E-DRUG: BMJ on Indian national immunisation programme against rotavirus
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[The BMJ recently published papers giving arguments for and against rotavirus immunisation in India - thanks to Dr Gopal Dabade for the pointer. The two viewpoints are given below - as Fair Use - for colleagues without internet access to them. Warning - long post! Please go to the BMJ links for the full articles and references. - DB]
India is considering including rotavirus vaccine in its national childhood immunisation programme. Johnie Rose and Umesh Parashar (doi:10.1136/bmj.e7818) support the move, but Jacob Puliyel and Joseph Mathew (doi:10.1136/bmj.e7832) question the evidence used to support vaccination
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Should India launch a national immunisation programme against rotavirus? No
Jacob M Puliyel, consultant paediatrician, Joseph L Mathew
BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7832 (Published 30 November 2012)
Cite this as: BMJ 2012;345:e7832
The programme to immunise all the world’s children with the rotavirus vaccine is based on mistaken assumptions. Careful evaluation of available evidence does not support the launch of the programme in India. It will divert funds from more life saving interventions and could cause harm.
Inappropriate extrapolations
The World Health Organization recommended universal rotavirus vaccination well before regional evidence of its effectiveness was collected. This is a distortion of the standard procedure whereby recommendations are made based on local evidence. The distortion came about in two stages. In 2007, the WHO committee looking at rotavirus vaccination for developing countries decided that efficacy data from one population can be extrapolated to other populations that are in an “equivalent child mortality strata.”1 This presumes that the prevalent virus strains are the same in different regions with similar socioeconomic status and mortality rates. There is no scientific evidence to support this assumption. Following this in 2009, using data from Malawi (one of the poorest regions in the world),2 Nicaragua, and a handful of developed countries, WHO recommended rotavirus vaccine for all regions of the world.3
Rationale
According to the GAVI Alliance, which funds vaccination for children in poor countries, rotavirus vaccination is a key step towards lowering child mortality and achieving the millennium development goal for reduction of deaths among children under 5 years of age.4 Worldwide, rotavirus is said to cause 527 000 deaths. 5 In India it is estimated to cause 122 000 to 153 000 deaths annually.5 It is hoped that the vaccine will reduce diarrhoeal deaths by 40% and the overall mortality rate of children under 5 by 5%.6
The estimate of deaths from rotavirus was arrived at by multiplying the mean rotavirus detection rate in a country by the diarrhoea case fatality rate, assuming a uniform mortality rate for all causes of diarrhoea.7 This is inappropriate for two reasons. Firstly, deaths from rotavirus infection can be prevented by simple measures to correct dehydration.8 Bacterial diarrhoea, on the other hand, is more often associated with sepsis and systemic complications and is likely to have a higher mortality. Secondly, in up to 58% of cases positive for rotavirus there is coinfection with other pathogens. Attributing all deaths to rotavirus whenever the virus is isolated overestimates rotavirus mortality.9
Natural infections not protective in India
Data from Mexico show that two successive, naturally occurring rotavirus infections protect against subsequent infections.10 Although these data pertain to protection against natural infections of rotavirus strains prevalent in the area, it was projected as evidence that any rotavirus vaccine (the monovalent RV1 or pentavalent RV5) would provide similar protection against all strains of the infection and in every part of the world.11
The local rotavirus strains in India are different from those in other regions.12 Furthermore, new strains are continuously emerging through reassortment between animal and human strains.12 Studies have shown that two episodes of natural infection in India, unlike in Mexico, afford little protection against subsequent infections,13 perhaps because of the rapidly evolving strains. Given that these data contradict the Mexico data that was used as evidence for launching universal vaccination, urgent reappraisal of the recommendation is warranted.
No reduction in mortality
No studies have looked at the efficacy of the vaccine in India, but studies from Bangladesh and Vietnam show vaccine efficacy against rotavirus diarrhoea is 48%.14 This is much lower than in the West, where efficacy is around 90%.15 16 The main reason given for advocating immunisation is that it would reduce childhood mortality. However there was no significant reduction in deaths among the 1009 receiving the vaccine (four deaths) compared with the 1007 placebo recipients (three deaths).14 A Cochrane meta-analysis (55 704 vaccine recipients and 44 813 placebo recipients) found mortality was marginally higher in the vaccinated group than the placebo group (174 v 106 deaths; absolute risk increase=0.00312, number needed to harm=1333).17 These analyses show that the vaccine is unlikely to become a major lifesaving intervention or help in achieving the millennium development goal.
Faulty cost-benefit projection for India
Two analyses specifically evaluating the Indian context have concluded that the vaccine is cost effective. One study suggests that at a price of $0.15/dose (8 rupees; £0.09; €0.12) the vaccine would save 44 000 lives and be cost saving.18 The market price is $50/dose in middle income countries.19
Rose and colleagues used more sophisticated Markov modelling techniques,20 pegging the cost of vaccine at $7/dose. Incidentally, this is the price negotiated by Brazil.21 Using efficacy data from the West they suggested that the vaccine would prevent 41 000 deaths (avoiding one death for every 470 children immunised) and would cost $164 per disability adjusted life year saved.
Both studies extrapolated data acquired elsewhere. If the findings of the Cochrane meta-analysis showing absence of reduction in mortality were incorporated into the calculations, the projected cost per life saved and cost per life year gained would have been substantially higher.
To promote the uptake of expensive vaccine, GAVI often supplies vaccines to developing countries at highly subsidised rates for a limited period. Later, the subsidy is withdrawn and poor countries have to pay the full market price. In this manner they are often unfairly lured into a debt trap.22 Developing countries must estimate affordability and cost-benefits of vaccines against the market price at which it will be available to them in the long term.
In India, vaccinating the birth cohort of 25 million with a vaccine that costs $14/child (two doses) would cost $350m. The entire immunisation budget for 2011-12 was $240m.23 Only 52% of the population receives three doses of the diphtheria-tetanus-pertussis (DPT) vaccine. 24 The cost for all three doses of DPT is $0.30/child. Logically, the country’s first priority must be to reach inexpensive established vaccines to its rural poor who are unvaccinated at present.
Inclusion of rotavirus vaccine in the national immunisation programme is a long term and binding commitment. It must be based on hard nosed, pragmatic evaluation of the evidence. The commercial interests of the manufacturers must not be allowed to influence decision making. Unfortunately the existing evidence does not support the inclusion of current rotavirus vaccines into the immunisation programme in India.
Notes
Cite this as: BMJ 2012;345:e7832
Footnotes
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; JMP is a member of the National Technical Advisory Group on Immunization of the Government of India.
The views expressed in this article are those of the authors and do not necessarily represent those of the institution where they work.
Provenance and peer review: Commissioned; not externally peer reviewed.
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Should India launch a national immunisation programme against rotavirus? Yes
BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7818 (Published 30 November 2012)
Cite this as: BMJ 2012;345:e7818
Johnie Rose, senior instructor , Umesh D Parashar, medical epidemiologist
The World Health Organization recommends inclusion of rotavirus vaccination of infants into all national immunisation programmes, with a strong recommendation for introduction of vaccine in countries like India where diarrhoeal deaths account for ≥10% of child mortality.1 The health burden of rotavirus in India is well established. WHO estimated that 98 621 Indian children died from rotavirus gastroenteritis in 2008, representing about one third of deaths from diarrhoeal disease and 4% of all child deaths in India.2 More recent data from the Million Death Study, a nationally representative survey of 1.1 million Indian households, estimated that the virus causes 113 000 deaths a year.3 Both of these figures are conservative compared with an estimate of 147 000 annual rotavirus deaths obtained by directly extrapolating rates of laboratory confirmed rotavirus mortality from a contemporary community based birth cohort study in India.4
Non-fatal rotavirus gastroenteritis results in around 880 000 hospital admissions and 1.26 million clinic visits annually in Indian children, costing $65m (358 crore; £41m; €51m).5 Because rotavirus affects essentially all children in both developing and industrialised countries by the age of 5 years, interventions to improve hygiene and provide clean water alone are considered inadequate to prevent transmission. In addition, although severe and fatal outcomes of rotavirus diarrhoea can be reduced by timely access to medical treatment, a national survey in 2005-6 found that a quarter of Indian children under 5 years with diarrhoea received no treatment and only 39% received oral rehydration therapy.6 Vaccination is therefore the best method to prevent deaths and morbidity.
Efficacious vaccines with favourable benefit:risk ratio
Two internationally licensed rotavirus vaccines have shown 85%-98% efficacy against severe rotavirus disease in large clinical trials in middle and high income countries 7 8 and their routine use has led to notable reductions in severe morbidity and mortality from childhood diarrhoea.9 10 Neither vaccine has been tested for efficacy in India. Concerns about local efficacy have been raised, especially given the large diversity of rotavirus strains prevalent in India. However, pre-licensing and post-licensing data from diverse settings indicate that both vaccines provide good protection against a range of strains (including vaccine mismatch strains).9 11 The efficacy of the vaccines in India is likely to be similar to that in low income countries in Africa and Asia (40%-60%, including 42.7% in Bangladesh).12 Although this efficacy may seem low, the absolute public health benefits of vaccination are likely to be substantial because of the large health burden of rotavirus disease. With coverage similar to the first two doses of diphtheria-tetanus-pertussis (DTP) vaccine (73% and 63%, respectively), a 50% efficacious rotavirus vaccine would prevent around 44 000 deaths and 290 000 hospital admissions in Indian children each year.5
The benefits of rotavirus vaccination have to be weighed against possible risks. An earlier rotavirus vaccine was withdrawn in the United States in 1999 after it was linked to an increased risk of intussusception (about one case per 10 000 vaccinated infants).13 However, risk of intussusception was not increased in pivotal trials of both currently licensed rotavirus vaccines conducted in over 60 000 infants each.7 8 Post-licensing data have shown a small risk of intussusception, mainly in the first week after the first vaccine dose, in some high and middle countries but not in others.14 Data on intussusception risk from India or from other low income settings are lacking. Even if we assumed that the intussusception risk seen in some international settings (1-2 cases per 100 000 vaccinated infants) were to exist in India, the benefits of vaccination (around 44 000 rotavirus deaths prevented) would far exceed this risk. Similar benefit-risk considerations in other settings have led WHO and other policy bodies to continue support for use of rotavirus vaccines globally.14
Vaccines are cost effective and being locally developed
In a country where health spending is $54 per capita, cost effectiveness and affordability of vaccination are important considerations. Two separate analyses evaluated cost effectiveness of vaccination at prices ranging up to $7 per dose for a two dose schedule and showed that rotavirus vaccines could be considered very cost effective based on international standards, although substantial resources would be required to provide vaccine at the higher end of the price range.5 15 Currently, India has the opportunity to apply for financial support from the GAVI Alliance for procurement of rotavirus vaccines with a cofinancing requirement of $0.20 a dose.
Meanwhile, several Indian companies are manufacturing rotavirus vaccines, including an Indian neonatal rotavirus strain vaccine set to finish phase III testing in 2013.6 13 14 If trial results are favourable, this vaccine could be licensed in India within two years. The manufacturer has pledged to provide vaccine at $1 per dose,16 which would make a vaccination programme highly cost effective. Furthermore, the potential availability of low cost, indigenously manufactured vaccines would allay concerns about long term sustainability of financial support from donors and would assure adequate vaccine supply.
Notes
Cite this as: BMJ 2012;345:e7818
Footnotes
Competing interests: Both authors have completed the ICJME unified declaration form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.
The views expressed in this article do not necessarily represent those of the US Centers for Disease Control and Prevention.
Provenance and peer review: Commissioned; not externally peer reviewed.