1 Rotavirus Vaccine Updates & WHO Position Vikash R. Keshri Dept. of Community Medicine

Introduction Problem statement Epidemiology Rotavirus Vaccines Evidences for WHO Position WHO position Recommendations in India

Introduction: Rotaviruses; leading cause of severe, dehydrating diarrhoea in children <5 years globally. Estimated >25 million outpatient visits and >2 million Hospitalizations. Severe rotavirus gastroenteritis largely limited to children aged 6–24 months. The primary infection usually most significant but Re infection also occurs.

Problem Statement

Problem Statement……..... Countries with the greatest number of rotavirus-related deaths Number of deaths due to rotavirus-related diarrhoea (and proportion of the worldwide total). Source: Lancet Infect Dis 2012; 12: 136–41

Epidemiology: AGENT Derived from the Latin word Rota, means “wheel,” Classified as a genus in the family of Reoviridae. Double-stranded RNA virus Composed of three concentric shells that enclose 11 gene segments. Two important proteins—VP7, or G-protein, and VP4, or P-protein. Five strains (G1–4, G9) account for 90% cases. G1 strain account > 75%. Very stable and may remain viable in the environment for weeks or months if not disinfected.

Host Factor: Reservoir: Human Age ; - Most commonly 6 months to 3 years of age Sex ; - Incidence is equal Immunity- Primary Infection render immunity but re- infection can occur Nutritional status: Malnutrition Important contributory factor. Mortality several times higher in malnutrition cases

Environmental Factor Geographic Region: Throughout world but varies from country to country Seasonal: During rainy and winter season. Period of Communicability: From 2 days before to 10 days after onset. Poor socio- economic condition. Poor sanitation

Mode of Transmission Feco – Oral Route Rotaviruses are shed in very high concentrations (>10¹² particles/gram) and for many days in the stools and vomitus.

Clinical Features & Diagnosis Watery Diarrhea Fever Vomiting Rapid test Kit Using EIA

Prevention and Control Good sanitation and hygiene Exclusive Breast feeding Improved water quality PREVENTION Vaccination

Rotavirus Vaccine History: Rota Shield (Wyeth- Lederle) licensed in the United States in Shortly Recommended for routine use in US infants. Extensive evaluations before licensure indicated vaccine safe and efficacious. After first of the 3 oral vaccine doses. Excess number of cases of intussusceptions reported. Predominantly in infants >3 months of age. Consensus attributable risk of 1 per vaccinated infants. Withdrawn from market.

Rotavirus: Current Vaccines The monovalent human rotavirus vaccine (Rotarix™) Multiple passages in tissue culture resulting in attenuated vaccine strain, RIX4414 The pentavalent bovine– human reassortant rotavirus vaccine (RotaTeq™). Contains 5 reassortant rotaviruses developed from human and bovine (WC3) parent rotavirus strains.

Rotarix Vaccine Approved in Live attenuated vaccine. Vaccine strain and characteristics:  Originates from a G1P[8] strain isolated from a case of infantile gastroenteritis.  Undergoes multiple passages in tissue culture, and the resulting attenuated vaccine strain, RIX4414. Storage:  lyophilized vaccine should be kept at 2–8 °C in its original package, protected from light.  Should not be frozen.  Vaccine shelf-life is 3 years.

Optimal Age: Rota 1 Rota 2 6 Birth weeks Rota 1 Rota 2 6 Birth weeks

Administration  Administered orally in a 2-dose schedule.  Route: Oral –Dilution: Reconstitution in calcium carbonate buffer contained in a single-dose, pre-filled oral applicator given promptly. Dose:  Consists of two 1-mL doses. Infant Feeding No evidence to suggest that breast-feeding reduced the protection.

Indication and precaution:  Prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4, and G9).  Approved for use in infants 6 weeks to 32 weeks only. Contraindication:  Hypersensitivity  Gastrointestinal Tract Congenital Malformation  History of Intussusception  Severe Combined Immunodeficiency Disease

Warnings and Precautions:  Latex  Gastrointestinal Disorders: Administration of ROTARIX should be delayed in infants suffering from acute diarrhea or vomiting.  Altered Immunocompetence  Shedding and Transmission: Possibility that the live vaccine virus can be transmitted to non-vaccinated contacts.  Intussusception Adverse Reactions: Common (≥5%) solicited adverse events includes: – Fussiness/irritability, –Cough/runny nose, –Fever, –Loss of appetite, and vomiting.

RotaTeq Vaccine : Initial approval in US Rotavirus Vaccine, Live, Oral, Pentavalent Vaccine strain and characteristics:  Contains 5 reassortant rotaviruses developed from human and bovine (WC3) parent rotavirus strains. Storage: In refrigerated at 2–8 °C for up to 24 months. No preservatives or thimerosal. After removal from refrigeration, the vaccine should be used promptly.

Indications and Usage –Prevention of rotavirus gastroenteritis caused by the G1, G2, G3 and G4 serotypes. –Approved for use in infants 6 weeks to 32 weeks of age. Dosage and Administration  For oral use only. not for injection.  Series consists of three ready-to-use liquid doses.  Starting at 6 to 12 weeks of age,  Subsequent doses administered at 4- to 10-week intervals.  The third dose should not be given after 32 weeks..

Dose and Strengths: 2 mL solution contains a minimum of 2.0 – 2.8 x 10 6 infectious units (IU) per reassortant dose. Contraindications:  A demonstrated history of hypersensitivity to the vaccine or any component of the vaccine.  History of Severe Combined Immunodeficiency Disease (SCID).  History of intussusception.

Warnings and Precautions: No safety or efficacy data available for immunocompromised (e.g., HIV/AIDS). No safety or efficacy data available infants with a history of gastrointestinal disorders. e.g.,  Active acute gastrointestinal illness,  Chronic diarrhea,  Failure to thrive,  History of congenital abdominal disorders, and  H/o abdominal surgery Vaccine virus transmission to non vaccinated contacts reported.

Adverse Reactions: Most common adverse events included –Diarrhea, –Vomiting, –Irritability, –Otitis media, –Nasopharyngitis, and bronchospasm. Use in Specific Populations: Pediatric Use: Safety and efficacy not established in infants 32 weeks Data available from clinical studies support the use of RotaTeq in Pre-term infants according to their age in weeks.

Evidences for WHO Position

Source: Rotavirus Efficacy and Safety Trial (REST). N Engl J Med 2006;354:23-33.

Rotavirus Vaccine and Intussusception: Source: Guillermo M R et al.. Safety and Efficacy of an Attenuated Vaccine against Severe Rotavirus Gastroenteritis. N Engl J Med 2006;354:11-22.

WHO Position: WHO Position on Vaccines: General Considerations Vaccines for large-scale public health interventions should meet the current WHO quality requirements. Be safe and significant impact against the actual disease in all target populations. If intended for infants or young children, be easily adapted to the schedules and timing of national childhood immunization programmes. Don’t interfere significantly with the immune response to other vaccines given simultaneously; Be formulated to meet common technical limitations, e.g. in terms of refrigeration and storage capacity. Be appropriately priced for different markets

WHO Position on Rotavirus Vaccine 2007 Main goal of rotavirus vaccination: Prevent death and severe disease caused by rotavirus. 2 rotavirus vaccines proven to be safe and efficacious. In industrialized countries, routine immunization has the potential to reduce significantly the large number of emergency consultations & Hospitalizations. Save considerable direct and indirect costs associated with acute rotavirus disease in the youngest age groups

In developing countries; Introduction of vaccines reduce the heavy burden of severe rotavirus diarrhoea. WHO strongly recommends;  The inclusion of rotavirus vaccination into the national immunization programmes of regions and countries  Where vaccine efficacy data suggest a significant public health impact and  Where appropriate infrastructure and financing mechanisms are available to sustain vaccine utilization.

Source: Weekly epidemiological record, No , 18 December 2009

Current WHO Position (2010) Newer Evidences: Trials of rotavirus vaccines ha conducted in Asian and African countries. Trials have also included countries where sanitation is poor and Where there is high mortality from diarrhoeal diseases and a high maternal prevalence of HIV. Rotarix has been evaluated in Malawi and South Africa. RotaTeq has been studied in Ghana, Kenya and Mali in Africa, and in Bangladesh and Viet Nam in Asia. SAGE on Immunization and GACVS reviewed new evidences.

Taking into account new evidence, WHO now recommends infants worldwide be vaccinated against rotavirus. WHO recommends rotavirus vaccine for inclusion in all national immunization programmes Strongly Recommended in countries where diarrhoeal deaths account for ≥10% of mortality among children aged <5 years. First dose of either RotaTeq or Rotarix be administered at age 6–15 weeks.

The maximum age for last dose should be 32 weeks. 2 doses of Rotarix be administered with the first and second doses of DTP rather than with the second and third doses. Rotavirus vaccines be part of a comprehensive strategy to control diarrhoeal diseases including interventions:  Improvements in hygiene and sanitation,  Zinc supplementation,  Community-based administration of oral rehydration solution and  Overall improvements in case management

Recommendations in India Not included in National Immunization Schedule. Indian Academy of Paediatrics recommends but not routine. Rotavirus vaccine can be given after discussion with parents Dose and Schedule same

Conclusions: Duration of Protection? Cost Effectiveness ? Role other Contributory factors ? Evidences from developing countries not convincing. Even Small no. of serious AEFI unacceptable?