Correspondence
A Quadrivalent Rotavirus Vaccine
N Engl J Med 1998; 338:620-622February 26, 1998
- Article
To the Editor:
The paper by Pérez-Schael et al. (Oct. 23 issue)1 on the efficacy of rotavirus vaccine in Venezuela and the accompanying editorial by Drs. Keusch and Cash 2 deserve comment. The study included mostly children of low socioeconomic status, who are representative of much of the population of the developing world. The results are similar to those from three other trials in diverse settings and provide strong evidence of vaccine efficacy in comparable regions around the world (Finland, the United States, and an Indian reservation in the United States).3-5 The lower vaccine efficacy in the Peruvian and Brazilian trials may be related to the use of a lower dose of vaccine.6,7 In Peru there were few moderate-to-severe episodes of diarrhea after vaccination, probably because of active surveillance with frequent home visits and perhaps in part because placebo recipients had a high seroprevalence of IgA antibody, indicating that most infants in the study had been exposed to wild-type rotavirus before or during vaccine administration.
There is strong evidence to suggest that rotavirus and oral poliovirus vaccines do not interfere with each other.8 Poor serotype-specific immune responses certainly reflect poor assay sensitivity, since assays that measure broad antigenic profiles detect responses. Longitudinal studies that are better able to confirm exposure to rotavirus than the vaccine trials have consistently demonstrated that certain serum and fecal antibody titers are predictive of protection against natural infections.9,10 Testing of similar samples from vaccine trials should be standardized for the assays used in studies in which antibody correlates of protection have been identified; antibody titers should be assessed in addition to serologic responses.
10 ReferencesMiguel L. O'Ryan, M.D.
University of Chile, Santiago, ChileDavid O. Matson, M.D., Ph.D.
Eastern Virginia Medical School, Norfolk, VA 235011
Perez-Schael I ,Guntinas MJ ,Perez M , et al. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. N Engl J Med 1997;337:1181-1187
Full Text | Web of Science | Medline2
Keusch GT ,Cash RA . A vaccine against rotavirus -- when is too much too much? N Engl J Med 1997;337:1228-1229
Full Text | Web of Science | Medline3
Bernstein DI ,Glass RI ,Rodgers G ,Davidson BL ,Sack DA . Evaluation of rhesus rotavirus monovalent and tetravalent reassortant vaccines in US children. JAMA 1995;273:1191-1196
CrossRef | Web of Science | Medline4
Rennels MB ,Glass RI ,Dennehy PH , et al. Safety and efficacy of high-dose rhesus-human reassortant rotavirus vaccines -- report of the National Multicenter Trial. Pediatrics 1996;97:7-13
Web of Science | Medline5
Vesikari T. Clinical experience with rotavirus vaccine in Finland. Presented at the 2nd Satellite Symposium of the 14th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), Elsinore, Denmark, 18–21 June 1996.
6
Lanata CF ,Midthun K ,Black RE , et al. Safety, immunogenicity, and protective efficacy of one and three doses of the tetravalent rhesus rotavirus vaccine in infants in Lima, Peru. J Infect Dis 1996;174:268-275
CrossRef | Web of Science | Medline7
Linhares AC ,Gabbay YB ,Mascarenhas JD , et al. Immunogenicity, safety and efficacy of tetravalent rhesus-human, reassortant rotavirus vaccine in Belem, Brazil. Bull World Health Organ 1996;74:491-500
Web of Science | Medline8
Rennels MB ,Ward RL ,Mack ME ,Zito ET . Concurrent oral poliovirus and rhesus-human reassortant rotavirus vaccination: effects on immune responses to both vaccines and on efficacy of rotavirus vaccines. J Infect Dis 1996;173:306-313
CrossRef | Web of Science | Medline9
O'Ryan ML ,Matson DO ,Estes MK ,Pickering LK . Anti-rotavirus G type-specific and isotype-specific antibodies in children with natural rotavirus infections. J Infect Dis 1994;169:504-511
CrossRef | Web of Science | Medline10
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
Full Text | Web of Science | Medline
To the Editor:
Drs. Keusch and Cash express unwarranted pessimism in recommending against rotavirus vaccination in developing countries. First, they attribute the lower efficacy of the rotavirus vaccine in Peru and Brazil to failure in a poorer, sicker population rather than to the considerably lower doses used in those studies.1,2 With respect to vaccine immunogenicity and protection (e.g., for oral poliovirus3 and rotavirus4 vaccines), the dose is important. Poor poliovirus-vaccine immunogenicity in developing countries has led to the need for additional doses or an alternative vaccine, but never to the absence of vaccination.
They question the practicality of the vaccine if it cannot be given with oral poliovirus vaccine, noting that it has not been given in combination in trials in developing countries. The study protocols for those trials were last revised before the availability of data showing that the two vaccines do not interfere with each other. Keusch and Cash acknowledge that the immunogenicity of poliovirus vaccine is unaltered by rotavirus vaccine; the efficacy of rotavirus vaccine against severe disease was 64 to 80 percent when it was administered with oral poliovirus vaccine to over 600 infants in two U.S. trials.5,6
Keusch and Cash speculate whether a two-dose regimen might be sufficient and less expensive than a three-dose regimen. Determining how little vaccine might be enough, a legitimate subject for future research, will ultimately involve trade-offs and is not a reason to withhold an available, safe, and effective vaccine that might save so many lives.
Finally, they indicate that at $30 a dose, the vaccine is far too expensive for developing countries. That U.S. price was derived from models; a double-blind trial that actually measured costs arrived at a considerably lower figure.7 Moreover, vaccines are sold on the basis of “tiered pricing.” This explains why the price of an infant dose of recombinant hepatitis B vaccine is $24 in the U.S. private market but under $1.40 in the public market of certain developing countries. The United Nations Children's Fund (UNICEF) and the World Health Organization can provide vaccines at even lower cost where they are needed most.
Must the vaccine pass additional tests, despite its proven success among poor Venezuelan children and others? Drs. Keusch and Cash should reconsider their opposition and help make this successful vaccine available to the developing countries that need it most.
7 ReferencesBruce L. Davidson, M.D., M.P.H.
301 S. 19th St., Philadelphia, PA 191031
Lanata CF ,Midthun K ,Black RE , et al. Safety, immunogenicity, and protective efficacy of one and three doses of the tetravalent rhesus rotavirus vaccine in infants in Lima, Peru. J Infect Dis 1996;174:268-275
CrossRef | Web of Science | Medline2
Linhares AC ,Gabbay YB ,Mascarenhas JD , et al. Immunogenicity, safety and efficacy of tetravalent rhesus-human, reassortant rotavirus vaccine in Belem, Brazil. Bull World Health Organ 1996;74:491-500
Web of Science | Medline3
Patriarca PA ,Wright PF ,John TJ . Factors affecting the immunogenicity of oral poliovirus vaccine in developing countries. Rev Infect Dis 1991;13:926-939
CrossRef | Medline4
Flores J ,Perez-Schael I ,Blanco M , et al. Reactogenicity and immunogenicity of a high-titer rhesus rotavirus-based quadrivalent rotavirus vaccine. J Clin Microbiol 1993;31:2439-2445
Web of Science | Medline5
Santosham M, Moulton LH, Reid R, et al. Efficacy and safety of high-dose rhesus-human reassortant rotavirus vaccine in a high-risk population. J Pediatr (in press).
6
Rennels MB ,Glass RI ,Dennehy PH , et al. Safety and efficacy of high-dose rhesus-human reassortant rotavirus vaccines -- report of the National Multicenter Trial. Pediatrics 1996;97:7-13
Web of Science | Medline7
Griffiths RI ,Anderson GF ,Powe NR , et al. Economic impact of immunization against rotavirus gastroenteritis: evidence from a clinical trial. Arch Pediatr Adolesc Med 1995;149:407-414
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Drs. O'Ryan and Matson and Dr. Davidson question our interpretation of the trial of rotavirus reassortant vaccine in Venezuela. We reiterate that we are impressed with the scientific vision, technological achievement, and persistence of the vaccine's developers. Data on vaccine efficacy in industrialized countries, especially for severe episodes,1 support the use of this vaccine for infants in countries able to pay for it, because the vaccine will reduce morbidity, save lives, and save money.
The question remains whether to promote this vaccine for use in developing countries now. Given the limited health budgets of poor countries and the realization that when something is added to these budgets something else must be deleted, we think it is mandatory to know the cost-effectiveness ratio of the new strategy first.
Unfortunately, two factors differ between prior studies in Brazil and Peru with poor results and the more successful Venezuelan trial — namely, the increased antigenic load of vaccine and the lower background rate of diarrhea in Venezuela. Whenever two factors differ between studies with divergent results it becomes impossible to ascribe the improved performance to just one of them. Thus, we said that we simply did not know whether the improved results in Venezuela were due to an increased vaccine load or reduced environmental contamination with potentially interfering enteroviral infections or, possibly, better nourished subjects.
Because no correlation between immune response and protection was obvious, we also questioned whether it had been proved that three doses of vaccine were needed. This was not studied, however, and whatever price is set for this vaccine, two doses will cost only two thirds as much as three doses. We also are not convinced that the absence of immunologic incompatibility between rotavirus and poliovirus vaccines in the United States proves that the same is true in developing countries.
Finally, there is the issue of cost. Many factors affect vaccine pricing, including public scrutiny and the involvement of international organizations such as the World Health Organization, UNICEF, and others. We hope that the price of rotavirus vaccine will drop; however, we will still need to prioritize which vaccines to use, even if rotavirus vaccine becomes affordable. Current data on the effect of conjugate vaccines against Haemophilus influenzae type b in poor, developing countries are compelling 2 and strongly support the early introduction of this vaccine.3 To prioritize the introduction of rotavirus vaccine, we must have similar data in populations representative of the poor countries and those at highest risk.
3 ReferencesGerald T. Keusch, M.D.
Tufts–New England Medical Center, Boston, MA 02111Richard A. Cash, M.D., M.P.H.
Harvard School of Public Health, Boston, MA 021151
Joensuu J ,Koskenniemi E ,Pang X-L ,Vesikari T . Randomised placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Lancet 1997;350:1205-1209
CrossRef | Web of Science | Medline2
Mulholland K ,Hilton S ,Adegbola R , et al. Randomised trial of Haemophilus influenzae type-b tetanus protein conjugate for prevention of pneumonia and meningitis in Gambian infants. Lancet 1997;349:1191-1197[Erratum, Lancet 1997;350:524.]
CrossRef | Web of Science | Medline3
It's “all systems go” for the Hib vaccine. Vaccine & Immunization News. Vol. 4. Geneva: World Health Organization, June 1997.
