Abstract
Well-ordered soluble HIV-1 envelope glycoprotein (Env) spike mimetics such as Native Flexibly Linked (NFL) trimers display high homogeneity, desired antigenicity, and high in vitro stability compared to previous generation soluble HIV-1 Env trimers. Glutaraldehyde (GLA) cross-linking was shown to further increase the thermostability of clade C 16055 NFL trimers and enhance the induction of tier 2 autologous neutralizing antibodies in guinea pigs. Here, we investigated if GLA fixation affected other aspects of the Env-specific immune response by performing a comparative immunogenicity study in C57BL/6 mice with non-fixed and GLA-fixed 16055 NFL trimers administered in AbISCO-100 adjuvant. We detected lower Env-specific binding antibody titers and increased skewing toward Th2 responses in mice immunized with GLA-fixed trimers compared to mice immunized with unfixed trimers, as shown by a higher Env-specific IgG1:IgG2b antibody subclass ratio. These results suggest that the presence of GLA adducts on Env influences the quality of the induced antibody response.
Highlights
Most licensed vaccines mediate protection through the induction of highly specific IgG serum antibodies
To confirm that the trimers remained as single particles following cross-linking and negative selection, we performed negative-stain Electron Microscopy (EM) and observed no marked difference in trimers at this level of resolution comparing unfixed to fixed populations (Figure 1C, right)
We performed a comparative study in mice to examine the magnitude and quality of the envelope glycoprotein (Env)-specific immune responses induced by unfixed or GLA-fixed 16055 native flexibly linked (NFL) TD CC trimers
Summary
Most licensed vaccines mediate protection through the induction of highly specific IgG serum antibodies. A central goal for HIV-1 vaccine development is to induce antibody responses that are capable of neutralizing a broad range of circulating HIV-1 strains. These early generation trimers were structurally heterogeneous and suboptimal antigenic mimics of the functional HIV-1 spike. New generation trimers such as the BG505 SOSIP.664 trimers [3, 4] and various forms of the native flexibly linked (NFL) trimers [5] were designed. These soluble spikes display superior threefold symmetric order and improved antigenic profiles. The NFL trimers were constructed by replacing the furin cleavage site that is naturally present
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