The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial

Abstract

Background Microneedle patches provide an alternative to conventional needle-and-syringe immunization, and potentially offer improved immunogenicity, simplicity, cost-effectiveness, acceptability and safety. We describe safety, immunogenicity and acceptability of the first-in-human study on single, dissolvable microneedle patch vaccination against influenza. Methods The TIV-MNP 2015 study was a phase 1, partially blinded, placebo-controlled, randomized clinical trial conducted at Emory University that enrolled non-pregnant, immunocompetent adults (age 18–49 years) from Atlanta (USA) and naïve to 2014–2015 influenza vaccine. Participants were equally randomized among four groups and received a single dose of inactivated influenza vaccine 1) by microneedle patch or 2) by intramuscular injection, or received 3) placebo by microneedle patch, all administered by an unblinded healthcare worker; or received 4) inactivated influenza vaccine by microneedle patch self-administered by study participants. Primary safety outcomes were reactogenicity, grade 3 adverse events and serious adverse events within 8, 28 and 180 days and secondary safety outcomes were new-onset chronic illnesses within 180 days and unsolicited adverse events within 28 days all analyzed by intention to treat. Secondary immunogenicity outcomes were antibody titers at day 28 as well as seroconversion and seroprotection rates all determined by hemagglutination inhibition antibody. The trial is completed and registered with ClinicalTrials.gov, NCT02438423. Findings Twenty-five participants per group were enrolled between June 23 and September 25, 2015. There were no related serious adverse events, no related grade 3 or higher adverse events and no new-onset chronic illnesses. Overall incidence of solicited and unsolicited events was similar among vaccinated groups. Reactogenicity was mild, transient and most commonly reported as tenderness at 60% (95% CI, 39– 79%) and pain at 44% (95% CI, 24–65%) after intramuscular injection and tenderness at 66% (95% CI, 51–79%), erythema at 40% (95% CI, 26–55%) and pruritus at 82% (95% CI, 69–91%) after vaccination by microneedle patch application The geometric mean titers were comparable at day 28, between the microneedle patch administered by healthcare worker and the intramuscular route with values of 1197 (95% CI, 855– 1675) and 997 (95% CI, 703–1415) (p=0.5), respectively, for the H1N1 strain; 287 (95% CI, 192–430) and 223 (95% CI, 160–312) (p=0.4), respectively, for the H3N2 strain and 126 (95% CI, 86–184) and 94 (95% CI, 73–122) (p=0.06), respectively, for the B strain. Similar GMT titers were observed in participants who self-administered the microneedle patch. The seroconversion rates were significantly higher at day 28 after microneedle patch vaccination compared to placebo and were comparable to intramuscular injection. Interpretation Use of dissolvable microneedle patches for influenza vaccination was well-tolerated and generated robust antibody responses. Funding National Institutes of Health.

Polymeric microneedles for transdermal protein delivery

“…Most studies utilize commercial available hollow MN infusion systems, and a few cases have investigated the effectiveness of using polymeric MN for protein drug delivery. For example, a Phase I study investigating the safety and immunogenicity of the dissolvable MN for the delivery of H1N1, H3N2 and B seasonal influenza virus vaccine strains has been published (ClinicalTrials.gov identifier: NCT02438423) [185]. A coated transdermal MN delivery system has been completed in phase II clinical study for the systemic delivery of a parathyroid hormone-related protein (ClinicalTrials.gov identifier: NCT01674621).…”

Improving Vaccine and Immunotherapy Design Using Biomaterials

“…A new first-in-human trial using dissolvable microneedle patches for influenza vaccination revealed the vaccines were stable for more than 1 year and generated titers similar to those of existing injectable vaccines even when self-administered by recipients [43– 45]. Such advances could transform the way vaccines are delivered, as well as the accessibility of effective formulations in developing regions.…”

An Industry update: the Latest Developments in Therapeutic Delivery

“…Although studies have shown that solid microneedles future science group www.futuremedicine.com can enhance the permeability of drugs for up to 5 h, there is a lack of data on how quickly the pores created by the device will close which could increase the risk of transfer of infection through the skin. However, research published by a research team at Emory University, Atlanta, from a clinical trial looking at the use of dissolvable microneedle patches for influenza vaccination showed the approach was well tolerated and generated effective antibody responses [15]. About 70% of patch recipients said that they preferred this approach over other methods of delivery, so it is highly likely that the concerns mentioned above will be addressed and microneedle devices will be seen in the market in the next few years.…”