Rotavirus Prevention and Control Dr Simba Takuva, MBChB, MSc.
Outline of Presentation Introduction Epidemiology and Disease Burden The Rotavirus Clinical Presentation Prevention and Control Vaccination Surveillance WHO Recommendations Conclusion
Introduction Rotavirus (RV) is the commonest cause of severe diarrhoeal disease in infants and young children globally 527 000 children die each year Children under 5 most vulnerable Majority in low-income countries (85%) Country-specific data show 80-90 children die every day in Nigeria from the disease, 50-60 deaths occur daily in Cameroon, and 10-12 in South Africa Estimated cost to healthcare system: USD 264 to 318 million per year Estimated societal costs: USD 890 to 1 billion per year
Epidemiology and Disease BurdenCauses of Death in Children Under 5 Worldwide, 2008 15% Diarrhoea Pneumonia 37% 19% Other infections Non communicable diseases 7% 22% Neonatal causes 15% = 1.3 million deaths annually ! Black RE, Lancet 2010; 375:1969-1987
Transmission Primary mode of transmission is feacal to oral Highly communicable and transmissible Close person-to-person contact and environmental surfaces are common vectors of transmission Incubation period is 1 – 3 days
Transmission Large quantities of virus are shed in stool from just prior to onset of symptoms until about 10 days after onset Amount of virus shed in stool: 10-100 billion virions/gram of stool ! Amount of ingested virus required to cause infection: As few as 10 infective virions ! Amount of stool that needs to be ingested to potentially result in infection: ≈ 0.000001mg !
The RotavirusFirst recognized in 1973, rotavirus belongsto the viral family ReoviridaeIts wheel-like shape under an electronmicroscope earned it the name of “rota”virusThe rotavirus genome consists of 11double-stranded RNA segments, eachencoding one viral protein A triple-layered capsule surrounds theRNAScientists have described seven rotavirusgroups (A to G)Only groups A, B, and C infect humans Group A, which has multiplestrains, causes the majority of childhoodinfectionsVaccine candidates are designed to protectagainst Group A rotaviruses
The Rotavirus The G-type and P-type define the serotype They are critical to vaccine developmentbecause they are the vaccine targets forstimulating a protective immune responseSEROTYPES Source : WWW.ROTAPICTURES/BU/EDU G1P is the most common serotype worldwide and accounts for over twothirds of rotavirus infections worldwide Infections with G1, G2, G3, G4, and G9 together comprise almost 95% ofrotavirus serotypes observedBecause the 2 gene segments that encode these proteins can segregateindependently, a typing system consisting of both G and P types is used. i.e.G1P, G2P, G3P, G4P, G9P, and G9P
Clinical PresentationTimeline of Rotavirus Pathogenesis Source:
Clinical PresentationClinical Triad of Rotavirus Infection
Clinical PresentationPathogenesis The virus causes diarrhoea by three principle mechanisms: infection of villus epithelial cells causes cell destruction, decreased absorption of salt and water, and decreased disaccharidase activity, increasing the osmotic load in the gut lumen stimulation of the enteric nervous system, leading to increased fluid secretion direct enterotoxin effects of nonstructural protein 4 (NSP4), the first viral enterotoxin to be described The osmotic load in the gut and increased fluid secretion lead to diarrhoea and, if unchecked and without fluid replacement, can ultimately lead to dehydration and acidosis
Clinical PresentationComplications• The major complication is the dehydration, which can lead to acidosis and eventually to circulatory collapse. Also been associated with aseptic meningitis, necrotizing enterocolitis, acute myositis, hepatic abscess, pneumonia, Kawasaki disease, SIDS and Crohns disease Rotavirus induced gastroenteritis in children with immunodeficiency may cause persistent infection lasting weeks or months Self-limited illness in immunocompetant
Clinical PresentationDiagnosis Mostly clinical Rapid antigen detection by ELISA of rotavirus in stool specimens. Isolates may be further characterized by reverse- transcriptase polymerase chain reaction
Clinical Presentation In infants, natural rotavirus infection confers protection against subsequent infection By the age of 2 years, nearly every child in a cohort of children in Mexico had experienced at least one rotavirus infection These children had greater protection against severe diarrhoea with subsequent infections Two natural infections were required for 100% protection against moderate-to-severe diarrhoea The first exposure to rotavirus also protected 87% (95% CI, 54%, 96%) of children from having severe disease from the second infection The protection rates observed with one natural infection are similar to those observed with vaccine-induced protection Vaccination protects 84% to 98% of children against severe outcomes of a second rotavirus infection Thus, the vaccines are mimicking the protection rates of one natural infection Source: Velazquez, FRet al. N Engl J Med. 1996;335:1022-1028
Clinical Presentation Probability of RV Infection by AgeCumulative Probability of First and Subsequent Natural Rotavirus Infections during theFirst Two Years of life (Source: Velazquez, FRet al. N Engl J Med. 1996;335:1022-1028.)
TreatmentTherapy for rotavirus-induced diarrhoea involves replacement of fluids andelectrolytes lost during infection.Priorities feeding (breast milk or diluted formula in infants and lactose free carbohydrate rich foods in older children) within 24 hours after onset of illness the use of oral rehydration therapy in children with mild or moderate dehydration.Fruit juices and soft drinks are not recommended due to their high glucosecontent, low sodium content and high osmolarity.Antibiotics, antisecretory drugs, antimotility drugs, absorbents andantiemetics do not ameliorate acute infection, prevent reinfection or reducefluid losses during rotavirus induced gastroenteritis, and therefore do notplay a role in treatment.Children with immunodeficiency disorders may be treated with rotavirus-specific immunoglobolin preparation. Administer orally to decrease sheddingand ameliorate disease .
Prevention and Control Infection Control Vaccination
Infection ControlIn the Home and Day-Care Facilities Hand-washing areas Food-preparation areas Diaper-changing surfaces Diaper disposal containers ToysIn Hospital Areas and Clinics Hand-washing areas Medication-preparation areas Equipment Patient care areas
Rotavirus Vaccines Two oral, live, attenuated rotavirus vaccines Rotarix (GlaxoSmithKline Biologicals,Rixensart, Belgium) RotaTeq (Merck & Co. Inc., West Point, PA, USA) Available internationally Both vaccines are considered safe and effective WHO now recommends that infants worldwide be vaccinated against Rotavirus Vaccines differ in composition and dosing schedule Rotarix (RV1) is a monovalent vaccine given in a 2-dose schedule Rotateq (RV5) is a pentavalent vaccine given in a 3-dose schedule
Rotavirus Vaccines RotaTeq RotarixManufacturer Merk & Co. GSKGenetic framework Bovine Rotavirus – WC3 Human Rotavirus-89-12Composition 5 Human, Bovine reassortant Single Human rotavirusGenotypes G1, 2, 3, 4 and [P8] G1 [P8]Dosage Schedule 3 doses at 2, 4 and 6 months 2 doses at 2 and 4 monthsRoute oral oralPresentation liquid Lysophilized-reconstitutedEfficacy against severe 85% 95%diseaseVirus shedding Up to 13 % 17 % - 27%
Vaccine EfficacyRotavirus Efficacy in Clinical Trials in Africa and AsiaVaccine Region Country EfficacyRV1 (Rotarix) Africa South Africa, 62% (44% - 73%) MalawiRV5 (RotaTeq) Asia Bangladesh, 51% (13% - 73%) VietnamRV5 (RotaTeq) Africa Ghana, Kenya, 64% (40% - 79%) MalawiMadhi SA, et al. N Engl J Med 2010;362:289-298Armah GE, et al. Lancet 2010;376:606-614Zaman K, et al. Lancet 2010;376:615-623
Vaccine EfficacyFactors to Consider in Rotavirus EfficacyEfficacy of Rotavirus Vaccines by Mortality Stratum and CountryMortality rate RV vaccine Countries were studiesdefined by WHO efficacy estimates were performedHIGH 50 – 64 % Ghana, Kenya, Malawi, Mali 46 – 72 % Bangladesh, South AfricaINTERMEDIATE 72 – 85 % Vietnam, the AmericasLOW 85 – 100 % The Americas, Western Pacific and EuropeAdapted from WHO. Wkly Epidemiol Rec 2009;84:533-40
Rotavirus Surveillance in South Africa Diarrhoea sentineal surveillance programme implemented in April 2009 by the NICD Five hospitals in four provinces (Gauteng, North-West, Kwazulu Natal and Mpumalanga) The aim of the programme is to evaluate the prevalence of rotavirus in diarrhoea cases and to monitor the effect of the introduction of the Rotarix vaccine into the EPI The rotavirus vaccine was introduced in August 2009 Children < 5 years admitted (slept overnight in hospital) to one of the sentinel hospitals for acute diarrhoea (3 loose stools in 24 hour period and onset within 7 days) are eligible for enrolment in the surveillance Stool specimens are collected and tested at the NICD/NHLS and at the Diarrhoeal Pathogens Research Unit, MEDUNSA, using the Rotavirus ELISA kit
Rotavirus Surveillance in South AfricaIn the first year, coverage was less than 50%; data from early2010 indicated uptake of 50-75%Rotavirus in South Africa is a very seasonal disease, usuallypeaking in May, with a second smaller peak a few months laterIn summer months there is little rotavirus but quite a bit ofother diarrheal diseaseData collected from the sentinel sites through June 2010showed a major decline in RV-positive stool samples in the 2010rotavirus season, the first following the vaccine’s introductionIn vaccinated children, rotavirus was detected in 11% of stoolsamples during the surveillance period, while in the unvaccinatedchildren the rate was 20%
Rotavirus Surveillance in South Africa Cumulative number of specimens tested rotavirus positive and total number of samples collected by hospital - Reporting period: 04/01/2010 to 30/12/2010.Hospital Rotavirus Positive Total SamplesChris Hani Baragwanath 128 541Edendale 16 84George Mukhari 46 232Mapulaneng 10 67Matikwane 41 218Total 241 1142Rotavirus also has a distinct seasonality with peaks in the winter months intemperate climatesserotype G1 accounts for approximately 50% of infections in South Africa.Other serotypes causing infection in South Africa include G2, G8, G9 and G12Data courtesy of NICD Epidemiologic Report; ROTA Surveillance, 2011.
Rotavirus Surveillance in Africa25-40% of African children hospitalized withdiarrheal illness are infected with rotavirusBy 18 months of age, 83% of children will havecontracted the virusG1 is most prevalent strain in Africa, estimated50% of cases, followed by G3 at 30%G2 strain occurs in “waves” every 3 to 4 yearsG4 and G8 strains occur in sporadic isolationG9 is emerging in countries across thecontinentMixed serotypes are increasingly commonOf the P genotypes, P6 is the mostcommon, accounting for 50-60% ofcases, followed by P8 (35-40% of cases).An unusual VP4 serotype has also beendetected African Rotavirus Surveillance Network (AFRSN) – www.afro.who.int/en
Other Effects of Rotavirus Vaccination Health Impact decrease in all-cause diarrhoea Herd Immunity protection extends to the unvaccinated Age specific incidence of disease change in age of exposure Season specific incidence of disease shift in onset of epidemics. Helps guide surveillance systems Long-term interaction of rotavirus vaccination and strain ecology Strains may changes post-vaccination
Rotavirus in HIV-infected Infants HIV infected children with RV diarrhoea have similar short- term clinical course and outcome. HIV infected children 4.7 fold more likely to have ongoing, prolonged asymptomatic shedding of RV four weeks post-diarrhoeal illness. RV IgG and IgA seroconversion post wild type RV illness similar between HIV-infected and -uninfected children RV infection does not affect blood HIV viral load or CD4cell counts RV vaccine not associated with progression of immune- deficiency in HIV infected children. Cunliffe NA et al. The Lancet; 2001; 358: 550-555 ; Jere C et al. AIDS 2001; 15: 1439-42
Rotavirus Vaccine SafetyIntussuseption 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 Rotarix and RotaTeq, as well as postmarketing safety data from Australia, Latin America and the United States• Previous association with the now withdrawn vaccine, RotaShield
Rotavirus Vaccine SafetyContraindications 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 diverticulumVaccine-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 - EPI Recommendations RV vaccine 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 recommends that the first dose of either RotaTeq or Rotarix be administered at age 6–15 weeks The maximum age for administering the last dose of either vaccine should be 32 weeks. It is recommended that 2 doses of Rotarix be administered with the first and second doses of DTP rather than with the second and third doses This ensures maximum immunization coverage and reduces the potential for late administration beyond the approved age window This schedule will be reviewed as new data become available 6 and 14 weeks in RSA EPI schedule
Conclusions Rotavirus vaccines are not the solution to controlling this disease Disease Control involves an integrated approach Zinc treatment Improved oral rehydration solution (ORS) Exclusive breastfeeding Improved nutrition Community education Safe water, adequate sanitation and hygiene These can complement the impact of vaccines and together have a huge impact in reducing the burden of diarrhoea – one of the largest killer of young children.
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