Rotavirus: realising the potential of a promising vaccine

In view of previous knowledge that the two drugs, given research grants from Novo Nordisk, GlaxoSmithKline, and Abbott. I have separately, increase blood pressure, awareness of the consulted for Otsuka, Merck Sharp & Dohme, Vivus, and 7TM, and was a member of an advisory board for NovoNordisk until 2009. NovoNordisk and cardiovascular eff ects of this drug combination is a major Neurosearch have covered my travel and accommodation expenses for issue. Greenway and colleagues report that treatment with attendance at scientifi c meetings.
Bray G. Contemporary diagnosis and management of obesity, 2nd edn. naltrexone plus bupropion produced initial and transient Newtown, PA, USA: Handbooks in Health Care, 2003.
increases in blood pressure. After 56 weeks, blood 2 Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Effi cacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised pressure was not reduced as much as would normally trials. Lancet 2007; 370: 1706–13.
be seen with a 5-kg weight loss, and the reduction was 3 European Medicines Agency. Questions and answers on the suspension of medicines containing sibutramine. Jan 21, 2010. http://www.ema.europa.
less than that in the placebo group. Additionally, the eu/pdfs/human/referral/sibutramine/Sibutramine_Q&A_80817909en.pdf combination treatment did not reduce LDL cholesterol Greenway FL, Fujioka K, Plodkowski RA, et al, for the COR-I Study Group. more than did placebo. The investigators concluded that Eff ect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, the combination improved several cardiometabolic risk placebo-controlled, phase 3 trial. Lancet 2010; published online July 30. factors; but how relevant are improvements in plasma Davidson J. Seizures and bupropion: a review. J Clin Psychiatry 1989; triglycerides, HDL cholesterol, and high-sensitivity 50: 256–61.
C-reactive protein when the reductions in blood pressure 6 US Food and Drug Administration. Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed and LDL cholesterol that normally occur with weight as Zyban, Wellbutrin, and generics). July 1, 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand loss are absent? Experience with sibutramine perhaps Providers/DrugSafetyInformationforHeathcareProfessionals/ucm169986.
suggests that more data are needed to get a better Beyens MN, Guy C, Mounier G, Laporte S, Ollagnier M. Serious adverse overall assessment of cardiovascular risk of this otherwise reactions of bupropion for smoking cessation: analysis of the French promising combination therapy for obesity.
Pharmacovigilance Database from 2001 to 2004. Drug Saf 2008;
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Thase ME, Haight BR, Johnson MC, et al. A randomized, double-blind, placebo-controlled study of the eff ect of sustained-release bupropion on blood pressure in individuals with mild untreated hypertension. Department of Human Nutrition, Faculty of Life Sciences, J Clin Psychopharmacol 2008; 28: 302–07.
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10 Anon. Low-dose naltrexone combined with bupropion to stop smoking with less weight gain. May 6, 2010. http://clinicaltrials.gov/ct2/show/NCT I am a member of the European Almond Advisory Board, the Communications 00129246?term=NCT00129246&rank=1 (accessed June 25, 2010).
and Scientifi c Advisory Board of the Global Dairy Platform, the advisory board for Jennie Craig, and the executive board of Nordic Food Lab. I have received Rotavirus: realising the potential of a promising vaccine
Published Online
In 2006, two studies that described the effi In 2007, WHO recommended routine immunisation of of two new oral rotavirus vaccines were joint winners infants against rotavirus only for those in regions where of The Lancet’s Paper of the Year.1–3 These trials had been the eff ectiveness of the vaccines had been proven.6 WHO See Articles pages 606 and 615
done in infants in high-income and middle-income also recommended that further trials of both vaccines be countries in the Americas and Europe, but no effi cacy done for children in poor countries of Africa and Asia. In data were available for infants in low-income populations April, 2009, WHO’s Strategic Advisory Group of Experts in Africa and Asia where 85% of the more than (SAGE)7 reviewed data from the fi rst trials of Rotarix in 500 000 deaths from rotavirus occur.4 Unlike parenteral Malawi and South Africa, together with post-introduction vaccines, live oral vaccines have behaved diff erently in eff ectiveness data from El Salvador and Nicaragua. In high-income and low-income populations because of Malawi, the effi various immunological factors such as higher titres of any high-income or middle-income country.8 Despite transplacental or breast-milk antibodies, host problems this lower effi cacy, the incidence of severe disease was related to micronutrient malnutrition, interfering gut greater in Malawi than elsewhere; therefore the vaccine fl ora (tropical enteropathy), intercurrent infections, or an was still quite benefi cial. On the basis of these data, SAGE altered distribution of circulating strains.5 recommended that rotavirus vaccines be included in www.thelancet.com Vol 376 August 21, 2010
all national immunisation programmes, particularly in countries where diarrhoeal deaths account for more than 10% of deaths in children younger than 5 years.7 Two studies in The Lancet today provide new data for cacy of Merck’s pentavalent rotavirus vaccine, RotaTeq.9,10 These randomised trials, undertaken in Ghana, Kenya, Mali, Bangladesh, and Vietnam, enrolled over 7000 infants in urban and rural settings. Over 2 years, cacy against severe rotavirus gastroenteritis was lower in the African countries (39·3%, 95% CI 19·1–54·7) than in the Asian countries (48·3%, 95% CI 22·3–66·1). Again, the increased prevalence of severe disease meant that the vaccines could still substantially improve child health and survival (fi gure11–14). Consequently, in December, GDP per head purchasing power parity US$ 2007 2009, on the basis of the results from today’s two studies,
WHO decided to extend their recommendation to include Figure: Point estimates of Rotarix* and RotaTeq† vaccine effi cacy, and cases of severe rotavirus
gastroenteritis prevented per 100 vaccinated infants by gross domestic product (GDP) per head
all children.15 This recommendation would allow the GAVI Data for Hong Kong and Singapore from pooled estimates over 2-year follow-up. Cases of severe rotavirus gastroenteritis (Vesikari score ≥11 or admission to hospital or emergency department visit for USA) prevented Alliance to accelerate introduction of the vaccine into per 100 vaccinated infants are shown in parenthesis.11–14the national immunisation programmes of the world’s 72 lowest-income countries by subsidising vaccine purchase fact that rotavirus is the most common cause of severe for a limited time at a price of US$0·10–0·30 per dose.
diarrhoea in children that kills more than 1500 children Will national decision makers in low-income countries a day. Because diarrhoea is responsible for an estimated now heed WHO’s advice and introduce rotavirus 1·5 million deaths per year, and nearly 20% of mortality vaccines? Although the reduced price might entice in children less than 5 years old, rotavirus vaccination some policy makers, many are concerned that without a will be needed as part of a package of strategies to guaranteed reduction in price in the future, their rotavirus improve child survival and to achieve Millennium immunisation programmes will become unsustainable Development Goal 4.17when the subsidy ends. The price of vaccines is expected Some countries that introduced rotavirus vaccines into to decrease when developing country manufacturers their national programmes early on have already begun enter the market but, for now, rotavirus vaccine is only to see tremendous benefi t. In the USA, high vaccine-available from the two multinational manufacturers.
coverage has resulted in a more than 50% decrease in The introduction of rotavirus vaccines in national hospital admissions for childhood diarrhoea,18 and in programmes, even in high-income countries, has been Mexico, diarrhoea-related deaths have been markedly slow.4 Apart from issues of their lower eff ectiveness in reduced.19 Furthermore, in the USA, the eff ectiveness of low-income countries and concerns about vaccine price, the vaccine seems to be greater than that predicted by there are still some perceptions about adverse eff ects initial trials, suggesting herd protection not appreciated and intussusception from the earlier vaccine, Rotashield. from the earlier trials.18The fi nding of DNA fragments of porcine circovirus What is needed next to promote the rotavirus agenda in both the Rotarix and RotaTeq vaccines has raised worldwide and to assess the impact of this important questions about vaccine safety despite reviews by WHO, intervention to improve children’s health? First, we the US Food and Drug Administration, and the European will not be able to assess the true eff ectiveness of the Medicines Agency that deemed the vaccines to be safe.
vaccines in low-income settings and the possible benefi t Criticism of the industry’s potential role in form- of herd protection until these products are more widely ulating WHO’s pandemic H1N1 recommendations used and their eff ects are properly evaluated. Reassuring might negatively skew decision makers who wish to governments in low-income countries that they will demonstrate their immunity to outside infl uence.16 be able to purchase vaccine at a reasonable price, when All these issues, however, should not detract from the support from the GAVI Alliance ends, will be the quickest www.thelancet.com Vol 376 August 21, 2010
way to encourage their introduction and to establish 4 Widdowson MA, Steele D, Vojdani J, Wecker J, Parashar U. Global rotavirus whether these vaccines will stand alongside smallpox, surveillance: determining the need and measuring the impact of rotavirus
vaccines. J Infect Dis 2009; 200 (suppl 1): S1–S8.
measles, and poliomyelitis vaccines in their public health 5 Patel M, Shane AL, Parashar UD, Jiang B, Gentsch JR, Glass RI. Oral rotavirus vaccines: how well will they work where they are needed most? benefi ts.1 Beyond this, there is a clear need for further J Infect Dis 2009; 200 (suppl 1): S39–S48.
cacy of both live oral 6 WHO. Rotavirus vaccines. MMWR Wkly Epidemiol Rec 2007; 82: 285–95.
WHO. Meeting of the immunization Strategic Advisory Group of Experts, rotavirus vaccines is lower among children in low-income April 2009—conclusions and recommendations. MMWR Wkly Epidemiol Rec countries than high-income countries. Could simple 2009; 84: 220–36.
Cunliff e NA, Steele D, et al. Eff ect of human rotavirus vaccine on interventions, such as slightly delaying immunisation, severe diarrhea in African infants. N Engl J Med 2010; 362: 289–98.
adding an additional dose of vaccine, or withholding 9 Zaman K, Anh DD, Victor JC, et al. Effi cacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries breast milk around the time of vaccine administration, in Asia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; cacy of the vaccine in these challenging published online Aug 6. DOI:10.1016/S0140-6736(10)60755-6. 10 Armah GE, Sow SO, Breiman RF, et al. Effi settings? Finding an answer to these questions could vaccine against severe rotavirus in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial. Lancet add value to these new vaccines while doing much to 2010; published online Aug 6. DOI:10.1016/S0140-6736(10)60889-6.
improve the health and survival of children.
11 UN Development Programme. Human Development Report 2009 http:// hdrstats.undp.org/en/indicators/91.html (accessed Jun 12, 2010). 12 Vesikari T, Karvonen A, Prymula R, et al. Effi *E Anthony S Nelson, Roger I Glass vaccine against rotavirus gastroenteritis during the fi rst 2 years of life in European infants: randomised, double-blind controlled study. Lancet 2007; Department of Paediatrics, Chinese University of Hong Kong, 370: 1757–63.
Hong Kong Special Administrative Region, China (EASN); and 13 Vesikari T, Itzler R, Matson DO, et al. Effi Fogarty International Center, National Institutes of Health, vaccine in reducing rotavirus-associated health care utilization across three
regions (11 countries). Int J Infect Dis 2007; 11 (suppl 2): S29–35.
14 Phua KB, Lim FS, Lau YL, et al. Safety and effi vaccine during the fi rst 2 years of life in Asian infants: randomised,
double-blind, controlled study. Vaccine 2009; 27: 5936–41.
EASN has received funding from Merck and Wyeth for diarrhoeal and respiratory 15 WHO. Rotavirus vaccines: an update. MMWR Wkly Epidemiol Rec 2009; disease surveillance studies, has participated in vaccine studies funded by Baxter, 84: 533–38.
GlaxoSmithKline, MedImmune, and Wyeth, including a phase 3 Rotarix study, 16 Cohen D, Carter P. WHO and the pandemic fl u “conspiracies”. BMJ 2010; and has received lecture fees and travel support from GlaxoSmithKline, Merck, 340: 1274–79.
Intercell, and Wyeth. RIG declares that he has no confl icts of interest.
17 Wardlaw T, Salama P, Brocklehurst C, Chopra M, Mason E. Diarrhoea: why Butcher J. Paper of the year 2006. Lancet 2007; 369: 91–92.
children are still dying and what can be done. Lancet 2010; 375: 870–72.
Vesikari T, Matson DO, Dennehy P, et al, for the Rotavirus Effi 18 Curns AT, Steiner CA, Barrett M, Hunter K, Wilson E, Parashar UD. Reduction Safety Trial (REST) Study Team. Safety and effi in acute gastroenteritis hospitalizations among US children after human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006; introduction of rotavirus vaccine: analysis of hospital discharge data from 354: 23–33.
18 US states. J Infect Dis 2010; 201: 1617–24.
Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al, for the Human 19 Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, et al. Eff ect of Rotavirus Vaccine Study Group. Safety and effi rotavirus vaccination on death from childhood diarrhea in Mexico. vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; N Engl J Med 2010; 362: 299–305.
354: 11–22.
Childhood cancer survivors: stillbirth and neonatal death
See Articles page 624
As an oncologist, one assumes that the benefi t of In The Lancet today, Lisa Signorello and collaborators survivorship outweighs the cost of side-eff ects, justi fying report a retrospective cohort analysis of the Childhood complex multidisciplinary care, including the mainstay Cancer Survivor Study (CCSS), looking at the rates of treatments of surgery, chemotherapy, and radiotherapy. stillbirth and neonatal death.1 Enrolled cohort members Children with cancer do not typically make the choice, as were diagnosed between 1970 and 1986 with leukaemia, adults do, of whether to receive treatment or not, and lymphoma, sarcoma, CNS cancer, Wilms’ tumour, kidney parents understandably want to provide their children cancer, or neuroblastoma. Whereas previous reports with every possible option for cure. These options from the CCSS and others analysed the rates of acute can include aggressive, novel treatment strategies ovarian failure,2,3 premature menopause,4 miscarriage,5 with unknown potential consequences decades later. and babies with low birthweight5–7 in female survivors, Suff ering severe sequelae of cancer treatment might today’s analysis includes both male and female cancer substantially aff ect long-term quality of life, including survivors and reports the risk of stillbirth (defi ned as a the ability to bear children.
fetal death occurring after the 20th gestational week) and www.thelancet.com Vol 376 August 21, 2010

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