Phase I trial of RV3-BB rotavirus vaccine: A human neonatal rotavirus vaccine
Introduction
Rotavirus vaccines have the potential to make a major contribution to the global reduction of childhood mortality, which is recognised as a key component of the United Nations Millennium Development Goals. Since the global recommendation for rotavirus vaccines in June 2009 by the World Health Organization (WHO) [1], the two licensed rotavirus vaccines (RotaTeq®, RV5, Merck, USA; and Rotarix®, RV1, GlaxoSmithKline, Belgium) have been introduced into National Immunisation Programs in the USA, Australia, Mexico and Brazil, and more recently into more than 40 countries globally, and have been linked with a significant decline in hospitalisations and emergency department visits due to rotavirus disease[2], [3].
Notwithstanding these achievements in high and middle-income countries, 90% of deaths due to rotavirus occur in developing countries in Africa and Asia. Rotavirus vaccine efficacy in these and other developing countries has been shown to be lower than in developed country trials, where the efficacy has been reported to be 95–100% against severe disease. The monovalent human rotavirus vaccine (RV1) was reported to provide a protective efficacy of 61% against severe rotavirus gastroenteritis in the combined study populations in Malawi and South Africa [4] and the pentavalent bovine-human reassortant rotavirus vaccine (RV5) was found to be 60% effective against severe rotavirus gastroenteritis in Nicaragua [5] and only 48% effective against severe disease in Bangladesh and Vietnam [6].
As rotavirus infection tends to occur at an earlier age in developing countries [7] the current vaccines administered from 6 weeks of age, with completion of a 2- or 3-dose course at 4–6 months may be too late to protect some infants [8]. An alternative approach to optimise protection is to deliver a rotavirus vaccine at birth. The best immunisation opportunity is immediately after birth, when attendant health care workers commonly have access to the infant and mother. Neonatal administration would also enable the administration of 3 doses of a rotavirus vaccine prior to age 3 months under an Expanded Program of Immunisation (EPI) schedule of 0, 6 and 10 weeks. Finally, the first rotavirus vaccine, Rotashield, was withdrawn from the market due to an apparent association with intussusception, a rare bowel condition [9]. As the natural intussusception risk is lowest in the neonatal period, newborn immunisation should minimise any potential risk of intussusception after the first dose.
RV3 is a human neonatal rotavirus strain (G3P[6]) that was identified in the stool of an asymptomatic healthy full term infant and was endemic in Melbourne obstetric hospital nurseries in the 1970s [10]. Natural infection with this RV3-related strain was associated with asymptomatic infection in healthy newborns and was shown to protect against clinically severe disease during reinfection with heterotypic rotavirus strains in the first three years of life [10]. RV3 is naturally attenuated and replicates well in the presence of high titres of maternal antibodies and breast feeding [10]. RV3 was initially formulated as a low titre vaccine (6.5 × 105 fcfu/mL), and tested in Phase I and II clinical trials in Melbourne, Australia [11], [12]. RV3 low titre vaccine was well tolerated but the immunogenicity was sub-optimal, with only 45% of infants developing significant serum IgA and/or copro-antibody responses. The higher titre RV3-BB [Bishop–Barnes] vaccine has been developed to 8.3 × 106 FFU/mL (average) in the WHO-approved Vero cell line under Good Manufacturing Practice (GMP) conditions at Meridian Life Sciences, Memphis (USA) (see Appendix A).
The ultimate aim of the RV3 Rotavirus Vaccine Program is to develop an affordable and accessible human neonatal rotavirus vaccine to protect infants from rotavirus disease from birth in developing countries. The primary objective of this Phase I trial was to assess the safety and tolerability of RV3-BB vaccine in adults, children and infants, with assessment of immunogenicity as a secondary endpoint, prior to future assessment in the neonatal age group.
Section snippets
Methods
This was a single-centre, double-blind, randomised placebo-controlled Phase I study to evaluate the safety, tolerability and immunogenicity of a single 1 mL oral dose of the second generation rotavirus vaccine, RV3-BB in 60 participants. The study was conducted at the Royal Children's Hospital and Murdoch Childrens Research Institute in Melbourne, Australia (Clinical Trial Registration: ACTRN12610000525088). The study was approved by the Royal Children's Hospital Human Research Ethics Committee
Results
Sixty-six participants were screened for study eligibility (adults: 22; children: 20; infants: 24) and 60 participants were randomised. Characteristics of the 60 participants are summarised in Table 1. One adult subject withdrew from the study after receiving IP but prior to study completion due to personal reasons.
Discussion
The RV3-BB rotavirus vaccine is a naturally attenuated, human neonatal rotavirus vaccine that replicates well in the newborn gut and in this Phase I safety trial, was well tolerated in all age cohorts. In the infant cohort, loose bowel motions and vomiting or posseting occurred equally as commonly in the treatment groups and the single infant who experienced diarrhoea was in the placebo group. There was no suggestion of a difference in the occurrence of fever between the two treatment groups in
Disclosures
MCRI has received funds from GlaxoMithKline and CSL Biologicals for investigator initiated post-marketing surveillance activities of Julie Bines, Margie Danchin and Jim Buttery. Carl Kirkwood is director of Australian Rotavirus Surveillance Program, which is supported by research grants from vaccine manufacturers CSL and GSK, as well as Department of Health and Aging.
Acknowledgements
We would sincerely like to thank the participants and their families for participating in this study. We would also like acknowledge the contribution of consultants to this study Sue Mitchell, Pene Amor from Mitchell Consulting, Mark Sullivan, Gerhard Rank, Amanda Handley from Medicines Development and Jim Ackland, the managing director at Global BioSolutions. We thank the Vaccine and Immunisation Research Group (VIRGo) at Murdoch Childrens Research Institute for access to their immunisation
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