Microneedle patch delivery of replication-inducible monkeypox vaccine

ABSTRACT Monkeypox virus (MPXV) was declared a global health emergency of international concern with over 96,000 cases globally in 117 countries. Various nations, including the USA, UK, and Canada, have implemented a "ring vaccination" strategy to curb MPXV spread, a selective vaccination approach successful in containing smallpox and Ebola outbreaks. The Centers for Disease Control and Prevention (CDC) recommends vaccination for individuals at high risk of MPXV infection. However, there is currently no vaccine specifically developed against MPXV. Smallpox vaccines, assumed to be 85% effective and providing cross-protective immunity, are recommended by the WHO and CDC. Despite minimal testing against MPXV, these vaccines, including JYNNEOS (Imvanex or Imvamune) and ACAM2000, have been applied to prevent MPXV infection. JYNNEOS, a live non-replicating virus vaccine, is administered in two injections over four weeks, while ACAM2000, a live replication-competent virus preparation, is given by pricking the skin surface. Both vaccines have side effects, with JYNNEOS causing mild reactions like headache, fatigue, nausea, and injection site reactions. ACAM2000, on the other hand, presents more adverse complications, including fever, rash, lymph node swelling, and serious concerns such as high rates of myocarditis and pericarditis. It is considered unsafe for specific populations, such as pregnant women, infants, immunocompromised individuals, or those living with HIV. JYNNEOS stands out for its lower reactogenicity compared to traditional smallpox vaccines. To address existing concerns and limitations, we propose testing a novel MPXV vaccine based on a replication-inducible ACAM2000 vaccine. Through genetic engineering, we have generated ACAM2000 live vaccine strain Tet-On replication-inducible in the presence of tetracyclines (DOX), hypothesizing that this modification will retain comparable immunogenicity of ACAM2000 with an enhanced safety profile. To localize replication at the immunization site, we propose delivering the replication-inducible vaccine and DOX intracutaneously using our microneedle array (MNA) delivery patch platform. Our aims are to a) develop a tetracycline-dependent replication-inducible MPXV vaccine, b) compound the vaccine and tetracyclines into MNA delivery patches, c) assess immunogenicity and safety in mouse and non-human primate models, and d) evaluate the selected vaccine in SIV immunocompromised non-human primates.