Vaccine-elicited HIV/SIV-specific immune responses in breast milk - PowerPoint PPT Presentation

Loading...

PPT – Vaccine-elicited HIV/SIV-specific immune responses in breast milk PowerPoint presentation | free to download - id: 47f7be-YWM3N



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Vaccine-elicited HIV/SIV-specific immune responses in breast milk

Description:

Vaccine-elicited HIV/SIV-specific immune responses in breast milk Sallie Permar, MD, PhD Beth Israel Deaconess Medical Center Children s Hospital, Boston – PowerPoint PPT presentation

Number of Views:58
Avg rating:3.0/5.0
Slides: 23
Provided by: sper80
Learn more at: http://hvtn.org
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Vaccine-elicited HIV/SIV-specific immune responses in breast milk


1
Vaccine-elicited HIV/SIV-specific immune
responses in breast milk
Sallie Permar, MD, PhD Beth Israel Deaconess
Medical Center Childrens Hospital, Boston New
England Regional Primate Center
2
Breast milk transmission of HIV
  • Half of the new 350,000 infant HIV
    infections/year occur via breastfeeding
  • Formula feeding associated with high rates of
    infant morbidity in developing regions
  • Maternal/infant antiretroviral prophylaxis
    reduces transmission
  • requires up to 2 yrs of treatment
  • toxicities and impact of antiviral resistance not
    well understood
  • Immunologic interventions needed to promote safe
    breastfeeding

3
Maternal HIV vaccination
  • Passive immunization of fetus/infant
  • humoral immune responses
  • Reduce maternal mucosal shedding of HIV
  • Milk virus load correlates with risk of
    transmission
  • Can vaccine-elicited immune responses in breast
    milk limit infant virus acquisition?

4
HIV-specific cellular immune responses in milk
  • Robust SIV/HIV-specific CD8 T lymphocyte
    response identified in breast milk
  • Evidence of local production of breast milk
    SIV/HIV
  • Groups of nearly identical viruses in milk
  • CTL escape of breast milk virus
  • Local breast milk immune responses may control
    virus replication in breast milk

5
HIV-specific humoral immune responses in milk
  • HIV-specific IgG gt sIgA responses in milk
  • Broadly neutralizing antibodies block oral SHIV
    acquisition in infant monkeys
  • HIV-specific IgG/IgA (2F5, b12) block virus
    interaction with GI epithelial cells
  • HIV-specific humoral immune responses in milk
    could block virus acquisition in the infant gut

6
HIV/SIV vaccination of lactating rhesus monkeys
  • Important Questions
  • Is vaccination of lactating mothers safe?
  • Limited milk CD4 T cell activation
  • Limited increase in milk CD4CCR5 T cells
  • Are vaccine-elicited responses detectable in milk
    after systemic vaccination?
  • How do vaccine-elicited responses in milk compare
    to those in blood?

7
Systemic SIV DNA prime/virus vector boost of
lactating monkeys
Colon and vaginal biopsy
5 hormone-induced, lactating Mamu A01 female
monkeys
Intracellular cytokine staining
Intracellular cytokine staining
Intracellular cytokine staining
  • Weekly blood and milk tetramer staining
  • Weekly milk activation staining

0
4
8
12
28
38
46
108 pfu NYVAC SIV Gag-Pol, Env I.M. and I.D.
1010 vp rAd5 SIV Gag, Pol, Env I.M.
5 mg rDNA SIV Gag-Pol, Env I.M.
Permar et al, JI, 2011
8
Minimal increase in milk CD4 activation and
CD4CCR5 T cells after systemic vaccination
9
Vaccine-elicited immunodominant Gag-specific CD8
T cell response in milk
Blood
Milk
10
Vaccine-elicited subdominant Env-specific CD8 T
cell response in milk
Milk
Blood
11
Vaccine-elicited polyfunctional cellular
responses in milk
12
Robust vaccine-elicited cellular responses in
milk compared to other mucosal compartments
10
8
6
Gag p11C CD8 T cells
4
2
blood
milk
colon
vagina
13
Limited milk IgA response following DNA/NYVAC/rAd
vaccination
Blood
Milk
14
Low level tier 1 SIV neutralization in milk
following virus vector boost
Blood
Milk
15
Enhancement of vaccine-elicited HIV Env-specific
responses in milk
  • Improved Env immunogen design
  • Transmitted/founder HIV Envs (CHAVI)
  • Adjuvent
  • TLR agonists
  • Model vaccine strategy of RV144
  • Pox virus prime/protein boost
  • Mucosal vaccine administration?

16
Neutralizaton responses to T/F Env vaccinated
guinea pigs
log10 IC50
1086.C
Bart Haynes, Larry Liao, Bette Korber and Teams
Pseudotyped Envs (Tier 1 -gt Tier 2)
geometric mean IC50 of 4 animals x 36
pseudotyped viruses
17
Binding Reactivity of HIV 1086c Env Protein
C1 CD4i CD4bs V2 Quaternary Quaternary Quaternary Quaternary Carb
A32 17b VRC01 2158 697D PG9 PG16 CH01 2G12
Monomeric gD gp120/CHO - /- -
MonomericgD neg gp120/CHO - /- -
Oligomeric gp140 - - -
Bart Haynes and immunogen design teams
18
HIV Env 1086c vaccination of lactating monkeys
Ab binding and neutralization
Ab binding and neutralization
Intracellular cytokine staining
Intracellular cytokine staining
4 hormone-induced, lactating female monkeys
weeks
0
4
8
12
20
24
5 mg rDNA HIV Env 1086c I.M.
100µg HIV Env 1086c MF59 I.M.
4 hormone-induced, lactating female monkeys
weeks
0
12
16
4
109 pfu rMVA HIV Env 1086c I.M.
100µg HIV Env 1086c MF59 I.M.
19
Robust HIV 1086c Env-specific cellular responses
in milk following DNA/MVA prime
DNA prime
MVA prime
Blood
Milk
Blood
Milk
1.8
1.4
CD4
1
.6
.2
1086c Env-specific cytokine-producing T cells
1.8
1.4
1
CD8
.6
.2
270
monkey number
20
HIV 1086c Env-binding responses in milk following
DNA/MVA prime
DNA prime
MVA prime
Blood
Milk
Blood
Milk
5
IgG
4
HIV-Specific IgG (ng/mL eq)
3
2
1
3
HIV-Specific IgA (ng/mL eq)
2
IgA
1
Pre
Post
Pre
Post
Pre
Post
Pre
Post
21
Tier 2 neutralization in A3R5 cells following
systemic HIV Env 1086c vaccination
Blood
Milk
Cut off gt3 SD above prevaccine neutralization
3
DNA prime
2
ID50
ID50
1
ID50 in A3R5 cells
3
MVA prime
2
1
Tier 2 clade C viruses
Du422
Ce1086
Ce1176
Ce2010
Ce1086
Cap45.2.00
22
Conclusions
  • Robust vaccine-elicited cellular immune responses
    in milk following systemic virus vaccination
  • Control local virus replication?
  • Vaccine-elicited HIV-neutralizing/blocking
    antibody responses in milk may be enhanced by use
    of improved immunogen
  • Block virus transmission in infant gut?

23
Acknowledgements
  • Beth Israel Deaconess Medical Center
  • Norman Letvin
  • Dan Barouch
  • Mike Seaman
  • Keith Reimann
  • Helen Kang
  • Piya Sircar
  • Andrew Wilks
  • Liz Ehlinger
  • Katie Rizzolo
  • Tatenda Mahlokozera
  • Anje Chand
  • New England Regional Primate Center
  • Angela Carville
  • Eurovac
  • Gepi Panteleo

Duke University Giny Fouda Celia Labranch David
Montefiori Georgia Tomaras Bart Haynes Kelly
Soderberg Larry Liao David Pickup Los
Alamos Bette Korber
  • Supported by
  • National Institute of Allergy and Infectious
    Diseases (NIAID)
  • National Institutes of Health (NIH)
  • Division of AIDS (DAIDS)
  • U.S. Department of Health and Human Services
    (HHS)
  • Center for HIV/AIDS Vaccine Immunology (CHAVI)
    U19 AI067854-05
About PowerShow.com