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