the potential of attenuated mycobacterium tuberculosis or bcg vaccines to enhance oral siv...
TRANSCRIPT
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