Innate, Adaptive and Mucosal Immune
Responses in HIV-1 Exposed Uninfected
Infants: A Human Model to Understand
Correlates of Immune Protection
Canadian HIV Vaccine Initiative (CHVI)
AIDS Vaccine 2012
Boston
INFANT Study
Innate factors associated (with) nursing
transmission
The HIV-exposed uninfected infant
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Development of HIV vaccines has been informed by studies of
acute HIV infection, LTNPs, elite controllers, and HIV-exposed
uninfected (EU) individuals.
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Cohorts at high risk of HIV infection, including MSM, CSWs,
discordant couples, IDUs have been developed.
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The EU breastfed infant represents a novel model of studying
immune correlates and, unlike other high risk cohorts, HIV
exposure thru breastfeeding can be better quantified.
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The stability of the mother-infant dyad makes them amenable to
prospective cohort studies where factors that interfere or
enable HIV transmission can be identified.
Breastfeeding and HIV
Why study mother-to-child transmission?
Exclusively breast feed (EBF) infants are 2 to 10-fold less likely to be
infected compared to infants who are non-EBF.
10.1 %
Non-exclusive BF
4.0%
Exclusive B F
P=0.002
Hypothesis
Short-lived innate factors present in breast
milk inhibit vertical transmission of HIV-1
from mother-to-child.
Hypotheses
1) Innate immunomodulatory and anti-viral factors in
human milk protect infants against HIV infection.
2) Exposure to microbial products in the infants
developing gut after mixed breastfeeding leads to
immune activation/inflammation and increased
susceptibility to HIV infection.
3) Increased innate activation in the mixed breastfed
infant will alter innate and adaptive Irs to pediatric
vaccinations.
4) Social practices that determine breastfeeding
modes will be associated with the level of immune
system activation in the EU infant.
Study Design
A prospective observational cohort study with routine
evaluations, standardized questionnaires, relevant
maternal & infant biological sampling and comprehensive
data collection. 500 HIV+ mother-infant pairs will be
followed prospectively from birth to evaluate immune
activation, HIV transmission and vaccine responsiveness in
the infant in relation to EBF or mixed feeding. BM will be
evaluated for innate factors that may alter MTCT via
breastfeeding. Also 100 HIV uninfected mothers and their
infants followed to evaluate influence of maternal HIV on
milk composition, feeding practice and immune activation
and vaccine responsiveness in absence of HIV. Also 100
HIV+ mothers and their formula-fed infants enrolled to
evaluate ongoing HIV exposure via breastfeeding on
immune activation and vaccine response.
Study Populations
• The South African cohort will be recruited
from Khayelitsha. Mother-infant pairs will be
enrolled at Maternal Obst Unit; est 30-32%
deliveries are to HIV-infected mothers.
• The Nigerian cohort will be recruited from
the Plateau State Specialist Hospital. Approx
1/3 of women present at delivery; 20% are
HIV-infected.
Unique opportunity to expand our understanding
of the factors that would interfere with
breastfeeding & willingness of mothers to enroll
their infants into vaccine trials.
Thus, we aim to identify and describe the
barriers and enablers of adherence to feeding
guidelines amongst HIV+ women and what
parameters mothers would consider in evaluating
whether to enroll their HIV uninfected infants
into HIV vaccine trials.
OBJECTIVES
1)
To evaluate the role of breastfeeding practice in the EU
infant on:
a) HIV transmission
b) Infant gut permeability
c) Mucosal inflammation of the infant gut and oral
cavity
d) Systemic immune activation in the infant
e) Stool microbial makeup
f) Immunogenicity of pediatric rotavirus, oral polio and
BCG vaccines.
2)
To
a)
b)
c)
d)
e)
identify breast milk factors associated with:
HIV transmission
Immune activation in the infant gut
HIV-RNA levels in milk
HIV inhibition in vitro
Maternal HIV infection
OBJECTIVES (2)
3) To evaluate the role of mucosal inflammation,
systemic immune activation and gut permeability
in the EU breast-fed infant on
a) HIV transmission
b) Vaccine responsiveness to Rotavirus, oral polio and
BCG vaccines
c) HIV susceptibility following pediatric vaccination
OBJECTIVES (3)
3) To evaluate social practices and beliefs regarding
breastfeeding mode, MTCT and vaccine testing to
determine:
a) The barriers & facilitators to adhering to exclusive
b)
c)
d)
e)
and appropriate feeding guidelines to prevent vertical
HIV transmission.
The various role players involved in decision-making
and practice around breastfeeding.
Factors that influence the use of infant formula or
other supplements by this group of mothers.
The key barriers and facilitators to women enrolling
their HIV negative infants in a future HIV vaccine
trial.
The specific decision making process that mothers go
thru when deciding whether to enroll their children in
a hypothetical HIV vaccine trial.
THE TEAM
• Dr. Clive Gray – UCT
• Dr. Heather Jaspan – UCT
• Dr. Jonathan Blackburn - UCT
THE TEAM
• Dr. Alash’le Abimiku - IHV-Nigeria
• Dr. Bill Cameron - U Ottawa
• Dr. Blake Ball - U Manitoba/PHAC
• Dr. Adam Burgener – PHAC
THE TEAM
• Dr. Mark Tomlinson - U Stellenbosch
• Dr. Ashraf Kagee - U Stellenbosch
• Dr. Joel Singer – UBC
• Johanna Spaans - U Ottawa
Participating Labs:
• Nigeria: Plateau State Human Virology
Research Center (PLASVIREC)
• South Africa: University of Cape Town (UCT)
Division of Immunology & Blackburn Lab
• Canada:
– McMaster Immunology Research Centre &
Level III lab
– Univ. Manitoba & National Microbiology
Laboratories (NML)
Innate factors in human milk
• Discovery:
– Proteomic studies of human milk (HIV+ and HIV-): Drs. Ball &
Burgener (Univ. Manitoba & PHAC).
– Lipidomic analysis of breast milk: Dr. Blackburn (UCT).
• Characterization of innate factors in human milk
– Meso Scale Discovery (MSD) multiplex platform: Dr.
Rosenthal (McMaster Univ)
Training
• CAPT Network will be involved in capacity building
ensuring broad multilevel training opportunities for
junior researchers & research staff.
• Good clinical practice training at both clinical sites
will be also be provided by CAPTN.
• PHAC and UCT will provide lab support training; e.g.
lab QA training.
• Training exchange programs for HQP.
• International exchanges.
• Social scientists (Stellenbosch) develop capacity in
Nigeria.
Concluding remarks
This proposal represents a multidisciplinary
approach to HIV vaccine research, exploiting the
human model of mother-to-child HIV exposure to
identify correlates of infant immune protection
from infection. Interwoven will be social
behavioral approaches of assessing breastfeeding
practices and attitudes towards infant
vaccinations.
Progress
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Budget
INFANT STUDY PROTOCOL
Study Operations Manuel
Participant Information Sheet
Consent Forms & CRFs
Table of Specimens
Inter-Institutional Agreements
Sub-Contracts with each Institution/Investigator
IRB & Ethics Approvals
Int’l Clinical Trials Co-ordinator (job description)
Research Progress
• Successfully received historic breast milk
specimens from past feeding study in Nigeria.
• Completed initial characterization of innate
factors in the milk specimens using multiplex
platform.
• Identified marked differences between a
particular innate factor (sTLR2) in milk from
women in North America vs Nigeria and,
importantly, between milk from HIV-infected
and uninfected women.
Canada Africa Prevention Trials Network
Meeting – Entebbe, Uganda 2012