Containment of SHIV89.6P Infection
in Rhesus Macaques after DNA/MVA Immunization: Influence of Application Strategies
and Vaccine Components
Kurt Bieler1, Petra Moji2,
Josef Köstler1, Christiane Stahl-Henning3, Hans Wolf1,
Bernhard Moss4, Jon Heeney2, Ralf Wagner1,5
.
1Institute of Medical
Microbiology and Hygiene, Regensburg, Germany; 2Biomedical Primate Research Centre (BPRC), Rijswijk,
Netherlands; 3Department of Virology and Immunology (DPZ),
Göttingen, Germany;4Laboratory of Viral Diseases, National Institutes
of Health, Bethesda, USA. 5GENEART GmbH, Regensburg, Germany.
e-mail: kurt.bieler@klinik.uni-regensburg.de
The development of successful
HIV specific DNA vaccines has almost for a decade been limited by concerns
regarding both their safety and efficacy in primates. Therefore the primary
goal of the presented monkey studies was to develop and test safe HIV-specific
DNA vaccines lacking unfavorable cis- and trans acting regulatory elements
and, at the same time test (i) different application routes (i.m./i.d. vs.
nasal), (ii) the effect of co administrated cytokines (IL-12 and IL-18) (iii)
and the influence of a multi-component vaccine versus a single antigen vaccine.
Extensive codon usage modifications
allowed to remove RNA packaging signals, to bypass the complete REV/RRE system
and to significantly enhance transgene expression levels and immunogenicity.
Accordingly, different DNA vaccine constructs were developed expressing SIVmac239
GagPol in addition to envelope derivatives derived from SHIV 89.6P. The immunogenicity
and efficacy of such DNA vaccines was tested in a pathogenic SHIV / rhesus
macaque model.
Each monkey received a repeated
primary i.m./i.d. DNA immunization that was followed by two injections with
recombinant Modified Vaccina Ancara (MVA) expressing the corresponding set
of antigens. MVA booster immunizations were given either i.m./i.d. or intranasally. All rhesus macaques were challenged in
this study with 40 MID50 of SHIV89.6P via the rectal route. All immunized
animals revealed a 1-2 log virus load reduction regarding the initial viremia
and at set point. Three out of four intranasally boostered animals and one
of the animals with exclusively i.m./i.d. injections managed to fully eliminate
the virus after 4 weeks as determined by quantitative PCR analysis. Stringent
virus containment was paralleled by a sustained levels of CD4 positive T cells.
These data suggest that stringent
virus containment in a relevant animal model can be provided depending on
the type and route of delivered immunogens. In an other study (ii) we saw
an increased immune response after application of IL-12 and IL-18 during
priming but no increase of protection after challenge. In a further study
(iii) we could demonstrate the beneficial effect of a multicomponent vaccine.