Active Immunization of Neonatal Monkeys

1
Active Immunization of Neonatal
Monkeys Ghent/International AIDS
Society/Clinical Trials Partnership Group on HIV
in Women an Children Prevention of HIV
Transmission through Breastfeeding Strengthening
the Research Agenda Ghent, Belgium - December
12-13, 2002 Ruth Ruprecht, M.D., Ph.D. Harvard
Medical School, Boston
2
DNA Prime/Protein Boost Vaccination in Newborn
Rhesus Macaques
SHIV
-
SHIV
-
SHIV
SHIV
-
SHIV
-
SHIV
vpu
vpu
89.6P
vpu
vpu
89.6P




DNA
gp160
gp160
Months
21
6
11
26
26
.5 30
32
34
0 1

• DNA vaccination gag, pol, nef of SIVmac239 env
  of HIV-1 IIIB
• Initial homologous SHIV challenge
• - viral containment in 4 of 15 DNA prime/gp160
  boost-vaccinated
• macaques and 3 of 4 macaques given gp160
  boost only
• - all protected animals had high neutralizing
  antibody titers
• 2nd homologous challenge
• - viral containment in 6 of 6 macaques

Rasmussen et al., J Med Prim 2002 3140
3
Is it possible to vaccinate against one strain of
virus without compromising the immune systems
ability to subsequently generate antibody
responses against an antigenically divergent
virus strain?
4
Original Antigenic Sin?
5
Original Antigenic Sin (def.)
.describes the tendency of humans to generate
antibody responses shared between the original
strain of a virus and subsequent related viruses,
while ignoring other highly immunogenic epitopes
on the second and subsequent viruses. Immunobiolog
y. The Immune System in Health and Disease
Fourth edition. CA Janeway, P Travers, M Walport,
JD Capra, (eds.). 1999. Elsevier Science
Ltd/Garland Publishing.
6
Original Antigenic Sin or deceptive imprinting
could be problematic for.

• chronic HIV infection
• novel quasispecies emerge as neutralization
  escape mutants and will not be neutralized
  subsequently
• heterologous HIV strains that superinfect will
  never be neutralized
• breakthrough infections with heterologous HIV
  strains in AIDS vaccine recipients
• no nAbs would be generated against the infecting
  HIV strain
• designing multivalent anti-HIV envelope
  glycoprotein vaccines

7
DNA Prime/Protein Boost Vaccination in Newborn
Rhesus Macaques
SHIV
-
SHIV
-
SHIV
SHIV
-
SHIV
-
SHIV
vpu
vpu
89.6P
vpu
vpu
89.6P




DNA
gp160
gp160
Months
21
6
11
26
26
.5 30
32
34
0 1

• Initial homologous SHIV challenge
• - viral containment in 4 of 15 DNA prime/gp160
  boost-vaccinated
• macaques and 3 of 4 macaques given gp160
  boost only
• - all protected animals had high neutralizing
  antibody titers
• 2nd homologous challenge
• - viral containment in 6 of 6 macaques
• Heterologous SHIV89.6P rechallenge
• - No or limited SHIV89.6P infection and normal
  CD4 T cell counts in 4 of 6 macaques

Rasmussen et al., J Med Prim 2002 3140
8
Neutralizing Antibody Responses
9
Vaccinated rhesus macaques were no sinners...

• Despite prior high levels of neutralizing
  antibodies to SHIV-IIIB, three animals developed
  new, high-titer anti-SHIV89.6P neutralizing
  antibodies.

10
Original Antigenic Sin

• was not committed in rhesus monkeys vaccinated
  with DNA prime/gp160 boosts. The animals
  developed potent neutralizing antibody responses
  after superinfection with the heterologous
  SHIV89.6P.
• did not prevent human subjects vaccinated with
  HIVSF2 Env from developing neutralizing antibody
  responses to breakthrough infecting viruses.
• may not present an insurmountable obstacle for
  AIDS vaccine development.

11
Acknowledgements
DFCI / Harvard Medical School Regina
Hofmann-Lehmann Weidong Xu Robert
Rasmussen Flavia Ferrantelli Pei-Lin Li Timothy
Baba Vladimir Liska Beverly Smith-Franklin Josef
Vlasak Beth Israel-Deaconess Medical
Center Marcelo Kuroda Norman Letvin Keith
Reimann Joern Schmitz Lisa Cavacini Marshall
Posner
Duke University School of Medicine David
Montefiori
Institute of Applied Microbiology, Vienna,
Austria Hermann Katinger Gabriela
Stiegler University of Massachusetts Medical
Center Shan Lu University of Washington Shiu-Lok
Hu
University of Texas, MD Anderson Cancer
Center Bruce Bernacky Tahir Rizvi Russell
Schmidt Lori Hill Michale Keeling
Yerkes Regional Primate Research Center Harold
McClure Harriet Robinson Daniel
Anderson
Harvard School of Public Health Janet
Andersen Yichen Lu
University of Nebraska Charles Wood Qiujiang Du
Jun He
Memorial Sloan-Kettering Cancer Center Ting-Chao
Chou
Univ. Teaching Hosp., Lusaka, Zambia Ganapati
Bhat Chipepo Kankasa
The Scripps Research Institute Dennis Burton