• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of bmjBMJ helping doctors make better decisionsSearch bmj.comLatest content
BMJ. Sep 2, 2000; 321(7260): 525–526.
PMCID: PMC1118429

The future of research into rotavirus vaccine

Benefits of vaccine may outweigh risks for children in developing countries
Charles Weijer, bioethicist and assistant professor of medicine

The future of a potentially lifesaving vaccine for developing countries has been imperiled by its recent withdrawal from the United States market. In August 1998, tetravalent rhesus rotavirus vaccine was licensed for routine vaccination in the United States on the basis of randomised controlled trials there and in Finland. The trials showed that the vaccine had an efficacy of 49-68% in preventing rotavirus diarrhoea overall and, importantly, 69-91% efficacy in preventing severe disease.14

In July 1999 the US Centers for Disease Control and Prevention reported a clustering of cases of intussusception in the weeks after vaccination with tetravalent rhesus rotavirus vaccine, representing an additional risk of 1 in 10 000 for this complication.5 On the basis of this finding they recommended “postponing administration of tetravalent rhesus rotavirus vaccine to children,” and in October 1999 the manufacturer voluntarily withdrew the product from the United States market. This leaves researchers with a moral quandary: should randomised controlled trials of tetravalent rhesus rotavirus vaccine proceed in developing countries?

Firstly, it may be thought that other vaccines in development (for example, human-bovine rotavirus vaccine) may not cause intussusception. This is pure speculation. About one million children have been vaccinated with tetravalent rhesus rotavirus vaccine. Other vaccines in development have two or three orders of magnitude less experience in humans, numbers far too small to rule out a complication in the order of 1 in 10 000. Indeed, we cannot rule out the possibility that rotavirus itself causes intussusception in children who are predisposed to this problem; thus, vaccination with any live oral agent may be a triggering event.6 Secondly, the public health community generally believes that one must do no harm.

Assuming a worst case scenario of a 25% fatality rate from intussusception in developing countries, widespread use of tetravalent rhesus rotavirus vaccine could cause 2000-3000 deaths a year. For some, the prospect of causing this many deaths—or perhaps even any deaths—is morally untenable. The context of developing countries differs starkly from North America. Despite efforts to prevent death with programmes of oral rehydration therapy, about three million children die of diarrhoea annually.7 Of these deaths, approximately 600 000 to 800 000 are caused by rotavirus diarrhoea. Tetravalent rhesus rotavirus vaccine may prevent 80% of these deaths. If the next vaccine in development takes three to five years to get to the stage where tetravalent rhesus rotavirus vaccine is now, the choice to wait must be weighed against the cost of waiting: 1.4 to 3.2 million preventable deaths. Some have falsely assumed that inaction is a morally neutral state. But if one is culpable for vaccine related deaths, then one is also culpable for deaths caused by withholding the vaccine.

Is there a moral difference between a treatment that may cause a sick child to die and a vaccine that may cause a healthy child to die? Because public health doctors treat unhealthy populations rather than unhealthy patients the risk of death or serious disability must be lower with vaccines than with clinical treatments. The risks of tetravalent rhesus rotavirus vaccine seem comparable to the risks associated with measles, mumps, and rubella vaccine.8 The moral yardstick for the public health physician is ultimately the same as for clinicians: do the benefits of vaccination exceed the risks? In a developing country in which a child's risk of death from rotavirus diarrhea is 1 in 200 or greater the answer may well be yes.

Thirdly, as a result of the controversy over randomised controlled trials on the prevention of perinatal transmission of HIV in Africa and Thailand, there is sensitivity surrounding such trials in developing countries.911 Some critics of the HIV trials believe that there should be a universal standard of care for a disease that is independent of the care that is available locally.9,10 Others argue more convincingly that this would lead to randomised controlled trials that are less responsive to the health needs of developing countries.11

To make the standard of care in the United States the universal standard of care would only be unjust and would perpetuate the unjust distribution of healthcare resources globally. Tetravalent rhesus rotavirus vaccine was withdrawn from the market in the United States because the possibility of a 1 in 10 000 risk of intussusception seemed unduly high in comparison to only 20 deaths annually from rotavirus diarrhoea.12 It is imperialistic to transfer this standard of care to a country in which 1 in 200 children die of rotavirus infection, and thereby to deny even further study of the tetravalent rhesus rotavirus vaccine.

Ethical randomised controlled trials must begin with an honest null hypothesis.13 Though the recent success of a randomised controlled trial of tetravalent rhesus rotavirus vaccine in Venezuela provides grounds for optimism, randomised controlled trials in other developing countries are needed because of various factors such as serotypical variance in rotavirus and the fact that the disease has an earlier onset and lacks the seasonality seen in developed countries.14,15 We don't know whether tetravalent rhesus rotavirus vaccine will be as effective in developing countries, but starting with an honest null hypothesis makes it ethical to proceed.


CW's work is supported by a Medical Research Council of Canada Scholar Award and Operating Grant as well as a Dalhousie University Clinical Research Scholar Award.

The author is grateful to Drs Françoise Baylis, Anthony Belardo, Robert Crouch, Carolyn Ells, Scott Halperin, and Nuala Kenny for their comments on earlier versions of this commentary.


1. Bernstein DI, Glass RI, Rodgers G, Davidson BL, Sack DA.for the US Rotavirus Vaccine Efficacy Group. Evaluation of rhesus rotavirus monovalent and tetravalent reassortant vaccines in US children JAMA 1995. 2731191–1196.1196 [PubMed]
2. Rennels MB, Glass RI, Dennehy PH, Bernstein DI, Pichichero ME, Zito ET, et al. Safety and efficacy of high-dose rhesus-human reassortant rotavirus vaccines—report of the National Multicenter Trial. Pediatrics. 1996;97:7–13. [PubMed]
3. Joensuu J, Koskenniemi E, Pang XL, Vesikari T. Randomized placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Lancet. 1997;350:1205–1209. [PubMed]
4. Santosham M, Moulton LH, Reid R, Croll J, Weatherholt R, Ward R, et al. Efficacy and safety of high-dose rhesus-human reassortant rotavirus vaccine in Native American populations. J Pediatr. 1997;131:632–638. [PubMed]
5. Intussusception among recipients of rotavirus vaccine—United States, 1998-1999. MMWR. 1999;48:577–581. [PubMed]
6. Konno T, Suzuki H, Kutsuzawa, Imaj A, Katsushima N, Sakamoto S, et al. Human rotavirus infection in infants and young children with intussusception. J Medl Virol. 1978;2:265–269. [PubMed]
7. Bern C, Martines J, de Zoysa I, Glass RI. The magnitude of the global problem of diarrheal disease: a ten year update. Bull WHO. 1992;70:705–714. [PMC free article] [PubMed]
8. Advisory Committee on Immunization Practices. Update. Vaccine side effects, adverse reactions, contraindications, and precautions. MMWR. 1996;45(RR-12):1–35. [PubMed]
9. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med. 1997;337:853–856. [PubMed]
10. Angell M. The ethics of clinical research in the third world. N Engl J Med. 1997;337:847–849. [PubMed]
11. Crouch RA, Arras JD. AZT trials and tribulations. Hastings Center Report. 1998;28(6):26–34. [PubMed]
12. Tucker AW, Haddix AC, Bresee JS, Holman RC, Parashar UD, Glass RI. Cost-effectiveness analysis of a rotavirus immunization program for the United States. JAMA. 1998;279:1371–1376. [PubMed]
13. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317:141–145. [PubMed]
14. Perez-Schael I, Guntinas MJ, Perez M, Pagone V, Rojas AM, Gonzalez R, et al. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuala. N Engl J Med. 1997;337:1181–1187. [PubMed]
15. Bresee JS, Glass RI, Ivanoff B, Gentsch JR. Current status and future priorities for rotavirus vaccine development, evaluation and implementation in developing countries. Vaccine. 1999;17:2207–2222. [PubMed]

Articles from BMJ : British Medical Journal are provided here courtesy of BMJ Group
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...