Monophosphoryl Lipid A‐Adjuvanted Virosomes with Ni‐Chelating Lipids for Attachment of Conserved Viral Proteins as Cross‐Protective Influenza Vaccine

Abstract

Induction of CD8 cytotoxic T cells (CTLs) to conserved internal influenza antigens, such as nucleoprotein (NP), is a promising strategy for the development of cross-protective influenza vaccines. However, influenza NP protein alone cannot induce CTL immunity due to its low capacity to activate antigen-presenting cells (APCs) and get access to the MHC class I antigen processing pathway. To facilitate the generation of NP-specific CTL immunity the authors develop a novel influenza vaccine consisting of virosomes with the Toll-like receptor 4 (TLR4) ligand monophosphoryl lipid A (MPLA) and the metal-ion-chelating lipid DOGS-NTA-Ni incorporated in the membrane. In vitro, virosomes with incorporated MPLA induce stronger activation of APCs than unadjuvanted virosomes. Virosomes modified with DOGS-NTA-Ni show high conjugation efficacy for his-tagged proteins and facilitate efficient uptake of conjugated proteins by APCs. Immunization of mice with MPLA-adjuvanted virosomes with attached NP results in priming of NP-specific CTLs while MPLA-adjuvanted virosomes with admixed NP are inefficient in priming CTLs. Both vaccines induce equally high titers of NP-specific antibodies. When challenged with heterosubtypic influenza virus, mice immunized with virosomes with attached or admixed NP are protected from severe weight loss. Yet, unexpectedly, they show more weight loss and more severe disease symptoms than mice immunized with MPLA-virosomes without NP. Taken together, these results indicate that virosomes with conjugated antigen and adjuvant incorporated in the membrane are effective in priming of CTLs and eliciting antigen-specific antibody responses in vivo. However, for protection from influenza infection NP-specific immunity appears not to be advantageous.

Advances in Development and Application of Influenza Vaccines

“…However, due to a lack of adjuvants, virosomes are inefficient in activating APCs and thus in triggering crosspresentation, which limits the induction of CTL immunity. Therefore, adding suitable adjuvants can overcome this short coming (91). Dong Since the virosomes influenza vaccine was first proposed in the 1970s (93), after more than 20 years of development, influenza virosome vaccines have gathered sufficient clinical experimental data and have resulted in two products Epaxal ® and Inflexal ® that were produced in 1994 and 1997 by the Swiss Serum and Vaccine Institute, Bern, Switzerland (94,95).…”

Design and application of nanoparticles as vaccine adjuvants against human corona virus infection

“…As a TLR4 receptor agonist, it can be used in influenza vaccines. In vitro, virions with monophosphoryl lipid A (MPLA) can induce the activation of APCs to a higher degree than virions without adjuvants [ 83 ]. The immunisation of mice with MPLA-adjuvanted virosomes with attached nucleoproteins can induce nucleoprotein-specific cytotoxic T lymphocyte and elicit antigen-specific antibody responses and can prevent severe weight loss when the virosomes are inoculated with allotype influenza virus.…”

General characteristics of adjuvants and their mechanisms of action (part 2)

“…Для формирования NP-специфического иммунитета разрабатывается новая вакцина против гриппа, состоящая из виросом, MPL и липида DOGS-NTA-Ni, который хелатирует ионы металлов, встроенных в мембрану. Отмечается, что виросомы с конъюгированным АГ и адъювантом, включенным в мембрану, эффективны при праймировании цитотоксических Т-лифоцитов и индукции ответа специфических АТ в условиях in vivo [23].…”