Enhancing vaccine immunogenicity through heterologous prime-boost regimen with multiple nasal boosting with liposomal TLR7 ligand.

OBJECTIVES

Despite the clinical efficacy of current intramuscular influenza vaccines in reducing the severity of seasonal infection, they exhibit limited induction of mucosal immunity, which is essential for preventing viral transmission. In addition, intranasal vaccination can induce superior mucosal immunity, enhancing clinical efficacy and reducing transmission, and its self-boosting potential may improve coverage in older adults and those with mobility limitations.

METHODS

We developed Lipo-1V270, a liposomal nanoparticle formulation of the synthetic TLR7 agonist 1V270 using 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol for mucosal vaccine delivery. In vitro immune stimulation and in vivo immunogenicity were evaluated using intramuscular and intranasal routes in mouse models, including a heterologous prime-boost regimen with inactivated influenza A virus [IIAV, A/California/04/2009 (H1N1)pdm09] adjuvanted monophosphoryl lipid A (MPLA) priming.

RESULTS

In vitro analysis showed that Lipo-1V270 exhibited attenuated innate immune potency compared to unformulated 1V270. However, in vivo co-administration of Lipo-1V270 with IIAV significantly enhanced antigen-specific IgG1 and IgG2a responses. Subsequently, intranasal boosting with Lipo-1V270, following intramuscular priming with IIAV adjuvanted with MPLA - a component included in FDA-approved vaccines - elicited robust influenza-hemagglutinin (HA)-specific mucosal IgA and IgG responses in nasal wash. This heterologous prime-boost regimen also induced strong splenic T-cell responses and HA-specific IgG and IgA antibodies in nasal wash without causing significant weight loss for 7 days post-boost in immunized mice.

CONCLUSIONS

Intranasal administration of Lipo-1V270 in a heterologous prime-boost vaccination regimen effectively enhances mucosal immunity against influenza virus infection, with an acceptable innate immune-mediated adverse effects profile. This strategy may be applicable to vaccines against other respiratory infectious diseases.