OVERVIEW OF RESEARCH PROJECTS AND RESEARCH INTERESTS

1
HIV and Childhood Vaccines Interaction
Jeffrey Mphahlele HIV/AIDS and Viral Hepatitis
Research Laboratory Department of
Virology Medical University of Southern
Africa PRETORIA, South Africa WORKSHOP Introduct
ion of New Vaccines into the EPI in Southern
Africa Public Health, Educational and Economical
Aspects 13-15 Oct 2004 CAPE TOWN
2
IMMUNIZATION SAVES LIVES

• PREVENTION is better than CURE
• Immunization is one of the most cost-effective
  health interventions
• Immunization is among the safest of modern
  medical interventions
• Immunization is the foundation of the public
  health system

3
34 MILLION CHILDREN ARE NOT FULLY IMMUNIZED FROM
VACCINE-PREVENTABLE DISEASES
4
HIV GLOBAL PUBLIC HEALTH BURDEN

• AIDS - the most devastating disease humankind has
  ever faced
• UNAIDS, 2001
• Since 1981
• gt 60 million people infected with HIV worldwide
• gt 25 million died from HIV/AIDS
• Of 42 million people (approx 1.2 global
  population) currently living with HIV/AIDS
• 29.4 (70) million reside in sub-Saharan Africa
  UNAIDS, 2002
• The adult HIV prevalence in sub-Saharan Africa is
  estimated at 8.8
• In 2001, over 5 million new HIV infections
  occurred
• Of these, more than 90 were in Sub-Saharan
  Africa and South East Asia
• South Africa harbours nearly 5.3 million (i.e.
  around 18) of HIV/AIDS people living in the
  sub-Sahara South African Department of Health,
  2003
• GREATERIMPACT OF HIV ON CHILDHOOD VACCINES IN
  SUB-SAHARAN AFRICA

5
Classification of Vaccines

• Killed or inactivated vaccines
• - Whole
• viral
• bacterial
• - Subunit and Fractional
• protein-based
• toxoid
• subunit
• polysaccharaide-based
• pure
• conjugate
• Live attenuated vaccines
• - Viral
• - bacterial

6
Examples of Licensed Vaccines

• Killed or inactivated vaccines
• - IPV
• - Whole cell pertussis
• - (hepatitis A)
• - Influenza, rabies, cholera, etc
• Live attenuated vaccines
• - OPV
• - BCG - Bacillus Calmette-Guerin
• - Measles
• - (Yellow Fever, mumps, rubella)
• - vaccinia, varicella influenza, oral typhoid
  (rotavirus), etc
• Subunit and Fractional vaccines
• - Hepatitis B - plasma or recombinant
• - Diphtheria, tetanus
• - Haemophilus influenza type b
• - Acellular pertussis
• - (pneomococcal, meningococcal)

7
PRESENTATION LAYOUT

• BACKGROUND INFORMATION
• Principles of immunisation
• Disease burden of HIV
• HIV and Human Immune System
• Overview of Childhood Vaccines
• IMPACT OF HIV ON CHILDHOOD VACCINES
• Childhood Vaccines and HIV infection
• Impact of HIV on Underutilized and Newly
  Available Vaccines
• - Hib Vaccine
• - Hepatitis B Vaccine

8
Attenuated Vaccines Potential Safety Concerns

• Weakened from pathogenic strain
• Replicate in host cells
• - cautious about host immune status
• e.g. immunocompromised, pregnant women, etc
• - severe reactions possible
• Reversion to virulence possible
• - underattenuation
• - back mutation
• - recombination with wild viruses
• Heat labile
• Contamination with adventitious agents found in
  culture
• Interference with circulating antibody e.g.
  maternal Abs

9
Immunological Principles of Vaccination

• Vaccination is artificial immunisation - adaptive
  immunity
• Specific antigen (Ag) administered host immune
  response
• Ag - whole organism, protein, polysaccharide or
  toxoid
• Antigen and host interaction complex
• - Interaction of Ag with APC (macrophages and
  dendritic cells), lymphocytes (TH cells, TC
  cells and B cells) and MHC class I and II CMI
  and/or Humoral Immunity
• - CD4 TH cells central to immune response
  provide
• - help to B cells to produce antibodies to T
  cell-dependent Ags
• - stimulatory signals for B cells to
  proliferate, differentiate into IG-producing or
  memory cells
• - Successful vaccination results in
• - serological response i.e. production of
  specific antibody to specific Ag
• - long lasting (often life long) immunity
• Immunological Memory (IM)
• - IM ability of the immune system to respond
  rapidly and with higher amplitute
• to Ag or pathogen previously encountered

10
HIV and Immune System Interaction

• HIV directly infects and replicates within cells
  of immune system
• HIV replicates within macrophages and CD4 TH
  cells loss of CD4 TH cells increased risk of
  susceptibility to infections or poor IR due to
• - defective Ag processing (macrophages,
  dendritic cells and CD Th cells)
• - defective immunological memory failure to
  prime memory cells or failure of primed
• B cells differentiate into memory cells
• - loss of immunological memory of T and B cells
  after priming i.e. clonal deletion or
  depletion
• Vaccination of HIV-infected person may cause
  activation and proliferation of T cells,
  cytokines release, and increased HIV replication,
  with consequent immunological deterioration
• - Vaccination stimulates more APCs and CD4 TH
  cells, hence increase in HIV replication
• - Studies reported increase in viral
  replication for both T-dependent (e.g. influenza
  and
• DT) and T-independent
  (pneumococcal polysaccharide) vaccines for
  children and adults
• - Vireamia return to baseline levels 6-8 weeks
  post-vaccination without immediate serious
  consequences
• - long term consequences of repeated increases
  in vireamia unknown
• Vaccination still better than infection
• - If vaccination results in transient viraemia,
  exposure to infection would probably result in
  substantial increase in viral replication and
  CD4 T cell depletion
• - Thus, the risk of vaccination far outweighs
  risk of infection

11
Implications for Immunisation Programmes

• Immuno-compromised individuals do not respond
  optimally to vaccines
• - e.g. HIV positives, haemophiliacs, renal
  transplant patients, etc
• In sub-Saharan Africa, gt90 of paediatric HIV
  infections acquired through MTCT
• - In SA, 70 000 - 80 000 babies born each year
  are infected with HIV
• - Children experience more rapid progression of
  HIV infection than adults
• HIV impact on childhood vaccines
• - Endemicity of HIV infection in the region
• - High rate of MTCT of HIV
• Limited data on immunogenicity and effectiveness
  of childhood vaccines in HIV endemic regions
• - Are vaccines safe (AEs) in HIV infected
  individuals?
• - Are there vaccines which are particularly NOT
  safe in HIV-infected persons?
• - Will vaccination overburden the IS?
• - Will vaccination lead to activation APCs and T
  cells, thereby increase HIV viral load?
• - Will the vaccine achieve reasonable
  immunogenicity?
• - What about the strength of antibody titre?
• - Vaccine effectiveness?

12
(No Transcript)
13
Adverse Events associated with BCG vaccination in
HIV-infected children (Reviewed by Moss et al,
Bull WHO, 2003)
14
Immunogenicity and Safety of Polio Vaccines in
HIV-infected children (Reviewed by Moss et al,
Bull WHO, 2003)
15
Immunogenicity of Diphtheria, Tetanus and
Pertussis Vaccines in HIV-infected children
(Reviewed by Moss et al, Bull WHO, 2003)
16
Immunogenicity of Measles vaccine in HIV-infected
children (Reviewed by Moss et al, Bull WHO, 2003)
17
Recent Outbreak of Measles in South Africa

• South Africa targeted measles for elimination
• Outbreak of measles in 2003
• Increase of measles in lt9 month-olds
• (Schoub BD, Vaccinology Meeting, Western Cape,
  11-13 Oct 2004)
• 2003 3.05 (n60) in lt 6 months and 6.60
  (n53) in lt6-8 months
• 23 Sept 2004 9.71 (n 96) in lt6 months and
  24.29 (n136) lt6-8 months
• Why outbreak and increase in lt9 month-olds?
• - Reduced vaccine efficacy? NOT VACCINATED YET
• - Susceptible population no measles for long
  time
• - Waned maternal antibodies?
• - Increased nosocomial infection?
• - High background of HIV infection in mothers
  and children?

18
Recent Outbreak of Measles in South
Africa(Schoub BD, Vaccinology Meeting, Western
Cape, 11-13 Oct 2004)

• HIV and Measles
• - Reduced immune response to vaccine
• - Defective transfer of maternal antibodies from
  HIV-infected mothers
• - More severe clinical manifestations
• - Prolonged shedding
• - Unusual clinical presentations absence of
  rash
• - Nosocomial transmissions
• Targeted measles vaccination in SA
• - Vaccination at 6 months for all hospital
  admissions and HIV-infected babies
• nosocomial infections and poorer immune
  response in HIV (effective T-cell response
  in HIV prime IS while immunocompetent)
• - ?vaccination of other at-risk populations
• day care centres, families of HIV ves, etc

19
(No Transcript)
20
EFFICACY of Hib CV in Developed and Developing
World (Madhi SA, Vaccinology Meeting, Western
Cape, Oct 2004)
21
EFFECTIVENESS OF Hib-CRM197 CONJUGATE VACCINE IN
20 000 SOUTH AFRICAN CHILDREN
CI95 59.4 91.8
CI95 76.2 99.6
CI95 78.3 78.4
Madhi SA et al. PIDJ 2002
22
QUANTITATIVE antibody response to Hib CV among
HIV-infected and HIV-uninfected children (Madhi
SA, Vaccinology Meeting, Western Cape, Oct 2004)
23
Experience with HBV vaccines in sub-Saharan Africa

• The Gambia 1st African country
• Number of countries have introduced hepatitis B
  vaccine in national immunisation programmes are
  increasing
• - Botswana, Mauritius, Reunion, Seychelles,
  South Africa, Swaziland, and Zimbabwe by end of
  2001
• - Côte dIvoire, Ghana, Kenya, Madagascar,
  Mozambique, and Tanzania by March 2002
• - Burkina Faso, Gabon, Mali, Senegal, Zambia,
  and others have either introduced, or are in
  the planning stages
• Limited data on effectiveness of hepatitis B
  vaccine few studies (mainly from the The Gambia
  and South Africa) indicated that
• - hepatitis B vaccine is both immunogenic and
  efficacious
• Fortuin et al, 1993 Lancet, 341 1129
  Whittle et al, 1995 Lancet 345 1089 Aspinall
  et al, 1998 S Afr Med J, 88 36 Viviani et al,
  1999 Vaccine, 17 2946 Tsebe et al, 2001
  Vaccine 19 3919 Schoub et al, 2002 Bull of
  WHO 80 (4) 277
• Evidence that hepatitis B vaccine will reduce the
  rate of new infections in immunised children, and
  thereby reduce the burden of HBV related liver
  disease, especially cirrhosis and HCC later in
  life

24
HIV and Hepatitis B vaccine in Developing World

• The immunogenicity and effectiveness of hepatitis
  B vaccine in HIV infected babies in sub-Saharan
  Africa is largely unknown
• - One South African study suggested that the
  response to the HBV vaccine in HIV positive
  babies may be sub-optimal
• Gray et al, J.Clin Virol 2000 18 97 Abstract
  P-76
• - Another South African study reported vaccine
  failure in a baby possibly due to HIV
  immunosuppression the baby had history of
  failure to thrive and was born to HIV positive
  mother
• Schoub et al, Bull World Health Organ 2002
  80 277

25
Impact of HIV on hepatitis B vaccination and HBV
chronic carriage in South African children

• Assess healthy vaccinated babies (attendees of
  EPI clinic) for
• Attendees of EPI clinic (5-2 year olds)
• HIV-infected and HIV-uninfected
• Sero-conversion rates (anti-HBs lt or gt 10 mIU/ml
  and GMTs)
• Sero-protection rates (anti-HBs 10 mIU/ml and
  GMTs)
• Protective efficacy (against HBV chronic carriage
  i.e. HBsAg positivity)
• Assess immunity and chronic carriage to HBV in
  hospitalised babies with unknown immunisation
  status
• Hospitalised babies (5-2 year olds)
• HIV-infected and HIV-uninfected
• Sero-conversion rates (only anti-HBs lt or gt 10
  mIU/ml and GMTs)
• Sero-protection rates (only anti-HBs 10 mIU/ml
  and GMTs)
• HBV chronic carriage i.e. HBsAg positivity

26
Sero-conversion and sero-protection rates of the
hepatitis B vaccine between HIV-infected and
HIV-uninfected healthy vaccinated babies
27
Effectiveness of Hepatitis B vaccine within EPI
(SA) Comparison with previous field studies

• Schoub et al, Bull of WHO 2002 80 (4) 277 - 281
• Tsebe et al, Vaccine 2001 19 3919 - 3926

28
Immunogenicity of hepatitis B vaccine in
HIV-infected children (Reviewed by Moss et al,
Bull WHO, 2003)
29
Immunity and chronic carriage to HBV between
healthy vaccinated babies and hospitalised babies
with unknown vaccination status
30
Immunogenicity of hepatitis B vaccine in
HIV-infected children (Reviewed by Moss et al,
Bull WHO, 2003)
31
SUMMARY Interaction of HIV with Childhood
Vaccines

• Most HIV-infected children have the capacity to
  mount both cellular and humoral immune responses
  during the first two years of life, or when
  relatively healthy
• Studies of the immunogenicity of EPI-recommended
  vaccines have shown satisfactory seroconversion
  rates in the early stages of HIV infection
• Antibody levels or seroprotection rates induced
  by the  EPI vaccines tend to be lower in
  HIV-infected individuals and to fall more rapidly
  over time than in non-infected persons.
• Proportion of responders decreases with
  progression from HIV infection to AIDS (decline
  in cellular and humoral immune responses)
• Certain EPI vaccines are contraindicated in
  symptomatic HIV individuals
• - BCG
• - Yellow Fever
• Ideally, other EPI vaccines (live attenuated
  vaccines) should be used with caution in
  symptomatic HIV persons. Practical?
• - Measles, OPV and DTwP
• The increasing HIV infection in babies could
  reverse the gains made by infant immunisation
  programmes in HIV endemic regions (e.g.
  sub-Saharan Africa), if no intervention of MTCT
  of HIV is made.

32
THANK YOU FOR YOUR ATTENTION