Efficient Delivery of Dengue Virus Subunit Vaccines to the Skin by Microprojection Arrays

Abstract

Dengue virus is the most important arbovirus impacting global human health, with an estimated 390 million infections annually, and over half the world’s population at risk of infection. While significant efforts have been made to develop effective vaccines to mitigate this threat, the task has proven extremely challenging, with new approaches continually being sought. The majority of protective, neutralizing antibodies induced during infection are targeted by the envelope (E) protein, making it an ideal candidate for a subunit vaccine approach. Using truncated, recombinant, secreted E proteins (sE) of all 4 dengue virus serotypes, we have assessed their immunogenicity and protective efficacy in mice, with or without Quil-A as an adjuvant, and delivered via micropatch array (MPA) to the skin in comparison with more traditional routes of immunization. The micropatch contains an ultra-high density array (21,000/cm2) of 110 μm microprojections. Mice received 3 doses of 1 μg (nanopatch, intradermal, subcutaneous, or intra muscular injection) or 10 μg (intradermal, subcutaneous, or intra muscular injection) of tetravalent sE spaced 4 weeks apart. When adjuvanted with Quil-A, tetravalent sE vaccination delivered via MPA resulted in earlier induction of virus-neutralizing IgG antibodies for all four serotypes when compared with all of the other vaccination routes. Using the infectious dengue virus AG129 mouse infectious dengue model, these neutralizing antibodies protected all mice from lethal dengue virus type 2 D220 challenge, with protected animals showing no signs of disease or circulating virus. If these results can be translated to humans, MPA-delivered sE represents a promising approach to dengue virus vaccination.

cGAMP/Saponin Adjuvant Combination Improves Protective Response to Influenza Vaccination by Microneedle Patch in an Aged Mouse Model

“…In the preliminary screening, we observed a small scab on the skin surface at the site of intradermal injections of vaccine formulated with 10 μg Quil-A. Thus, we kept the amount of Quil-A delivered with MNPs to 5 μg which is similar to 3 μg dose recently used to adjuvant tetravalent Demge sE in Nanopatch ( 42 ). The visual inspection of the MNP application sites did not reveal skin irritation or scabs.…”

A chimeric dengue virus vaccine candidate delivered by high density microarray patches protects against infection in mice

“…As such, the efficacy of the BinJV-based chimeras to protect against viral challenge in mouse models for Zika (ZIKV), West Nile (WNV) and yellow fever (YFV) viruses have already been established 12 – 14 . However, producing potent virus-neutralizing antibodies from vaccination with non-replicating vaccines can be challenging, and so we explored the use of the high-density microarray patch (HD-MAP) for vaccine delivery 15 – 17 .…”

Microarray patches enable the development of skin-targeted vaccines against COVID-19

“…Coated MAPs have been evaluated with several different vaccine types (e.g., live attenuated, viral vector, inactivated virus, subunit, DNA, and VLPs) for numerous viral infections, such as influenza, hepatitis B, rotavirus, RSV, Ebola, dengue, measles, polio, HIV, HPV, West Nile virus, chikungunya, HSV, and hepatitis C [ 270 , [275] , [276] , [277] , [278] , [279] , [280] , [281] , [282] , [283] , [284] , [285] , [286] , [287] , [288] , [289] , [290] , [291] , [292] , [293] , [294] , [295] , [296] , [297] , [298] , [299] , [300] , [301] , [302] , [303] ]. Vaccines delivered by coated MAPs have been mainly tested in mice, but there also have been a limited number of studies in rat, guinea pig, porcine, and non-human primate models [ 221 , 291 , 294 , 296 , 304 , 305 ].…”

“…To further improve the quality of MAP-based skin-targeted vaccination, several chemical and biological adjuvants (also known as immune-enhancers) have also been evaluated in pre-clinical studies [ 195 , 270 , 289 , 290 , 319 , 320 , 322 , [345] , [346] , [347] , [348] , [349] , [350] , [351] , [352] ]. For instance, one study investigated the effects of two different TLR agonists (imiquimod, a TLR7 agonist, and polyinosinic:polycytidylic acid (poly(I:C)), a TLR3 agonist) on humoral and cell-mediated immune responses in mice immunized with coated MAPs loaded with influenza antigen [ 351 ].…”