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Epidemiological ReviewsCopyright © 1999 by The Johns Hopkins University School of Hygiene and Public HealthAll rights reserved

Vol. 21, No. 1Printed in U.S.A.

Public Health Considerations for the Introduction of New Rotavirus Vaccinesfor Infants: A Case Study of Tetravalent Rhesus Rotavirus-based ReassortantVaccine

John Clemens,1-23 Neysa Keckich,2-3 Abdollah Naficy,23 Roger Glass,4 and Malla Rao2>:

INTRODUCTION

Rotavirus was discovered to be an etiology of child-hood diarrhea by Bishop and colleagues in 1973 (1).Since this discovery, numerous epidemiologic studieshave established that rotavirus is the major nonbacter-ial etiology of acute diarrhea, as well as the mostimportant cause of dehydrating acute diarrhea in chil-dren worldwide (2, 3). Appreciation of the epidemio-logic and public health importance of rotavirus hasspurred considerable efforts to develop an anti-rotavirus vaccine.

At present, a vaccine consisting of a rhesus rotavirustogether with three human-rhesus reassortants (RRV-TV) is the first to have achieved licensure in theUnited States (4). RRV-TV has recently been officiallyendorsed as a routine infant vaccine, given at 2, 4, and6 months of age, in the United States (5, 6). Moreover,several other rotavirus vaccines are undergoing pre-licensure studies (7). It is therefore timely to considerthe rationale for employing rotavirus vaccines in pub-lic health practice, both in industrialized and in less-developed countries. In this review, we provide aframework for decisions about deployment of anti-rotavirus vaccines. Because RRV-TV is the only vac-

Received for publication August 17, 1998, and accepted for pub-lication March 6, 1999.

Abbreviations: CDC, Centers for Disease Control and Prevention;DTP, diphtheria toxoid-tetanus toxoid-pertussis; EPI, ExpandedProgramme on Immunisation; G type, glycoprotein type; HIV, humanimmunodeficiency virus; IPV, inactivated poliomyelitis vaccine; OPV,oral poliomyelitis vaccine; P type, protease-cleaved protein type; pfu:plaque-forming units; RRV-TV, tetravalent rhesus rotavirus-basedreassortant vaccine; VP, viral protein; WHO, World HealthOrganization.

1 International Vaccine Institute, Seoul, Korea.2 Division of Epidemiology, Statistics, and Prevention Research,

National Institute of Child Health and Human Development,Bethesda, MD.

3 World Health Organization Collaborating Centre on the ClinicalEvaluation of Vaccines in Developing Countries, National Institute ofChild Health and Human Development, Bethesda, MD.

4 Centers for Disease Control and Prevention, Atlanta, GA.Reprint requests to John Clemens, M.D., International Vaccine

Institute, P.O. Box 14, Kwanak, Seoul 151-600, Korea.

cine to have acheived licensure in the United States, wefocus on RRV-TV in our discussion, and we considerpublished evidence bearing on its use as a componentof routine infant immunization.

THE AGENT

Rotavirus is a genus in the family Reoviridae (8).Structurally, rotaviruses are approximately 75 nm indiameter, and have a characteristic triple-layeredicosahedral protein capsid, consisting of an outer layer,an intermediate layer, and an inner core. The term"rota" refers to the characteristic wheel-like appear-ance of the virus (9) when viewed with transmissionelectron microscopy. Within the inner core is the viralgenome, consisting of 11 segments of double-strandedRNA that encode structural and nonstructural proteins(10).

RNA segment 6 encodes a viral protein (VP) termedVP6. Rotaviruses are classified into seven distinctgroups (termed A through G) on the basis of antigenicdifferences of VP6 proteins (11). Groups A-C arefound in humans and animals, whereas groups D-Ghave only been detected in animals. Because group Arotaviruses are the only group to have been identifiedas a major etiology of dehydrating diarrhea in children,efforts to create anti-rotavirus vaccines have focusedon vaccines against this group.

The outer capsid contains two structural proteinsthat are considered most relevant to vaccine develop-ment because they induce virus-neutralizing serumantibodies (12) and because they are capable of induc-ing immune protection against rotavirus disease in ani-mal models (13). The first, VP7, is usually encoded bythe seventh gene segment. Antigenic variants of thisprotein are termed glycoprotein types (G types), corre-sponding to the glycoprotein constitution of this anti-gen. Human rotaviruses express 10 different G types,though four, Gl, G2, G3, and G4, are most commonlyfound in isolates from cases of diarrheal disease. Thesecond important structural protein of the outer capsid,VP4, is encoded by the fourth gene segment. This pro-

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Public Health Considerations for Rotavirus Vaccines 25

tein is cleaved by the protease trypsin. Accordingly,variants of VP4 are termed P types. There are seven Ptypes commonly identified among human isolates.Although reassortment of 10 G types by seven P typescould yield 70 different P-G combinations, only foursuch combinations are isolated from human diarrhealcases with appreciable frequency: P[8]G1, P[8]G3,P[8]G4, and P[4]G1 (14).

Transmission

The person-to-person spread of rotaviruses appearsto be very efficient, in part because of their stability inthe environment and their resistance to ambient tem-peratures and to routine disinfection (15). Rotavirusesare excreted in large numbers in the feces of childrenwith rotavirus diarrhea, and children are thought totransmit the virus between one another primarily via afecal to oral pathway. Human volunteer studies haveconclusively demonstrated that oral ingestion ofrotavirus can result in diarrheal illness (16). Whereasthe source of infection of an infant or young child maybe an ill child, it may also be an asymptomaticallyinfected older child or adult, as suggested by familystudies (17). Waterborne transmission has been docu-mented in industrialized countries (18), but it does notappear to be of major importance in these settings andis of uncertain significance in developing countries(19). Similarly, although rotavirus has been isolatedfrom respiratory secretions of infected individuals, andseveral indirect lines of evidence suggest that trans-mission by the respiratory route can occur (20, 21), theimportance of this route remains to be elucidated.Finally, animal-to-human transmission has not beendocumented by epidemiologic studies. However,recent molecular typing of human isolates has revealedsome that appear to be recombinants of human andanimal rotaviruses (22).

Infection and disease

Serologic surveys of children indicate that infectionsby rotaviruses begin shortly after birth and that almostall children are infected within the first few years oflife (23, 24). Most infections occurring very early inlife are asymptomatic. Clinical illnesses are predomi-nantly seen in children aged 3 months to 3 years(25-28).

Clinical studies have demonstrated that diarrheabegins within 48 hours of rotavirus ingestion (29).Clinical illnesses associated with rotavirus infectionsare characterized by vomiting and diarrhea and oftencause dehydration, which can be of life-threateningseverity. The diarrhea caused by rotavirus is typicallynoninvasive in character. Correspondingly, the intesti-

nal pathologic lesions caused by rotavirus are limitedto the small intestine and consist of shortening andatrophy of villi, mononuclear cell infiltrates of thelamina propriae, and, occasionally, denudation of themicrovilli (30, 31). In comparison with childhood diar-rheas caused by agents other than rotavirus, rotavirusdiarrhea is clinically more severe, due to its attendantdehydration. As a result, the proportion of hospitalizedchildren with diarrhea excreting rotaviruses is gener-ally higher than the proportion of rotavirus excretersamong children with milder diarrheas detected in thecommunity or in outpatient clinics (19). Rotavirus isthe most common cause of death from acute waterydiarrheal illnesses among children in both industrial-ized and less-developed settings (32).

TETRAVALENT RHESUS ROTAVIRUS-BASEDREASSORTANT VACCINE

Development

Efforts to create a successful vaccine againstrotavirus have been supported by a considerable bodyof evidence indicating that natural rotavirus infectionsare immunizing (33, 34), and that this natural immuneprotection seems to result primarily from induction ofvirus-specific secretory immunoglobulin A antibodiesin intestinal mucosa (35, 36). A carefully conductedcohort study of children from birth to 2 years of age inMexico showed that, relative to children who had hadno previous rotavirus infection, those with one, two,and three previous rotavirus infections had a 77, 83,and 92 percent, respectively, lower risk of subsequentrotavirus diarrhea (37). These observations suggestthat a logical approach would be to create attenuatedlive oral vaccines that could simulate the protectionconferred by natural rotavirus infection.

RRV-TV vaccine represents the culmination of yearsof work to create "Jennerian" vaccines againstrotavirus. The "Jennerian" approach follows EdwardJenner's use of the animal virus cowpox to immunizehumans against smallpox (38). According to this con-cept, live rotavirus strains from animals are naturallyattenuated for humans, due to restrictions in their hostranges, but are still capable of eliciting protectiveimmune responses in humans because human and ani-mal rotaviruses share a major common antigen (39).Various animal rotaviruses have been used to createthese vaccines, including bovine, rhesus, and lambstrains (40).

The first rhesus-rotavirus vaccine, MMU 18006, hada VP7 (G) type similar to human G3 strains. MMU18006 was found to be safe and immunogenic whenadministered to adults (41), but induced self-limitedfebrile reactions 3 to 4 days after dosing of 6-month-

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26 Clemens et al.

old infants (42). When tested for efficacy in infants,MMU 18006 yielded variable results. Although pro-tective in Venezuelan 1- to 4-month-old infants (43),MMU 18006 failed to protect US infants in severaltrials (44-46).

Although the immune correlates of protection againstrotavirus infection and disease are not completelyunderstood, it was suspected that the reason for thesevariable results was that MMU 18006 failed to induceresponses to all of the epidemiologically prevalent Gtypes, G1-G4. There are observations to indicate het-erotypic protection by both natural infections and byimmunization (47, 48). Nevertheless, several lines ofevidence supported the approach of modifying the vac-cine to induce broadened protection against rotavirus Gantigens. Cross-challenge studies in animals suggestedthat protection might be serotype-specific. Moreover,natural history studies of rotavirus infections in chil-dren have demonstrated homotypic protection relatedto the G type of the infecting rotavirus (37, 48).

Accordingly, subsequent modifications of therhesus-based rotavirus vaccine strain, MMU 18006,focused on broadening coverage to include all fourepidemiologically prevalent G types (G1-G4). Toaccomplish this, rhesus-human reassortant viruseswere created in which 10 genes from the rhesus parentstrain MMU 18006 were retained, and a single geneencoding a VP7 protein from a human rotavirus wasinserted. This strategy was employed to maintain theattenuation in the human host of the rhesus parentstrain while adding neutralization specificity to thehuman G serotypes.

Initially, single gene reassortant vaccines to Gl (D xRRV), G2 (DS-1 x RRV), and G4 (ST3 x RRV),respectively, were created (since the parent strainMMU 18006 already had a VP7 gene resembling thehuman G3, it was not necessary to create a reassortantfor the G3 type). The single reassortants proved to besafe, inducing only the self-limited febrile reactionsobserved for the parent strain, and to be immunogenic.However, as was the case for the parent strain, MMU18006, the single reassortants conferred erratic levelsof protection, with protective efficacy rates against anyrotavirus diarrhea of 66 percent and 77 percent inFinland and Rochester, New York, respectively, butpoor efficacy in Peru (49-51). Therefore, a tetravalentvaccine (RRV-TV), containing a mixture of the Gl,G2, and G4 reassortants together with the parent strain,was created. Although serum anti-RRV antibodyresponses and serum neutralizing antibodies to the fourG serotypes in the vaccine have not been demonstratedto correlate well with vaccine protection, theseimmune responses have been used to evaluate theimmunogenicity of RRV-TV. A three-dose regimen of

RRV-TV was supported by the observation that eachsequential dose of a three-dose regimen seemed torecruit additional vaccine responders as judged bythese serum antibodies (52).

Field trials

To date, seven field trials have assessed the protec-tive efficacy of RRV-TV in infants (tables 1 and 2). Allof these trials have been randomized and placebo-controlled. Initially, three trials were done to evaluatethe performance of a three-dose regimen in which theRRV-TV contained 4 x 104 plaque-forming units (pfu)per dose—1 x 10" pfu of each of the four componentstrains. These trials, whose results are shown in table 1,were conducted in the United States (53), Peru (54),and Brazil (52). Substantial levels of protection wereobserved in a US multicenter trial (57 percent protec-tion overall against rotavirus gastroenteritis, 82 percentprotection against clinically severe rotavirus gastro-enteritis). However, levels of protection proved to bedisappointing when the vaccine was tested in twodeveloping countries, although the tendency for protec-tion to be greater against severe than against nonseveredisease persisted in these settings. In Peru, protectionwas 24 percent against all episodes of disease and 30percent against severe disease. In Brazil, protection was35 percent overall and 46 percent against severe dis-ease. As a result of this inconsistent performance of the4 x 104 pfu dose, subsequent trials were designed toevaluate the performance of three-dose regimens ofRRV-TV given at a higher (4 x 105 pfu) dose.

Four field trials of the efficacy of this higher-dose reg-imen of RRV-TV have been conducted (table 2). Twowere done in general populations residing in industrial-ized countries—the United States (55) and Finland (56).The other two were done in less-developed environ-ments—Caracas, Venezuela (57), and on Indian reser-vations in Arizona and New Mexico (58). Levels of vac-cine protection observed in the US multicenter trial (49percent overall and 80 percent against severe disease)were similar to those seen in the earlier US multicentertrial of the lower dose of RRV-TV (table 1), and evenmore encouraging levels of protection were documentedin Finland (68 percent overall and 91 percent againstsevere disease). The trials in developing settings yieldeddiscordant findings, hi Venezuela, protection was sub-stantial: 48 percent overall and 88 percent protectionagainst severe disease. In contrast, when tested inAmerican Indian populations, protection declined to 39percent overall and 66 percent against severe disease.

Although RRV-TV was proven to be protective inthese trials, particularly against clinically severerotavirus infections, and although each of the trialsevaluated serum antibody responses to the diverse


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antigenic components of RRV-TV, no measurement ofthe immune response to RRV-TV differentiated chil-dren who were protected versus those who were not(59). The failure to identify an immunologic correlateof vaccine protection in these trials limits the interpre-tation, of these immunologic responses to RRV-TV andunderscores the need for direct assessments of clinicalprotection when comparing the performance of theRRV-TV in different populations or under differentconditions of vaccine administration.

CONSIDERATIONS FOR THE INTRODUCTION OFRRV-TV

In deliberating about the use of RRV-TV (or anyrotavirus vaccine) in the public health armamentariumof immunizations for infants, several issues are rele-vant (table 3).

Availability of alternative or complementary non-vaccine interventions

Arguments to use RRV-TV would carry more weightif currently available strategies for the treatment andprevention of rotavirus diarrhea were known to be inad-equate. Oral and intravenous rehydration have clearlybeen shown to be effective approaches to preventingdeaths due to dehydration in rotavirus gastroenteritis.Yet, epidemiologic data (vide infra) document thatrotavirus diarrhea persists as a major cause of morbid-ity and mortality worldwide, despite nearly twodecades of efforts to promote the use of proper rehy-dration therapy for children with acute diarrhea. Thus,there is a clear need to prevent this disease entity.

Unfortunately, there is little evidence to suggest thatinterventions to improve water and hygiene will lowerthe risk of rotavirus diarrhea. If such improvementswere effective, one would expect rotavirus diarrhea tobe less frequent in industrialized countries than indeveloping countries. However, epidemiologic studieshave clearly documented the incidence of rotavirusdiarrhea to be similar in industrialized and developingcountries (60), although rotavirus is generally a lesssevere illness in industrialized countries. Similarly,although breastfeeding has been shown to prevent cer-tain enteric infections such as cholera (61) and shigel-losis (62) in developing countries, a comparably potentpreventive effect has not been identified againstrotavirus. If breastfeeding does indeed preventrotavirus diarrhea, the prevention is likely to be limitedto infants, and may even be canceled by a higher rateof rotavirus diarrhea in breastfed than in nonbreastfedchildren during the second year of life (63). In aggre-gate, these observations highlight the need for aneffective vaccine against rotavirus.


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TABLE 2. Efficacy of three-dose regimens of RRV-TV (4 x 10s plaque-forming units (pfu) per dose) in the United States, Finland and Venezuela

C o m t r v Study A9,e A 9 f s F O " ° W - U P Major G Efficacy againstfC o u n t r V (reference no.) ^ j j ^ ^ T y p e D u r a t i o n types* Allrotavirus

Industrialized settings

United States—general Rennels et al. (55) 5-25 weeks >3 week dosing intervals§ Active 4-12 months G1 (80%) 49% (31%, 63%) 80% (56%, 91%)population multicenter G3 (20%)

Joensuu et al. (56,90) 50-130 days 50-130daysH Active 6-18 months G1 (90%) 68% (57%, 76%) 91% (82%, 96%)Finland 80-160 days G4 (9%)

110-202 days(21-90 days dosing

intervals)

Developing settings

Venezuela Perez-Schael et al. (57) 8-11 weeks 8-11 weeksH Passive 19-20 months G1 (96%) 48% (33%, 61%) 88% (61%, 96%)12-16 weeks16-20 weeks

United States—Indian Santosham et al. (58) 6-24 weeks >3-week dosing intervals§ Active 15-24 months G1 (8%) 39% (19%, 54%) 66% (35%, 82%)reservation G3(91%)

* Distribution of G types from rotavirus isolates in trial participants with diarrhea.t 95% confidence interval for protective efficacy is given in parentheses.i Severity defined on basis of 20-point additive scoring system, based on duration of diarrhea, vomiting, maximum number of stools per day, maximum number of times vomited per

rTi day, dehydration, fever, and solicitation of medical care. "Severe" was defined as >11 for the Finnish study, >14 for the US study, and >15 for the American Indian and Venezuelan stud-5; ies.3> § Doses were not given in specific age ranges for each dose, but according to interdose intervals.5. H Age ranges for doses 1, 2, and 3, respectively.

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TABLE 3. Issues to consider in making decisions about theuse of RRV-TV in routine infant immunization programs

1. Availability of alternative or complementary nonvaccineinterventions

2. Burden of disease3. Epidemiologic features of rotavirus disease

• Epidemic versus endemic disease• Age distribution of cases• Serotype distribution of cases

4. Protective characteristics of the vaccine in efficacy trials• Developed versus developing countries• Clinical spectrum of protection• Duration of vaccine protection

5. Clinical effectiveness of the vaccine• Clinical acceptability• Integratability into existing immunization schedules• Logistical requirements• Suitability for the range of infants encountered in

practice• Effects of concomitant vaccines and dietary practices• Potential for interrupting transmission of rotavirus

6. Balance between costs and benefits of vaccination

Burden of disease

The case for using RRV-TV would be buttressed ifthe burden of rotavirus disease could be demonstratedto be similar to the burdens of other childhood infec-tions for which immunization is now routinely under-taken. In the United States, whose rotavirus diseaseburden estimates probably apply to much of the indus-trialized world, it is estimated that about 80 percent ofchildren will experience at least one episode ofrotavirus gastroenteritis during the first 5 years of life(27). It is also estimated for the United States thatapproximately 410,000 physician visits, 50,000 hospi-talizations, and 20 deaths due to rotavirus occur annu-ally in children under the age of 5 years (64-66). Thus,the case for rotavirus vaccine in the United States, andprobably other industrialized settings, is motivated bythe need to reduce rotavirus disease rather than theneed to prevent rotavirus deaths.

Estimates of disease burden in developing countriesare necessarily more speculative than those for theUnited States, but multiple estimates using differentmethods consistently point to a large burden of diseaseand death among infants and young children. Giventhe limited access to medical care in many populationsin developing countries, estimates of physician visitsand hospitalizations in such settings have relatively lit-tle meaning. However, over a decade ago an expertcommittee convened by the Institute of Medicine esti-mated that rotavirus causes approximately 130 millionepisodes of diarrhea in infants and young childrenannually in the developing world, and that theseepisodes account for approximately 870,000 deaths(67). More recently, the annual burden of mortality has

been estimated to be 580,000 to 640,000 deaths peryear, or about 20 percent of the annual global burdenof death due to diarrhea (32, 68, 69). These estimatesof mortality indicate that, in contrast to the situation inindustrialized countries, the case to be made for usinga rotavirus vaccine in developing countries resides inthe ability of such a vaccine to prevent rotavirus diar-rhea of life-threatening severity.

It is useful to place these estimates of rotavirus dis-ease burden in the context of estimates of burdens ofother diseases for which routine childhood immuniza-tion has already been endorsed. Table 4 shows esti-mates of the annual burden of disease due to diphthe-ria, pertussis, poliomyelitis, and measles, expressed asnumbers of hospitalizations and deaths, in the UnitedStates just before licensure of the first vaccines againsteach of these diseases (70). The current burden ofrotavirus disease in the United States, expressed asnumbers of hospitalizations, is greater than the pre-immunization annual burden of hospitalizations forpoliomyelitis, and is somewhat lower in magnitude tothe preimmunization burdens of measles, diphtheria,and pertussis.

Table 4 also shows estimates of contemporary num-bers of deaths due to immunizable diseases in lieu ofvaccination in the developing world. The current esti-mate of mortality due to rotavirus is greater than cor-responding estimates for poliomyelitis and diphtheria,and somewhat less than those for pertussis, neonataltetanus, and measles.

It could justifiably be argued that these comparisonsare simplistic and ignore such issues as the burden ofchronic disability after infections as well as differingpatterns of health care utilization in different secular eras.Moreover, for the developing world, the estimates arebased on limited data. Nevertheless, it would seem thatthe burden of rotavirus disease, expressed in terms of

TABLE 4. Comparative burdens of selected childhood dis-eases, in lieu of vaccination, in the United States and thedeveloping world

DiphtheriaPertussisNeonatal tetanusPoliomyelitisMeaslesRotavirus

United

Hospitalizations

196,600120,700

26,00055,800-465,000

50,000

States*

Deaths

12,6001,594

1,711432

20

Developing

deathst

300,0001,000,0001,200,000

250,0002,700,000

580,000-640,000

* Estimates for the United States for all diseases except rotavirus repre-sent annual estimates for the period just prior to licensure of vaccines forthese diseases, as cited by Orenstein et al. (70). For rotavirus, estimates arederived from Tucker et al. (66).

t Estimates for non-rotavirus diseases in the developing world arederived from estimates for the current annual burden of mortality, in lieu ofvaccination, produced by the Children's Vaccine Initiative. That for rotaviruswas obtained from the World Health Organization (32).


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hospitalizations in industrialized countries, and ofdeaths in developing countries, is of a magnitude that,finances permitting, would warrant commitment ofresources to an effective vaccine.

Epidemiologic features of rotavirus disease

As discussed earlier, RRV-TV has its greatest effectin preventing clinically severe rather than clinicallymild rotavirus diarrhea. This is important, since theburden of rotavirus infections, both in industrializedand in developing countries, resides in their ability tocause severe illnesses requiring medical care or evenresulting in death. Three epidemiologic features ofsevere rotavirus diarrhea are of critical importance todecisions about using RRV-TV vaccine in a publichealth program: the relative importance of endemicversus epidemic disease; the ages at which infants andchildren become ill with rotavirus diarrhea; and thedistribution of rotavirus serotypes accounting for theseillnesses.

Epidemic versus endemic disease. Although smallepidemics of rotavirus diarrhea undoubtedly happen,and although the occurrence of rotavirus infections intemperate climates exhibits clearly defined peaks dur-ing the cooler months of the year, the crucial epidemi-ologic feature of rotavirus infections is that they con-stitute a virtually "inevitable" infection of infancy andchildhood. Thus, the use of RRV-TV, or any other vac-cine against rotavirus, must focus on application as aroutine immunization during infancy rather than as avaccine to contain outbreaks.

Age distribution of cases. For RRV-TV to have amajor impact on rotavirus disease, it must induce pro-tective immunity at an age before an appreciable pro-portion of rotavirus cases occur. Existing trials of RRV-TV have not evaluated whether fewer than three dosesof RRV-TV vaccine are protective. Accordingly, esti-mates of the proportion of severe rotavirus cases notpreventable by RRV-TV, by virtue of their occurrencebefore the age at completion of the vaccine regimen,must take the third dose as the time at which the vac-cine can be considered to be protective. Review of sev-eral studies (71-74) that provided the age-distributionof rotavirus diarrhea cases <36 months of age, detectedin medical treatment settings in the United States andEngland, revealed that a median of about 15 percent ofall such cases occurred before 6-7 months of age. Ifthree doses of RRV-TV are needed for protection, thisfraction would not be preventable by RRV-TV deliv-ered in the 2-, 4-, 6-month age schedule used for rou-tine immunizations in the United States. In these stud-ies the median fractions of cases occurring in the first,second, and third years of life were 45 percent, 37 per-cent, and 18 percent, respectively.

Review of selected treatment center-based caseseries in which rotavirus diarrheal cases <36 months ofage were systematically detected in developing coun-tries (75-82), demonstrated that a median of about 25percent of such cases occurred before 6-7 months ofage. However, a median of only 3 percent of casesoccurred in the first 3-4 months of age, prior to thescheduled age at which the third dose of RRV-TVwould be given if it were administered together withother routine infant immunizations according to theschedule recommended by the Expanded Programmeon Immunisation of the World Health Organization(WHO-EPI). A median of 74 percent, 23 percent, and5 percent of cases occurred in the first, second, andthird years of life, respectively, in these studies.

These data suggest that for the United States, aboutone-seventh of severe rotavirus cases may not be pre-ventable by RRV-TV due their occurrence before com-pletion of the three-dose RRV-TV series. Moreover,because about one-fifth of severe rotavirus cases occurin the third year of life, long-term protection, up to 3years of age (about 2/4 years after dosing), may benecessary for RRV-TV to exert a major overall impacton the problem of severe rotavirus diarrhea in theUnited States and perhaps other industrialized settings.If RRV-TV is given according to the WHO-EPI sched-ule in developing countries, very few cases will not bepreventable by RRV-TV due to onsets before comple-tion of the vaccine regimen. Moreover, since virtuallyall severe rotavirus cases occur in the first 2 years oflife in these settings, vaccine protection will need to besustained only until about 2 years of age (about 20months after dosing) for the vaccine to achieve a majorpublic health impact.

Serotype distribution of cases. It is thought thatimmunity to the VP7 (G type) antigen of the rotavirusouter capsid is a major determinant of the spectrum ofprotection conferred by RRV-TV (59). RRV-TV con-tains only G types 1-4, and it is unknown whether theprotection conferred by RRV-TV will extend beyondthese G types. This is not terribly concerning for indus-trialized countries, where G1-G4 rotaviruses appear toaccount for the vast majority of clinical cases (14).However, recent epidemiologic studies in Brazil andIndia have revealed an unexpectedly high incidence ofrotavirus diarrhea due to G5 and G9 strains, respec-tively (83, 84). Indeed, in India, G1-G4 strainsaccounted for only 43 percent of typeable strains.Thus, while the G1-G4 formulation of RRV-TV appearsadequate for industrialized settings, RRV-TV protec-tion may be vitiated in some developing countries dueto a high prevalence of other G types.

Another common epidemiologic feature of rotavirusis that, in a given population, only one G type tends to


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predominate, at least during a single calendar year. It ispossible in theory, although unproven in practice, thatcirculation of a single rotavirus serotype per se mightfavor higher levels of overall vaccine protection thanthose that would be seen in settings where multipleserotypes co-circulate. Such a scenario would occur ifindividuals protected by the vaccine against oneserotype were not well protected against other circu-lating serotypes and became ill when exposed to theseother serotypes (85, 86). This may be relevant, becausein some tropical environments multiple G types circu-late simultaneously. For example, in Bangladesh in1985-1986, cases of rotavirus diarrhea in childrenunder 36 months of age receiving medical treatmentdisplayed the following G type distribution: Gl (24percent of isolates), G2 (15 percent of isolates), G3 (43percent of isolates), and G4 (17 percent of isolates)(87). The degree to which RRV-TV will protect popu-lations in this sort of epidemiologic milieu is unknownand will require further study.

Protective characteristics of the vaccine inefficacy trials

Several features of RRV-TV's protective efficacyrequire consideration in making a decision to deployRRV-TV as a component of immunizations routinelygiven to infants.

Developed versus developing countries. It has longbeen recognized that the Sabin oral poliomyelitis vac-cine (OPV) is less immunogenic in infants in certaindeveloping countries than in infants in industrializedcountries (88). Similarly, an early-generation, live oralvaccine against rotavirus, RIT 4237, conferredmarkedly inferior protection among infants in severaldeveloping countries than among infants in Finland(89). The potential reasons for the poorer protectionconferred by these live, oral viral vaccines in less-developed settings are multiple, and include, amongothers, the possibilities that infants in impoverishedsettings have a high prevalence of malnutrition and ofcoinfection by enteric viruses. Regardless of the rea-son, however, the gradient of vaccine protection fromdeveloped to developing countries makes it imperativethat judgements about the efficacy of RRV-TV indeveloping settings be based on trials conducted inthese settings.

Table 2 suggests that the efficacy of a three-doseregimen of 4 x 105 pfu of RRV-TV is substantial inboth developed and less-developed settings. However,this conclusion must be considered tentative, sinceboth trials done in developing settings (in Venezuelaand on US Indian reservations) were conducted in pop-ulations that were much better off both materially andin health status than the populations of the poorer

countries of Asia, Latin America, and Africa wherelive oral viral vaccines have exhibited diminishedimmunogenicity or efficacy. Indeed, as shown in table1, it was precisely in such poorer settings in Peru andBrazil that 4 x 104 pfu of RRV-TV failed to protectinfants against rotavirus, in contrast to the substantialprotection conferred by this dose to infants in theUnited States. For this reason, until further trials areconducted in impoverished settings, it would beunwise to consider RRV-TV as suitable for use in thedeveloping world at large.

Clinical spectrum of protection. As shown in bothtables 1 and 2, RRV-TV confers high-grade protectiononly against clinically severe rotavirus gastroenteritis.While severe disease is clearly the rotavirus outcomeof greatest public health interest, use of RRV-TVshould not be undertaken in hopes of providing highlevels of protection against all grades of severity ofrotavirus disease.

In deciding to use RRV-TV, public health decisionmakers must also contemplate the ability of the vac-cine to protect against rotavirus infections of each Gtype contained in the vaccine. Table 2 shows that Glrotavirus infections predominated in three of the fourtrials of 4 x 105 pfu of RRV-TV, while G3 infectionsconstituted the vast majority in the fourth trial. RRV-TV conferred significant levels of protection againstboth of these types, and also conferred high-grade vac-cine protection against G4 rotavirus infections, whichconstituted a minority of infections in the Finnish trial.There is currently no evidence adequate to judgewhether 4 x 105 pfu of RRV-TV protects against G2rotavirus infections.

Finally, in developing, but not in industrializedcountries, an appreciable fraction of infants and chil-dren with rotavirus diarrhea are coinfected by otherenteric pathogens. If these nonrotaviral copathogensparticipate in the pathogenesis of the diarrheal ill-nesses, these mixed infections could conceivably viti-ate the protection of RRV-TV against rotavirus diar-rhea. It is, therefore, important to know whetherRRV-TV confers equivalent protection against etiolog-ically pure versus etiologically mixed rotavirus diar-rhea. The Venezuelan trial (table 2) documented equiv-alent vaccine protection against etiologically pure (43percent) and etiologically mixed (54 percent) cases ofrotavirus diarrhea, suggesting that the efficacy of RRV-TV is not diminished by enteric coinfections.

Duration of vaccine protection. As described earlier,analysis of the age-distribution of severe rotaviruscases suggests that, to have a major public healthimpact, RRV-TV should confer protection until 3 yearsof age (for about 30 months after completion of theregimen) in industrialized countries and until 2 years


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32 Clemens et al.

of age (for about 20 months after completion of theregimen) in developing countries. Since no trial hasevaluated the effect of booster doses of RRV-TV, theduration of protection conferred by a primary three-dose series is important in judging the potential publichealth value of RRV-TV.

In the US multicenter trial of 4 x 105 pfu of RRV-TV(table 2), subjects were followed for only 1 year afterdosing. In contrast, the Finnish trial of this dose con-ducted active surveillance for 2 years, finding nodecline in protection over this interval. Moreover, hos-pital surveillance was maintained for 3 years; protec-tion against hospitalized rotavirus gastroenteritisremained between 96 to 100 percent in each of the 3years of follow-up. A less clear picture of the durationof RRV-TV, given at the higher (4 x 105 pfu) dose,emerged from the two trials in developing settings.Protection was sustained for 2 years in Venezuela, butvanished during the second year of follow-up in thetrial conducted on US Indian reservations.

Clinical effectiveness of the vaccine

Considerations outlined above address the perfor-mance of the vaccine under the relatively idealizedconditions of pre-licensure trials of vaccine efficacy.However, vaccines do not always perform in the fash-ion predicted by efficacy trials when they are subjectedto the vagaries of public health practice. It is, therefore,important to consider factors that may modify the clin-ical effectiveness of RRV-TV, or the balance betweenbeneficial and detrimental outcomes, when RRV-TV is

administered under the ordinary conditions of publichealth programs.

Clinical acceptability. Central to this balance is theoccurrence and severity of side effects induced byRRV-TV. Side effects observed in the four trials of 4 x105 pfu of RRV-TV are presented in table 5. Sideeffects attributable to RRV-TV have been seen onlyafter the first dose of three-dose regimens, presumablybecause immunity induced by the vaccine mitigatesadverse reactions due to subsequent doses. After thefirst dose, the side effect most commonly attributed toRRV-TV is fever, usually on days 3-5 after dosing.Although these febrile reactions have often beendescribed as being infrequent and mild, data from thetrials do not consistently support this characterization.In the Finnish trial (56, 90), 35 percent of vaccineesversus 6 percent of placebo recipients had fevers(>38°C rectally), and in 3.5 percent of vaccinees ver-sus 0.5 percent of placebo recipients the fevers were ofhigh magnitude (>39°C rectally). In this trial, therewas also an excess of unusual irritability (37 percentversus 29 percent, p <0.001), decreased appetite (18percent versus 9 percent, p <0.001), excessive crying(49 percent versus 39 percent, p <0.001), abdominalcramping (25 percent versus 22 percent, p <0.05), anddiarrhea (2.8 percent versus 1.4 percent, p <0.05) inRRV-TV vaccinees versus placebo recipients, andthese symptoms were associated with the presence offever. One RRV-TV vaccinee (out of 1,184) in theFinnish trial was admitted to the hospital with feverand excessive crying 3 days after dosing. In the USmulticenter trial (55), fevers >39°C rectally were not

TABLE 5. Adverse effects following the first dose of RRV-TV (4 x 10s plaque-forming units (pfu) per dose) in field trials conductedin the United States, Finland, and Venezuela

Country andnumber under follow-up

Study(reference no.)

Study methods Occurrence of (%):

Surveillance Body Temperature

Type Duration temperature > 3 8 ° c DurationDiarrhea Vomiting

United States—generalpopulation

Vaccine (n = 428)Placebo (n = 425)

FinlandVaccine (n= 1,184)Placebo (n = 1,197)

VenezuelaVaccine (n = 1,247)Placebo (n = 1,233)

United States—Indianreservation

Vaccine (n = 396)Placebo (n = 391)

Rennels et al. (55)

Joensuu et al. (56)

Perez-Schael et al. (57)

Santosham et al. (58)


Daily parental diaries 5 days Axillary

Daily parental diaries 5 days

Developing settings

Visits to health facility

Daily parental diaries

6 days

5 days

Rectal

Rectal

Rectal

74

35f6

15t7

2117

NR*NR

3.5t0.5

NRNR

NRNR

76

NRNR

97

76

45

NRNR

1616

67

* NR, not reported.t p < 0.001 (one-tailed) for the vaccine versus placebo comparison.


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separately tabulated, but it is noteworthy that 7 percentof vaccinees versus 4 percent of placebo recipients hadaxillary temperatures >38°C, which are roughly equiv-alent to temperatures >39°C rectally. In this trial two(0.5 percent) RRV-TV recipients, versus no placeborecipients, were hospitalized for fever, vomiting, anddiarrhea, both on days 3-4 after dosing. Finally, inVenezuela (57), passive surveillance for post-dosingside effects among children brought to treatment cen-ters found fever in 15 percent of vaccinees versus 7percent of placebo recipients. In aggregate, these datasuggest that use of RRV-TV may cause symptomssevere enough to provoke physician visits, particularlysince fever in an infant under 3 months of age (whenfirst doses of RRV-TV would be scheduled in practice)is a matter of potentially serious medical concern.

Integratability into existing immunization schedules.Rotavirus is a significant disease only during the first 3years of life, and imposes a major burden of illness dur-ing infancy. Thus, to have a major public health impact,RRV-TV must be administered early in infancy. Theargument for adding RRV-TV to the current battery ofrecommended vaccines for infants would be strength-ened if RRV-TV could be given at the same visitsscheduled for delivery of the currently recommendedvaccines. At least two considerations support this asser-tion (70). First, economic analyses of vaccines regu-larly identify the costs of delivering a vaccine as amajor determinant of a vaccine's cost-effectiveness(91). In the current era of cost-containment for healthcare in industrialized countries and of sparse resourcesfor health care in developing countries, a favorablecost-effectiveness profile is very important in decidingwhether to introduce a new vaccine such as RRV-TV.Second, a vaccine will only be as effective as the levelof coverage achieved by the vaccine delivery system.Administration of a new vaccine at times scheduled fordelivery of conventional vaccines, rather than at addi-tional visits, offers considerable advantages in attaininghigh levels of vaccine coverage.

There are no published data on vaccine efficacy tosupport the use of RRV-TV at the first contact rou-tinely used to deliver vaccines, shortly after birth,although reports of the natural protection conferred byneonatal rotavirus infection suggests that neonatalimmunization with a suitable rotavirus vaccine is apotentially attractive possibility (92). Moreover, notrials have addressed whether fewer than three dosesare protective. In addition, as shown in table 2, no trialhas evaluated whether dosing can begin earlier than at5 weeks of age or later than 25 weeks of age. The dos-ing schedules used by the four trials shown in the tablewere somewhat different. The two trials done in theUnited States required initiation of dosing anywhere

between 5-6 and 24—25 weeks of age. Neither trialspecifically tested the use of RRV-TV within the 2-, 4-,6-month schedule recommended for infant immu-nizations in the United States, although a fraction ofparticipants in each trial probably received RRV-TVaccording to this schedule (93). Reports of three trialsstated that at least 3 weeks were required betweendoses, while that for the fourth trial (57) did not note aminimum interdose interval requirement. The twotrials done outside the United States evaluated three-dose regimens within age-bands used for routine infantimmunizations in Finland and Venezuela, respectively.However, neither trial conducted in a developing set-ting (Venezuela, US Indian reservations) examined theuse of RRV-TV in the 6-, 10-, 14-week schedule rec-ommended by the WHO-EPI for the delivery of diph-theria toxoid-tetanus toxoid-pertussis (DTP) vaccinein developing countries.

This omission could be important, becausematernally-derived anti-rotavirus antibodies, whichdecline with age during infancy, are thought to inter-fere with the immunogenicity of RRV-TV (94-96), butto have the beneficial effect of mitigating the reacto-genicity of the vaccine (97). Thus, it cannot beassumed that the level of protection found for RRV-TVwhen delivered later in infancy, when maternally-derived anti-rotavirus serum antibodies are present inlow titer, will also be found when the vaccine is givenaccording to the WHO-EPI schedule early in infancy,when maternal antibodies are present in higher titer.Finally, as noted below, there are no published dataaddressing the safety and protectivity of RRV-TVwhen it is given during febrile illnesses or when theinfant has diarrhea. Other routine immunizations arerecommended for infants with mild febrile illnesses(98) to avoid "missed opportunities." Selective defer-ral of RRV-TV until after such illnesses have resolved,due to the lack of data about using RRV-TV duringthese illnesses, would generate logistical complexitiesand increased costs, and might diminish levels of cov-erage with RRV-TV.

The implications of these considerations are thatpublic health programs contemplating use of RRV-TVin infants must employ a three-dose schedule initiatedbetween 5-25 weeks of age, with at least 3 weeks sep-arating each dose. How RRV-TV will perform whengiven within routine immunization schedules is some-what uncertain, since, although numerous three-doseschedules have been tested, neither the one used by theUnited States nor the one currently recommended bythe WHO-EPI has been specifically evaluated.Whether RRV-TV should be given with other routineimmunizations during mild febrile illnesses isunknown. Deferring RRV-TV doses for this reason


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34 Clemens et al.

would constitute a major impediment to attaining highlevels of vaccine coverage and to delivering RRV-TVat low cost.

Logistical requirements. RRV-TV is formulated as alyophilized solid, which has been demonstrated to bestable for 24 months when stored between 20-25 °C,though freezing inactivates the vaccine. Thus, RRV-TV can be conveniently stored in a manner identical toDTP vaccine, inactivated poliomyelitis vaccine (IPV),and protein-conjugate vaccines against Haemophilusinfluenzae type b. Although RRV-TV is acid-labile andmust be delivered with buffer, it requires reconstitutionin only 2.5 ml of buffered diluent, facilitating oraladministration to young infants. Once reconstituted,the vaccine remains stable at room temperature foronly up to 60 minutes and in the refrigerator for up to4 hours. Together, these features make RRV-TV read-ily integratable into the logistics of storing and distrib-uting existing infant immunizations, and quite easilyadministered even to young infants.

Despite its attractive properties for industrializedcountries, the single-dose, lyophilized formulation ofRRV-TV, and the need to reconstitute the vaccine inbuffer before ingestion, may have some disadvantagesfor developing countries.

The use of lyophilization and of single-dose packag-ing both increase the expense of the vaccine.Moreover, there is concern that the inclusion of bufferfor reconstitution may result in erroneous injectionrather than ingestion of the vaccine. Future researchwill therefore focus on development of cheaper multi-dose liquid formulations for use in these settings.

Suitability for the range of infants encountered inpractice. All four of the major efficacy trials of 4 x 105

pfu of RRV-TV (table 2) enrolled only infants judgedto be healthy, and the Venezuela trial specificallyexcluded infants who were born prematurely. Whilesuch restrictions are conventional in pre-licensuretrials, they leave doubt about the performance of RRV-TV in the full range of infants who can be expected tobe seen in routine public health practice. Of specialconcern in this regard are infants who were born pre-maturely, since it is conceivable that immuneresponses to vaccine could be attenuated by immuno-logic immaturity in these infants, and that vaccine sideeffects could be more frequent or more severe due tolower titers of maternally derived anti-rotavirus serumantibodies. The second group of concern consists ofinfants who are immunocompromised, including thosewith vertically transmitted human immunodeficiencyvirus (HIV) infection. Without data on the safety andefficacy of RRV-TV in these subgroups, it is unknownwhether these infants should be included in routineimmunization programs. Exclusion of such infants

from immunization programs in industrialized coun-tries is feasible, and the number of immunocompro-mised infants is small. However, the proportion ofinfants born preterm is not negligible, approximately11 percent in the United States (99). Thus, if suchexclusions were made, they would diminish the over-all preventive impact of programs of vaccination withRRV-TV on the burden of rotavirus diarrhea.

Effective implementation of such exclusions indeveloping countries, however, is less straightforward.It is often impossible to identify infants born prema-turely in most such settings, due to the limited use ofprenatal care and to the common occurrence of birthsoutside of hospital facilities. Moreover, few suchcountries conduct the comprehensive HIV screening ofmothers that would be necessary to identify potentiallyinfected infants. If such exclusions proved necessary, itis difficult to envisage how RRV-TV could be given inroutine immunization programs without inadvertentlyimmunizing these subgroups of infants. Moreover,even if such exclusions could be operationalized inpractice, the high combined prevalence of maternalinfection by HIV and of prematurity in many develop-ing countries, especially in sub-Saharan Africa andAsia, would severely constrain the numbers of infantswho could be vaccinated, thereby limiting the abilityof vaccination programs to impact on the burden ofrotavirus diarrhea in these settings.

As noted earlier, another subgroup of infants forwhom the safety and efficacy of RRV-TV is not cur-rently known consists of infants with febrile or diar-rheal illnesses at the time of vaccination. Two of thefour trials in table 2 (in Finland and Venezuela) specif-ically deferred dosing in such situations, and the othertwo trials provided no data to indicate whether such ill-nesses affected vaccine efficacy or safety. In lieu ofsuch information, the need for such deferrals is uncer-tain. Because of the high frequency of such acute ill-nesses in infants, especially in developing countries,such deferrals could have a major negative effect onvaccine coverage, by necessitating additional visits,and could substantially increase the cost of vaccinat-ing.

Effects of concomitant vaccines and dietary prac-tices. If RRV-TV is to be integrated into the routineschedule of infant immunizations, it must be givenconcomitantly with other vaccines, including OPV (orIPV), DTP vaccine, polysaccharide-protein conjugatevaccines against H. influenzae type b, and hepatitis Bvaccine. It is thus necessary to be sure that RRV-TVdoes not interfere with immune responses to these vac-cines, and that the other vaccines do not interfere withimmune responses to RRV-TV. It is also important toascertain that RRV-TV, given simultaneously with the


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additional vaccines, does not cause unacceptable sideeffects.

In the US multicenter trial shown in table 2, only aproportion of participants received OPV concomi-tantly with RRV-TV. It was therefore possible to assessimmune responses to three doses of 4 x 105 pfu ofRRV-TV given alone versus given concomitantly withOPV. This analysis revealed no significant diminutionof serum anti-rotavirus antibody responses attributableto coadministration of OPV, and no inhibition of serumneutralizing antibodies to poliovirus serotypes 1, 2, or3 in infants who concomitantly received RRV-TV(100). Moreover, analysis of RRV-TV vaccine efficacyshowed no diminution of efficacy in infants whoreceived concomitant OPV, although the statisticalpower of the trial to detect such a decline in efficacywas limited.

There are no published studies addressing whetherthere is immune interference between RRV-TV andDTP, IPV, polysaccharide-protein conjugate vaccinesagainst H. influenzae type b, or hepatitis B vaccine.However, in the Finnish trial of 4 x 105 pfu of RRV-TV(table 2), coadministration of the first dose of RRV-TVwith a DTP vaccine containing pertussis whole cells,in comparison with administration of RRV-TV withoutDTP, led to a one-third increase in the incidence of anyfever >38°C (29 percent to 39 percent) and over a dou-bling of the incidence of fevers >39°C (2 percent to 5percent) on days 3-5 after the first dose (90). Sincenone of the four major trials shown in tables 2 and 5routinely gave RRV-TV concurrently with DTP vac-cine, it is unclear whether the rates of side effectsshown in table 5 fully reflect this combined vaccineeffect. Moreover, it is unknown whether such interac-tions occur with DTP vaccines using less reactogenicacellular pertussis components.

Because breast milk is known to contain immuneand nonimmune factors that can inhibit rotavirus, andbecause it will be difficult in practice to isolate dosingwith RRV-TV from ingestion of breast milk, it isimportant to be certain that RRV-TV does not performless well in breastfed infants. Several studies in indus-trialized countries have demonstrated that 4 x 104 pfuof RRV-TV induces comparable immune responses inbreastfed versus nonbreastfed infants (101, 102), evenwhen breast milk is given just prior to dosing (103).Moreover, one trial of the efficacy of this dose of RRV-TV (53, 101) demonstrated clinical protection to besimilar in breastfed versus nonbreastfed infants. Todate, however, no such studies have been done for the4 x 105 pfu dose of RRV-TV proposed for licensure,though one would not expect inhibition of the higherdose when none was found for the lower dose. Ofgreater concern is the fact that no such studies have

been done in developing countries, where it is possiblethat levels of anti-rotavirus factors in breast milk maybe higher than in industrialized countries and wherethe prevalence of breastfeeding of infants is also gen-erally higher.

Potential for interrupting transmission of rotavirus.Because of the likely importance of person-to-persontransmission of rotavirus between infants and youngchildren, mass rotavirus immunization of infants couldlead to even better than expected vaccine performanceas a result of vaccine-induced reduction of person-to-person transmission of rotavirus. Such a reductioncould occur both by protection of vaccinees, withresulting diminution of excretion of rotavirus in thecommunity, and by inadvertent transmission of RRV-TV from vaccinees to nonvaccinees, with resultingimmunization of these contacts. That the latter mightoccur is suggested by the results of the Venezuela trial(57), which detected the vaccine strain, concomitantlywith wild rotavirus, in 15 percent of episodes ofrotavirus diarrhea in vaccinees and in 13 percent ofsuch episodes in nonvaccinees. However, excretion ofthe vaccine strain in these cases was at such low con-centrations that the strain could be detected only witha polymerase chain reaction assay, not with conven-tional assays. It is not clear whether excretion and hor-izontal transmission of the vaccine can occur in suffi-cient amounts to immunize contacts of vaccinees. Inany event, if use of RRV-TV does interrupt the inten-sity of rotavirus transmission, this interruption couldenhance the impact of RRV-TV both by protectingnonvaccinees (104) and by enhancing the protectionconferred to vaccinees (85). At present, such indirectbenefits remain only hypothetical possibilities, sincethe individual randomization used by pre-licensuretrials precluded assessment of indirect vaccine protection(105).

Balance between costs and benefits ofvaccination

An important consideration in decisions to use RRV-TV in public health programs is the balance betweencosts and benefits of vaccination. Table 6 summarizesseveral cost-effectiveness analyses of the use ofrotavirus vaccines in both the United States and indeveloping countries. In the United States and otherindustrialized countries, the focus has been on the netcosts or savings resulting from the use of RRV-TV (ora vaccine having the price, dosing requirements, andefficacy of RRV-TV), rather than the costs per deathprevented, since rotavirus causes very few deaths inthe industrialized settings.

An analysis done by the US Centers for DiseaseControl and Prevention (CDC) in the mid-1990s (106)


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TABLE 6. Analysis of costs and effects of adding rotavirus vaccine to the existing immunization schedule for infants

I'3

Iro

Country and year*

United States, 1992

United States, 1993

United States, 1996

Finland. 1993

Less developed countries,1982



Study(reference no.)

Griffiths etal. (107)

Smith etal. (106)

Tucker et al. (66)

Takala etal. (108)

de Zoysa and Vesikari(109)

de Zoysa and Feachem(110)

Creese (111)

Vaccine

Regiment

3 doses at 36-161 days,62-184 days, and83-209 days

3 doses at 2, 4, and 6months





All doses completedby 6 months

All doses completedby 6 months

3 doses completed by6 months

3 doses completed by6 months

PE (%)t Cost§

Post-vaccinationfollow-up


49

50

50

50

50

68

NR**

$30.00

$30.00

$20.00

$20.00

NR

£1 year after last dose

<5 years of age

<5 years of age

<5 years of age

<5 years of age

<26 months of age

Developing settings

60

80

70-90

70-90

$2.00

$2.00

$2.00

$15.00

<5 years of age

<5 years of age

<5 years of age

<5 years of age

Perspective^

Society

Health system

Society

Health system

Society

Society

Health system

Health system

Health system

Health system

Base-case increased costper prevented:

Case

NR

Cost-saving

Cost-saving

$103.00

Cost-saving

NR

$5.00

$4.00

$2.20-$5.70

$16.70-$42.90

Death

NR

NR

NR

NR

NR

NR

$222.00

$312.00

$139.00-$357.00

$1,042.00-$2,679.00

Break-even costper dose#

$3.67

$40.00

NR

$9.00

$51.00

$7.30

NR

NR

NR

NR

* Denotes the year of US currency used for the analysis,t Regimens and ages for dosing.$ Denotes protective efficacy (PE) against all cases of rotavirus diarrhea.§ For the studies of Tucker et al. and Smith et al., cost refers to cost of dose of vaccine. For the remaining studies, cost refers to the total incremental costs of giving the vaccine

(including vaccine costs and vaccine delivery costs).H Perspective refers to the range of costs considered in the analysis—health system costs: those only directly related to health care provision; social costs: health system costs

plus other expenditures of personal finances (e.g., transportation, loss of salary) by patients and their families related to acquisition of health care.# Cost per dose of vaccine (Tucker et al. and Smith et al.) or total incremental costs of giving a dose of vaccine, including vaccine cost and vaccine delivery costs (Griffiths et al.

and Takala et al.), for which increased costs arising from vaccine administration would exactly match money saved due to prevented rotavirus illness.** NR, not reported.

COCOCO

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found that even if a vaccine with the characteristics ofRRV-TV were to cost $20.00 (1993 currency) per dose,the use of a three-dose regimen, integrated at an addi-tional cost of $10.00 per visit into the normal scheduleof infant immunizations, would be cost-saving from theperspective of the health care system. In contrast, anupdate of the first CDC analysis (66), which assumedthat a lower proportion of rotavirus diarrhea episodeswould result in health care visits, concluded that ifRRV-TV were to be administered in three doses, inte-grated with the normal schedule of infant immuniza-tions, and if, as in the first analysis, RRV-TV were tocost $20.00 (1996 currency) per dose together with anadditional $10.00 cost for administering each dose, theuse of RRV-TV would not be cost-saving to the healthsystem. Instead, it would cost the health system$103.00 per case of rotavirus diarrhea prevented. Thebreak-even cost—the cost of vaccine at which the costof vaccinating and the costs saved due to prevention ofrotavirus diarrhea exactly cancel out one another—didnot occur until the cost of each dose declined to $9.00.In contrast, if all societal costs were considered, includ-ing both health system costs and all losses of personalincome in relation to obtaining health care, vaccina-tion was cost-saving at prices up to $51.00 per dose.However, because neither of the two CDC analysesconsidered health system and personal costs attri-butable to vaccine side effects, it is possible that bothanalyses underestimated the net costs of implement-ing a program of RRV-TV immunization in USinfants.

Two analyses of RRV-TV in industrialized settingsconsidered costs attributable to side effects (107, 108).Both analyses evaluated costs from the societal per-spective. One analysis, done in the United States(107), found that RRV-TV was not cost-saving to soci-ety at $20.00 (1992 currency) per dose, and that itbecame cost-saving only when all costs related to pur-chasing and administering the three-dose regimen fellbelow $11.00 (e.g., $3.67 per dose). A second analysis,performed in Finland (108), came to the conclusionthat RRV-TV would be cost-saving in that setting ifvaccine and vaccine delivery costs (1993 currency) forthree doses were to fall below $17.80 (e.g., $5.93 perdose). Because the currently marketed RRV-TV vac-cine is sold by the manufacturer for $38.00 per dose,the findings of these two analyses imply that societymust be willing to expend additional money in order toenjoy the preventive benefits of RRV-TV.

Cost-effectiveness analyses for developing countries(table 6) have been performed generically for rotavirusvaccines, not specifically for RRV-TV. These analyseshave assumed, perhaps optimistically, that levels ofvaccine protective efficacy will be 70-90 percent and

have failed to account for costs attributable to vaccineside effects. Both of these features might have led toestimates of cost-effectiveness that were too favorableto the vaccine. Because the major goal of usingrotavirus vaccines in developing countries is to preventrotavirus deaths rather than to lower the burden ofrotavirus diarrhea on the health care system, theseanalyses have focused on the cost per death avertedowing to use of rotavirus vaccine. Two of the analyses(109, 110) assumed, somewhat unrealistically, that thetotal additional cost (vaccine plus administration) ofgiving a complete regimen of rotavirus vaccine, inte-grated into the existing schedule of infant immuniza-tions, will be only $2.00 (1982 currency). With thisassumption, the cost to the health care system of pre-venting a rotavirus death with immunization would bebetween $222.00 and $312.00. With the more realistic,albeit still low, assumption that the cost for a completevaccine regimen would be $15.00 (1982 currency), athird analysis (111) found that between $1,042.00 and$2,679.00 would be required to prevent a rotavirusdeath. By comparison, it has been estimated that themedian costs (in 1982 currency) per childhood diar-rheal death prevented would be only $140.00 formeasles immunization and $220.00 for oral rehydra-tion therapy programs, but would be of a similar orderof magnitude (approximately $1,000.00) for breast-feeding promotion and hygiene promotion programs(112).

COMMENT

In this review we have provided an outline of con-siderations relevant to deliberations about the use ofrotavirus vaccines during infancy. We have focused onRRV-TV, since this vaccine is the first to haveachieved licensure in the United States and since theUnited States is now officially recommending the useof RRV-TV as a routine immunization at 2, 4, and 6months of age (6). However, the considerations that weused for our assessments of RRV-TV are potentiallyapplicable to any rotavirus vaccine being consideredfor use in infants.

Several factors underscore the need for an effectivevaccine against rotavirus. First, the burden of rotavirusdisease—as measured by health provider visits andsocietal costs in industrialized countries and by diar-rheal deaths in developing countries—is immense.Second, this high burden persists today despite exten-sive promotion of rehydration therapy for acute waterydiarrheas of childhood. Third, it is unlikely that non-vaccination approaches will effectively preventrotavirus diarrhea, since breastfeeding appears to beminimally effective in preventing rotavirus disease andsince improvements of water quality and hygiene have


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38 Clemens et al.

not reduced disease incidence in industrialized relativeto developing countries.

The question, therefore, is not whether an effectiverotavirus vaccine is needed, but whether the current baseof evidence is adequate to recommend integration ofRRV-TV into the routine schedule of immunizations forinfants in both industrialized and developing countries.Several observations argue strongly for the use of RRV-TV in industrialized settings. Three-dose regimens ofhigh-dose (4 x 105 pfu) RRV-TV conferred substantialprotection against severe rotavirus diarrhea when testedin two trials in industrialized settings (table 2). In thesesettings, relatively few cases of rotavirus diarrhea occurbefore 6 months of age, when the three-dose regimen ofRRV-TV should be complete, and the vast majority ofcases are due to rotaviruses manifesting G types \^\contained in the vaccine. Moreover, clinical trials inindustrialized settings have shown the vaccine to preventrotavirus disease due to three of these G types (1,3, and4). One of these trials, done in Finland, has also demon-strated that the vaccine confers long-lasting protectionfor the 3 years following dosing, a feature that is impor-tant because of the appreciable occurrence of diseaseduring each of the first 3 years of life in many industrial-ized settings. RRV-TV is amenable to storage within theexisting logistical system used for conventional vaccinesfor infants, is easy to administer, and is integratable intothe existing schedule of infant immunizations (concomi-tantly with DTP vaccine, protein-polysaccharide conju-gates against H. influenzae type b, hepatitis B vaccine,and OPV or IPV). Importantly, no immune interferencehas been detected when RRV-TV has been given con-comitantly with OPV, although published evaluations ofimmune interactions between RRV-TV and the othervaccines given at the same times as OPV are lacking.Finally, coadministration of breast milk, at least frommothers in industrialized countries, does not seem tointerfere with vaccine immunogenicity or efficacy.

What uncertainties still exist about the use of RRV-TV in industrialized settings? One is the performanceof the vaccine when it is actually given according to the2-, 4-, and 6-month age schedule used in the UnitedStates. It is reassuring that the vaccine has been testedaccording to several schedules with reasonably consis-tent results (table 2). However, no trial has presenteddata on the performance of the vaccine when adminis-tered according to the 2-, 4-, 6-month age schedule ofthe United States, or according to many of the verydiverse schedules used in other industrialized countrieswhere RRV-TV will be considered for licensure in thefuture (113). Another lingering question is the clinicalacceptability of RRV-TV. An appreciable percentage(up to 35 percent in one study (90)) of vaccine recipi-ents have been observed to develop fever after the first

dose, at times resulting in hospitalization, and existingevaluations may have underestimated the magnitude ofpost-dosing fevers by not routinely giving RRV-TVconcomitantly with DTP vaccine. A third uncertaintycomes from the lack of data on whether the vaccineprotects against G type 2 rotavirus diarrhea. Althoughthis G type was not common in the sites where field tri-als were conducted, a summary of G-typing of clinicalisolates from nine countries between 1982 to 1992found that G2 accounted for 27 percent of isolates (14).

There are, in addition, important gaps in our knowl-edge about the efficacy and safety of RRV-TV inimmunocompromised infants, as well as those bornprematurely. Moreover, the safety and efficacy of RRV-TV has not been evaluated in infants with febrile ordiarrheal illnesses. If it proves necessary to defer vac-cination with RRV-TV in such situations, these defer-rals will necessitate additional visits and increasedmedical costs, and may result in diminished levels ofcoverage with RRV-TV. In addition, although RRV-TVmight in theory interrupt transmission of rotavirus, andthereby exert a greater than expected preventive effectwhen used in mass immunization programs, no studieshave addressed this important possibility. Finally, at theprice currently charged by the manufacturer of RRV-TV ($38.00 per dose), it is not clear whether RRV-TVwill be cost-saving or will generate additional costs(table 6). From the perspective of the health system ofthe United States, the break-even cost per dose, that isthe cost above which use of the vaccine will generateadditional costs, has ranged from $40.00 (106), whichis above the current vaccine price, to the more recentestimate of $9.00 (66), which is well below the currentvaccine price. From a societal perspective, break-evencosts from analyses of the United States and Finlandhave ranged from $3.67 (107) to $51.00 (66), and twoanalyses from the United States and Finland (107, 108)have found the combined break-even cost of vaccineand vaccine administration of single dose of RRV-TVto range from $3.67 to $5.93—well below the currentprice of the vaccine per se. The net economic impact ofdeploying RRV-TV as a routine infant immunizationthus remains in doubt.

Decision making about the use of RRV-TV in devel-oping countries is frought with even more uncertainties.It is true that RRV-TV performed quite well in urbanVenezuela and conferred significant, though not asimpressive, protection in infants on US Indian reserva-tions (table 2). However, despite the results of these twotrials, we currently lack several pieces of evidence thatare needed for deliberations about recommendations foruse of RRV-TV in infants residing in developing coun-tries. Previous experience with two other live oral viralvaccines, OPV and RIT 4237, revealed that the vaccines


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were often disappointingly immunogenic and protec-tive in infants residing in the poorest developing coun-tries, despite good results among infants in more afflu-ent settings (88, 89). A similar picture emerged for thelower dose (4 x 10" pfu) version of RRV-TV in field tri-als done in Brazil and Peru, in comparison with the highlevels of efficacy seen for this dose in the United States(table 1). Although substantial levels of efficacy wereobserved for 4 x 105 pfu doses of RRV-TV in Venezuela(table 2), this setting was much more affluent than thesettings for the earlier Peru and Brazil trials, and thetrial of the same dose of RRV-TV in US Indians foundthat efficacy persisted for only 1 year after dosing,declining to nil during the second year. As articulatedby a recent WHO consensus group (114), the uncertain-ties created by these observations can only be addressedby future studies of RRV-TV in the truly impoverishedsettings of Asia, Africa, and Latin America where ear-lier live oral viral vaccines failed.

We also lack published data about the performanceof RRV-TV when given in the 6-, 10-, and 14-weekschedule recommended by the WHO-EPI for develop-ing countries. Will high levels of maternally derivedanti-rotavirus serum antibodies interfere with protec-tion by dosing this early in infancy? Moreover, welack evidence about performance of RRV-TV againstG types other than G1-G4, such as the G5 and G9strains found to be prevalent in Brazil and India,respectively (14). Although RRV-TV and OPV werenot found to interfere with one another when givensimultaneously to infants in industrialized countries(100), evidence about vaccine interactions is stillneeded for infants in developing countries. Similarly,since the anti-rotaviral properties of mothers' breastmilk in developing countries may differ from those ofmothers in industrialized countries, assessment of thepossibility of interference with RRV-TV by breast-feeding needs to be specifically evaluated in develop-ing countries where breastfeeding is prevalent.Because of difficulties in correctly identifying infantsand mothers in developing countries who are HIV-infected, as well as infants who are born prematurely,the lack of data addressing vaccine safety and efficacyin these subgroups poses operational problems for theuse of RRV-TV in many developing countries.Equally needed are data on vaccine safety andimmunogenicity in infants with febrile or diarrheal ill-nesses, which are especially common among infantsin developing countries. Studies of RRV-TV in infantswith these conditions are required before RRV-TV canbe feasibly delivered by the Expanded Programme onImmunisation of most developing countries.

The high rate of post-dosing fevers sometimesobserved when RRV-TV when given concomitantly

with whole cell pertussis-based DTP vaccine (90) ispotentially concerning for developing countries andrequires further study, since it is unlikely that thesecountries will have access to DTP products containingsafer acellular components in the foreseeable future.As in industrialized countries, we need evidence aboutwhether RRV-TV can augment direct protection ofvaccinees by interrupting transmission in developingcountries. Finally, regardless of the answers to thesequestions, RRV-TV will not be a public health tool forthe developing world unless it is made available at lowcost (115).

It probably will not be necessary to launch new stud-ies to address all of these gaps in our knowledge aboutRRV-TV. For example, there may be unpublished datato address several of these issues. Moreover, someissues, such as the effects of RRV-TV when givenaccording to the 2-, 4-, 6-month age schedule used inthe United States or to the 6-, 10-, 14-week schedulerecommended by the WHO-EPI, may be addressableby conducting subanalyses of completed trials.Publication of such analyses in peer-reviewed journalswould be helpful in placing future discussions about thepublic health role of RRV-TV on an objective plane.

Our analysis of the public health prospects for RRV-TV, summarized in this review, also provides lessonsfor the evaluation of other new-generation rotavirusvaccines currently under development. Many of theuncertainties that we now have about RRV-TV can beavoided for future rotavirus vaccines if clinical evalu-ations of these vaccines are designed to provide asbroad a picture as possible about the likely publichealth effects of the vaccines when they are deployedin the diverse spectra of infants to be targeted by pub-lic health programs and under the usual conditions ofthese programs. Moreover, because of the complexi-ties in making judgements about the use of rotavirusvaccines for infants in the developing world, and theimpossibility of projecting the performance ofrotavirus vaccines in the developing world on the basisof data from more affluent countries, future rotavirusvaccines should be evaluated in impoverished settingsof the developing world as components of thesequence of pre-licensure studies. Otherwise, we mayagain find ourselves in the position of being ready tooffer an effective rotavirus vaccine to infants in indus-trialized countries, where rotavirus is a medical nui-sance, but unable to render a judgement about the suit-ability of the vaccine for infants in developingcountries, where rotavirus is a major killer.

ADDENDUM: In pre-licensure studies of RRV-TV,five cases of intussusception occurred in 10,054 recipi-ents of vaccine, a risk that was not statistically higherthan the risk observed for nonvaccinees (one out of


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40 Clemens et al.

4,633 controls). On the basis of these data, intussus-ception was listed as a potential adverse reaction in thepackage insert, and post-licensure surveillance for thisadverse event was recommended by the AdvisoryCommittee on Immunization Practices. During theperiod September 1, 1998, to July 7, 1999, 15 cases ofintussuseption were reported to the Vaccine AdverseEvent Reporting system of the US Food and DrugAdministration and the CDC. Thirteen of these infantsdeveloped intussuseption after the first dose of RRV-TV, and 12 infants developed this syndrome within 1week of receiving any dose of RRV-TV. Additionalpost-licensure studies of this adverse event by theNorthern California Kaiser Permanente Health Systemand the Minnesota State Health Department revealedsuggestive elevations of risk among RRV-TV vacci-nees, though the evidence was not conclusive. A mul-tistate investigation is now underway. Pending theresults of the multistate study, the CDC has recom-mended withholding doses of RRV-TV to infants,including those who have already been partially immu-nized (116).

ACKNOWLEDGMENTS

The authors gratefully acknowledge useful informationprovided by Drs. Ruth Brenner, Albert Kapikian, ClaudioLanata, David Sack, Margaret Rennels, and Richard Ward.

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