The Potential of

Attenuated Mycobacterium tuberculosis or BCG Vaccines

to Enhance Oral SIV Acquisition

in Infant Macaques

IAS Meeting-VancouverJuly 22, 2015

Kristina De Paris, PhDUNC Chapel Hill

No Disclosures

Prevention of Mother-To-Child-Transmission of HIV-1

Infection rate: 3% of children / year

Median age: 12-15 mo.HIV-TB co-infection: 30-50%

+ Tuberculosis

BCG

- administration at birth (PO / ID)- immunogenic- risk of dissemination in HIV+ infants

Breast milk transmission of HIV-1

An auxotroph mutant of human-adapted M. tuberculosis H37Rv

(i) is attenuated for replication and pathogenicity,

(ii) can be manipulated for increased immunogenicity, and

(iii) modified to express HIV antigens.

Pediatric HIV-TB Combination Vaccine

Auxotroph rMtb-HIV vaccines, administered at birth, may present a safe alternative to BCG that could protect against oral HIV-1 acquisition and TB infections.

mc26435: ΔleuCDΔpanCDΔsecA2:pSIV Gag/pSIV Env/pSIV Pol

Jensen et al., 2012 and 2013

Repeated Low-Dose Oral Challenge Model (SIVmac251)

- recapitulate repeated exposure to HIV-1 in breast-feeding infants- start at 9 weeks of age

Probability of infection / exposure = 0.246

n=15

Vaccine Efficacy:

sterilizing immunityor

partial efficacy (No. of SIV exposures)

Challenge Outcome in Vaccinated Infant Macaques

rMtb-SIV/ rMtb-SIV rMtb-SIV/ MVA-SIV

- rMtb-SIV at birth (PO)- homologous boost (ID): wk. 3

- single rMtb-SIV at birth (PO)- heterologous boost (IM): wks. 3+6

4/6 7/8

Vaccine-induced Enhancement of Infection?!

Independent of: strain,route,boost, and

SIV inserts.

Probability of infection / exposure:

Mtb vaccines 0.340BCG 0.353

Mtb Vaccine15/19

Repeat and Confirm:

BCG (ID)

6/7

Oral SIV Acquisition

Biological Significance

1.4-fold risk enhancementNS

STAT Trivia:To detect a 1.65-fold higher risk

with 80% power, 45 animals/group are required.

Oral SIV Acquisition Risk

- enhanced infection risk in two separate studies

…and increased peak viremia (BCG)

Peak Viremia

Systemic Immune Activation (TOC)

37-plex (NHP)

- only 4 differ!

sCD14 sCD163

MCP-1

Increased Monocyte Activation + Function

Target cells of mycobacteria: monocytes/ macrophages and DC

CCR5 CD69

Blood and TissuesPersistence up to 18 wks.!

PBMC Ax.LN Subm.LN Tonsil

TNF-a

Vaccine-induced CD4+T Cell Activation

Increased SIV target cells at TOC?!

( Ki67, CD69, PD-1 )

CCR5+CD4+ T

Potential Viral Entry Sites(16-18 wks.)

ColonRetrophar.LN

Ki-67

PBMC

Summary

Mtb- and BCG-based vaccines

cause persistent immune activation of myeloid cells (monocytes/ mDC),

increase the numbers of potential SIV/HIV target cells, and thereby

may enhance risk of oral SIV/HIV acquisition, and

alter challenge outcome as immune activation persists even post-challenge.

Enhanced risk of oral SIV infection was not associated with genetic markers.

BCG-induced “trained immunity” (Netea)

- epigenetic changes in monocytes enhance functional capacity - increased responsiveness to mycobacterial and unrelated Ags for up to 1 yr!

Supporting Evidence from HUMAN Studies

consistent with the persistent increased functional capacity ofmonocytes and mDC in vaccinated infant macaques

BCG – risk factor for HIV?

- BCG vaccination in SA infants results in increased CCR5+CD4+T cells (Jaspan)- Mtb-exposed CD4+T cells show increased HIV-1 infection in vitro (Page)

consistent with increased CD4+T cell activation in blood and tissues ofinfant macaques vaccinated with Mtb or BCG vaccines

Potential Health Impact TB vaccine development:

- auxotroph BCG and auxotroph Mtb strains, similar to our strain- combination HIV-BCG vaccines are being tested

(Hanke, Joseph, Williamson)

Protective efficacy against TB infection

BUT: Safety risk for pediatric population?

- increased susceptibility to oral HIV-1 infection - increased morbidity due to higher viremia and persistent immune activation- include testing for immune activation in TB vaccine safety assessment

THANK YOU to:

Kara JensenMyra dela PenaMaggie Conner

Michael MengualNeelima Choudhary

Michael HudgensKatie Mollan

CNPRC

Koen Van RompayVeterinary Staff

rMtb Vaccine

Michelle LarsenGlenn Fennelly

Bill JacobsUma Ranangathan

Virology

Mike PiatakJeff Lifson

Pam KozlowskiRobert Wilson

Angela Amedee

LSUHSC

NIH: R01 DE019064 and R01 DE019064-S1 to ML, GF, and KDP

De Paris Lab

Histology

Jake EstesCarissa Lucero

NIH HIV/ AIDS and TB Program Officers