Human Immunodeficiency virus (HIV) has infected 76 million people globally and claimed the lives of an estimated 35 million (http://www.who.int/hiv/en/).
Soluble Env (e.g. gp140) in its native-like, trimeric form has been considered one of the most promising HIV vaccine platforms. Several ‘design’ strategies containing specific mutations in the Env sequence have been proposed for trimer stabilization. Despite encouraging success, these designs are not applicable to diverse HIV strains and subtypes and often encounter significant difficulties in trimer production, for which complicated purification methods and additional mutations have been used as patch-up solutions. Moreover, it has proven challenging to display these trimer designs on virus-like particles (VLPs), which are known to be a more effective form of vaccine that has achieved great success (e.g. human papillomavirus, or HPV, vaccine). Lastly, trimers alone have failed to elicit tier 2 autologous neutralizing antibodies in mice and required 6 to 12 months of immunization to generate such antibody responses in rabbits and non-human primates (NHPs).
The cause of ‘Env metastability’, a term referring to the inherent instability of Env, has been unclear until recently. An uncleaved prefusion-optimized (UFO) design was proposed that stressed the importance of a critical region undergoing drastic conformational change during virus entry [1,3]. UFO can be applied to diverse HIV strains and subtypes, with substantial trimer yield, purity, and stability. UFO trimers can be readily displayed on self-assembling nanoparticles, providing a new type of VLP vaccines with unparalleled yield, purity, and stability when produced in GMP-compatible CHO cells [2,3]. The patented technology for UFO trimer stabilization and nanoparticle display, a.k.a. UFOTON (see the schema below), was developed by Dr. Zhu’s laboratory at TSRI (https://www.jzhulab.org/). This technology leads to not only an ideal form of HIV vaccine but also a simple and easy-to-implement process for industrial manufacture of a vaccine product.
Efficacy is the final testimony to the effectiveness of any medicine – no exception for HIV vaccine. So far, UFOTON has demonstrated its superior immunogenicity in small animals (see the schema below) [3]. In mice, UFO nanoparticles elicited a robust tier 2 autologous neutralizing antibody response at week 8, whereas trimers did not, regardless of the design strategy and the immunization protocol. In rabbits, a UFO nanoparticle induced a potent tier 2 neutralizing antibody response at week 6, which was two months earlier than and remained statistically different from that elicited by a trimer throughout the course of vaccination.
Two 1c-SApNP vaccine candidates, BG505NP and CH505NP are being manufactured under GMP conditions for Phase I clinical studies. Seeing is believing. Electron microscope images of the nanoparticle vaccine products are shown below.
References:
- Kong, L. et al. Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability. Nat. Commun. 7:12040.
- He, L. et al. Presenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles. Nat. Commun. 7:12041.
- He, L. et al. HIV-1 vaccine design through minimizing Env metastability. Sci. Adv. 4:eaau6769.
