Optimization of HIV-1 Envelope DNA Vaccine Candidates within Three Different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques.

Marie Borggren,Johanna Repits,Roger Grand,Marianne Jansson,Nathalie Dereuddre-Bosquet,Rogier Sanders,Lasse Vinner,Tara Elvang,Anders Fomsgaard,Priscilla Biswas,Betina Andresen,Mark Melchers,Guillaume Stewart-Jones,Leo Heyndrickx,Emma Bowles,Berit Grevstad,Gabriella Scarlatti,Frédéric Martinon

doi:10.3390/vaccines1030305

Abstract

HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing antibodies (bNAb). We compared three different animal models: guinea pigs, rabbits and cynomolgus macaques. Envelope genes from the prototype isolate HIV-1 Bx08 and two elite neutralizers were included. Codon-optimized genes, encoded secreted gp140 or membrane bound gp150, were modified for expression of stabilized soluble trimer gene products, and delivered individually or mixed. Specific IgG after repeated i.d. inoculations with electroporation confirmed in vivo expression and immunogenicity. Evaluations of rabbits and guinea pigs displayed similar results. The superior DNA construct in rabbits was a trivalent mix of non-modified codon-optimized gp140 envelope genes. Despite NAb responses with some potency and breadth in guinea pigs and rabbits, the DNA vaccinated macaques displayed less bNAb activity. It was concluded that a trivalent mix of non-modified gp140 genes from rationally selected clinical isolates was, in this study, the best option to induce high and broad NAb in the rabbit model, but this optimization does not directly translate into similar responses in cynomolgus macaques.

Highlights

The ability to elicit HIV-1 neutralizing antibodies (Nabs) is likely to be an essential feature of protective HIV-1 vaccines
We have previously shown that the codon-optimized envBx08 can induce NAbs with limited breadth [18,33,34]
To optimize the DNA vaccine to elicit a high and broad immune response in rabbits, the initial evaluation of env DNA concerned the use of gp140 or gp150 genes

Summary

Introduction

The ability to elicit HIV-1 neutralizing antibodies (Nabs) is likely to be an essential feature of protective HIV-1 vaccines. The HIV envelope spike is the only glycoprotein presented on the virion and on the surface of infected cells for antibody binding and neutralization, by broadly neutralizing antibodies (bNAbs). Five areas on the HIV trimeric spike have been identified so far as conserved targets for broadly neutralizing monoclonal antibodies cloned from patients including elite neutralizers [1]. Extensive attempts have been undertaken to construct immunogens and use different vaccine strategies to direct antibodies to these areas and to improve functionality, encompassing antibody-dependent cell-mediated cytotoxicity (ADCC) [2]. Lessons may still be learned from envelopes of rationally selected and/or modified clinical HIV-1 strains e.g. from patients with bNAbs, ADCC and/or a defined favorable clinical course The growing knowledge of neutralizing epitope structures on the HIV-1 Env does not automatically translate into the generation of improved immunogens, emphasizing the importance of continuing all approaches in the search for HIV-1 vaccine immunogens.

Results

Discussion

Conclusion