Cationic Lipid/DNA Complex-Adjuvanted Influenza A Virus Vaccination Induces Robust Cross-Protective Immunity

Abstract

Influenza A virus is a negative-strand segmented RNA virus in which antigenically distinct viral subtypes are defined by the hemagglutinin (HA) and neuraminidase (NA) major viral surface proteins. An ideal inactivated vaccine for influenza A virus would induce not only highly robust strain-specific humoral and T-cell immune responses but also cross-protective immunity in which an immune response to antigens from a particular viral subtype (e.g., H3N2) would protect against other viral subtypes (e.g., H1N1). Cross-protective immunity would help limit outbreaks from newly emerging antigenically novel strains. Here, we show in mice that the addition of cationic lipid/noncoding DNA complexes (CLDC) as adjuvant to whole inactivated influenza A virus vaccine induces significantly more robust adaptive immune responses both in quantity and quality than aluminum hydroxide (alum), which is currently the most widely used adjuvant in clinical human vaccination. CLDCadjuvanted vaccine induced higher total influenza virus-specific IgG, particularly for the IgG2a/c subclass. Higher levels of multicytokine-producing influenza virus-specific CD4 and CD8 T cells were induced by CLDC-adjuvanted vaccine than with alum-adjuvanted vaccine. Importantly, CLDC-adjuvanted vaccine provided significant cross-protection from either a sublethal or lethal influenza A viral challenge with a different subtype than that used for vaccination. This superior cross-protection afforded by the CLDC adjuvant required CD8 T-cell recognition of viral peptides presented by classical major histocompatibility complex class I proteins. Together, these results suggest that CLDC has particular promise for vaccine strategies in which T cells play an important role and may offer new opportunities for more effective control of human influenza epidemics and pandemics by inactivated influenza virus vaccine.

Liposomes as vaccine delivery systems: a review of the recent advances

“…An influenza A virus vaccine adjuvanted with CLDC or alum was tested by Hong and colleagues. CLDC induced more robust adaptive immune responses with higher levels of virus-specific IgG2a/c and CD4 + and CD8 + T cells plus cross protection from lethal viral challenges [Hong et al 2010]. In another influenza A vaccine study, Dong and colleagues showed that addition of CLDC (JVRS-100) to a H5N1 split vaccine induced higher virus-specific responses than adjuvant-free formulations.…”

A cationic liposome–DNA complexes adjuvant (JVRS-100) enhances the immunogenicity and cross-protective efficacy of pre-pandemic influenza A (H5N1) vaccine in ferrets

“…Furthermore, JVRS-100 adjuvanted inactivated influenza H1N1 vaccine provided significant cross-protection from heterosubtypic H3N2 challenges in mice (Hong et al, 2010). Both cellular and antibody-mediated immunity likely played a role in such cross-protection from antigenically distinct influenza viruses (Hong et al, 2010; Lay et al, 2009).…”

“…Furthermore, JVRS-100 adjuvanted inactivated influenza H1N1 vaccine provided significant cross-protection from heterosubtypic H3N2 challenges in mice (Hong et al, 2010). Both cellular and antibody-mediated immunity likely played a role in such cross-protection from antigenically distinct influenza viruses (Hong et al, 2010; Lay et al, 2009). Occasionally, seasonal influenza vaccine antigens are antigenically drifted from circulating viruses which may in some cases lead to lower vaccine effectiveness (Flannery et al, 2015; Klimov et al, 1999; McNeil et al, 2015).…”

“…CLDC formed adjuvants such as JVRS-100 were particularly effective in eliciting strong T cell responses, even at low antigen doses (Hong et al, 2010; Lay et al, 2009; Zaks et al, 2006). The CD4 + and CD8 + T cells elicited by JVRS-100 adjuvanted influenza vaccine secrete multiple cytokines with a poly-functional phenotype in non-human primates (Lay et al, 2009).…”

“…It has been demonstrated that the addition of CLDC to influenza vaccines can induce robust CD4 + Th1 response and predominant IgG2a/c antibody responses in mice (Chang et al, 2009; Dong et al, 2012; Hong et al, 2010; Lay et al, 2009). Most noteworthy, enhanced multicytokine-producing influenza virus-specific CD4 + and CD8 + T-cell responses were demonstrated in mice and non-human primates, and enhanced cross-protection were demonstrated in mice with addition of CLDC to influenza vaccines (Hong et al, 2010; Lay et al, 2009). In a previous study, we demonstrated that a JVRS-100 adjuvanted clade 1 H5N1 split vaccine showed significantly improved immunogenicity and antigen-sparing effect, stimulated enhanced cross-clade antibody and CD4 + T-cell responses, and provided significant cross-clade protection in mice (Dong et al, 2012).…”