Prevention of Rotavirus Infections. Dr. ANCA DRAGANESCU INBI Matei Bals Bucuresti

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1 Prevention of Rotavirus Infections Dr. ANCA DRAGANESCU INBI Matei Bals Bucuresti

2 Worldwide, Rotavirus Accounted for ~215,000 Childhood Deaths Annually 1 ( ) In children less than 5 years of age: Almost all are infected 2 Rotavirus is leading cause of severe diarrhea 1 Rotavirus accounts for 37% of all deaths due to diarrhea 1 Deaths 1 215,000 Hospitalizations 2,000,000 Outpatient Visits 25,000,000 Episodes 111,000,000 Annual estimates 3 1. Tate JE et al. CID. 2016;62 (Suppl 2):S96-S Tate JE et al. Exp Rev Vaccines. 2010;9(4): Parashar et al. Emerg. Infect. Dis. 2003; 9(5):

3 Rotavirus Gastroenteritis (RVGE) Is a Potentially Serious Disease Rotavirus disease can be severe especially for: Infants 1 Immunocompromised patients1 Most cases are mild but severity is unpredictable 2,3 A mild case can rapidly become severe and life threatening 2 Symptoms : Forceful vomiting 3, profuse diarrhoea 1,fever 3 Most frequent complications include: Severe dehydration (isotonic or hypertonic) 1,4 Others : Seizure 4; Electrolyte imbalance 4 1. Raebel MA, Ou BS. Pharmacotherapy 1999;19(11): Van Damme P et al. Lancet Infect Dis 2006;6: Clark HF et al. Pediatr Ann 2004;33(8): Leung AKC et al. Adv Ther 2005;22(5):

4 Clinical Manifestations Symptoms include Vomiting Can be Click more to frequent, edit Master longer duration title than stylewith other pathogens Diarrhea Can range from mild and limited duration to bowel movements/day Duration can be longer than with other gastroenteritisassociated pathogens Stools generally non-bloody, no fecal leukocytes Fever Average duration GI symptoms approximately 3-7 days Most severe disease typically occurs in children 6 24 months of age who are experiencing their first infection Management: Supportive Care: replacement of fluid & electrolyte loss IV hydration may be necessary

5 Rotavirus Transmission Fecal oral route 1 Concentration in stool: up to 100 billion particles/ml Low infectious dose: 10 plaque-forming units/ml Physically hardy virus 1 Can persist in low-humidity environment 1,2 Relevantly resistant to hand soaps and common disinfectants 1 Inactivated by high concentrations of alcohol, chlorine, or iodine 1 Can occur before and after symptoms 3 Infected persons shed large quantities of virus in their stool 2 days before to 10 days after onset of symptoms 1. Dormitzer PR. In: Mandell GL et al, eds. Mandell, Douglas, and Bennett s Principles and Practice of Infectious Diseases. 8th ed. Elsevier Saunders. 2015: Paul MO et al. J Clin Microbiol. 1982;15: Centers for Disease Control and Prevention (CDC). cdc.gov/vaccines/pubs/pinkbook/downloads/rota.pdf. Accessed April 16, 2016.

6 Natural Rotavirus Infection: Cumulative Probability by 24 Months of Age 1 100% ~40% of children had at least 3 rotavirus infections by age 2 years 1st infection Probability of Rotavirus Infection 80% 60% 40% 20% 0 0 N= nd infection 3rd infection 4th infection 5th infection Age (months) Note: This slide contains information about protection conferred after natural infection. Immune correlates of protection from rotavirus infection and disease are not fully understood. 1. Velázquez FR et al. N Engl J Med. 1996;335: From N Engl J Med, Velazquez FR et al, Rotavirus infections in infants as protection against subsequent infections, Vol 335, p Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

7 Nearly 90% of rotavirus gastroenteritis occur between 3 months and 3 years of age S Peak occurrence of rotavirus gastroenteritis (RVGE) is observed in children 6-24 months of age S 86 % of all RVGE are between 3 months and 3 years children. 45% 40% 40% 35% 30% Percentage 25% 20% 15% 10% 5% 2% 6% 24% 16% 8% 4% 0% < 3 months n= months n= months n= months n= months n= months n= months n=40 Distribution of RVGE cases by age in all settings in Europe children ( ) 1. Van Damme P et al. J Infect Dis 2007;195(suppl 1):S4-S REVEAL global report July 2007;SPMSD data on file. From REVEAL study 1 : prospective, observational study of AGE in 2846 children <5 years of age seeking health care, in , in selected areas of 7 countries Total AGE cases: 2 841

8 Rotavirus accounts for >50% of hospitalizations due to acute gastroenteritis (AGE) in Europe S In the EU, 1 in 54 children is hospitalised each year due to rotavirus gastroenteritis (RVGE) 1 Percentage of RVGE among AGE Estimated numbers Belgium N= France N=1944 NA Germany N= Percentage of rotavirus cases among AGE cases in Europe according to countries and settings ( ) 2 33 Italy N= Spain N= Sweden N= UK N= % Hospitalisation Emergency visit Primary care SRVGE causes a considerable burden on the family and health care systems 3 1. Soriano-Gabarró M et al. Pediatr Infect Dis J 2006;25:S7-S Giaquinto C et al. J Infect Dis 2007;195(suppl 1):S26-S Van der Wielen M et al. ESPID 2007;abstract and poster. From REVEAL: prospective, observational study of AGE in 2846 children <5 years of age seeking health care, in , in selected areas of 7 countries

9 Circulating rotavirus strains in humans: Unpredictable circulation from year to year and from region to region % of serotypes samples from children under 5 years Olgivie I et al, BMC Infectious Diseases, 2012

10 Rotavirus (RV) genotypes distribution in EU countries between Six genotypes* G1P[8],G4P[8],G2P[4],G9P[8] and G12P[8] = 92% of strains Overall distribution of the 6 more frequent rotavirus genotypes between 2006 and 2015 in EuroRotanet database. (N=57,434) *with a prevalence >1% ** Other excludes strain mixtures and partially typed strains. M Iturriza-Gomara, ESPID, (abstract)

11 Hospital-based surveillance to estimate the burden of rotavirus gastroenteritis in children below five years of age in Romania February 2008 and December 2009, nine hospitals in Romania with an estimated coverage of 28% of the pediatric population of Romania 1212 RV test results were available Hospitalizations [n=677], ER visits [n=398] Nosocomial GE [n=137] Proportions of rotavirus gastroenteritis (RVGE) Hospitalizations 51.70% (350/677; 95%CI: ) ER visits 36.18% (144/398; 95%CI: ) Anca et al The burden of rotavirus gastroenteritis GERMS 2014; 4(2): 30-40

12 Rotavirus gastroenteritis in Romania -age The highest number of cases was observed in children < 3 years 86% 82% 12 Anca et al The burden of rotavirus gastroenteritis GERMS 2014; 4(2): 30-40

13 Rotavirus gastroenteritis in Romania - seasonality In low income countries, the RV-.-epidemiology is characterized by episodes of intense viral transmission against a background of year-.-round RV-.-circulation In high income countries of temperate climate, a distinct winter seasonality is typically observed. 13 Anca et al The burden of rotavirus gastroenteritis GERMS 2014; 4(2): 30-40

14 Genotype distributions in rotavirus gastroenteritis in Romania G9 G1 G4 VP4 defines the P-serotype and VP7 defines G-serotype SEROTYPES G1P[8] is the most common serotype worldwide and accounts for over two thirds of rotavirus infections worldwide Infections with G1, G2, G3, G4, and G9 together comprise almost 95% of rotavirus serotypes observed 14 Anca et al The burden of rotavirus gastroenteritis GERMS 2014; 4(2): 30-40

15 Infection Control In the Home and Day-Care Facilities Hand-washing areas Food-preparation areas Diaper-changing surfaces Diaper disposal containers Toys In Hospital Areas and Clinics Hand-washing areas Medication-preparation areas Equipment Patient care areas

16 Prevention and Control Infection Control Vaccination

17 What is the Rationale for a Multivalent and Multidose Rotavirus Vaccine? Multivalent Predominance of individual serotypes can vary from year to year and by geographic region. 1 Immunity following primary infection is thought to be predominantly serotype specific. 2 Multidose Primary infections are usually associated with more severe disease than subsequent infections. 2 Protection against disease is thought to increase with each subsequent infection Santos N et al. Rev Med Virol. 2005;15: Velázquez FR et al. N Engl J Med. 1996;335:

18 Rotavirus Vaccines Two oral, live, attenuated rotavirus vaccines RotaTeq (Merck & Co. Inc., West Point, PA, USA) Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) Available internationally Both vaccines are considered safe and effective

19 Rotavirus Vaccines: live, oral, attenuated RV RotaTeq Rotarix Manufacturer Merk & Co. GSK Genetic framework Bovine Rotavirus WC3 Human Rotavirus Composition 5 Human, Bovine reassortant Single Human rotavirus Genotypes G1, 2, 3, 4 and [P8] G1 [P8] Dosage Schedule 3 doses at 2, 4 and 6 months 2 doses at 2 and 4 months Route oral oral Presentation liquid Lysophilized-reconstituted Efficacy against severe disease 95% 95% Virus shedding Up to 13 % 17 % - 27%

20 Natural Reassortment RotaTeq Bovine (WC3) Rotavirus P7[5] (VP4) G6 (VP7) G1P1A[8] Human Rotavirus G2P2[6] Human Rotavirus G3P1A[8] Human Rotavirus G4P2[6] Human Rotavirus G1 (P7[5]) P1A[8] (G6) G2 (P7[5]) G3 (P7[5]) G4 (P7[5]) Human Bovine Reassortant Rotavirus Vaccine Strains Offit PA, Clark HF. Pediatr Ann. 2006;35:29 34.

21 Rotarix (Rotavirus Vaccine, Live, Oral) 1 Human Rotavirus G1P1A[8] Attenuated by serial passage in cell culture Rotarix G1P1A[8] 1. Rotarix Prescribing Information. Accessed 5 July Rotarix (Rotavirus Vaccine, Live, Oral) is a registered trademark of GlaxoSmithKline.

22 3 Phase III Prelicensure Studies - 71,725 Subjects Evaluated 36,165 in Vaccine Group 35,560 in Placebo Group United States Finland Sweden Navajo & White Mt. Apache Nations Mexico Guatemala Costa Rica Germany Belgium Puerto Rico Jamaica Italy Taiwan Data on file, MSD Dennehy PH, et al. Int J Infect Dis. 2007;11(Suppl 2):S36 S42. Subjects Lost to Follow-Up: 81 (0.2%) V: 97 (0.3%) P

23 Efficacy Against Rotavirus Gastroenteritis Caused by Serotypes G1, G2, G3, and G4 Through the 1st rotavirus season after vaccination: 98% efficacy 74% efficacy Up to 2 years after vaccination: ~95% reduction Against severe rotavirus (N=5,673: 2,834 vaccine; 2,839 placebo) Against any severity of rotavirus (N=5,673: 2,834 vaccine; 2,839 placebo) Up to 3.1 years after vaccination (Finland): ~94% reduction In combined incidence of hospitalizations/ed visits for rotavirus (N=68,038: 34,035 vaccine; 34,003 placebo) In combined incidence of hospitalizations/ed visits for rotavirus (N=20,736: 10,367 vaccine, 10,365 placebo) Vesikari T et al. N Engl J Med. 2006; Vesikari T et al. Ped Inf Dis J 2010

24 RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) is a trademark of MSD. RotaTeq: Reductions in Office Visits & Lost Work Days Rotavirus caused by serotypes G1, G2, G3, and G4 Endpoints N subjects contributing to analysis Office visits 2 N=4,451 Parental Work Day Lost 1 N=57,134 % Rate Reduction 95% CI 86% (74,93) 87% (78,92) Up to 2 years postvaccination 1. Vesikari T, et al. N Engl J Med. 2006;354: Vesikari T, et al. Int J Infect Dis. 2007;11(Suppl 2):S29 S35.

25 Intussusception and Rotavirus Vaccination An association with intussusception led RotaShield to be voluntarily withdrawn from US Largest increased risk seen 3 to 7 days after first dose Attributable risk was ~1 additional case per 10,000 recipients in post-marketing studies Intussusception cases during REST Time Period Vaccine N=34,837 Placebo N=34,788 Within 7 days after any dose 1 0 Within 42 days after any dose 6 5 Within 1 year after vaccination N= Subjects vaccinated; REST= Rotavirus Efficacy and Safety Trial; Cases were adjudicated by external independent committee blinded to treatment RotaShield, a vaccine for rotavirus developed by Wyeth Laboratories. 1. Heyse JF et al. Clin Trials. 2008;5: Punnoose AR et al. JAMA. 2012;307: Vesikari T et al. N Engl J Med. 2006;354: Shui IM et al. JAMA. 2012;307: Illustration Copyright 2012 Nucleus Medical Media, All rights reserved.

26 RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) is a trademark of MSD. Long-term Consistency in Protection for RotaTeq Over Time and By Year of Life Vaccine Effectiveness (%) with 95%CI Year Payne DC et al. Clin Infect Dis. 2015, 1-7 Year of Life 26

27 New Information in European Label for RotaTeq EMA RotaTeq Summary of Product Characteristics Accessed on May 3, 2016

28 Rotavirus Vaccine Safety Intussuseption Currently NO data supports hypothesis of increased risk of intussuseption with RV vaccines Rotavirus vaccines are safe Reviewed safety data from phase III efficacy studies of RotaTeq and Rotarix, as well as post-marketing safety data from Australia, Latin America and the United States Previous association with the now withdrawn vaccine, RotaShield WHO Weekly epidemiological record 2013 (8): 49-64

29 Rotavirus Vaccine Safety Contraindications Severe Combined Immunodeficiency Syndrome History of: severe allergic reaction to a prior dose of RV Severe allergic reaction to latex Intussuseption Some congenital GI malformations e.g. Meckel diverticulum Vaccine-vaccine interactions RV vaccines have been found not to interfere significantly with the immunogenicity or safety of other childhood vaccines However, OPV appears to have an inhibitory effect on the immune response to the first dose of RV vaccine WHO Weekly epidemiological record 2013 (8): 49-64

30 Impact on Public Health in the US Before introduction of rotavirus vaccine in US 55, ,000 hospitalizations/ year In 2012, 94% reduction in rotavirus hospitalizations Later onset and shorter duration of rotavirus season in post vaccine era Some years without a defined rotavirus season MMWR. Vol 64; No. 13. April 10, 2015 JAMA. Vol 313; No. 22. June 9,

31 RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) is a trademark of MSD. Effectiveness of RotaTeq by Predominant Rotavirus Strains in the US, Hospitalizations and Emergency Department Visits Vaccine Effectiveness (%) Payne DC et al. Clin Infect Dis. 2013;57:13 20

32 50 RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) is a trademark of MSD. National Immunization Program (NIP) of Finland with RotaTeq Schedule 2, 3 and 5 months Rotavirus Cases in Tampere, Finland in Vaccine Coverage 90% in 2009, 95-97% in NIP Outpatients Hospitalized Rota infections of all AGE cases : 52% : 26% : 13% Sep 06 Dec 06 Mar 07 Jun 07 Sep 07 Dec 07 Mar 08 Jun 08 Oct 09 Jan 10 Apr 10 Jul 10 Oct 10 Jan 11 Apr 11 Jul 11 Nov 12 Feb 13 May 13 Aug 13 Nov 13 Feb 14 May 14 Aug 14 Hemming M. et al. Eur J pediatr 2013;172: Vesikari International Rotavirus Symposium, India, Sept 2014

33 RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) is a trademark of MSD. Real-life Effectiveness of RotaTeq in Finland Cases RGE EIA+ RT-PCR+ Controls GE EIA- RT-PCR- Children eligible for vaccination Adjusted Vaccine Effectiveness (95% CI) Fully vaccinated 95.8% ( ) At least one dose 93.9% ( ) RGE=Rotavirus gastroenteritis; EIA= Enzyme immunoassay; RT-PCR= Real time polymerase chain reaction Vesikari International Rotavirus Symposium, India, Sept 2014

34 AGE=acute gastroenteritis; NIP=National Immunization Program Clarke MF et al. Vaccine. 2011;29: RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) is a trademark of MSD. Decrease in Seasonal Peak of Rotavirus and All-cause Gastroenteritis After Introduction of RotaTeq in South Australia Postvaccination Period ( ) vs Prevaccine Era ( )

35 World Health Organization Recommends Rotavirus Vaccines For All Children Worldwide WHO recommends that rotavirus vaccine for infants should be included in all national immunization programmes. In countries where diarrhoeal deaths account for 10% of mortality among children aged <5 years, the introduction of the vaccine is strongly recommended. WHO reiterates that rotavirus vaccines are an important measure that can be used to reduce severe rotavirus-associated diarrhoea and child mortality. The use of rotavirus vaccines should be part of a comprehensive strategy to control diarrhoeal diseases

36 Take Home Messages Rotavirus is a major cause of severe diarrhea and vomiting under 5 years of age in Europe. RVGE is highly infectious, unavoidable and unpredictable RVGE is usually mild, but it can be severe and potentially lifethreatening RVGE causes a considerable burden on the family and health care systems 5 rotavirus serotypes are responsible for the great majority of RVGE cases in Europe

37 Thank you Questions? Click to edit Master title style