Rotavirus Vaccines An example of a recently developed viral childhood vaccine

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Rotavirus VaccinesAn example of a recently
developed viral childhood vaccine

• John Tumbo and Duncan Steele
• Medical University of Southern Africa and
  Initiative for Vaccine Research, WHO

Introduction of New Vaccines into EPI in Southern
Africa 13-15 October 2004 Cape Town, South Africa
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Global Need for Rotavirus Vaccines

• Birth cohort 135 million / year
• Under 5 mortality 12,2 million / year
• Diarrhoeal deaths 2,8 million / year
• Rotavirus deaths 500,000 / year
• 85 of these occur in developing countries
• International prioritization of rotavirus
  vaccines
• (WHO, GAVI, PATH, BMGF etc)

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Global distribution of deaths due to rotavirus
Parashar et al, 2003
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Rotavirus Epidemiology

• Rotavirus is ubiquitous - 95 of children
  worldwide infected by 35 years of age1
• Peak incidence of clinical illness among children
  aged 624 months - the younger the child, the
  higher the risk of severe disease,
  hospitalization or death2
• Rotavirus accounts for approximately one third of
  cases of severe vomiting and diarrhoea requiring
  hospitalization1

1Parashar et al, Emerg Infect Dis 1998 4(4)
5615702Linhares and Bresee, Pan Amer J Public
Health 2000 8(5) 305330
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Rotavirus Disease burden
Estimated global prevalence of rotavirus disease1
Event
Risk of Particular Event
1 293
440,000 deaths
1 65
2 million inpatient visits
1 5
25 million outpatient visits
111 million domiciliaryepisodes
1 1
1Parashar et al, Emerg Infect Dis 2003 9(5)
565572
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Burden of Rotavirus Disease Studies in Africa

• 145 000 rotavirus-related deaths in Africa
• Guinea Bissau1
• 3.4 rotavirus deaths / 1000 infants per year
• Sub-Saharan Africa2
• 110-155 000 rotavirus-related deaths per yr
• Country-specific mortality3,4
• Nigeria 80-90 deaths per day
• Cameroon 50-60 deaths per day
• South Africa 10-12 deaths per day

1Mølbak et al, Vaccine 2000 19 393-395 2Miller
McCann, Health Econ 2000 9 19-35 3Parashar et al,
Emerg Infect Dis 2003 4Steele et al, Vaccine
2003 21(1) 354-360 Afr Health Sc J 2002 9(4)
103-107
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Epidemiology of Rotavirus in Africa

• Rotavirus infection occurs in 20-40 of children
  hospitalized with diarrhoeal illness
• More common in hospitalized children than in
  outpatients
• Rotavirus occurs in
• 17 of infants less than 6 months of age
• 75 of infants less than 12 months of age
• 83 of children under 18 months of age
• Seasonal distribution with peak in cool, dry
  months

Cunliffe et al, Bull WHO 1998 76(5)
525-537 Steele et al, Vaccine 2003 21(1) 354-360
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Age Distribution of the Children Shedding
Rotavirus at Ga-Rankuwa Hospital Pretoria
Occurs at young age
Percentage
Age intervals (months)
Steele et al, J Clin Micro 1986 23(12) 992-994
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Characteristics of rotavirus important for
vaccine development
Complex triple layered virus particle Five common
VP7 serotypes in humans (G1-G4, G9), but 5 others
identified One common VP4 genotype P8, but four
others detected Ideal vaccine would be one that
protects against the different serotypes.
VP7
VP4
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Rotavirus Vaccine Candidates

• Licensed vaccines
• RotaShield - licensed 1998 by FDA, remains in
  place
• Lanzhou Lamb RV (LLR) licensed in China
• Rotarix (GSK) - licensed in Mexico Dom Rep in
  2004
• Late phase III clinical evaluation
• RotaTeq (Merck) - phase III clinical trials
• Rotarix GSK-phase 111 clinical studies in Latin
  America, RSA
• Early phase II clinical development
• UK bovine reassortant vaccine (NIH)
• RV3 neonatal human vaccine strain (Melbourne)
• 116E bovine-human reassortant strain (US-Indo)

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RotaShield and Intussusception

• RotaShield licensed by FDA in Aug 1998 and
  recommended for use in US infants
• 15 cases of intussusception picked up by July
  1999 after 10000 babies were vaccinated.
• Vaccine withdrawn market by Wyeth Ayerst Oct 1999
• Recommendation for use was withdrawn by Oct 1999

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RotarixGSK Biologicals

• Dick Ward David Bernstein, Gamble Institute, US
• Human monovalent strain 89-12 (G1P1a8)
• Early trials showed it was safe and immunogenic
• Protective efficacy of 89 in phase III clinical
  trials
• (Bernstein et al, Lancet 1999 354 287-90)
• Protective efficacy also shown in second year
• (Bernstein et al, JID 2002 1861487-89)

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TM
Finland 405 infants vaccinated at 2 and 4 months
of age Two doses at 105 ffu Immunogenicity
(IgA) 80 Efficacy any rotavirus GE 69
severe rotavirus GE 90 No difference in
reactogenicity when compared to placebo group
Comparable to RotaShield in this population
Vesikari et al, ICAAC, San Diego, 2002
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TM
Venezuela, Brazil and Mexico 1986 infants 6-12
weeks of age vaccinated Two doses of different
viral concentrations (104, 105, 106
ffu) Immunogenicity (IgA) 60-65 Efficacy
against any rotavirus GE 56-73
severe rotavirus GE 68-87 RV
hospitalisation 61-92
Comparable to RotaShield in this
population Protection shown against non-G1 strains
Perez-Schael, ICAAC, San Diego, 2002Ruiz
Palacios, WSPID, Santiago, 2002
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TM
Beatrice de Vos, personal communication, 2004

• Conducting large scale safety and efficacy
  trial globally (mostly Latin America and Asia)
• gt63 000 infants vaccinated to date
• Intussusception surveillance on all infants for 6
  months post last dose of vaccine
• Efficacy follow-up on 20,000 for protection
  against all and severe rotavirus gastroenteritis
• Independent Data Safety Monitoring Board is
  closely monitoring trial no concern indicated
• File submitted to Mexico and other Latin American
  countries in 2004
• License approved in Mexico in July 2004

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RotaTeqMerck Co
G1

• Fred Clark Paul Offit, Wistar Institute, US
• Bovine strain WC-3 (G6P7)
• Early trials with monovalent strain gave
  non-conclusive results
• Reassortant strains developed with combinations
  of human rotavirus VP7 and VP4 genes
• VP7 serotype genes (G1, G2, G3 G4)
• VP4 type gene (P1a8)

G2
G3
G4
P1a
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RotaTeq (Merck)

• Finland
• 1946 infants, 2-8 months of age vaccinated
• 3 doses of vaccine
• different viral concentrations (104, 105 or 106
  ffu)
• Immunogenicity (IgA) 81-97
• Efficacy against any RV diarrhoea 59-77
• Efficacy against severe RV diarrhoea gt95
• No difference in reactogenicity when compared to
  placebo group

Comparable to RotaShield in this population
Vesikari et al, IDSA, Chicago, 2002
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RotaTeq (Merck)John Boslego, personal
communication, 2004

• Conducting large scale safety and efficacy
  trial in 11 countries (mostly USA and Europe)
• gt68 000 infants vaccinated to date
• Intussusception surveillance on all 70,000
  infants for 42 days post any dose of vaccine
• Efficacy follow-up on 20,000 for protection
  against all and severe rotavirus gastroenteritis
• Data Safety Monitoring Board is closely
  monitoring trial and has not indicated any
  concern
• Recruitment will be completed in December 2004
• File submitted to FDA by end of 2005

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Rationale to conduct parallel rotavirus clinical
trials in Africa

• Distinct medical problems
• High levels of HIV, TB, malaria
• High background of enteric infections
• Malnutrition
• Diversity of circulating rotavirus serotypes
• W.H.O. accelerated schedule of EPI-concerns
• Younger age of immunization - maternal antibody
• Potential interference with oral polio vaccine
  (OPV)
• Potential interference with other enteric
  pathogens

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The South African scenario

• On going burden of disease studies
• On going Health Utilisation Survey for diarrhoea
• Planned prospective study on intussuception
• Multiple laboratory studies on strain
  characterisation of rotavirus
• Phase 11 study completed on interaction between
  OPV and HRV
• Dose ranging phase 11 study completed

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Study area
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Planned studies

• Safety, reactonicity, immunogenicity of HRV in
  HIV infected infants
• Phase 111 study to examine efficacy of HRV in
  infants in South Africa and Bangaladesh.
• Estimation of cost and qualitative influence of
  diarrhoea on households.

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New Paradigm forRotavirus Vaccine Development

• Private / Public Partnership for rotavirus
  vaccine parallel clinical evaluation in Africa
  and Asia
• "Rotavirus Action Partnership for Immunization
  and Development"
• Parallel trials are ongoing in Africa and Asia
• GSK human rotavirus vaccine candidate
• Trials in South Africa and Bangladesh
• Investigating issues for developing world
• EPI schedule (6 weeks old at 1st dose)
• Polio vaccine interaction
• Dose regimen for developing world
• Safety of live oral rotavirus vaccine in HIV
  infants
• Phase III efficacy trials planned for 2005

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Rotavirus Vaccines Summary

• Two efficacious vaccine candidates developed by
  the international pharmaceutical multinational
  companies (Merck and GSK)
• Probably be available for the private market in
  2005/06
• Several other credible vaccine candidates in
  development
• New public / private partnerships
• RAPID
• GAVI ADIP
• Global commitment to rotavirus vaccine
  development
• Need to evaluate the protective efficacy of the
  vaccines in developing world populations, where
  they are needed

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Are there alternatives to vaccination against
rotavirus?

• Sanitation - has not worked
• Nutrition - recovery is good
• - but does not reduce incidence
• Breast feeding - less diarrhoea overall
• - but possibly postpones onset
• - issue of HIV transmission
• ORS therapy - too late in infection
• - not universally useful or
• managed

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Does Africa need a rotavirus vaccine?

• Rotavirus burden is high
• Rotavirus infects infants early in life
• Sanitation and clean water is not going to help
• Rotavirus vaccines are nearing availability

• Rotavirus vaccine trials are going on in South
  Africa to provide African data.
• South Africa will be an early adaptor of
  rotavirus vaccine

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Challenges

• Lack of African Data on Burden of Rotavirus
  disease
• Lack of data on Health Utilisation patterns and
  surveillance systems
• Influence of HIV on introduction of live vaccines
• Poor dissemination of scientific information to
  program managers.
• Difficulties of getting political buy-in in the
  face of other priorities-HIV/AIDS

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Financial implications

• The wythe vaccine cost USD 38/dose
• Rotarix estimated to cost USD 23
• For Africa
• Quote from the 6th International Rotavirus
  conference All I can say is USD 10 for a set of
  vaccines is too much. No price is affordable for
  Africa.

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Thank you