To the Editor: The rotavirus vaccines in the clinical trialsreported on by Ruiz-Palacios and colleagues and Vesikari andcolleagues (Jan. 5 issue)1,2 may reduce mortality from rotavirusless efficaciously in Third World regions where rotavirus expressesthe VP4, VP6, and VP7 serotypes not included in the vaccines.Furthermore, because of the "original antigenic sins" of B cells3and T cells,4 infants who are vaccinated before contractingnatural rotavirus infections may become hyporesponsive to indigenousrotavirus because of the development of recall immunity, whichis anamnestically more reactive with vaccine than with localserotypes. Paradoxically, if this recurrent vaccine-specificresponse at each reinfection is focused more on homotypic epitopesthan on heterotypic epitopes, it may be considered harmful tovaccines, since it dampens the protective responses. It remainsto be confirmed whether Rotarix (GlaxoSmithKline) and RotaTeq(Merck) are less protective against antigenically differentindigenous rotaviruses. If this were to be found, then type-specificrotavirus vaccines might solve efficacy problems due to viraldiversity and original antigenic sins.
Giuseppe A. Molinaro, M.D. Loma Linda University Loma Linda, CA 92350 gmolinaro{at}llu.edu
Dean A. Lee, M.D., Ph.D. Baylor College of Medicine Houston, TX 77030
References
Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006;354:11-22. [Free Full Text]
Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354:23-33. [Free Full Text]
Francis T Jr. Influenza: the new acquayantance. Ann Intern Med 1953;39:203-221. [ISI][Medline]
Klenerman P, Zinkernagel RM. Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 1998;394:482-485. [CrossRef][Medline]
To the Editor: The recent reports of two new rotavirus vaccinesconclude that these vaccines are both efficacious and safe.However, neither vaccine has been shown to be safe in immunocompromisedpatients. Oral poliovirus vaccine is also an orally administered,live attenuated vaccine. Because of its transmissibility andits ability to cause severe illness, oral poliovirus vaccineis contraindicated for immunocompromised patients and theirclose contacts. The rotavirus vaccine Rotarix is of particularconcern, because, as noted by the editorialists Glass and Parashar,1the vaccine strain is shed by more than 50 percent of vaccinerecipients after the first dose. It remains to be shown whetherthe new rotavirus vaccines can be safely given to immunocompromisedpatients.
Ping-Ing Lee, M.D., Ph.D. National Taiwan University Hospital Taipei 10002, Taiwan pinging{at}ntumc.org
References
Glass RI, Parashar UD. The promise of new rotavirus vaccines. N Engl J Med 2006;354:75-77. [Free Full Text]
To the Editor: Glass and Parashar note that because the riskof intussusception associated with RotaShield (Wyeth) —the first licensed rotavirus vaccine — is age-dependent,second-generation vaccines "might cause intussusception if administeredto older infants." Studies conducted after licensure of thevaccine will be critical, because in the prelicensure trialsconducted by GlaxoSmithKline1 and Merck,2 the vaccine was administeredto infants with a mean age at the first dose of approximately60 and 70 days, respectively, leaving the effect of first doseson older infants unstudied.
In retrospect, RotaShield might have been used safely in a two-doseschedule completed by 60 days of age.3,4 Such a schedule wouldhave discouraged "catch-up" immunization of older infants, apractice that led to 81 percent of the vaccineassociated casesof intussusception that caused the withdrawal of RotaShieldfrom the market.3 In contrast, no cases of intussusception occurredin the approximately 70,000 infants who received a first doseat less than 60 days of age. A neonatal schedule would alsoavoid the administration of the vaccine to infants four to ninemonths of age — the period of highest susceptibility toboth vaccine-related and "background" intussusception events.3,4Because intussusception might also beset new vaccines if givento older infants, the prudent course would be to discouragecatch-up immunization. No one wants to see rotavirus vaccinessuffer another setback.
Lone Simonsen, Ph.D. Robert J. Taylor, Ph.D. Albert Z. Kapikian, M.D. National Institute of Allergy and Infectious Diseases Bethesda, MD 20892 lsimonsen{at}mail.nih.gov
Dr. Kapikian reports being one of the developers of the RotaShieldvaccine.
References
Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006;354:11-22. [Free Full Text]
Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354:23-33. [Free Full Text]
Simonsen L, Viboud C, Elixhauser A, Taylor RJ, Kapikian AZ. More on RotaShield and intussusception: the role of age at the time of vaccination. J Infect Dis 2005;192:Suppl 1:S36-S43.
Kapikian AZ, Simonsen L, Vesikari T, et al. A hexavalent human rotavirus-bovine rotavirus (UK) reassortant vaccine designed for use in developing countries and delivered in a schedule with the potential to eliminate the risk of intussusception. J Infect Dis 2005;192:Suppl 1:S22-S29.
To the Editor: Glass and Parashar mention that RotaShield waswithdrawn from the market because it was associated with anintussusception rate of 1 case per 10,000 infants vaccinated.1The package insert for RotaShield recommended that the firstdose be given to infants at two months of age. Simonsen et al.2recently reported that many cases of intussusception attributedto RotaShield reflected the later age (three to seven months)at receipt of the first dose among infants who received thisvaccine. They reported that there were no cases in 71,058 infantsreceiving their first dose of RotaShield before 60 days of age,and 9 cases among 268,202 infants receiving their first dosebefore 90 days of age (0.0034 percent). The effect of age mayapply also to other vaccines: in younger infants, Vesikari etal. report that intussusception occurred in none of 34,035 infantsafter receiving their first dose of RotaTeq at 6 to 12 weeksof age, but there were a total of 12 cases within one year ofthe first dose in the same 34,035 who later received their secondand third doses (0.035 percent). Ruiz-Palacios et al. reportsimilar results with Rotarix. Considering these data, our planis to bring RotaShield back to the market with a defined dosingschedule.
Leonard P. Ruiz, Jr., Ph.D. BIOVIRx Shoreview, MN 55126 lpruiz{at}biovirx.com
Dr. Ruiz reports being the president and chief executive officerof and a shareholder in BIOVIRx, which is moving toward commercializationof the oral rotavirus vaccine RotaShield.
References
Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001;344:564-572. [Erratum, N Engl J Med 2001;344:1564.] [Free Full Text]
Simonsen L, Viboud C, Elixhauser A, Taylor RJ, Kapikian AZ. More on RotaShield and intussusception: the role of age at the time of vaccination. J Infect Dis 2005;192:Suppl 1:S36-S43.
Dr. Ruiz-Palacios and colleagues reply: Heterotypic protectionhas been suggested previously in animal models1 and in community-basedstudies of the natural history of rotavirus infection.2 Ourclinical trial suggests that a monovalent attenuated G1P[8]human rotavirus (HRV) vaccine can induce heterotypic protectionagainst other strains. The HRV vaccine proved to be highly protectiveagainst severe rotavirus infections caused by G1, G3, and G9serotypes that share the same VP4 antigen (P[8]); a similarefficacy is likely against G4 strains. Protection against G2P[4]strains, which differ from the vaccine strain in containingboth VP7 and VP4 antigens, is less,3 but it is still approximately67 percent (95 percent confidence interval, 15 to 87 percent)in a meta-analysis of all studies involving HRV.3 SerotypesG1, G2, G3, and G4 and genotypes P[8] and P[4] have predominatedin episodes of rotavirus in the industrialized and developingworld during the past couple of decades, perhaps because thoseserotypes and genotypes are more adapted to the human intestinethan other serotypes. Thus, we believe that the HRV vaccinewill probably have a substantial effect on rotavirus-associatedmorbidity and mortality in the developing world. However, continuousserotype surveillance and monitoring of vaccine performanceare warranted.
The recommendation is to administer the first dose of the HRVvaccine to infants between 6 and 14 weeks of age, because childrenoften are infected at a very young age. We believe that thedata on HRV convincingly show that the vaccine is not associatedwith intussusception when given at this age. Vaccination ofolder children, however, might be indicated during an outbreak,as part of overall outbreak management.
Miguel O'Ryan, M.D. University of Chile Santiago 70007, Chile moryan{at}med.uchile.cl
Guillermo M. Ruiz-Palacios, M.D. National Institute of MedicalScience and Nutrition 14000 Mexico City, Mexico
Ralf Clemens, M.D., Ph.D. GlaxoSmithKline Biologicals 22783-110 Rio de Janeiro, Brazil
References
Feng N, Vo PT, Chung D, Vo TV, Hoshino Y, Greenberg HB. Heterotypic protection following oral immunization with live heterologous rotavirus in a mouse model. J Infect Dis 1997;175:330-341. [Medline]
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. [Free Full Text]
Perez-Schael I, Linhares AC, Vesikari T, et al. Two doses of the human attenuated rotavirus vaccine RIX4414 (Rotarix) show heterotypic protection in Latin America and Europe. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., December 16–19, 2005.
Dr. Vesikari and colleagues reply: Dr. Ping-Ing Lee raises theissue of giving live vaccines to immunocompromised infants.Only healthy infants were enrolled in the Rotavirus Efficacyand Safety Trial, so that our study cannot address this question.Live viral vaccines are generally not recommended for infantswith severe immunodeficiencies. However, since rotavirus infectsnearly all children, the effect of wild-type disease shouldbe considered along with the potential risks and benefit ofvaccination with an attenuated rotavirus vaccine.
Drs. Molinaro and Lee ask whether vaccine strains will providesufficient protection in the developing world. Human serotypesG1, G2, G3, and G4 and P[8] were included in the pentavalenthuman–bovine (WC3) reassortant vaccine, because they covermore than 85 percent of the strains circulating during the pasttwo decades in both developed and developing countries. Withrotavirus, in contrast to influenza, the phenomenon of "originalantigenic sin" does not appear to limit robust immune responsesto diverse serotypes.1 Primary immunity to wild-type infectionis predominantly serotype-specific and is followed by a broadeningof immune responses with subsequent infections. The developmentof homotypic immunity against each vaccine serotype, unbiasedby previously induced immune responses, is possible with multipledoses. Vaccine efficacy in the developing world, where unusualserotypes may be encountered, will soon be evaluated in studiesin Africa and Asia.
Dr. Simonsen and colleagues caution against catch-up vaccinationswith the new rotavirus vaccines on the basis of the age-relatedincidence of intussusception associated with the rhesus–humanreassortant rotavirus (RRV) vaccine (RRV-TV, Wyeth Laboratories).Our study was designed with the first dose of vaccine givenat 6 to 12 weeks of age, when the background incidence of intussusceptionis low, in order to detect an increased risk of intussusceptionas early as possible. The absence of association between intussusceptionand the pentavalent vaccine may be explained by its differencesfrom the RRV vaccine. In contrast to studies of RRV,2 in ourstudy the frequencies of fever, vomiting, diarrhea, and hematocheziawere similar among recipients of the pentavalent vaccine andof placebo. Rhesus rotaviruses have been shown to invade gut-associatedlymphoid tissue in experiments in animals to a greater extentthan do bovine rotaviruses,3 suggesting that intussusceptionmay be a particular complication of RRV. Because of the inclusioncriteria used for the phase 3 studies, these data can supportonly a recommendation for giving the first vaccine dose at approximatelytwo months of age and completing the full series by six to eightmonths of age. The trade-off is that age restrictions may haveuntoward public health consequences, such as potentially preventablemorbidity from rotavirus gastroenteritis among unvaccinatedolder children.
Timo Vesikari, M.D. University of Tampere Medical School FIN-33014 Tampere, Finland
Mark J. DiNubile, M.D. Penny M. Heaton, M.D. Merck Research Laboratories West Point, PA 19486 penny_heaton{at}merck.com
References
Clark HF, Lawley D, Shrager D, et al. Infant immune response to human rotavirus serotype G1 vaccine candidate reassortant WI79-9: different dose response patterns to virus surface proteins VP7 and VP4. Pediatr Infect Dis J 2004;23:206-211. [CrossRef][Medline]
Haber P, Chen RT, Zanardi LR, et al. An analysis of rotavirus vaccine reports to the Vaccine Adverse Event Reporting System: more than intussusception alone? Pediatrics 2004;113:e353-e359. [Free Full Text]
Moser CA, Dolfi DV, Di Vietro ML, Heaton PA, Offit PA, Clark HF. Hypertrophy, hyperplasia, and infectious virus in gut-associated lymphoid tissue of mice after oral inoculation with simian-human or bovine-human reassortant rotaviruses. J Infect Dis 2001;183:1108-1111. [CrossRef][ISI][Medline]
The editorialists reply: The association between the age atwhich rotavirus vaccine is administered and the risk of intussusceptionhas become a central issue in reassessing the future of RotaShieldand in testing and recommending the next generation of rotavirusvaccines. When the ages of patients with intussusception fromthe Centers for Disease Control and Prevention (CDC) case–controlstudy to assess the association of RotaShield with intussusception1were compared with the ages at vaccination with RotaShield ofinfants in the National Immunization Survey2 for a similar setof states in which the case–control study was conducted,no cases of intussusception were identified among approximately70,000 infants vaccinated at less than 60 days of age, 9 werereported in the approximately 200,000 infants immunized between60 and 89 days of age, but 36 occurred in the approximately165,000 infants vaccinated at 90 days of age or older. Thisfinding has emboldened Dr. Ruiz to bring RotaShield back intocommercial production and Dr. Simonsen and colleagues to suggestthat administering two doses to infants less than 60 days ofage might be safe. Although the data are most suggestive, theconfidence limits around this age-associated risk are wide.3The World Health Organization's Global Advisory Committee onVaccine Safety concluded that the evidence for this lower riskin younger infants still remains inconclusive.4
With regard to the two newer vaccines (Rotarix and RotaTeq),clinical trials involving approximately 130,000 infants whoreceived their first doses at 6 to 12 weeks of age have demonstratedno association with intussusception. The CDC's Advisory Committeeon Immunization Practices (ACIP) has just recommended routineuse of the Rotateq vaccine for American children5 but limitedthe initial dose to infants less than 90 days of age. This decisionseems reasonable for two reasons. First, although the vaccineis not associated with intussusception, administering the firstdose to young infants will reduce the number of background casesof intussusception that would occur by chance alone. Second,if the vaccine were associated with a small increase in therelative risk of intussusception that was not detected in thetrials, the number of cases attributable to the vaccine mightbe amplified only in older infants who are also more susceptibleto natural intussusception. The age restriction recommendedby the ACIP should avoid the problem of catch-up immunization(i.e., starting immunizations in older infants who missed theirfirst scheduled dose).
Neonatal immunization with RotaShield, as proposed by Simonsenet al., might reduce the risk of intussusception. However, apreliminary study6 demonstrated that even though neonatal immunizationwith RotaShield reduced the side effect of fever, it also dampenedthe immune response to vaccine.
Finally, we agree with Dr. Ping-Ing Lee that rotavirus vaccineswill need to be studied in immunocompromised patients, particularlyin children infected with the human immunodeficiency virus,before the vaccines are recommended for widespread use. Thesestudies are just being initiated.
Roger I. Glass, M.D., Ph.D. Umesh D. Parashar, M.B., B.S., M.P.H. Centers for Disease Control and Prevention Atlanta,GA 30333
References
Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001;344:564-572. [Erratum, N Engl J Med 2001;344:1564.] [Free Full Text]
Smith PJ, Schwartz B, Mokdad A, et al. The first oral rotavirus vaccine, 1998-1999: estimates of uptake from the National Immunization Survey. Public Health Rep 2003;118:134-143. [CrossRef][ISI][Medline]
Rothman KJ, Young-Xu Y, Arellano F. Age dependence of the relation between reassortant rotavirus vaccine (RotaShield) and intussusception. J Infect Dis 2006;193:898-898. [Medline]
Global Advisory Committee on Vaccine Safety, 1–2 December 2005. Wkly Epidemiol Rec 2006;2:15-7. (Also available at http://www.who.int/wer/2006/wer8102.pdf.)
CDC's advisory committee recommends new vaccine to prevent rotavirus. Press release of the Centers for Disease Control and Prevention, Atlanta, February 21, 2006. (Accessed March 30, 2006, at http://www.cdc.gov/od/oc/media/pressrel/r060221.htm.)
Vesikari T, Karvonen A, Forrest BD, et al. Neonatal administration of rhesus rotavirus tetravalent vaccine. Pediatr Infect Dis J 2006;25:118-122. [Medline]
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