Chimeric virus-like particles containing influenza HA antigen and GPI-CCL28 induce long-lasting mucosal immunity against H3N2 viruses

Abstract

Influenza virus is a significant cause of morbidity and mortality, with worldwide seasonal epidemics. The duration and quality of humoral immunity and generation of immunological memory to vaccines is critical for protective immunity. In the current study, we examined the long-lasting protective efficacy of chimeric VLPs (cVLPs) containing influenza HA and GPI-anchored CCL28 as antigen and mucosal adjuvant, respectively, when immunized intranasally in mice. We report that the cVLPs induced significantly higher and sustainable levels of virus-specific antibody responses, especially IgA levels and hemagglutination inhibition (HAI) titers, more than 8-month post-vaccination compared to influenza VLPs without CCL28 or influenza VLPs physically mixed with sCCL28 (soluble) in mice. After challenging the vaccinated animals at month 8 with H3N2 viruses, the cVLP group also demonstrated strong recall responses. On day 4 post-challenge, we measured increased antibody levels, ASCs and HAI titers with reduced viral load and inflammatory responses in the cVLP group. The animals vaccinated with the cVLP showed 20% cross-protection against drifted (Philippines) and 60% protection against homologous (Aichi) H3N2 viruses. Thus, the results suggest that the GPI-anchored CCL28 induces significantly higher mucosal antibody responses, involved in providing long-term cross-protection against H3N2 influenza virus when compared to other vaccination groups.

CCL28 chemokine: An anchoring point bridging innate and adaptive immunity

“… GPI-anchored CCL28 in influenza VLPs promoted long-term mucosal protective immunity. [59] , [60] , [61] HIV/AIDS CCL28 with HIV-1IIIB VLPs enhanced the migration of IgA ASCs to mucosal sites in a mouse immunization model. CCL28-including constructs prevented HIV infection of the gastro-intestinal mucosal lamina propria (MLP) via modulation of IgA ASC.…”

“…Because of its specific role in orchestrating the localization of IgA ASCs at mucosal sites [19] , we also analyzed the long-lasting mucosal adjuvanticity of GPI-anchored CCL28 co-incorporated into influenza VLPs. Data suggest that the GPI-anchored CCL28 induced significantly higher mucosal antibody responses involved in providing long-term cross-protection against H3N2 influenza virus when compared to other vaccination groups [60] . GPI-anchored CCL28 could be used to develop vaccines against other viruses such as: the human immunodeficiency virus-1 (HIV-1), simian immunodeficiency virus (SIV), Ebola virus, severe acute respiratory syndrome (SARS), coronavirus, and Rift Valley Fever virus (RVFV).…”

Progress in the development of virus-like particle vaccines against respiratory viruses

“…Mice immunized with VLPs modified by protein transfer with GPI-GM-CSF induced higher levels of IgG antibody responses and protection against a heterologous influenza virus challenge than unmodified VLPs in mice [83]. Intranasal immunization with chimeric VLPs containing influenza HA antigen and GPI-CCL28 was shown to induce long-lasting mucosal immunity against H3N2 virus infection [84]. GPI-anchored CCL-28 chemokine co-expressed on the surface of influenza HA VLPs was shown to be effective in reducing lung viral titers after virus challenge in vaccinated mice.…”

Influenza Management Prospects of Passive Immunotherapy

“…Also, a GPI-anchored CCL-28 that was incorporated into the VLPs boosted IgA secreting cell migration, which increased murine mucosal immunity to both drifted and homologous influenza A (H3N2) viruses, as well as the longevity of protection. (41). VLPs thus provide a platform for improved formulation of multivalent (containing heterologous epitopes) influenza vaccine.…”