ROTAVIRUS VACCINES. Virology

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1 ROTAVIRUS VACCINES Virology Rotavirus is a triple-layers viral particle belonging to the Reoviridae family. It contains 11 segments of double-stranded RNA, of which 6 are structural and 5 are non-structural proteins. The outer surface of rotavirus contains two important viral proteins VP7 (G-type) and VP4 (P-type). These antigens cause the host to produce neutralizing antibodies. In humans, there are at least 12 different G-types and 15 different P-types identified. Subtyping of rotavirus is performed by serotyping of G and P proteins. More than 90% of infections, globally, are caused by 5 serotypes: G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8]. The most common strain globally is G1P[8]. Epidemiology Rotavirus is highly contagious. The virus is mainly transmitted by the faecal oral route. Prior to rotavirus vaccination, rotavirus infection was the leading cause of severe, dehydrating diarrhoea in <5 year olds, infecting nearly 100% of children by 3-5 years. In 2000, it accounted for >2 million hospitalizations globally. In low income countries, the median age of infection is younger (i.e. 6-9 months) as compared to high income countries (i.e. 2-5 years). In 2004, an estimated deaths in <5 year olds were attributed to rotavirus. With the development of rotavirus vaccines, the mortality rate slightly reduced by 2008 to cases. Climatic conditions have a major influence on the incidence of rotavirus infections. In temperate climates, epidemic peaks in the cooler, drier months (i.e. winter periods). Seasonality is less pronounced in tropical climates and infections occur throughout the year with minor increase during the drier season. Page 1 Rotavirus vaccines

2 Pathogenesis and Clinical Manifestations Fecal-oral Fecal-oral Reinfection with rotavirus is common. Most first infections are symptomatic, later infections may be milder or asymptomatic. It is not possible to distinguish rotavirus from other causes of gastroenteritis on clinical signs alone and laboratory confirmation is essential. Treatment and prevention of rotavirus infection There is no specific therapy available. Treatment and prevention measures include: Hand washing Access to clean water and improved sanitation Breast feeding Use of zinc/ors in treatment of diarrhoea Vaccines Page 2 Rotavirus vaccines

3 Vaccines The first rotavirus vaccine, RotaShield, was licensed in the USA in However, it was withdrawn from the market 6 months later following an increased risk of intussusception (intestinal invagination which can lead to obstruction), within the first 2 weeks following vaccination. Since 2006, two oral live attenuated rotavirus vaccines are internationally available: Rotarix (monovalent) and Rotateq (pentavalent). Rotarix and Rotateq are given orally, respectively in a two dose and three dose schedule. More details on both vaccines can be found in Table 1. Interchangeable use has not been studied for these vaccines. Co-administration with other vaccines does not impact on immune response, with studies performed on Diphtheria, Tetanus, acellular Pertussis, Inactivated Polio Vaccine, Haemophilus influenzae type b, Hepatitis B and Pneumococcal Conjugate Vaccine. Table 1: Characteristics of globally licensed rotavirus vaccines Rotarix Rotateq Origin Human, monovalent Human and bovine, pentavalent Strains G1P[8] Four reassorted viruses expressing G1, G2, G3 and G4 (human) and P7[5] (bovine) 1 reassortant virus expressing P1A[8] (human) and G6 (bovine) Formulation Storage Vaccination schedule Single dose, oral squeeze tube 1.5 ml No preservatives Single dose, oral squeeze tube 2.0 ml No preservatives Storage at +2 to +8 C; must not be frozen; protect from light 2 doses Recommended schedule: 6-10 weeks No booster dose 3 doses Recommended schedule: weeks No booster dose Efficacy against severe gastroenteritis Combined efficacy of 58.7% (95% CI ) from studies in Malawi (49.2%) and South Africa (72.2%) in first year of life Combined efficacy of 84.7% (95% CI ) from studies in 11 Latin American countries and Finland Combined efficacy of 64.2% (95% CI ) from studies in Ghana (65.0%), Kenya (83.4%) and Mali (1.0%) in the first year of life. Combined efficacy of 39.3% (95% CI ) two years after vaccination Combined efficacy of 98.0% (95% CI ) from studies in USA and Finland Adverse effects Contraindications Risk of intussusception: 1-2 more cases per vaccinated Risk considered acceptable considering mortality associated with rotavirus disease, especially in low-income countries. Allergic reaction to a previous dose of rotavirus vaccine Severe immuno-deficiency History of intussusception or intestinal malformations Page 3 Rotavirus vaccines

4 Initially, age restrictions were introduced to reduce risk of intussusception, with the first dose given between 6 and 15 weeks of age and the last dose, no later than 32 weeks of age. However, many vulnerable children were excluded by this rather restrictive guideline, and the Strategic Advisory Group of Experts on Immunization (SAGE) of the WHO removed this restriction in April Early vaccination, however, is still recommended with no vaccination indicated after the age of 2 years. In view of the historic association of rotavirus vaccine and intussusception, countries are encouraged to perform post-marketing surveillance upon introduction of this vaccine in routine vaccination programmes. Caregivers should be informed on the risk of intussusception and counseled how to recognize early signs like stomach pain with severe crying, several episodes of vomiting, blood in the stool, weakness and irritability. Nationally available vaccines and upcoming products In addition to the two internationally licensed rotavirus vaccines, nationally available rotavirus vaccines are summarised in Table 2. Table 2: Nationally available rotavirus vaccines Vaccine Company Status Strains ROTAVAC Bharat Biotech International (India) Licensed in India. Began phased introduction in 2016 in 4 states. G9P[11] Rotavin-M1 POLYVAC Licensed in Vietnam Vietnamese G1P[8] Lamb rotavirus (lambhuman reassortant) LLR LLR+ Lanzhou Biologicals/Xinkexian Biological Technology (China) Licensed in China G10, P[12] + G1, G2, G3, G4 Products that are currently in development include: Bovine-human reassortant rotavirus vaccine (UK-BRV). Strains included: bovine G6P[5] + G1, G2, G3, G4 reassortants. Non-exclusive licenses for the development and production were granted to several manufacturers. Serum Institute and Shanta vaccines undergoing Phase 3 clinical trials. Human neonatal rotavirus vaccine (RV3-BB) from Biofarma (Indonesia) and MCRI (Australia). Strains included: G3P[6]. Early clinical trials ongoing in New Zealand and Indonesia. WHO recommendation 1. Use of rotavirus vaccines should be part of a comprehensive strategy to control diarrheal diseases and should include, among other interventions, breastfeeding, improvements in hygiene and sanitation, zinc supplementation, community-based administration of oral rehydration solution and overall improvement in case management. Page 4 Rotavirus vaccines

5 2. Prior to initiation of routine vaccination, it is essential to establish the baseline incidence of intussusception. 3. Rotarix should be administered at the same time as DTP1 and DTP2, whereas Rotateq should be administered at the same time as DTP1, DTP2 and DTP3. 4. Vaccination beyond 2 years of age is not recommended. Further reading Armah GE et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-saharan Africa, a randomized, double-blind, placebo-controlled trial. Lancet 2010; 376: Centers for Disease Control and Prevention. Rotavirus. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, Wolfe S, Hamborsky J, eds. 12th edition. Washington DC: Public Health Foundation, 2011; p Isanaka S et al. Efficacy of a low-cost, Heat-stable oral Rotavirus Vaccine in Niger. New England Journal of Medicine 2017; 376: Kirkwood CD, Ma L-F, Carey ME, Steele AD. The rotavirus vaccine development pipeline. Vaccine Kulkarni PS et al. A randomized Phase III clinical trial to assess the efficacy of a bovine human reassortant pentavalent rotavirus vaccine in Indian infants. Vaccine 2017; 35 (45): Madhi SA et al. Effect of human rotavirus vaccine on severe diarrhoea in African infants. New England Journal of Medicine 2010; 362 (4): Parashar UD, Cortese MM, Offit PA. Rotavirus vaccines. In: Plotkin SA, Orenstein WA, Offit PA, Edwards KM (eds). Vaccines 7 th Edition, Philadelphia, Elsevier 2018: Rota Council. World Health Organization. Rotavirus Vaccines. WHO position paper. Weekly Epidemiological Record No. 5, 2013; 88, World Health Organization/The United Nations Children s Fund. The Integrated Global Action Plan for Pneumonia and Diarrhoea (GAPPD) Last updated: March 2018 Page 5 Rotavirus vaccines