MANUSCRIPT CITATION

Bines JE, At Thobari J, Satria CD, Handley A, Watts E, Cowley D, et al. Human Neonatal Rotavirus Vaccine (RV3-BB) to Target Rotavirus from Birth. New England Journal of Medicine. 2018;378(8):719-30. PMID: 29466164

REVIEWED BY

Dr Kate Hodgson, MB BS(Hons), B.Med.Sci, FRACP
Neonatal Clinical/Research Fellow
The Royal Women’s Hospital, Melbourne, Australia

Dr Linny Kimly Phuong, BPharm (Hons), MBBS, MPH
Infectious Diseases and Microbiology Registrar
The Royal Women’s Hospital, Melbourne, Australia
The Royal Children’s Hospital, Melbourne, Australia

Dr Brett Manley, MB BS(Hons), PhD, FRACP
Consultant Neonatologist, Neonatal Services, The Royal Women’s Hospital, Melbourne, Australia
Senior Lecturer, Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, Australia
Honorary Fellow, Murdoch Children’s Research Institute, Melbourne, Australia

TYPE OF INVESTIGATION

Prevention

QUESTION

(P) In healthy term neonates, (I) is an oral human rotavirus vaccine administered on a neonatal schedule or infant schedule (C) more effective than placebo (O) at preventing rotavirus gastroenteritis (T) until age 18 months?

METHODS

• Design: A randomised, double-blind, parallel group, placebo-controlled trial. Oral human rotavirus vaccine (RV3-BB) was administered on a neonatal schedule (0-5 days, 8 weeks, and 14 weeks of age), or an infant schedule (8 weeks, 14 weeks, and 18 weeks of age), or as a placebo.
• Allocation: Allocation concealed.
• Blinding: The study was blinded to participant families, investigators, trial monitors, data managers, statisticians and other trial staff. Pharmacists were not blinded to assignments. Placebo was visually indistinguishable from RV3-BB vaccine.
• Follow-up period: Weekly telephone contact and monthly visits until 18 months
• Setting: Primary health centres and hospitals in Central Java and Yogyakarta, Indonesia between Jan 2013- Jul 2016.
• Patients:
  • Inclusion criteria:
    • Healthy neonate < 144 hours of age at time of first dose
    • Born at term (37-42 weeks’ gestation)
    • Birth weight 2500-4000 g
    • Main place of residence within the catchment areas in Indonesia
  • Exclusion criteria:
    • Any major congenital malformation, genetic disease, or illness
    • Maternal exposure to antenatal glucocorticoids, cytotoxic drugs, or blood products
• Intervention: Human neonatal rotavirus vaccine (RV3-BB), administered on a neonatal schedule or infant schedule, compared with placebo.

• Outcomes:
  • Primary outcome: Episodes of severe rotavirus gastroenteritis (defined as rotavirus gastroenteritis with a modified Vesikari score of >11) until 18 months of age in participants who received all four doses of vaccine (either neonatal schedule or infant schedule, per-protocol population)
  • Secondary outcomes: 
    • Efficacy against severe rotavirus gastroenteritis until 18 months of age (intention-to-treat population)
    • Immunogenicity of vaccine
    • Episodes of gastroenteritis (severe and any episodes), according to Vesikari scale, up to 12 months of age
    • Episodes of rotavirus gastroenteritis
    • Safety and tolerability of vaccine
    • Adverse events within 28 days after vaccine administration

• Analysis and sample size: 1649 infants underwent randomisation (intention-to-treat population) and 1513 participants who received all 4 doses of study drug were used to assess primary efficacy (per-protocol analysis). Using local data, the risk of severe rotavirus gastroenteritis was 3%. The sample size calculation (1647 infants) conferred 80% power to show a difference (reject the null hypothesis) between the combined vaccine group and the placebo group, with a predicted vaccine efficacy of 60%. Hence the predicted severe rotavirus gastroenteritis rate in the combined vaccine group was 1.2%. Vaccine response (serum immune response or shedding of RV3-BB in the stool) was assessed in 282 participants. The authors chose an one-sided alpha level of 0.1. It is unclear why this unconventional significance level was chosen, perhaps in order to limit the sample size required for the trial. Nevertheless, the results obtained for the primary outcome and vaccine efficacy had a far lower p values than this, therefore the interpretation of the results is unchanged.

• Patient follow-up:
  • % included in analysis 1588 (96%) of the 1649 patients who underwent randomisation were followed until 18 months of age.

MAIN RESULTS

The primary efficacy analysis was performed in 1513 participants (per-protocol population). Demographic characteristics did not differ between the three trial groups.

In the per-protocol analysis, 28/504 (5.6%) patients in the placebo group experienced severe rotavirus gastroenteritis by age 18 months. This was significantly higher than the incidence in the neonatal-schedule group (7/498, 1.4%) and the infant-schedule group (14/511, 2.7%). This correlated with a vaccine efficacy against severe rotavirus gastroenteritis up to 18 months of age of 75% in the neonatal schedule vaccine group (95% CI 44-91, p<0.001) and 51% in the infant-schedule vaccine group (95% CI 7-76, p=0.03). The combined vaccine efficacy was 66% (95% CI 34-80) (see table 1).

Table 1: Vaccine efficacy of RV3-BB

Serum immune response or shedding of RV33-BB in the stool was detected in 78/83 (94%) of participants in the neonatal-schedule vaccine group and 83/84 (99%) of participants in the infant-schedule vaccine group. As expected, cumulative vaccine response increased with subsequent doses. Rates of adverse events were similar across the trial groups. No episodes of intussusception were reported within 21 days of vaccine administration in all three trial groups.

CONCLUSION

The administration of a human neonatal rotavirus vaccine (RV3-BB), via a neonatal or infant vaccine schedule, is efficacious in preventing severe gastroenteritis until 18 months of age in children in Indonesia.

COMMENTARY

Rotavirus is a leading cause of morbidity and mortality for neonates and children. Worldwide, over 200,000 children die from rotavirus gastroenteritis each year (1) and more than 90 million infants still lack access to a rotavirus vaccine (2). Traditional vaccine schedules administer doses at 8 weeks, 14 weeks and 18 weeks of age. Therefore, neonates are often exposed to rotavirus before the first dose is given (3). This is of particular importance in low income countries, where access to vaccine is poor, there is earlier onset of rotavirus disease and the burden of disease significant (4).

Current vaccines approved for use are Rotarix^TM (GSK Vaccines, Wavre, Belgium) and RotaTeq^TM (Merck & Co, Kenilworth, USA). These have not been investigated with a neonatal dosing schedule. Furthermore, there is evidence of suboptimal vaccine efficacy in low- and middle-income countries (5).

RV3-BB is a novel vaccine which has been investigated in early phase trials in Australia (6) and New Zealand (7). It is developed from a human rotavirus strain, RV3 (G3P[6]) found in infants with asymptomatic infection. Dosing at birth is likely to be efficacious and safe: RV3-BB P[6] vaccine strains effectively adhere to the newborn gut (8), display minimal interference from maternal breast milk (9) and are naturally attenuated (2). This strain also provides heterotypic serologic responses, which may offer cross-protection against other circulating rotavirus strains (2). Further potential advantages of a neonatal schedule include improved uptake, particularly in low-income countries.

This randomised, double-blind, placebo-controlled trial in Indonesia demonstrated the efficacy of a human neonatal rotavirus vaccine in preventing severe rotavirus gastroenteritis before 18 months of age. When administered on a neonatal dosing schedule, RV3-BB had a vaccine efficacy of 94% at 12 months of age and 75% at 18 months of age. RV3-BB administered on both the neonatal and infant schedules demonstrated comparable or superior efficacy to other rotavirus vaccines in low-income countries (2). While the trial was underpowered to detect rare adverse events, no cases of intussusception were detected within 21 days of vaccine administration. Only one participant in the trial developed intussusception in the infant-schedule arm; at 8.5 months of age, 114 days after the third dose of vaccine.

The authors chose a one-sided alpha level of 0.1. It is unclear why this unconventional significance level was chosen, perhaps in order to limit the sample size required for the trial. Nevertheless, the results obtained for the primary outcome and vaccine efficacy had far lower p values than this, therefore the interpretation of the results is unchanged.

This is a large study with rigorous methodology that demonstrates the efficacy of a new human rotavirus vaccine in a low-income country with high burden of disease. While the benefits of a neonatal schedule are clear in this setting, the applicability to other settings with higher vaccine coverage is unknown. Furthermore, there has not been a direct comparison of this rotavirus vaccine with the other vaccines currently in use. Nevertheless, this vaccine shows promise for addressing the ongoing global burden of rotavirus disease.

REFERENCES

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2. Bines JE, At Thobari J, Satria CD, Handley A, Watts E, Cowley D, et al. Human Neonatal Rotavirus Vaccine (RV3-BB) to Target Rotavirus from Birth. New England Journal of Medicine 2018; 378 8:719-30.
3. Steele AD, Madhi SA, Cunliffe NA, Vesikari T, Phua KB, Lim FS, et al. Incidence of rotavirus gastroenteritis by age in African, Asian and European children: Relevance for timing of rotavirus vaccination. Human vaccines & immunotherapeutics 2016; 12 9:2406-12.
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8. Rippinger CM, Patton JT, McDonald SM. Complete genome sequence analysis of candidate human rotavirus vaccine strains RV3 and 116E. Virology 2010; 405 1:201-13.
9. Chen MY, Kirkwood CD, Bines J, Cowley D, Pavlic D, Lee KJ, et al. Rotavirus specific maternal antibodies and immune response to RV3-BB neonatal rotavirus vaccine in New Zealand. Hum Vaccin Immunother 2017; 13 5:1126-35.