugate vaccine composed of the capsular polysaccharides of groups A, C, Y, and W-135 – was licensed in the US in 2005 and is recommended there for use in teenagers. Endemic disease rates are lower in the US but a higher proportion is caused by group Y. However, the vaccine is poorly immunogenic in infants, the age in which meningococcal disease is most common. Another tetravalent (Novartis) A, C, Y, W-135, CRM 197 conjugate vaccine, which appears to be immunogenic in younger children,37 is approaching licensure in Europe. Given that nearly all residual meningococcal disease in the UK is caused by group B, the role for these vaccines within the UK schedule may only be for travellers and high-risk individuals.
decline seen in children aged 1–4 years. The fall in disease burden in both children and (unvaccinated) adults indicates a reduction in transmission and that substantial herd immunity has been achieved. Rates of hospital admission have also declined and age-adjusted mortality rates have fallen by 66%.26 Again, the greatest reduction in mortality (92%) was among children aged 1–4 years. Reactivation of the varicella zoster virus causes herpes zoster (shingles) – a painful vesicular rash. A vaccine programme has the potential to change the epidemiology of herpes zoster as well as varicella. In the longer term, the incidence should fall in an immunised population. Initially, however, there are theoretical concerns that the fall in exposure of adults to chickenpox would prevent boosting of virus-specific cell-mediated immune responses, resulting in an increase in the incidence of shingles. This has not been observed consistently in recent US literature,27 although it could be too soon to observe any such rise. In any case, universal vaccination of the over 60s against herpes zoster was recommended in the US in 2006.28 Two combination vaccines against measles, mumps, rubella and varicella (MMRV) have recently been licensed. ProQuad (Merck) was granted a license in the US in 2005 and in the European Union in April 2006. The vaccine contains a higher titre of attenuated varicella zoster virus than the single antigen preparations and the same amount of measles, mumps and rubella vaccine viruses as the MMR.21 A second MMRV vaccine – Priorix-Tetra (Glaxo) – was licensed in Germany and Australia in 2006. For both vaccines, seroconversion rates are 98% for their components after two doses of MMRV.29,30 A recent observation of higher incidence of uncomplicated febrile convulsions following MMRV vaccination has led to a US policy change so that there is no longer an expressed preference for MMRV over vaccination with MMR and single antigen varicella.31 Introduction of universal varicella immunisation is currently under consideration in the UK. A combination MMRV vaccine might simplify the implementation and increase the cost benefit of a childhood varicella vaccination programme but public acceptability may be an issue in the context of residual anxieties following the unfounded MMR-autism scare. While the process of rebuilding public confidence goes on, a temporary strategy could be implemented, extending selective immunisation to susceptible teenagers to prevent cases of severe disease in adults and generate positive publicity for primary prevention of varicella infection.32
Vaccines in the wings Influenza vaccine Annual epidemics of influenza virus infection occur each winter. Infection produces a varying clinical picture – from a mild respiratory tract illness to a severe bronchiolitis. Morbidity is highest in the elderly, those with chronic disease and in young children. Hence the current rationale for offering annual targeted paediatric immunisation with trivalent inactivated vaccine in the UK,24 although there is a general lack of direct evidence that this results in significant prevention. This contrasts with US recommendations to immunise all healthy children aged 6 months to 18 years.38 Although safety in children aged 6–23 months was recently confirmed in a large retrospective study,39 the efficacy of the vaccine in under 2-yearolds is uncertain.40 A live attenuated intranasal vaccine – ‘Flumist’ – is also widely used in the US programme in children aged 2 years and older38 and has been shown to have higher efficacy.41 It is possible that immunisation of young children could result in significant herd immunity and indirect protection of elderly people in whom mortality is highest.42 Definitive controlled studies demonstrating the efficacy of available influenza vaccines in young children are urgently needed to provide a sound evidence base for future recommendations. In addition, effective affordable strategies for reliable annual delivery of vaccine to this age group would need to be developed for any such programme to work.
Meningococcus groups A, C, Y and W-135 conjugate vaccines Neisseria meningitidis remains one of the leading causes of meningitis and septicaemia. The incidence of meningococcal disease is highest in children aged 0–9 years and overall mortality remains around 10% in the UK.33 The longer term morbidity is also high with 10–20% of survivors suffering complications, such as limb amputation, hearing loss and neurological damage.34 Although morbidity and mortality statistics have been improved by advances in treatment and education campaigns, the only way to eliminate the disease completely is by primary prevention through immunisation. N. meningitidis has at least 13 different serogroups, of which B and C were the most common in the UK prior to universal immunisation against group C. Other less frequent subgroups
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concerned with the health of children so that the choices made are the right ones. ◆
Hepatitis B Hepatitis B (HBV) is largely sexually transmitted. New infection and acute disease rates are highest in adults. Chronic infection is more likely in those infected either as infants or children and it is these patients that act as the main reservoir for continued HBV transmission and are at risk of hepatocellular carcinoma and cirrhosis. The current UK policy for selective hepatitis B immunisation contrasts with the WHO recommendation for universal vaccine use and has given rise to considerable recent debate.43,44 Combined DTaP/IPV/Hib/HepB vaccine is licensed and in use in other European countries and could, in principle, replace the ‘5-in-1’ vaccine currently used in the infant programme, although selective immunisation of perinatally exposed infants at birth would continue to be necessary. Adolescent immunisation, possibly in conjunction with the forthcoming programme for HPV, could also be considered either as an alternative or as a measure to accelerate the impact of a new programme during the 15 years between introduction and when immunised infants would reach the age at which transmission becomes a significant risk.
References 1 Trotter CL, Ramsay ME, Slack MPE. Rising incidence of Haemophillus influenzae type b disease in England and Wales indicates a need for a second catch-up vaccination campaign. Commun Dis Public Health 6: 517–519. 2 Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay M. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 2004; 364: 365–367. 3 Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, WHO International Agency for Research on Cancer. Carcinogenicity of human papillomaviruses. Lancet Oncol 2005; 6: 204. 4 Nubia Muñoz MD, Xavier Bosch F, Silvia de Sanjosé MD, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348: 518–527. 5 Von Krogh G. Management of anogenital warts. Eur J Dermatol 2001; 11: 598–604. 6 Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002; 347: 1645–51. 7 Harper DM, Franco EL, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004; 364: 1757–1765. 8 Villa LL, Costa R, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005; 6: 271–278. 9 The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356: 1915–1927. 10 Paavonen J, Jenkins D, Bosch X, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007; 369: 2161–2171. 11 Joint Committee on Vaccination and Immunisation. Influenza subgroup. Minutes of the Meeting held on Wednesday 17 October 2007. Available from: http://www.advisorybodies.doh.gov.uk/jcvi/ mins17Oct07.htm, (accessed 28.07.08). 12 Raffle EA. Challenges of implementing human papillomavirus (HPV) vaccination policy. BMJ 2007; 335: 375–377. 13 Soriano-Gabarro M, Mrukowicz J, Vesikari T, Verstraeten T. Burden of rotavirus disease in European Union countries. Pediatr Infect Dis J 2006; 25(Suppl): 7–11. 14 World Health Organization. Estimated rotavirus deaths for children under 5 years of age. Available from: http://www.who.int/ immunization_monitoring/burden/rotavirus_estimates/en/index.htm, 2004 (accessed: 28.07.08). 15 Santos N, Hoshino Y. Global distribution of rotavirus serotypes/ genotypes and its implication for the development and implementation of an effective rotavirus vaccine. Rev Med Virol 2005; 15: 29–56. 16 Velazquez FR, Matson DO, Calva JJ, et al. Rotavirus infection in infants as protection against subsequent infections. N Engl J Med 1996; 335: 1022–1028.
Respiratory syncytial virus Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and children worldwide but development of a successful vaccine has so far been elusive for three main reasons.45 Natural infection with RSV does not appear to produce immunity to re-infection, a phenomenon that remains poorly understood. RSV infection in children immunised with an early candidate (formalin-inactivated) vaccine induced enhanced disease, which was accompanied by a damaging inflammatory response. Finally, the optimum time to immunise would be in early infancy but maternal antibodies may interfere with the generation of a lasting immune response. Efforts to establish a successful vaccine will rely on tackling these issues. Meningococcus B Several vaccine candidates for prevention of meningococcus group B disease, against which the conjugated polysaccharide vaccine approach is thought by most authorities to be inappropriate, are under investigation. It is hard to predict how soon one or other of these will become available for use and it seems possible that many of the candidates may deliver, at best, protection against some but not all group B strains. Promising early results from one vaccine were recently presented46 and this vaccine is currently entering larger phase II studies in infants.
Conclusion Paediatric immunisation is developing and changing at an accelerating rate. As opportunities for primary prevention of disease grow, the field becomes more complex and the information and choices confronting policy makers, health professionals and parents become more bewildering. Future challenges will include maintaining a manageable schedule through development of easily administered combined formulations and ensuring that clear and accurate information is effectively communicated to all those
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32 Sengupta N, Booy R, Schmitt HJ, et al. Varicella vaccination in Europe: are we ready for a universal childhood program? Eur J Pediatr 2008; 167: 47–55. 33 Goldacre MJ, Roberts SE, Yeates D. Case fatality rates for meningococcal disease in an English population, 1963–98: database study. BMJ 2003; 327: 596–597. 34 Erickson L, De Wals P. Complications and sequelae of meningococcal disease in Quebec, Canada, 1990–1994. Clin Infect Dis 1998; 26: 1159–1164. 35 Ramsay M, Andrews NJ, Trotter CL, Kaczmarski EB, Miller E. Herd immunity from meningococcal serogroup C conjugate vaccination in England: database analysis. BMJ 2003; 326: 365–366. 36 Maiden MCJ, Stuart JM. Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination. Lancet 2002; 359: 1829–1831. 37 Snape M, Perrett KP, Ford K, et al. Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants. J Am Med Assoc 2008; 299: 173–184. 38 Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2008. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/ rr57e717a1.htm?s_cid=rr57e717a1_e (accessed 28.07.08). 39 Hambridge S, Glanz J, France E, et al. Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old. J Am Med Assoc 2006; 296: 1990–1997. 40 Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2008(2): CD004879. 41 Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007; 356: 729–731. 42 Heikkinen T, Booy R, Campins M, et al. Should healthy children be vaccinated against influenza? A consensus report of the Summits of Independent European Vaccination Experts.Eur J Pediatr 2006; 165: 223–228. 43 English P. Should universal hepatitis B immunisation be introduced in the UK? Arch Dis Child 2006; 91: 286–289. 44 Pollard AJ. Hepatitis B vaccination. BMJ 2007; 335: 950. 45 Bush A, Thomson AH. Acute bronchiolitis. BMJ 2007; 335: 1037–1041. 46 Borrrow R. Advances in the MenB vaccine development: an update. Novartis vaccine. 26th Annual Meeting of the European Society of Paediatric Infectious Diseases. Graz, Austria. 13–17 May 2008. Available from: http://www.kenes.com/espid2008/program_symposia/.
17 Glass R, Parashar UD, Bresee JS, et al. Rotavirus vaccines: current prospects and future challenges. Lancet 2006; 368: 323–333. 18 Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortment rotavirus vaccine. N Engl J Med 2006; 354: 23–34. 19 Ruiz-Palacios G, Pérez-Schael I, Raúl Velázquez F, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354: 11–22. 20 Glass R, Parashar U. The promise of new rotavirus vaccines. N Engl J Med 2006; 354: 75–77. 21 Heininger U, Seward JF. Varicella. Lancet 2006; 368: 1365–1376. 22 Bramley JC, Jones IG. Epidemiology of chickenpox in Scotland 1981–1998. Commun Dis Public Health 2001; 3: 282–287. 23 Cameron JC, Allan G, Johnston F, Finn A, Heath PT, Booy R. Severe complications of chickenpox in hospitalised children in the UK and Ireland. Arch Dis Child 2007; 92: 1062–1066. 24 Salisbury D, Ramsay M, Noakes K. Immunisation against infectious disease ‘The Green Book’, London: Department of Health, 2006. 25 Seward JF, Watson BM, Peterson CL, et al. Varicella disease after introduction of varicella vaccine in the United States, 1995–2000. J Am Med Assoc 2002; 287: 606–611. 26 Nguyen HQ, Jumaan AO, Seward JF. Decline in mortality due to varicella after implementation of varicella vaccination in the United States. N Engl J Med 2005; 352: 450. 27 Jumaan AO, Yu O, Jackson LA, Bohlke K, Galil K, Seward JF. Incidence of herpes zoster, before and after varicella-vaccination-associated incidence decreases in the incidence of varicella, 1992–2002. J Infect Dis 2005; 191: 2002–2007. 28 Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2008. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/ rr57e0515a1.htm (accessed 28.07.08). 29 Shinefield H, Black S, Digilio L, et al. Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr Infect Dis J 2005; 24: 665–669. 30 Knuf M, Habermehl P, Zepp F, et al. Immunogenicity and safety of two doses of tetravalent measles-mumps-rubella-varicella vaccine in healthy children. Pediatr Infect Dis J 2006; 25: 12–18. 31 Dickinson C. ACIP approves MMRV vaccine revision. Possible increased risk for febrile seizures found among children aged 12 to 23 months after receipt of MMRV vaccine. Infectious Diseases in Children April 2008. Available from: http://idinchildren.com/200804/ mmrv.asp (accessed 28.07.08).
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