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. 2023 Mar 13;9(3):1296-1306.
doi: 10.1021/acsbiomaterials.2c01516. Epub 2023 Feb 27.

Effect of Antigen Structure in Subunit Vaccine Nanoparticles on Humoral Immune Responses

Jaeyoung Park  1 , Julie A Champion  1
Affiliations

Effect of Antigen Structure in Subunit Vaccine Nanoparticles on Humoral Immune Responses

Jaeyoung Park et al. ACS Biomater Sci Eng. .

Abstract

Subunit vaccines offer numerous attractive features, including good safety profiles and well-defined components with highly characterized properties because they do not contain whole pathogens. However, vaccine platforms based on one or few selected antigens are often poorly immunogenic. Several advances have been made in improving the effectiveness of subunit vaccines, including nanoparticle formulation and/or co-administration with adjuvants. Desolvation of antigens into nanoparticles is one approach that has been successful in eliciting protective immune responses. Despite this advance, damage to the antigen structure by desolvation can compromise the recognition of conformational antigens by B cells and the subsequent humoral response. Here, we used ovalbumin as a model antigen to demonstrate enhanced efficacy of subunit vaccines by preserving antigen structures in nanoparticles. An altered antigen structure due to desolvation was first validated by GROMACS and circular dichroism. Desolvant-free nanoparticles with a stable ovalbumin structure were successfully synthesized by directly cross-linking ovalbumin or using ammonium sulfate to form nanoclusters. Alternatively, desolvated OVA nanoparticles were coated with a layer of OVA after desolvation. Vaccination with salt-precipitated nanoparticles increased OVA-specific IgG titers 4.2- and 22-fold compared to the desolvated and coated nanoparticles, respectively. In addition, enhanced affinity maturation by both salt precipitated and coated nanoparticles was displayed in contrast to desolvated nanoparticles. These results demonstrate both that salt-precipitated antigen nanoparticles are a potential new vaccine platform with significantly improved humoral immunity and a functional value of preserving antigen structures in vaccine nanoparticle design.

Keywords: antigen structure; humoral immune response; nanoparticles; salt precipitation; subunit vaccine.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
MD simulation of OVA proteins. (A) OVA proteins solvated with water (red) and 50:50 (v %/v %) methanol/ethanol (green). (B) Root mean square difference, radius of gyration, Gibbs free energy, and potential energy calculated from MD GROMACS. (C) Conformation of OVA simulated in the alcohol mixture and pure water for 20 ns. A part of OVA highlighted by a red box in the alcohol mixture shows a noticeable conformational change compared to that of OVA in water.
Figure 2
Figure 2
Physicochemical properties of NPs including particle size distributions and average diameter, polydispersity index (PDI), and ζ potential measured by DLS and Malvern ζ potential analyzer. The yield of each NP was calculated by measuring the amount of OVA proteins incorporated in each NP via BCA.
Figure 3
Figure 3
(A) Circular dichroism (CD) spectra of OVA NPs and soluble OVA and (B) CD signal intensity measured at 217 nm (β sheet) and 222 nm (α helix). *, p ≤ 0.05, **, p ≤ 0.01, ***, p ≤ 0.001, ****, p ≤ 0.0001.
Figure 4
Figure 4
(A) Schematic overview of vaccination study. Total IgG (B), IgG1 (C), and IgG2a (D) from vaccinated mice after prime (circles) and after boost (triangles). (E) Antibody affinity of OVA-specific total IgG at 8 weeks. N = 5–6. *, p ≤ 0.05, **, p ≤ 0.01, ***, p ≤ 0.001, ****, and p ≤ 0.0001. ns represent statistically nonsignificant differences.
Figure 5
Figure 5
Percent population of (A) CD11c+ DCs expressing MHC II and CD86, OVA-specific CD4+ T cells secreting (B) IFN-γ and (C) IL-4, and OVA-specific CD8+ T cells secreting (D) IFN-γ and (E) IL-4 obtained from spleens. N = 5–6. ns represents statistically non-significant differences.
Figure 6
Figure 6
Percent population of OVA-specific CD4+ T cells secreting (A) IFN-γ and (B) IL-4 and OVA-specific CD8+ T cells secreting (C) IFN-γ and (D) IL-4 obtained from lymph nodes. N = 5–6. *, p ≤ 0.05. ns represents statistically non-significant differences.
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