Rotavirus Inner Capsid VP6 Acts as an Adjuvant in Formulations with Particulate Antigens Only

Abstract

<jats:p>Novel adjuvants present a concern for adverse effects, generating a need for alternatives. Rotavirus inner capsid VP6 protein could be considered a potential candidate, due to its ability to self-assemble into highly immunogenic nanospheres and nanotubes. These nanostructures exhibit immunostimulatory properties, which resemble those of traditional adjuvants, promoting the uptake and immunogenicity of the co-administered antigens. We have previously elucidated an adjuvant effect of VP6 on co-delivered norovirus and coxsackievirus B1 virus-like particles, increasing humoral and cellular responses and sparing the dose of co-delivered antigens. This study explored an immunostimulatory effect of VP6 nanospheres on smaller antigens, P particles formed by protruding domain of a norovirus capsid protein and a short peptide, extracellular matrix protein (M2e) of influenza A virus. VP6 exhibited a notable improving impact on immune responses induced by P particles in immunized mice, including systemic and mucosal antibody and T cell responses. The adjuvant effect of VP6 nanospheres was comparable to the effect of alum, except for induction of superior mucosal and T cell responses when P particles were co-administered with VP6. However, unlike alum, VP6 did not influence M2e-specific immune responses, suggesting that the adjuvant effect of VP6 is dependent on the particulate nature of the co-administered antigen.</jats:p>

Rotavirus VP6: involvement in immunogenicity, adjuvant activity, and use as a vector for heterologous peptides, drug delivery, and production of nano-biomaterials

“…( A ) Different expression systems from prokaryotic E. coli [ 2 , 72 , 126 ] to eukaryotic systems such as yeast [ 17 ], insect cell/baculovirus systems (IC-BV) [ 38 , 67 ], mammalian cells [ 38 ], HSV-1 [ 90 ], and plant cells [ 37 , 89 , 127 ] have been used successfully to produce assembled structures of VP6 tubes/VLPs. ( B ) Applications of VP6 tubes/VLPs, as vaccines (immunogenicity and protection) [ 15 , 44 , 54 , 55 , 64 – 66 , 70 , 95 , 108 ], adjuvants [ 15 , 16 , 55 , 76 – 78 , 108 – 110 ], immunological carriers [ 49 , 53 , 92 , 96 , 102 , 111 ], drug delivery tools [ 5 , 91 , 122 , 126 ], and nano-biomaterials [ 5 , 23 , 24 , 41 , 42 , 50 , 91 , 122 , 126 ] …”

“…In this context, it was shown that despite higher induction of the cytokine IL-4 by co-administration of VP6 tubes with norovirus VLPs than with VP6 VLPs, both of these oligomeric VP6 assemblies exerted a similar dose-dependent adjuvant effect on norovirus-specific Ab responses [ 77 ]. More-recent studies have indicated that the particulate nature and size of the co-administered Ag might also affect the adjuvant effect of VP6 VLPs [ 55 ]. In this context, co-administration of VP6 VLPs with either a 20-nm norovirus P particle or a 23-mer extracellular domain of matrix protein M2 (M2e, a monomeric peptide, ~3 kDa) of human influenza A virus showed an adjuvant effect of VP6 VLPs only, enhancing Ab and T-cell immune responses against the preceding Ag (norovirus P particle), and not M2e [ 55 ].…”

Parenteral, non-live rotavirus vaccine: recent history and future perspective

“…When the VP6 nanotubes were vaccinated with noroVLP or Coxsackie VLP (di or tri-valent) as a combination vaccine, robust protective immunities were induced against both rota and Coxsackie, which also served as an immune modulating effect on VP6 nanotube [ 32 33 34 35 36 ]. On the other hand, recent studies have shown that VP6 nanotube does not exhibit adjuvant characteristics for monomeric antigens or short peptides [ 37 ]. Two types of small antigens, P particles derived from norovirus capsid protein and small peptides (23 mer) derived from extracellular matrix protein (M2e) of influenza virus were tested to demonstrate that VP6 nanotube had an immune supporting effect.…”

“…However, neither M2e peptide alone nor combination with VP6 nanotubes showed significant differences in serum IgG levels. This means that the immune modulating effect of VP6 nanotubes is only effective for antigens in particle form [ 37 ].…”

“…After three dose vaccinations, significantly improved immunogenicity was observed in S 60 -VP8* nanoparticles group [ 40 ] and further experiments with S 60 -mVP8* nanoparticles in which murine VP8* antigens are expressed, showed protective immune responses against murine RV (epizootic diarrhea of infant mice) challenge in mice [ 41 ]. Overall, it has been shown that nanoparticles resulting from the properties of capsid proteins such as the S and P proteins of norovirus can be effectively utilized for the transfer of RV antigens to immune system [ 37 ]. In addition to viral nanoparticles, other naturally occurring self-assembling nanoparticles have been purposed.…”