Abstract

The strategy of decreasing the morbidity and mortality associated with rotavirus gastroenteritis through vaccination is supported by studies demonstrating that wild-type rotavirus infection protects against subsequent rotavirus disease. Primary infection with wild-type rotavirus typically induces homotypic immunity. Vaccination of infants with a multivalent vaccine directed against prevalent rotavirus serotypes is the strategy most likely to provide the broadest degree of protection against rotavirus gastroenteritis. The pentavalent human-bovine reassortant rotavirus vaccine (HBRV) is directed against each of the most prevalent rotavirus serotypes, including G1, G2, G3, G4, and P1. The safety, immunogenicity, and efficacy of different reassortant compositions and formulations of the HBRV have been evaluated in clinical trials. An HBRV dose of ⩾8 × 106 plaque-forming units has demonstrated 68.8%–76.6% efficacy against any rotavirus gastroenteritis, regardless of severity, and ∼100% efficacy against severe rotavirus gastroenteritis for the first rotavirus infection season after vaccination. The HBRV has been generally well tolerated, with no increase in the incidence of fever, vomiting, diarrhea, or behavioral changes among vaccine recipients, compared with placebo recipients, during the 14- and 42-day periods after administration of any dose. Shedding of vaccine strains in feces is uncommon. A large-scale trial is under way to evaluate the efficacy and safety of the manufacturing-scale formulation of pentavalent HBRV.

The development of a vaccine to prevent rotavirus gastroenteritis is a public health priority. Rotavirus infection is the leading cause of gastroenteritis-related hospitalizations and deaths among infants and young children worldwide and is responsible for ∼50,000 hospitalizations and 20 deaths in the United States and ∼440,000 deaths worldwide annually [1–4]. The strategy of decreasing the morbidity and mortality associated with rotavirus gastroenteritis through vaccination is supported by observations that an initial infection with wild-type rotavirus protects against symptomatic rotavirus illness and that the degree of protection increases with the number of previous rotavirus infections. A growing body of knowledge about the epidemiology of rotavirus gastroenteritis has provided important information to guide the development of a vaccine against rotavirus.

Rotaviruses have 2 outer capsid proteins, the glycoprotein VP7 (G) and the protease-susceptible hemagglutinin VP4 (P). The viruses are classified according to their G serotype and P serotype or genotype. The 4 G serotypes responsible for most cases of rotavirus gastroenteritis worldwide are G1, G2, G3, and G4 [5, 6]. Studies indicate that serotype G9 has become more prevalent during the past decade [7]. The most common P serotype associated with these strains is P1 (genotype 8) [5]. Although the proportion of cases of rotavirus gastroenteritis caused by these serotypes varies by geography and season, serotypes G1, G2, G3, and G4 account for >90% of episodes of rotavirus gastroenteritis in the United States and >80% of rotavirus gastroenteritis episodes worldwide [5, 6]. Nearly all children have been exposed to rotavirus and acquire antibodies by age 3–5 years, with the most severe symptomatic disease occurring at 3–24 months of age [8, 9].

Characteristics of the Pentavalent Human-Bovine Reassortant Rotavirus Vaccine (HBRV)

The pentavalent HBRV is a live viral vaccine consisting of 5 human-bovine reassortants bearing the human outer surface rotavirus proteins G1, G2, G3, G4, and P1[8]. HBRV is given orally in a 3-dose regimen and does not require feeding or administration of an antacid before dosing. The reassortants are suspended in a formulation that includes a buffer to protect the vaccine from degradation by gastric acid and a stabilizer to allow for a 24-month shelf life and for storage at refrigerator temperatures [10]. Clinical trials have evaluated the safety and efficacy of HBRV given to infants following 2-, 4-, and 6-month and 2-, 3-, and 4-month schedules [10–12].

Rationale for Development of a Multivalent Rotavirus Vaccine

Studies of the natural history of wild-type rotavirus infection suggest that a rotavirus vaccine should provide broad coverage against the most common rotavirus serotypes associated with rotavirus gastroenteritis. Primary wild-type rotavirus infection provides the greatest protection against moderate and severe cases of rotavirus gastroenteritis, less protection against mild gastroenteritis, and the least protection against asymptomatic infection [13]. The protection provided by primary infection appears to be serotype specific. A cohort study of 200 children from Mexico City who were followed for 2 years showed that second rotavirus infections with the same serotype were unlikely to occur, even when the prevalence of the most common G serotypes was taken into account [13]. Primary wild-type rotavirus infections mainly induce serum neutralizing antibodies (SNAs) that are homologous to the infecting serotype [14]. Heterotypic SNA responses are typically observed after successive infections [14]. Vaccination at a young age with a multivalent vaccine directed against prevalent rotavirus serotypes is likely to provide the most comprehensive protection against the development of rotavirus gastroenteritis.

Development of the HBRV

The bovine rotavirus strain, Wistar calf 3 (WC3), is the backbone of the HBRV. The WC3 rotavirus strain was isolated from a calf in Chester County, Pennsylvania, in 1981, was plaque-purified, and was evaluated in clinical trials [15]. The WC3 vaccine was generally well tolerated and immunogenic and induced significant rotavirus-specific IgA responses and SNAs against the bovine rotavirus surface proteins G6 and P7[5] [15, 16]. However, the WC3 vaccine demonstrated variable efficacy against rotavirus gastroenteritis and did not induce cross-reacting SNAs against the outer surface G proteins of the common human rotavirus serotypes [15].

To combine the antigenic specificity of the most prevalent human rotavirus serotypes with the acceptable safety and immunogenicity characteristics of the WC3 vaccine, human-bovine reassortants were developed [15]. The development of reassortants took advantage of the natural ability of rotaviruses to exchange segments of their genomes in a mixed infection. Cell cultures were coinfected with WC3 rotavirus and a G1, P1[8] human rotavirus strain (WI79) [15]. Genetic reassortment occurred. Guinea pig antiserum to WC3 was used to select a reassortant bearing the human surface G1 protein (strain WI79-9), which was clinically evaluated. Three oral doses of this G1 reassortant vaccine were generally well tolerated and protective against rotavirus gastroenteritis (table 1) [15, 17]. Reassortants with human outer surface proteins of the other G serotypes responsible for most cases of rotavirus gastroenteritis worldwide (i.e., G2, G3, and G4) were developed in a similar fashion [15]. A P1[8] reassortant was also added to the vaccine, because it is the VP4 type that is identified in most G1, G3, and G4 strains and in approximately one-third of G9 strains and because it may provide broad cross-reactive protective immunity. The reassortants that have been included in the pentavalent HBRV are summarized in table 2.

Table 1

Efficacy of monovalent (G1) human-bovine reassortant rotavirus vaccine (HBRV).

 All episodes of rotavirus gastroenteritis Episodes of rotavirus gastroenteritis with clinical score >8a 
 
 

 
Study site Placebob Vaccineb Efficacy, % point estimate (95% CI) Placebob Vaccineb Efficacy, % point estimate (95% CI) 
Rochester 19/74 14/152 64.1 (32.5 to 80.9) 12/74 4/152 83.7 (51.4 to 94.6) 
Philadelphia 7/41 2/45 74.0 (−18.2 to 94.3) 6/41 0/45 100c 
 All episodes of rotavirus gastroenteritis Episodes of rotavirus gastroenteritis with clinical score >8a 
 
 

 
Study site Placebob Vaccineb Efficacy, % point estimate (95% CI) Placebob Vaccineb Efficacy, % point estimate (95% CI) 
Rochester 19/74 14/152 64.1 (32.5 to 80.9) 12/74 4/152 83.7 (51.4 to 94.6) 
Philadelphia 7/41 2/45 74.0 (−18.2 to 94.3) 6/41 0/45 100c 

NOTE. Data are from trials of monovalent (G1) HBRV conducted in Philadelphia, PA, and Rochester, NY, as described elsewhere [17]. 95% CI, 95% confidence interval.

a

A clinical score >8 indicates moderate and severe rotavirus gastroenteritis, on the basis of the scoring system used, as described elsewhere [18].

b

Data are no. of episodes/no. of patients evaluated. Only 1 episode/patient was counted.

c

The 95% CI was not calculated (P = .009).

Table 2

Human bovine (Wistar calf 3) reassortant rotaviruses and their surface protein composition.

Reassortants Surface protein composition 
WI79-9 P7[5], G1 
SC2-9 P7[5], G2 
WI78-8 P7[5], G3 
BrB-9 P7[5], G4 
WI79-4 P1[8], G6 
Reassortants Surface protein composition 
WI79-9 P7[5], G1 
SC2-9 P7[5], G2 
WI78-8 P7[5], G3 
BrB-9 P7[5], G4 
WI79-4 P1[8], G6 

Clinical Trials of the HBRV

The safety, efficacy, and immunogenicity of different formulations and reassortant compositions of the HBRV have been evaluated in several completed phase 1 and 2 clinical trials. In studies conducted to date, the vaccine has been generally well tolerated, with no associated increase in the incidence of fever, vomiting, diarrhea, or behavioral changes among vaccine recipients, compared with placebo recipients, [10–12]. Shedding of vaccine strains in feces is uncommon [10, 11]. The efficacy of the HBRV at a dose of ⩾8 × 106 pfu has been 100% against severe rotavirus gastroenteritis and has been 68.8%–76.6% against any rotavirus gastroenteritis, regardless of severity [11, 12].

Efficacy of the HBRV

The HBRV has been efficacious against the rotavirus serotypes circulating during the first rotavirus infection season after vaccination. In the clinical efficacy trials, the case definition for rotavirus gastroenteritis is identification of rotavirus in stool samples obtained from an infant who has forceful vomiting and/or ⩾3 watery or looser-than-normal stools within a 24-h period occurring at least 14 days after administration of the third dose. A clinical scoring system was used to assess the severity of episodes of acute gastroenteritis, as described elsewhere [18]. In 1993–1994, a blinded, randomized, placebo-controlled trial of quadrivalent (G1, G2, G3, and P1) HBRV, given in a dose of 4 × 107 pfu, was conducted among 439 infants (218 vaccine recipients) 2–6 months old [11]. The study showed that the vaccine prevented 100% of episodes of severe rotavirus gastroenteritis and 74.6% of episodes of any rotavirus gastroenteritis, regardless of severity, during the rotavirus season occurring after vaccination (table 3). The majority of rotavirus strains identified during this study were serotype G1.

Table 3

Efficacy of the quadrivalent (G1, G2, G3, and P1) human-bovine reassortant rotavirus vaccine (HBRV), by severity of the episode of rotavirus gastroenteritis.

 No. of episodes, by group  
 
 
 
Severity of rotavirus gastroenteritis Vaccine group (n = 187) Placebo group (n = 183) Efficacy, % point estimate (95% CI) 
Any severity 11 39 74.6 (49.5–88.3) 
Clinical score >8a 32 74.2 (44.7–89.2) 
Clinical score >16a 100 (43.5–100) 
 No. of episodes, by group  
 
 
 
Severity of rotavirus gastroenteritis Vaccine group (n = 187) Placebo group (n = 183) Efficacy, % point estimate (95% CI) 
Any severity 11 39 74.6 (49.5–88.3) 
Clinical score >8a 32 74.2 (44.7–89.2) 
Clinical score >16a 100 (43.5–100) 

NOTE. Data are from the quadrivalent (G1, G2, G3, and P1) HBRV trial conducted in the United States, as described elsewhere [11]. 95% CI, 95% confidence interval.

a

A clinical score >8 indicates moderate-to-severe rotavirus gastroenteritis, and a clinical score >16 indicates severe rotavirus gastroenteritis, on the basis of the scoring system used, which has been described elsewhere [18].

In 1998–2001, a study conducted in Finland evaluated the efficacy of pentavalent (G1, G2, G3, G4, and P1) HBRV [12]. The study was a double-blinded, randomized, placebo-controlled, dose-ranging study involving 1946 infants 2–8 months old. Preliminary data showed that, for the first rotavirus infection season after vaccination, the efficacy of 3 doses of the high (25 × 106 pfu), middle (8 × 106 pfu), and low (2.5 × 106 pfu) potencies of the pentavalent HBRV was 68.8%, 76.6%, and 58.9%, respectively, against any rotavirus gastroenteritis, regardless of severity (table 4). Preliminary data indicated that most rotavirus strains identified during this study were serotypes G1 and G4. Given these data, the expiry (i.e., end-of-shelf-life) dose for the final formulation of the pentavalent HBRV will be based on the middle-potency dose arm.

Table 4

Efficacy of the pentavalent (G1, G2, G3, G4 and P1) human-bovine reassortant rotavirus vaccine (HBRV) against rotavirus gastroenteritis of any severity (preliminary data), by potency of dose.

Parameter High-potency dose (n = 375) Middle-potency dose (n = 328) Low-potency dose (n = 324) Placebo (n = 322) 
No. of cases of rotavirus gastroenteritis 14 17 41 
Vaccine efficacy, % point estimate (95% CI) 68.8 (41.6–84.3) 76.6 (51.2–90.0) 58.9 (26.1–78.1) … 
Parameter High-potency dose (n = 375) Middle-potency dose (n = 328) Low-potency dose (n = 324) Placebo (n = 322) 
No. of cases of rotavirus gastroenteritis 14 17 41 
Vaccine efficacy, % point estimate (95% CI) 68.8 (41.6–84.3) 76.6 (51.2–90.0) 58.9 (26.1–78.1) … 

NOTE. Data are from a pentavalent (G1, G2, G3, G4, and P1) HBRV dose-ranging trial conducted in Finland, as described elsewhere [12]. 95% CI, 95% confidence interval.

Immunogenicity of the HBRV

The HBRV is immunogenic, as measured by SNA responses to human outer-surface proteins G1, G2, G3, G4, and P1[8], the bovine outer-surface proteins G6 and P7[5], and by serum anti-rotavirus IgA [10–12]. The HBRV induces a significant serum anti-rotavirus IgA response (⩾3-fold increase in the antibody titer between samples obtained before administration of the first dose and after administration of the third dose) among 88%–99% of vaccine recipients (dose, ⩾8 × 106 pfu) [10–12]. Preliminary immunogenicity data from the pentavalent (G1, G2, G3, G4, and P1) HBRV dose-ranging trial conducted in Finland are provided in table 5 [12]. Significant fecal anti-rotavirus IgA responses were also detected in more than one-half of the infants tested in a study of quadrivalent HBRV [19]. The proportion of infants with a significant response increased with administration of each successive dose [19]. An immunologic correlate of protection against rotavirus gastroenteritis has not yet been clearly established. Studies of wild-type rotavirus infection suggest that SNA, fecal anti-rotavirus IgA, and serum anti-rotavirus IgA may correlate with protection against subsequent rotavirus illness and infection [20–22]. The lack of identification of a definitive immunologic marker of efficacy among clinical vaccine trials may be explained by methodological differences among studies, differences in the assays utilized, and limitations on the frequency of sample collection from pediatric subjects.

Table 5

Percentage of infants who received pentavalent (G1, G2, G3, G4, and P1) human-bovine reassortant rotavirus vaccine (HBRV) who experienced a ⩾3-fold increase in G1 serum neutralizing antibody (SNA) titer and in serum anti-rotavirus IgA level from baseline to after administration of the third dose.

 Infants given pentavalent HBRV, by potency of dose 
 
 
Laboratory value High (n = 375) Middle (n = 328) Low (n = 324) 
G1 SNA titer 86.2 73.3 61.7 
Serum anti-rotavirus IgA level 96.8 91.1 80.9 
 Infants given pentavalent HBRV, by potency of dose 
 
 
Laboratory value High (n = 375) Middle (n = 328) Low (n = 324) 
G1 SNA titer 86.2 73.3 61.7 
Serum anti-rotavirus IgA level 96.8 91.1 80.9 

NOTE. Data are from a pentavalent (G1, G2, G3, G4, and P1) HBRV dose-ranging trial conducted in Finland, as described elsewhere [12].

Safety of the Reassortant Vaccine

In studies completed to date, the HBRV has been generally well tolerated. The adverse events of special clinical interest that have been evaluated with this live viral reassortant vaccine are fever, vomiting, diarrhea, and behavioral changes. The incidence of these adverse events was not greater among vaccine recipients than among placebo recipients during the 2- and 6-week periods after administration of any dose (tables 6 and 7) [10–12]. Shedding of vaccine strains in the feces of vaccine recipients is uncommon [10, 11]. In a trial of quadrivalent (G1, G2, G3, and P1) HBRV, shedding of vaccine strains in feces was evaluated for days 1–2, 3–5, and 7–9 and at ∼15 after administration of each dose. Shedding peaked during the 3–5-day period after administration of the first dose. Overall, 12 (6.8%) of 177 and 2 (7.1%) of 28 patients shed vaccine strains during the 15-day period after administration of doses 1 and 2, respectively [11].

Table 6

Percentage of infants with fever (as reported on a vaccine report card by parents/guardians), irritability, diarrhea, or vomiting on days 0–14 after administration of any dose of quadrivalent (G1, G2, G3, and P1) human-bovine reassortant rotavirus vaccine (HBRV) or placebo.

Adverse event Infants given quadrivalent HBRV (n = 218) Infants given placebo (n = 220) 
Fever 32.1 33.2 
Irritability 39.4 42.3 
Vomiting 26.6 23.6 
Diarrhea 44.5 36.4 
Adverse event Infants given quadrivalent HBRV (n = 218) Infants given placebo (n = 220) 
Fever 32.1 33.2 
Irritability 39.4 42.3 
Vomiting 26.6 23.6 
Diarrhea 44.5 36.4 

NOTE. Data are from a quadrivalent (G1, G2, G3, and P1) HBRV trial conducted in the United States, as described elsewhere [11]. No differences were statistically significant (P = .05).

Table 7

Percentage of infants with fever (as reported on a vaccine report card by parents/guardians), irritability, diarrhea, or vomiting on days 0–42 after administration of any dose of pentavalent (G1, G2, G3, G4, and P1) human-bovine reassortant rotavirus vaccine (HBRV) or placebo (preliminary data).

 Infants given HBRV, by potency of dose  
 
 
 
Adverse event High dose Middle dose Low dose Infants given placebo 
Fever 66.1 61.8 69.4 65.5 
Irritability 38.1 40.7 43.5 40.4 
Vomiting 17.1 15.6 18.5 19.3 
Diarrhea 58.7 55.4 61.4 57.5 
 Infants given HBRV, by potency of dose  
 
 
 
Adverse event High dose Middle dose Low dose Infants given placebo 
Fever 66.1 61.8 69.4 65.5 
Irritability 38.1 40.7 43.5 40.4 
Vomiting 17.1 15.6 18.5 19.3 
Diarrhea 58.7 55.4 61.4 57.5 

NOTE. Data are from a Pentavalent (G1, G2, G3, G4, and P1) HBRV dose-ranging trial conducted in Finland, as described elsewhere [12]. No differences were statistically significant (P = .05).

Reports of intussusception associated with the rhesus-based rotavirus vaccine (RotaShield; Wyeth-Ayerst) have raised questions about the possible association of intussusception with other rotavirus vaccines [23]. The pathogenesis of intussusception associated with RotaShield is unknown. However, epidemiologic studies have shown no increase in the number of hospitalizations associated with intussusception during the rotavirus infection season in the United States, which suggests that intussusception is not associated with wild-type rotavirus infection [24]. Thus, the intussusception associated with RotaShield may be unique to that vaccine. The sample sizes of the phase 1 and 2 clinical trials of the HBRV were insufficient for the evaluation of safety with respect to intussusception, which is an uncommon illness with an estimated annual incidence of ∼1 case/2000 infants <2 years old. Thus, a large-scale study was designed to evaluate the safety of the HBRV with respect to intussusception.

Large-Scale Rotavirus Efficacy and Safety Trial

A large-scale study is currently under way to evaluate the efficacy of the pentavalent HBRV (RotaTeq; Merck) against wild-type rotavirus gastroenteritis caused by human serotypes included (G1, G2, G3, and G4) or not included in the vaccine and the safety of the vaccine with respect to intussusception. More than 70,000 subjects have been enrolled in this double-blinded, randomized, placebo-controlled (i.e., 1 subject received vaccine for every subject who received placebo) international study. The study design uses intense, active surveillance for intussusception during the 6-week period after administration of each dose, with surveillance continuing for up to 1 year after administration of the first dose. Potential cases of intussusception are adjudicated by an independent committee (blinded to treatment arm) as they occur. For positively adjudicated cases of intussusception, an independent data and safety monitoring board unblinds the treatment arm and makes recommendations about continuing the study. The Rotavirus Efficacy and Safety Trial has been designed to detect clustering of intussusception cases, particularly during the 2 weeks after administration of any dose, which was the period of greatest risk reported for the cases of intussusception associated with RotaShield [23]. The statistical criteria for satisfying the primary safety hypothesis have been developed to demonstrate that the HBRV is clinically acceptable. Enrollment in this study has been completed on the basis of the recommendation of the unblinded data and safety monitoring board, which has monitored the study for all reported serious adverse events, including intussusception.

Summary

The HBRV has been efficacious against rotavirus gastroenteritis and has been generally well tolerated in studies conducted to date. Enrollment has been completed in an ongoing large-scale trial to evaluate the efficacy and safety of the final formulation of the pentavalent vaccine.

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Lack of an apparent association between intussusception and wild or vaccine rotavirus infection
Pediatr Infect Dis J
 , 
1998
, vol. 
17
 (pg. 
924
-
5
)

Author notes

Potential conflicts of interest: P.M.H., M.G.G., and J.M.M. are currently employed by Merck. P.O. and H.F.C. are coholders of the patent for the human-bovine reassortant rotavirus vaccine.