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Rotavirus Prevention and Control
Dr.Uday A. Pai MD DCH Mumbai
Outline of Presentation

    Introduction

    Epidemiology and Disease Burden

    The Rotavirus

    Clinical Presentation

    Prevention and Control

    Vaccination

    Surveillance

    WHO Recommendations
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
Epidemiology and Disease Burden
Causes of Death in Children Under 5 Worldwide, 2008




         15% = 1.3 million deaths annually !
                    Black RE, Lancet 2010; 375:1969-1987
Epidemiology and Disease Burden
Epidemiology and Disease Burden
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 !
The Rotavirus


 First recognized in 1973, rotavirus belongs
to the viral family Reoviridae

 Its wheel-like shape under an electron
microscope earned it the name of “rota”
virus

 The rotavirus genome consists of 11
double-stranded RNA segments, each
encoding one viral protein

  A triple-layered capsule surrounds the RNA

 Scientists 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

    SEROTYPES
                                                        Source : WWW.ROTAPICTURES/BU/EDU

    
     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]
Clinical Presentation

Timeline of Rotavirus Pathogenesis




    Source:
Clinical Presentation

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

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


                 Probability of RV Infection by Age




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 .
Prevention and Control


    Infection Control

    Vaccination
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

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
Rotavirus Vaccines

                                 RotaTeq                        Rotarix
Manufacturer                      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               85%                          95%
disease
Virus shedding                    Up to 13 %                    17 % - 27%
Rotavirus Vaccine Clinical Trials
Vaccine Efficacy
Rotavirus Efficacy in Clinical Trials in Africa and Asia

Vaccine                Region            Country         Efficacy
RV1 (Rotarix)          Africa            South Africa,   62% (44% - 73%)
                                         Malawi


RV5 (RotaTeq) Asia                       Bangladesh,     51% (13% - 73%)
                                         Vietnam
RV5 (RotaTeq) Africa                     Ghana, Kenya, 64% (40% - 79%)
                                         Malawi


Madhi SA, et al. N Engl J Med 2010;362:289-298
Armah GE, et al. Lancet 2010;376:606-614
Zaman K, et al. Lancet 2010;376:615-623
Vaccine Efficacy
Efficacy of Rotavirus Vaccines by Mortality Stratum and Country

Mortality rate             RV vaccine                    Countries were studies were
defined by WHO             efficacy                      performed
                           estimates
HIGH                            50 – 64 %                Ghana, Kenya, Malawi, Mali

                                46 – 72 %                Bangladesh, South Africa
INTERMEDIATE
                                72 – 85 %                Vietnam, the Americas
                               85 – 100 %                The Americas, Western Pacific
                                                         and Europe


   Adapted from WHO. Wkly Epidemiol Rec 2009;84:533-40
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 later

  In summer months there is little rotavirus but quite a bit of
other diarrheal disease

  Data 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 introduction

  In vaccinated children, rotavirus was detected in 11% of stool
samples during the surveillance period, while in the
unvaccinated children 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 Samples
Chris Hani Baragwanath                         128                         541
Edendale                                        16                          84
George Mukhari                                  46                         232
Mapulaneng                                      10                          67
Matikwane                                       41                         218
Total                                          241                         1142

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

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


 25-40% of African children hospitalized with
diarrheal illness are infected with rotavirus

 By 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 years

 G4 and G8 strains occur in sporadic isolation

 G9 is emerging in countries across the
continent

 Mixed serotypes are increasingly common

 Of 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

                               African Rotavirus Surveillance Network (AFRSN) – www.afro.who.int/en
Rotavirus Surveillance
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
Rotavirus Herd Immunity
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
    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
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.
References
•
    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
THANK YOU

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Rotavirus prevention and control

  • 1. Rotavirus Prevention and Control Dr.Uday A. Pai MD DCH Mumbai
  • 2. Outline of Presentation  Introduction  Epidemiology and Disease Burden  The Rotavirus  Clinical Presentation  Prevention and Control  Vaccination  Surveillance  WHO Recommendations
  • 3. 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
  • 4. Epidemiology and Disease Burden Causes of Death in Children Under 5 Worldwide, 2008 15% = 1.3 million deaths annually ! Black RE, Lancet 2010; 375:1969-1987
  • 7. 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
  • 8. 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 !
  • 9. The Rotavirus  First recognized in 1973, rotavirus belongs to the viral family Reoviridae  Its wheel-like shape under an electron microscope earned it the name of “rota” virus  The rotavirus genome consists of 11 double-stranded RNA segments, each encoding one viral protein  A triple-layered capsule surrounds the RNA  Scientists 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
  • 10. 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 SEROTYPES Source : WWW.ROTAPICTURES/BU/EDU  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]
  • 11. Clinical Presentation Timeline of Rotavirus Pathogenesis Source:
  • 12. Clinical Presentation Clinical Triad of Rotavirus Infection
  • 13. 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
  • 14. 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
  • 15. 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
  • 16. 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  Source: Velazquez, FRet al. N Engl J Med. 1996;335:1022-1028
  • 17. Clinical Presentation Probability of RV Infection by Age 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.)
  • 18. 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 .
  • 19. Prevention and Control  Infection Control  Vaccination
  • 20. 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 
  • 21. Rotavirus Vaccination  Rotavirus Vaccines  Vaccine Efficacy  Vaccine Safety  Rotavirus and HIV-infected infants  WHO - EPI Recommendations
  • 22. 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
  • 23. Rotavirus Vaccines RotaTeq Rotarix Manufacturer 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 85% 95% disease Virus shedding Up to 13 % 17 % - 27%
  • 25. Vaccine Efficacy Rotavirus Efficacy in Clinical Trials in Africa and Asia Vaccine Region Country Efficacy RV1 (Rotarix) Africa South Africa, 62% (44% - 73%) Malawi RV5 (RotaTeq) Asia Bangladesh, 51% (13% - 73%) Vietnam RV5 (RotaTeq) Africa Ghana, Kenya, 64% (40% - 79%) Malawi Madhi SA, et al. N Engl J Med 2010;362:289-298 Armah GE, et al. Lancet 2010;376:606-614 Zaman K, et al. Lancet 2010;376:615-623
  • 26. Vaccine Efficacy Efficacy of Rotavirus Vaccines by Mortality Stratum and Country Mortality rate RV vaccine Countries were studies were defined by WHO efficacy performed estimates HIGH 50 – 64 % Ghana, Kenya, Malawi, Mali 46 – 72 % Bangladesh, South Africa INTERMEDIATE 72 – 85 % Vietnam, the Americas 85 – 100 % The Americas, Western Pacific and Europe Adapted from WHO. Wkly Epidemiol Rec 2009;84:533-40
  • 27. 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 later  In summer months there is little rotavirus but quite a bit of other diarrheal disease  Data 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 introduction  In vaccinated children, rotavirus was detected in 11% of stool samples during the surveillance period, while in the unvaccinated children the rate was 20%
  • 28. 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 Samples Chris Hani Baragwanath 128 541 Edendale 16 84 George Mukhari 46 232 Mapulaneng 10 67 Matikwane 41 218 Total 241 1142  Rotavirus also has a distinct seasonality with peaks in the winter months in temperate climates  serotype G1 accounts for approximately 50% of infections in South Africa. Other serotypes causing infection in South Africa include G2, G8, G9 and G12 Data courtesy of NICD Epidemiologic Report; ROTA Surveillance, 2011.
  • 29. Rotavirus Surveillance in Africa  25-40% of African children hospitalized with diarrheal illness are infected with rotavirus  By 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 years  G4 and G8 strains occur in sporadic isolation  G9 is emerging in countries across the continent  Mixed serotypes are increasingly common  Of 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 African Rotavirus Surveillance Network (AFRSN) – www.afro.who.int/en
  • 31. 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
  • 33. 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 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
  • 34. 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
  • 35. 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
  • 36. 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.
  • 37. References • 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

Editor's Notes

  1. Rotavirus strains are serotyped according to the neutralization of one of the two proteins present in the outer capsid: VP7, a glycoprotein, is neutralized in G types, and VP4, a protease-cleaved hemagglutinin, is neutralized in P types. G types 1, 2, 3, and 4 are responsible for most infections in children. Rotavirus was given its name when scientists observed its wheel-like appearance; it was named after rota , the Latin word for wheel . The inner hub of the rotavirus (yellow on the slide) is usually referred to as the G-type, and the spokes coming off of the inner hub (red on the slide) are usually referred to as the P-type. The G-type and P-type define the serotype of the virus and are critical to vaccine development because they are the vaccine targets for stimulating a protective immune response.
  2. Two surface rotavirus proteins, VP7 (a glycoprotein—G protein) and VP4 (a protease-cleaved protein—P protein), induce homotypic and heterotypic neutralizing antibody responses that are suspected to partly provide protective immunity after natural infection and vaccination
  3. Before symptoms of rotavirus infection appear, feacal shedding occurs. Fever and vomiting precede diarrhoea, and hospitalization for dehydration usually occurs between days 2 and 6 after infection Fever and vomiting are usually the first symptoms, followed quickly by diarrhoea. Oftentimes the vomiting is a rate-limiting factor in attempts to provide oral rehydration. When hospitalization for dehydration does occur, it is usually 2 to 6 days into the illness, and intravenous fluid therapy is necessary.
  4. The diarrhoea is usually non-bloody, profuse, and lasts for up to 3-8 days. Compared with children with non-rotavirus-related diarrhoea, rotavirus-infected children experience more vomiting and have a greater number of diarrhoea episodes per day, which explains why dehydration is so common with this illness.[13] Dehydration is commonly isotonic. Diarrhoea is watery without blood or mucous. Although coryza and cough may precede GI symptoms, replication of rotavirus in the upper respiratory tract is not important in the spread of the virus (4). Neurologic symptoms may occur in severe cases as a result of electrolyte imbalance or direct viral infection of the central nervous system (1).
  5. Cause of disease Rotavirus replicates in certain cells that line the inside of the small intestine. This replication decreases the ability of the intestine to absorb salts and water. Rotavirus has never been detected consistently in the blood or in other sites far from the intestine.
  6. Cause of disease Rotavirus replicates in certain cells that line the inside of the small intestine. This replication decreases the ability of the intestine to absorb salts and water. Rotavirus has never been detected consistently in the blood or in other sites far from the intestine.
  7. In a cohort of Mexican children, nearly every child had a rotavirus infection by the age of 2 years. Rotavirus vaccination mimics the protection rates of one natural infection. The failure of a primary natural rotavirus infection to protect completely against subsequent infection may indicate the need for multiple vaccinations or for the administration of a polyvalent vaccine that can elicit full protection against all prevalent serotypes. It is encouraging that the degree of protection conferred by asymptomatic infection was similar to that afforded by symptomatic infection. The occurrence of two rotavirus infections, whether symptomatic or asymptomatic, resulted in complete protection against moderate-to-severe illness. This finding implies that an attenuated vaccine that caused asymptomatic infection could induce protective immunity. That two natural infections were required for complete protection against moderate-to-severe illness implies that more doses of an attenuated vaccine will be required to achieve efficacy similar to that from exposure to a wild-type strain adapted to the human intestine.
  8. In a cohort of Mexican children, nearly every child had a rotavirus infection by the age of 2 years. Rotavirus vaccination mimics the protection rates of one natural infection. The failure of a primary natural rotavirus infection to protect completely against subsequent infection may indicate the need for multiple vaccinations or for the administration of a polyvalent vaccine that can elicit full protection against all prevalent serotypes. It is encouraging that the degree of protection conferred by asymptomatic infection was similar to that afforded by symptomatic infection. The occurrence of two rotavirus infections, whether symptomatic or asymptomatic, resulted in complete protection against moderate-to-severe illness. This finding implies that an attenuated vaccine that caused asymptomatic infection could induce protective immunity. That two natural infections were required for complete protection against moderate-to-severe illness implies that more doses of an attenuated vaccine will be required to achieve efficacy similar to that from exposure to a wild-type strain adapted to the human intestine.
  9. Deaths also result from treatment. Hypotonic solution given in a large volume can create cerebral oedema. It is important to remember that the range of sodium excretion of rotavirus diarrhoea is around 30 to 60 mL equivalents per liter. Rehydration with fluid less than one-third normal saline causes total body sodium loss. The brain cannot correct fluid imbalance as quickly by moving solute as it can by moving water; patients who have been given too much free water may develop brain oedema and die.
  10. Where is RV found ? Parents cannot prevent their children from getting a rotavirus infection. The primary mode of rotavirus transmission is fecal to oral. Rotavirus is highly communicable and transmissible. Close person-to-person contact and environmental surfaces are common vectors of transmission. It is impossible to keep contaminated fingers and objects from going into children&apos;s mouths. Even if a child is not cared for in a daycare setting, he or she is likely to have contact with other children or objects that other children have touched.   Rotavirus is an extremely hardy pathogen. The incubation period is 1-3 days and large quantities of virus are shed in stool from just prior to onset of symptoms until about 10 days after onset. Rotavirus is highly transmissible. Under experimental conditions, almost 50% of rotavirus remains viable on contaminated hands for 60 minutes
  11. Where is RV found ? Parents cannot prevent their children from getting a rotavirus infection. The primary mode of rotavirus transmission is fecal to oral. Rotavirus is highly communicable and transmissible. Close person-to-person contact and environmental surfaces are common vectors of transmission. It is impossible to keep contaminated fingers and objects from going into children&apos;s mouths. Even if a child is not cared for in a daycare setting, he or she is likely to have contact with other children or objects that other children have touched.   Rotavirus is an extremely hardy pathogen. The incubation period is 1-3 days and large quantities of virus are shed in stool from just prior to onset of symptoms until about 10 days after onset. Rotavirus is highly transmissible. Under experimental conditions, almost 50% of rotavirus remains viable on contaminated hands for 60 minutes
  12. RV1, the live-attenuated human rotavirus vaccine, was approved by the FDA in 2008 and contains one strain of live-attenuated human rotavirus, a G1 P[8] strain. RV1 shares neutralizing identity with G1, G3, G4, and G9 through the P[8] VP4 protein. RV1 does not share neutralizing identity with G2 P[4] strains, and a major concern with the RV1 strain is efficacy against G2 P[4] strains. RV5 The RV5 vaccine contains five reassortant viruses developed from human and bovine parent rotavirus strains and shares neutralizing identity with G1, G2, G3, G4, and P[8], the same P serotype as many of the G9 strains observed in the US. Phase 3 trials included more than 70,000 infants in 11 countries.2 The vaccine demonstrated 74% overall efficacy and 98% efficacy for severe rotavirus disease. In a cohort of infants for which data from clinic and ED visits were collected, there was an 86% reduction in the need for a physician visit for diarrhea and a 96% reduction in hospitalization.2 RV5 was effective against all the G serotypes tested
  13. Defination of attenuated vaccine, monovalent, pentavalent
  14. Do the rapid immunoassays detect vaccine-strain virus? Yes, the threshold for detection is on the order of 105 or 106 for the enzyme immunoassay. There is a low rate of shedding with the RV5 vaccine, while the rate of shedding is higher for the RV1 vaccine. Shedding is higher for the monovalent vaccine in part because it is better adapted to the host for replication.
  15. Defination of attenuated vaccine, monovalent, pentavalent
  16. After 1 year of follow up, the efficacy of Rotarix in preventing severe rotavirus gastroenteritis was 61.2% (95% CI, 44–73%) in the combined study populations, 76.9% (95% CI, 56–88%) in South Africa and 49.5% (95% CI, 19–68%) in Malawi Despite its lower efficacy in Malawi, the number of episodes of severe gastroenteritis prevented by vaccination was higher (3.9/100 vaccinees) than in South Africa (2.5/100 vaccinees) because of the higher incidence of severe rotavirus gastroenteritis in young infants in Malawi.
  17. Rotavirus vaccination is effective and is now affecting epidemiology. Most severe infections occur during the first year of life, and it appears as though vaccination is affecting exposure, which means that a person’s age of first exposure might be delayed. A change in the age distribution of severe infection is likely to be seen. The concern when measles vaccination was introduced was that if all children were immunized, the epidemiology of the disease would shift and older children and adults, when infected, would experience more severe disease since they lack previous natural exposure. In fact, there was a temporary shift toward older individuals getting infected, but the overall absolute number of cases declined drastically, and as you know, endemic measles transmission was eliminated in the U.S. in 2000 (despite recent outbreaks related to importations and pockets of undervaccination).
  18. -25 countries based in Harare
  19. SLIDE SHOWS REDUCTION OF rv CASES AFTER INTRODUCTION rv VACCINE IN THE usa
  20. Routine immunization occurs in real-world conditions different from ideal clinical trial settings. Thus, monitoring postlicensure impact on rotavirus disease is crucial for ensuring that appropriate gains in terms of expected vaccination benefits are attained. Changes in the epidemiology of rotavirus disease might occur in the postlicensure era, such as shifts in average age at infection, seasonality of disease, and serotype distribution after vaccination or appearance of unusual genetic variants ensuring that protection is conferred through the first and second years of life when most severe disease and mortality from rotavirus occur will be crucial for the success of a rotavirus vaccination program. Finally, assessing whether vaccination has an affect on rotavirus transmission in the community, thus providing benefits to unvaccinated groups, is important. Monitoring impact with focus on these public health considerations will not only allow assessment of the effectiveness of rotavirus vaccines in routine use, but also generate the necessary evidence to inform public health policy decision-making and continued investment in rotavirus vaccines.
  21. Herd immunity is when a vaccine protects even subjects not vaccinated This study confirms on a national scale that the 2008 rotavirus season among children aged &lt;5 years was dramatically reduced compared to pre-RV5 seasons.  …  Based on the observed decrease during the 2008 season, we estimated that ~55,000 acute gastroenteritis hospitalizations were prevented during the 2008 rotavirus season in the United States. A decrease of this magnitude would translate into the elimination of 1 in every 20 hospitalizations among US children aged &lt;5 years. Interestingly, the reduction in gastroenteritis wasn’t only in vaccinated children: In 2008, acute gastroenteritis hospitalization rates decreased for all children aged &lt;5 years, including those who were either too young or too old to be eligible for RV5 vaccination . …These findings … raise the possibility that vaccination of a proportion of the population could be conferring indirect benefits (ie, herd immunity) to nonvaccinated individuals through reduced viral transmission in the community
  22. In December 2008, GACVS 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. GACVS concluded that these vaccines are safe and that a risk of intussusception of the order associated with the previously marketed, but now withdrawn, tetravalent reassortant rotavirus vaccine (RotaShield, Wyeth Lederle, Philadelphia, PA, USA) can be ruled out with confidence. In June 2009, GACVS stated that no data directly support a hypothesis that administration of rotavirus vaccine even outside of the age range 6–15 weeks for the first dose and 32 weeks for the second dose is associated with an increased risk of intussusception..
  23. In various settings, rotavirus vaccines have been found not to interfere significantly with the immunogenicity or safety of OPV or other childhood vaccines. OPV, however, appears to have an inhibitory effect on the immune response to the first dose of rotavirus vaccine, although this interference does not persist after administration of subsequent doses.
  24. South African schedule : 6 and 14 weeks