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

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.

Neutralizing Antibody Response and Antibody-Dependent Cellular Cytotoxicity in HIV-1–Infected Individuals from Guinea-Bissau and Denmark

“…21 However, a following phase IIb trial, HVTN 505, with the same immunization regime was halted prematurely due to lack of efficacy. 22 Future vaccine candidates may benefit from the recent development of stabilized soluble Env trimers, 23,24 which mimic the native envelope spike and could be useful both in DNA 25 and antigen vaccines. Despite the recent discovery of a large number of broadly neutralizing antibodies, it is unknown how to elicit such antibodies.…”

Boosting of HIV-1 Neutralizing Antibody Responses by a Distally Related Retroviral Envelope Protein

“…These results provide a proof of concept that a distally related retroviral SIV Env protein boost can increase pre-existing NAb responses against HIV-1. The HIV-1 DNA immunization schedule was based on a previously published optimization (49) and its effectiveness in this study is highlighted by the fact that strong binding titres as well as significant neutralization were already observed after the DNA immunization phase (Figs.2C and 3). It is conceivable that the use of attenuated vectors, or more effective DNA delivery systems/adjuvants, may be required for the induction of potent antibody priming in primates (69).…”

“…In a previous study we optimized a DNA prime regimen in which clade B gp140 env was delivered as a mixture composed of three synthetic codon optimized envs (from the clinical isolates HIV-1 Bx08, ctl21 and ctl27) with the aim to increase the proportional concentration of epitopes derived from shared regions (49). In the present study we used the same DNA prime followed by a highly heterologous trimeric SIV mac239 gp140 protein boost, hypothesizing that such a regime might focus the response to more conserved structures.…”

“…The construction of BX08 gp140 (GenBank JX473289) plasmid used codons from highly expressed human genes as described earlier (46–48) and two other primary envs from Danish patients (ctl21 (JX473290) and ctl27 (JX473291) (49) were similarly codon optimized and cloned in the same expression plasmid with the key elements CMV IE promotor-enhancer, tPA secretion signal, and a bovine growth hormone poly A signal. Clones were verified by sequencing.…”

Vector optimization and needle-free intradermal application of a broadly protective polyvalent influenza A DNA vaccine for pigs and humans

“…The use of electroporation in rabbit skin has been evaluated for efficacy 40 and safety 41 and the method has been used successfully in previous studies with DNA vaccines in rabbits. 42,43 For the vaccination procedure, the rabbits were anesthetized using intramuscularadministered Hypnorm Ò (fentanyl citrate:fluanisone mix) (Skanderborg Pharmacy, Denmark) 0.3 ml/kg. 2).…”