preventing rotavirus gastroenteritis: do you have the facts?
TRANSCRIPT
564 Journal of Paediatrics and Child Health 43 (2007) 564–567© 2007 The Authors
Journal compilation © 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
doi:10.1111/j.1440-1754.2007.01163.x
Key Points
1 Rotavirus vaccination will be included in the National Immuni-sation Program in Australia from 1 July 2007.
2 Two new vaccines (RotaTeq CSL Biotherapies/Merck and RotarixGlaxo Smith Kline) have been licensed for use in Australia: bothare safe and highly effective, but differ with regard to theircomposition and the timing and mode of administration.
3 Rotavirus is the major cause of gastroenteritis and vaccinationwill significantly decrease associated morbidity, outpatient andhospitalisation costs in Australia.
Correspondence: Professor Geoffrey Davidson, Gastroenterology Unit,Women's and Children's Hospital, 72 King William Road, North Adelaide,SA 5006, Australia. Fax: +61 88161 6088; email: [email protected]
Accepted for publication 18 May 2007.
CLINICAL PERSPECTIVE
Preventing rotavirus gastroenteritis: Do you have the facts?Geoffrey Davidson,1,2 Elizabeth J Elliott,3,4,5 Carl Kirkwood6 and Rodney Pearce7
1Women's and Children's Hospital, 2Discipline of Paediatrics, University of Adelaide, Adelaide, South Australia, 3Discipline of Paediatrics and Child Health,
University of Sydney, 4The Children's Hospital at Westmead, 5Centre for Evidence Based Paediatrics, Gastroenterology and Nutrition, Sydney, New South Wales, 6Murdoch Children's Research Institute, Royal Children's Hospital, Department of Paediatrics, University of Melbourne, Melbourne, Victoria and 7Athelstone
and Beulah Park Medical Centres, Adelaide, South Australia, Australia
Abstract: From 1 July 2007 two new rotavirus vaccines licensed for use in Australia (RotaTeq CSL Biotherapies/Merck and Rotarix Glaxo SmithKline) will be funded for the National Immunisation Program. The vaccines differ with respect to their composition and the timing and mode ofadministration. Both have been evaluated in huge randomised trials and shown to be highly effective in preventing rotavirus gastroenteritis,including severe disease requiring hospital admission. Neither has been associated with an increased rate of intussusception; however,surveillance for adverse effects following vaccination will be important. As rotavirus infection is ubiquitous in young children, funding of thisvaccine will significantly decrease the enormous morbidity and costs associated with this disease in our community.
Key words: Rotarix; RotaTeq; rotavirus infections; rotavirus vaccines.
Paediatricians will welcome the funding announcementbecause vaccination against rotavirus will substantially decreasethe burden from gastroenteritis on general practices, emergencydepartments and paediatric inpatient beds throughout Australiaand will have a significant impact on diarrhoea-associateddeaths.1 The planned introduction of the vaccine prior to thenext annual winter rotavirus epidemic is particularly pleasing.However, the timing also makes it important that paediatriciansare aware of the vaccines available – their efficacy, safety, modeof administration and potential adverse effects – so that theycan advocate for their use.
Rotavirus gastroenteritis affects children world-wide. Everychild will likely be infected before the age of 5 years but thepeak of disease incidence occurs between the ages of 6 and24 months. Children under the age of 2 years are most likely tobecome dehydrated and require admission. Recent data showthat within Australia vaccination could prevent at least 10 000hospitalisations for gastroenteritis each year in children underthe age of 5 years. In this age group rotavirus accounts foraround half of all hospitalisations for acute gastroenteritis.1 Inaddition, the vaccine could prevent a further 22 000 visits toEmergency Departments and around 115 000 visits to GeneralPractitioners by children aged under 5 years with rotavirus gas-troenteritis.1 A huge number of infections in the communitycould also be prevented. Thus, this vaccine will significantlydecrease the enormous social and economic burden of rotavirusdisease.1,2
The availability of the new vaccines from July 2007 highlightsthe need for providers to have sufficient information to informcarers and parents about vaccinating infants. Information toassist providers in Australia is contained in the fact sheets3 andImmunisation Handbook4 produced by the National Centrefor Immunisation Research and Surveillance of Vaccine
On 28 March 2007 the Australian Government announced thatit would provide $124.4 million dollars over 5 years to fund theinclusion of free rotavirus vaccines on the National Immunisa-tion Program. The vaccination program, to commence in July2007, will be available to infants born from 1 May 2007. Thefunding announcement followed swiftly after the 2006 recom-mendations by the Australian Technical Advisory Group onImmunisation and the Pharmaceutical Benefits Advisory Com-mittee, to fund the two rotavirus vaccines that had beenlicensed for use in Australia in May 2006. Since May the vac-cines have only been available privately, at a cost of approxi-mately $220 per course.
G Davidson et al. Preventing rotavirus gastroenteritis
Journal of Paediatrics and Child Health 43 (2007) 564–567 565© 2007 The AuthorsJournal compilation © 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Preventable Diseases. The two new oral rotavirus vaccineslicensed for use in Australia are RotaTeq (CSL Biotherapies/Merck)5 and Rotarix (Glaxo Smith Kline).6 Both vaccines weredemonstrated to be safe and highly effective in large-scale pre-licensure randomised controlled trials published simultaneouslyin the New England Journal of Medicine (Table 1).7,8 In these trialsadverse effects were no more common in the vaccine thanplacebo groups and neither vaccine was associated with anincreased rate of intussusception – a problem that led to thewithdrawal of a previous rotavirus vaccine used in the USA(Rotashield Wyeth laboratories).9 Because both vaccines aresafe and highly effective, decisions regarding their use rest onfactors such as serotype composition, ease of use, frequency ofadministration and licensing restrictions, outlined in Table 2.
In the initial trials (Table 1) the RotaTeq vaccine prevented98% of severe rotavirus gastroenteritis and 74% of rotavirusgastroenteritis of any severity. It reduced hospitalisations forrotavirus gastroenteritis by 96% and for gastroenteritis of anycause by 59%.7,9 Rotarix prevented 85% of severe rotavirusgastroenteritis and at least 79% of rotavirus gastroenteritis ofany severity.8,9 It reduced hospitalisations for rotavirus gastro-enteritis by 85% and for gastroenteritis of any cause by 42%.8,9
These figures highlight the likely enormous public healthimpact of the rotavirus vaccines.
Within Australia, the G1 rotavirus serotype has been mostprevalent during the last decade; however, G2, G3, G4 and G9serotypes also cause disease throughout the country.10,11 Bothoral rotavirus vaccines provide protection against a range ofserotypes. As indicated (Table 2) RotaTeq is a live attenuatedbovine-human pentavalent vaccine. It contains rotavirus reas-sortants G1, G2, G3, G4 and P1[8] derived from rotavirusesinfecting human and bovine species.5,7 Rotarix contains a liveattenuated strain of human rotavirus (G1P[8]).6,8 AlthoughRotarix does not contain G3 and G9 serotypes it has demon-strated protective efficacy against these strains.6,8 Similarly,although RotaTeq does not contain G9 serotype it significantlyreduces hospitalisations and ED visits due to this serotype.5,7
Although the efficacy of Rotarix was demonstrated againstserotypes G1, G3 and G9, specific protection against serotypeG4 was not demonstrated owing to insufficient numbers.8,9 The-oretically, however, this vaccine should be effective for allstrains containing P8 genotype, including serotype G4. Protec-tion by Rotarix against severe gastroenteritis due to G2 infectionwas low (41%) in the initial trial.8,9
A recently completed but unpublished trial of Rotarixaddresses some concerns about its serotype coverage and effi-cacy when given with other vaccines.12 The study, conducted inEurope (Czech Republic, Finland, France, Germany, Italy and
Table 1 Summary of key trials of rotavirus vaccines licensed for use in Australia
Vaccine Rotarix RotaTeq
Publication details Ruiz-Palacious et al. N Engl J Med 2006; 354:11–228 Vesikari et al. N Engl J Med 2006; 354:23–337
Study type Randomised controlled trial (Phase III)
Blinded, placebo controlled
Randomised controlled trial (Phase III)
Blinded, placebo controlled
Participants 63 225 healthy infants
6–13 weeks age at first vaccine dose
68 038 healthy infants
6–12 weeks age at first vaccine dose
Setting 11 countries in Latin America (Guatemala, Brazil, Mexico,
Venezuela, Panama, Nicaragua, Honduras, Salvador,
Colombia, El Salvador, Chile) and Finland.
11 countries including Scandinavia (Finland, Sweden);
USA (including American Indians); Europe (Germany,
Belgium, Italy); Taiwan; and Latin America
(Guatemala, Costa Rica, Puerto Rico) and Jamaica.
Outcome measures Efficacy (any, severe or hospitalised rotavirus
gastroenteritis) and safety up to 100 days after first
dose (9–10 months in subgroup)
Efficacy (any, severe, or hospitalised rotavirus
gastroenteritis; ED and clinic visits (USA) and safety up
to 1 year after first dose.
Evaluation of disease
severity
Vesikari 20-point severity scale (duration and
severity of diarrhoea, vomiting, fever, dehydration,
need for treatment, e.g. hospitalisation: score >11
indicates severe disease).
Clark 24-point scale (duration and severity of diarrhoea,
vomiting, fever and behavioural changes but not
dehydration or need for hospitalisation: score >16
indicates severe disease).
Outcomes of interest The vaccine prevented:
85% of hospitalisations for rotavirus gastroenteritis
(up till 1 year age); 84.7% of severe gastroenteritis
(1st season), 79% of severe gastroenteritis
(2nd season); 42% of hospitalisation for gastroenteritis
of any cause.
The vaccine prevented:
95.8% of hospitalisations for rotavirus gastroenteritis;
98.2% of severe gastroenteritis (1st season),
88% of severe gastroenteritis (2nd season)
59% of hospitalisation for gastroenteritis of any cause
86% GP of visits.
Seroconversion After two doses 95–100% had antirotavirus IgA
antibodies
After 3 doses 95% had antirotavirus IgA antibodies
(compared with 14% placebo group).
Safety (adverse
events)
Minor effects (fever, diarrhoea, vomiting, irritability)
similar in vaccine and placebo groups;
Hospitalisation and serious adverse events significantly
higher in placebo than vaccine group.
Minor effects similar in vaccine and placebo groups:
including fever, diarrhoea, vomiting, irritability;
Serious adverse events similar in vaccine and placebo
groups.
Intussusception rate Intussusception ≤31 days after either dose similar in
treatment and placebo groups.
Intussusception ≤42 days after any dose similar in
treatment and placebo groups.
566 Journal of Paediatrics and Child Health 43 (2007) 564–567© 2007 The Authors
Journal compilation © 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Preventing rotavirus gastroenteritis G Davidson et al.
Spain), included 3994 participants (all healthy infants aged 2–5 months) and the mean duration of follow-up was 6 months.Vaccine efficacy was assessed when Rotarix was given witheither placebo or one or more of Infanrix Hexa, Infanrix-IPV-Hib, Meningitec and/or Prevenar.12 After two vaccine doses,rotavirus gastroenteritis was reduced by 87% (95% CI 80–92)and severe rotavirus infection was reduced by 95.8% (95% CI89.6–98.7). The reduction in hospital admissions due to rotavi-rus gastroenteritis was 100% (95% CI 81.8–100). The immuneresponse to vaccines coadministered with Rotarix was notimpaired. Infants receiving the rotavirus vaccine developedantibodies against G1, G2, G4 and G9.
As noted by O'Ryan, no single Rotarix study has demon-strated heterotypic protection against G2 rotavirus gastroenteri-
tis. However, meta-analysis of six relevant trials suggestsprevention of 81% of cases of G2 rotavirus gastroenteritis ofany severity and 71% of severe cases. It will be interesting tofollow the epidemiology of rotavirus in the Northern Territorywhere the Rotarix vaccine has already been introduced into theimmunisation program. In the Northern Territory there havebeen three outbreaks of rotavirus diarrhoea caused by the G2serotype since 1993.
RotaTeq requires three oral doses (at 2, 4 & 6 months) withthe first dose given at between 6 and 12 weeks of age.5 Rotarixrequires two doses (at 2 and 4 months) with the first dosegiven at 6 to 14 weeks of age (Table 2).6 The differences areimportant because if an infant presents at 13 or 15 weeks,respectively, they will not be eligible for vaccination. All doses
Table 2 Properties of rotavirus vaccines licensed for use in Australia
Name Rotarix RotaTeq
Manufacturer Glaxo Smith Kline6 CSL Biotherapies/Merck5
Vaccine content Monovalent, human rotavirus (strain RIX 4414), live
attenuated vaccine.
∼1 × 106 infectious virus per vaccine dose but able to
replicate in the gut (viral shedding >50% after 1st dose)
Pentavalent, human-bovine, reassortant, live rotavirus
vaccine.
7–12 × 107 infectious virus per vaccine dose but little
viral replication in gut (viral shedding <9% after 1st
dose)
Serotype coverage G1, P1[8] G1, G2, G3, G4, P1[8]
Vaccination schedule 2 dose
2 and 4 months
Dose 1: 6–14 weeks age
Dose 2: before 24 weeks of age
Minimum 4 weeks between doses
3 dose
2,4,6 months
Dose 1: 6–12 weeks
Last dose: before 32 weeks of age
Minimum 4 weeks between doses
Administration Oral (1 mL/dose) Oral (2 mL/dose)
Approved use with
current NIP
vaccines
Can be combined with all vaccines listed on NIP at 2
and 4 months. Immune response of Rotarix not
affected when co-administered with DTPa, Hib, IPV,
hepatitis B, pneumococcal vaccines.
Can be combined with all vaccines listed on NIP at 2,
4 and 6 months.
Immune response to RotaTeq not affected when
coadministered with DTPa, Hib, IPV, hepatitis B and
pneumococcal vaccines.
Age limits; preterm
data
Minimum age 6 weeks; maximum age 24 weeks.
Well tolerated by 140 preterm infants
(29–36 weeks gestation) but protection unknown.
Minimum age 6 weeks; maximum age 32 weeks.
Safety (n = 2070) and efficacy (n = 204) evaluated in
preterm infants (25–36 weeks gestation).
TGA-approved for use in preterm infants.
Presentation Lyophilised powder in a glass vial requiring
reconstitution with calcium carbonate buffer solution.
Ready-to-use clear liquid (2 mL) in a plastic tube that
can go straight into the mouth.
Storage Store solution either in refrigerator (2°C to 8°C) or at
ambient temperature (≤37°C) but do not freeze.
After reconstitution refrigerate up to 24 h then discard if
not used.
Store at 2–8°C. Can be left at room temperature for up
to 48 h.
Precautions Vaccines should never be injected.
Postpone in infants with acute diarrhoea, vomiting or
severe febrile illness.
Withhold in infants with gastrointestinal illnesses.
No safety data available for patients with
immunodeficiency including HIV/AIDS.
Transmission risk of live virus to immunocompromised
close contacts of vaccinated infant.
No safety data for immunocompromised patients or
those in receipt of blood transfusion or blood
products, including immunoglobulins within 42 days;
active gastrointestinal illness, chronic diarrhoea or
growth retardation. Theoretical risk of transmission of
live virus to close immunocrompromised contacts of
vaccinated infant.
Contraindications Known hypersensitivity to any vaccine component or
signs of hypersensitivity after previous administration
of vaccine; uncorrected congenital malformation of the
gut; delay administration in acute severe febrile illness.
Known hypersensitivity to any vaccine component or
signs of hypersensitivity after previous administration
of vaccine.
G Davidson et al. Preventing rotavirus gastroenteritis
Journal of Paediatrics and Child Health 43 (2007) 564–567 567© 2007 The AuthorsJournal compilation © 2007 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
of Rotarix must be given by 24 weeks of age and RotaTeq by32 weeks.
RotaTeq is provided as a liquid formulation in a ready-to-useprefilled plastic vial that can be squeezed directly into theinfant's mouth.5 Rotarix is provided as a lyophilised powder thatrequires reconstitution with a buffered solution before use.6
Reports of the Rotarix vaccine being inadvertently administeredby injection has resulted in improved labelling of the product;clarification of instructions for its oral use; and additional edu-cation for GPs.13 Maintaining the cold chain is important for theRotaTeq vaccine, while the Rotarix vaccine must be used imme-diately following reconstitution. These practicalities may beimportant considerations when stocking vaccines or issuingthem as part of a National Immunisation Program.
RotaTeq is approved by the Therapeutic Goods Administra-tion (TGA) for use in preterm infants and data demonstratingits efficacy and safety in this age group are available.5,9 Rotarixis not currently approved by the TGA for use in preterm infantsalthough there are limited data in this age group indicating thatit is well tolerated.
The two rotavirus vaccines have not been directly comparedand differences in the vaccine trials7,8 in terms of the popula-tions studied, the definitions of rotavirus severity, and the tim-ing of vaccination in relation to rotavirus seasonality, makecomparison of efficacy difficult. For example, Rotarix was eval-uated in predominantly developing communities and RotaTeqin predominantly developed communities (Table 1). Neverthe-less, the available data support the fact that we now have twosafe and highly effective vaccines licensed and funded for usein Australia.
Following the introduction of RotaTeq on 3 February 2006 inthe USA, where over 3.5 million doses of the vaccine have nowbeen distributed, the Food and Drug Administration and Cen-tres for Disease control created a reporting system to allowdoctors and parents to report adverse events among infants whoreceived the vaccine. By 31 January 2007 the Vaccine AdverseEvent Reporting System (VAERS) had received 28 reports ofintussusception at between 0 and 73 days after RotaTeq vacci-nation: half the cases occurred within 21 days of vaccination.14
This equates to a rate of 1:100 000 doses, a rate considerablyless than that (1:2000) expected in healthy unvaccinated infantsin the USA. VAERS concludes that ‘Although the data we havereceived so far suggests that RotaTeq does not cause intussus-ception, it is possible that because of incomplete reporting ofcases to VAERS and other factors, some increased risk of intus-susception associated with RotaTeq vaccination could yet befound. Thus, CDC and FDA are continuing to carefully monitorreports of possible adverse effects of the vaccine.’
It will be important to ensure that surveillance for adverseeffects is conducted following introduction of these vaccineson the National Immunisation Program. In Australia, a study
to monitor intussusception in infants has been approved bythe Australian Paediatric Surveillance Unit and will commenceduring 2007. We urge paediatricians to notify intussusceptioncases, whether or not they are associated with rotavirusvaccination.
Acknowledgements
Elizabeth Elliott is supported by an Australian National Healthand Medical Research Council (NH&MRC) Practitioner Fellow-ship (457084). Carl Kirkwood is supported by an (NH&MRC RDWright Career Development award (334364)).
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