hiv vaccines and broadly neutralizing monoclonal...
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The views expressed are those of the authors and should not be construed to represent the
positions of the U.S. Army or the Department of Defense.
Sandhya Vasan, MD
US Military HIV Research Program, Henry M. Jackson Foundation
Armed Forces Research Institute of Medical Sciences
Bangkok, Thailand
HIV Vaccines and Broadly Neutralizing
Monoclonal Antibodies –
Role in the Cure Agenda
10th Workshop on HIV Pediatrics
July 20, 2018
Plotkin S. Correlates of Vaccine-Induced Immunity, Vaccines 2008
Vaccine Correlates of Protection
HIV ??????
Inverse Correlate of HIV Risk in RV144 Thai Trial
Total Vaccine Efficacy = 31.2%
Estimated Relative Risk High vs Low = 0.29
High V1V2
Low/Medium
V1V2
Haynes et al., NEJM 2012
Anti-V1V2 IgG Antibodies to Candidate HIV Vaccines in Infants
PACTG 230: infants vaccinated four times from Weeks 0 – 20 with placebo or:
Chiron rgp120 + MF-59 adjuvant or
VaxGen rgp120 + aluminum hydroxide
PACTG 326: infants vaccinated four times from Weeks 0 -12 with placebo or:
ALVAC vCP1452 alone or
ALVAC vcp1452 + AIDSVAC B/B + alum adjuvant
Martinez et al.,
Clin Vacc Immunol, 2016.
Anatomic
ReservoirsLatency & Integration
Antibodies alone are insufficient
for therapeutic vaccines
Immunologic
Sanctuaries
CD8+ T cell depletion in SIV controller macaques results
in rebound viremiaTC Friedrich et al., J Virol, 2007
Y. Fukazawa et al.,
Nat Med, 2015
Strategies to Improve CD8+ T Cell Effector Responses
Correlate Immunological parameter P-value
Virologic Control Gag Breadth (memory T cells)
Gag Magnitude (memory T cells)
0.0002
0.0058
Viral vectors: Cause MHC presentation of HIV antigens on cell surface
Poxvectors: ALVAC, NYVAC, Modified Vaccinia Ankara (MVA)
Adenoviral vectors: Ad5, Ad26, Ad35, Chimpanzee Ad
Replicating vectors: Cytomegalovirus (CMV)
Post-Vaccination SIV Challenge
Barouch et al., Nature 2012
Adjuvants:
Modulate the innate
response to vaccines to
improve immunogenicity
and alter Th1/Th2 cytokine
balance, e.g. aluminum
hydroxide, MF59, AS04
Hansen et al.,Nature 2011
Translating Therapeutic HIV Vaccines to Infants and Children
Disadvantages:
1) Increased regulatory T cells in fetal development can dampen
immune responses
2) Maternal antibodies can interfere with immune responses
3) Limited antigenic exposure from environment
Advantages in infants started on early ART:
1) Relatively intact immune system with normal B /T cell function
2) Smaller latent reservoir, e.g. “Mississippi baby”
3) Infants started on early ART may have lower viral diversity,
lowering the likelihood of viral escape from CTL
Vaccination of HIV-Infected Children
ACTG 218: HIV-infected infants and children vaccinated monthly from
Weeks 0 – 6 with three HIV envelope proteins or placebo
- safe and well tolerated
- 30-56% developed cellular lymphoproliferative responses to HIV env
- 65% developed antibodies to HIV-envelope
PEDVAC: HIV-infected children age 6 to 16 vaccinated 4 times with
DNA vaccines encoding HIV subtypes A/B/C Env, Rev, Gav, Tat
- safe and well tolerated
- cellular immune responses to gag
- lymphoproliferative responses to HIV envelope
- CD8+ perforin responses
Broadly Neutralizing Antibodies for Therapy
No single bNab infusion has achieved cure in adults
2016
Vaccine / bNab Clinical Trials in Children with HIV
bNAbs
VRC01 with early ART in infants (IMPAACT P2008; NCT03208231)
Phase I/II; randomized, n=68 HIV+ infants
VRC01 (Wk 0/2/6/10) administered with ART (through Wk 14)
safety and effect on HIV-1 DNA concentrations in peripheral blood
VRC01-LS+10-1074 in virally suppressed, early treated children (Botswana)
U01AI135940, Harvard University/Brigham and Women’s Hospital
HIV vaccines
HIVIS DNA/MVA-CMDR vaccines in Thailand, South Africa and Italy in virally
suppressed, early treated adolescents (EPIICAL network) U01AI135941
www.TAG.org; www.clinicaltrials.gov
Alternatives for antibody administration in children
“Dmabs” = Expression and assembly of monoclonal antibodies in vivo
after administration of DNA encoding antibodies
A. Patel, Nature Communications, 2018
Cellectra-3P Dermal
Electroporation Device
D. Amante, Human Gene
Therapy Methods, 2015
Don’t forget the adolescents…
National Department
of Health, South Africa