Rotavirus Prevention and Control

Dr Simba Takuva, MBChB, MSc.

Introduction Epidemiology and Disease Burden The Rotavirus Clinical Presentation Prevention and Control Vaccination Surveillance WHO Recommendations Conclusion

Outline of Presentation

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

Introduction

Epidemiology and Disease Burden

15%

19%

22%7%

37%

Causes of Death in Children Under 5 Worldwide, 2008

Diarrhoea

Pneumonia

Other infections

Non communicable diseases

Neonatal causes

Black RE, Lancet 2010; 375:1969-1987

15% = 1.3 million deaths annually !

Epidemiology and Disease Burden

Epidemiology and Disease Burden

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 !

Transmission

The Rotavirus

First recognized in 1973, rotavirus belongs to the viral family ReoviridaeIts wheel-like shape under an electron microscope earned it the name of “rota” virusThe rotavirus genome consists of 11 double-stranded RNA segments, each encoding one viral protein A triple-layered capsule surrounds the RNAScientists have described seven rotavirus groups (A to G)Only groups A, B, and C infect humans Group A, which has multiple strains, causes the majority of childhood infections Vaccine candidates are designed to protect against Group A rotaviruses

The Rotavirus

The G-type and P-type define the serotype They are critical to vaccine development because they are the vaccine targets for stimulating a protective immune response

Source : WWW.ROTAPICTURES/BU/EDU

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

Because the 2 gene segments that encode these proteins can segregate independently, a typing system consisting of both G and P types is used. i.e. G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and G9P[6]

Timeline of Rotavirus Pathogenesis

Clinical Presentation

Source:

Clinical Triad of Rotavirus Infection

Clinical Presentation

Pathogenesis 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 Presentation

Complications• 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 Crohn's disease

Rotavirus induced gastroenteritis in children with immunodeficiency may cause persistent infection lasting weeks or months

Self-limited illness in immunocompetant

Clinical Presentation

Diagnosis 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

Clinical Presentation

Source: Velazquez, FRet al. N Engl J Med. 1996;335:1022-1028

Probability of RV Infection by Age

Clinical Presentation

Cumulative Probability of First and Subsequent Natural Rotavirus Infections during the First Two Years of life (Source: Velazquez, FRet al. N Engl J Med. 1996;335:1022-1028.)

Treatment

Therapy for rotavirus-induced diarrhoea involves replacement of fluids and electrolytes 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 glucose content, low sodium content and high osmolarity. Antibiotics, antisecretory drugs, antimotility drugs, absorbents and antiemetics do not ameliorate acute infection, prevent reinfection or reduce fluid losses during rotavirus induced gastroenteritis, and therefore do not play a role in treatment. Children with immunodeficiency disorders may be treated with rotavirus-specific immunoglobolin preparation. Administer orally to decrease shedding and ameliorate disease .

Infection Control Vaccination

Prevention and 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

Infection Control

Rotavirus Vaccination

Rotavirus Vaccines

Vaccine Efficacy

Vaccine Safety

Rotavirus and HIV-infected infants

WHO - EPI Recommendations

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. GSK

Genetic framework Bovine Rotavirus – WC3 Human Rotavirus-89-12

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

85% 95%

Virus shedding Up to 13 % 17 % - 27%

Rotavirus Vaccine Clinical Trials

Vaccine Efficacy

Rotavirus Efficacy in Clinical Trials in Africa and Asia

Madhi 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 Region Country EfficacyRV1 (Rotarix) Africa South Africa,

Malawi62% (44% - 73%)

RV5 (RotaTeq) Asia Bangladesh, Vietnam

51% (13% - 73%)

RV5 (RotaTeq) Africa Ghana, Kenya, Malawi

64% (40% - 79%)

Vaccine Efficacy

Efficacy of Rotavirus Vaccines by Mortality Stratum and Country

Mortality rate defined by WHO

RV vaccine efficacy estimates

Countries were studies were performed

HIGH 50 – 64 % Ghana, Kenya, Malawi, Mali

INTERMEDIATE46 – 72 % Bangladesh, South Africa

72 – 85 % Vietnam, the Americas

LOW 85 – 100 % The Americas, Western Pacific and Europe

Factors to Consider in Rotavirus Efficacy

Adapted from WHO. Wkly Epidemiol Rec 2009;84:533-40

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 Africa

Rotavirus Surveillance in South Africa

In the first year, coverage was less than 50%; data from early 2010 indicated uptake of 50-75% Rotavirus in South Africa is a very seasonal disease, usually peaking in May, with a second smaller peak a few months laterIn summer months there is little rotavirus but quite a bit of other diarrheal diseaseData collected from the sentinel sites through June 2010 showed a major decline in RV-positive stool samples in the 2010 rotavirus season, the first following the vaccine’s introductionIn vaccinated children, rotavirus was detected in 11% of stool samples during the surveillance period, while in the unvaccinated children the rate was 20%

Cumulative number of specimens tested rotavirus positive and total number of samples collected by hospital - Reporting period: 04/01/2010 to 30/12/2010.

Rotavirus Surveillance in South Africa

Hospital Rotavirus Positive Total SamplesChris Hani Baragwanath 128 541

Edendale 16 84

George Mukhari 46 232

Mapulaneng 10 67

Matikwane 41 218

Total 241 1142

Data courtesy of NICD Epidemiologic Report; ROTA Surveillance, 2011.

Rotavirus also has a distinct seasonality with peaks in the winter months in temperate climatesserotype G1 accounts for approximately 50% of infections in South Africa. Other serotypes causing infection in South Africa include G2, G8, G9 and G12

Rotavirus Surveillance in Africa

African Rotavirus Surveillance Network (AFRSN) – www.afro.who.int/en

25-40% of African children hospitalized with diarrheal illness are infected with rotavirusBy 18 months of age, 83% of children will have contracted the virus

G1 is most prevalent strain in Africa, estimated 50% 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 the continentMixed serotypes are increasingly commonOf the P genotypes, P6 is the most common, accounting for 50-60% of cases, followed by P8 (35-40% of cases). An unusual VP4 serotype has also been detected

Rotavirus Surveillance

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

Other Effects of Rotavirus Vaccination

Rotavirus Herd Immunity

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.

Rotavirus in HIV-infected Infants

Cunliffe NA et al. The Lancet; 2001; 358: 550-555 ; Jere C et al. AIDS 2001; 15: 1439-42

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 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 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

Rotavirus Vaccine Safety

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

WHO - EPI Recommendations

6 and 14 weeks in RSA EPI schedule

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.

Conclusions

• WHO Weekly Epidemiological Record 2008; 83 (47), 27 November 2008• Global networks for surveillance of rotavirus gastroenteritis, 2001-2008. Wkly Epidemiol Rec 2008;83:421-428.• Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis

2003;9:565-72.• Chin, J. (Ed.). (2000). Control of Communicable Disease Manual. Wash. DC: American Public Health Association.• American Academy of Pediatrics. (1997). Rotavirus. In Red book: Report of the committee on infectious diseases. (24th ed., pp.454 - 456). Elk Grove

Village, IL:Author.• Velazquez F, Matson DO, Calya JJ, et al. Rotavirus infections in infants as protection against subsequent infections. N Engl J Med. 1996;335:1022-1028.• Offit, P. A. & Clark, M. F. (2000). In G. L. Mandell, J. E. Bennett, & R. Dolin (Eds)., Principles and practice of infectious diseases. (5th ed., pp.1696 -

1703). Philadelphia, PA: Churchill Livingstone• Estes M. Rotaviruses and their replication. In: Howley PM, ed. Fields Virology. 3rd ed. Vol. 2. Philadelphia, PA: Lippincott-Raven; 1996:1625-55.• Estes MK, Cohen J. Rotavirus gene structure and function. Microbiological Reviews 1989;53:410-49.• Glass RI, Bhan MK, Ray P, et al. Development of candidate rotavirus vaccines derived from neonatal strains in India. J Infect Dis 2005;192(Suppl):S30-

S5.• Ward RL, Bernstein DI. Lack of correlation between serum rotavirus antibody titers and protection following vaccination with reassortant RRV

vaccines. Vaccine 1995;13:1226-32.• Green KY, Taniguchi K, Mackow ER, Kapikian AZ. Homotypic and heterotypic epitope-specific antibody respones in adult and infant rotavirus

vaccinees: implications for vaccine development. J Infect Dis 1990;161:667-79.• Madhi S, Cunliffe NA, Steele D, Witte D, Kirsten M, et al. N Engl J Med 2010: 362: 289-98• Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med

2006;354:23-33.• CDC. Withdrawal of rotavirus vaccine recommendation. MMWR 1999;48:1007.• Peter G, Myers MG. Intussusception, rotavirus, and oral vaccines: summary of a workshop. Pediatrics 2002;54:110.• WHO. Report of the Global Advisory Committee on Vaccine Safety, December 1-2, 2005. Wkly Epidemiol Rec 2006;2:13-20.• African Rotavirus Surveillance Network (AFRSN) – www.afro.who.int/en• Rotavirus (ROTA) Surveillance: Rotavirus Report, National Institutes of Communicable Diseases, 2 March 2011.• WHO Weekly Epidemiological Record. No. 51-52, 2009, 84, 533-540.• Diarrhoea: why children are still dying and what can be done. Geneva, UNICEF and World Health Organization, 2009 (available from:

http://www.who.int/child_adolescent_health/documents/9789241598415/en/index.html; accessed November 2009).• CDC, unpublished data, 2006.

References

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