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Optimization of HIV-1 envelope DNA vaccine candidates within three different animal models, guinea pigs, rabbits and cynomolgus macaques

Optimization of HIV-1 Envelope DNA Vaccine Candidates within three different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques
Marie Borggren1, Lasse Vinner1, Betina S Andresen1, Berit Grevstad1, Johanna Repits1, Mark Melchers2, Tara L Elvang1, Rogier W Sanders2, Nathalie Dereuddre-Bosquet3, Guillaume Stewart-Jones4, Emma Bowles4, Priscilla Biswas5, Gabriella Scarlatti5, Marianne Jansson6, Leo Hendrickx7, Roger Le Grand3, Anders Fomsgaard1,8* for the NGIN Consortium#
HIV-1 DNA vaccines have many desired features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaques and human trials. Here we selected and optimized DNA vaccine candidates by systematic testing in rabbits for induction of broadly neutralizing antibodies (bNAb) and compared three different animal models guinea pigs, rabbits and cynomolgus macaques.
Env from the prototype Bx08 and two elite neutralizers were selected. Codon-optimized genes encoded secreted gp140 or membrane bound gp150, or were modified for stabilized soluble trimer products (SOSIP-R6-IZ mutations), and delivered individually or mixed. Specific IgG after repeated i.d. inoculations with electroporation confirmed in vivo expression and immunogenicity.
Evaluation in rabbits and guinea pigs displayed similar results. The optimal DNA construct in rabbits was a trivalent mix of non-modified codon-optimized gp140 envs (SSImix). Despite potent and broad NAb responses in guinea pigs and rabbits, the DNA vaccinated macaques displayed less bNAb activity.
It is concluded that a trivalent mix of non-modified gp140 genes from rationally selected clinical isolates is optimal to induce high and broad NAb in the rabbit model, but this optimization does not directly translate into cynomolgus macaques. This suggests species-specific differences in the quality of immune response to HIV-1 env DNA.