Innate, Adaptive and Mucosal Innate, Adaptive and Mucosal Immune Responses in HIV-1 Immune Responses in HIV-1

Exposed Uninfected Infants: A Exposed Uninfected Infants: A Human Model to Understand Human Model to Understand

Correlates of Immune ProtectionCorrelates of Immune ProtectionCanadian HIV Vaccine Initiative (CHVI)

AIDS Vaccine 2012

Boston

INFANT StudyINFANT Study

Innate factors associated (with) nursing transmission

The HIV-exposed uninfected The HIV-exposed uninfected infantinfant

• Development of HIV vaccines has been informed by studies of acute HIV infection, LTNPs, elite controllers, and HIV-exposed uninfected (EU) individuals.

• Cohorts at high risk of HIV infection, including MSM, CSWs, discordant couples, IDUs have been developed.

• 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.

• 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 HIVWhy 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.

Exclusive BF

Non-exclusive BF

4.0%

10.1%

P=0.002

Short-lived innate factors present in breast milk inhibit vertical transmission of HIV-1 from mother-to-child.

Hypothesis

Hypotheses1) 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 DesignStudy DesignA 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 PopulationsStudy 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.

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.

Unique opportunity to expand our understanding of the factors that would interfere with breastfeeding & willingness of mothers to enroll their infants into vaccine trials.

OBJECTIVES1) To evaluate the role of breastfeeding practice in

the EU infant on:a) HIV transmissionb) Infant gut permeabilityc) Mucosal inflammation of the infant gut and

oral cavityd) Systemic immune activation in the infante) Stool microbial makeupf) Immunogenicity of pediatric rotavirus, oral

polio and BCG vaccines.

2) To identify breast milk factors associated with:a) HIV transmission b) Immune activation in the infant gutc) HIV-RNA levels in milkd) HIV inhibition in vitroe) 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 ona) HIV transmissionb) Vaccine responsiveness to Rotavirus, oral

polio and BCG vaccinesc) HIV susceptibility following pediatric

vaccination

OBJECTIVES (3)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 and appropriate feeding guidelines to prevent vertical HIV transmission.

b) The various role players involved in decision-making and practice around breastfeeding.

c) Factors that influence the use of infant formula or other supplements by this group of mothers.

d) The key barriers and facilitators to women enrolling their HIV negative infants in a future HIV vaccine trial.

e) The specific decision making process that mothers go thru when deciding whether to enroll their children in a hypothetical HIV vaccine trial.

THE TEAMTHE TEAM• Dr. Clive Gray – UCT

• Dr. Heather Jaspan – UCT

• Dr. Jonathan Blackburn - UCT

THE TEAMTHE TEAM• Dr. Alash’le Abimiku - IHV-Nigeria

• Dr. Bill Cameron - U Ottawa

• Dr. Blake Ball - U Manitoba/PHAC

• Dr. Adam Burgener – PHAC

THE TEAMTHE TEAM• Dr. Mark Tomlinson - U Stellenbosch

• Dr. Ashraf Kagee - U Stellenbosch

• Dr. Joel Singer – UBC

• Johanna Spaans - U Ottawa

Participating Labs: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 milkInnate 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)

TrainingTraining

• 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 • 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 Canada Africa Prevention Trials Network Meeting – Entebbe, Uganda Network Meeting – Entebbe, Uganda

20122012