Evaluation of efficacy and safety of intradermal delivery of vaccines through microneedle(s) in human beings: a protocol for a systematic review
Authors: Bajwa Ishumeet Kaur , Kaur Navneet , Dsouza Jeanne M. , Mathew Joseph L. 
Published: August 2022

Abstract
Background
Microneedles are defined as micron-sized projections with an insertion length ranging from 20 to 1500 μm and an external diameter up to 300 μm. Medications administered through microneedles diffuse through the deeper layers of the skin, into the systemic circulation, with minimal stimulation of pain-sensitive nerve endings. The rich presence of dendritic cells in the dermis makes microneedle-based vaccine delivery an attractive option. This systematic review will evaluate the efficacy and safety of intradermal delivery of vaccines using microneedles, in human beings.

Methods
We will search the following databases for studies reporting the efficacy and/or safety of intradermal delivery of vaccines using microneedles: Epistemonikos and the Cochrane Library for systematic reviews and MEDLINE (through PubMed), EMBASE, Cochrane CENTRAL, LIVIVO, Web of Science, Scopus and CINAHL databases for primary studies. We will also search grey literature databases and hand search reference lists of relevant studies. We will include randomised and quasi-randomised trials in human beings (any age), using microneedles (any material, length or bore) to deliver vaccines intradermally, wherein outcomes reflecting efficacy, safety, pain responses, participant satisfaction or cost are reported. We will additionally include non-randomised observational studies for long-term safety outcomes that are not reported in trials. Eligibility for inclusion will be independently determined by two reviewers. The risk of bias of the included studies will be assessed using the Cochrane RoB2 Tool (for randomised trials) and Newcastle–Ottawa Scale (for other study designs). Data on efficacy and safety will be pooled through meta-analysis (where feasible). We will explore the heterogeneity amongst randomised trials, using the Higgins and Thompson I2 method. We will undertake sensitivity analysis to explore the impact of study quality and subgroup analysis based on the age of participants, length of microneedle and vaccine dosage. The GRADE approach will be used to estimate the confidence in the evidence.

Results
This is a protocol for a systematic review; hence, there are no results at this stage.

Discussion
The proposed systematic review will provide evidence on efficacy, safety, pain responses, participant acceptability and cost in human beings (adults and children) for vaccines administered through the intradermal route using microneedles. Since intradermal injections using microneedles are associated with less pain due to their short lengths and narrow bores, we anticipate that delivery of vaccine antigens using this method could be a safe, efficacious and less painful alternative compared with conventional injections using hypodermic needles. The evidence in this review will be useful for policymakers, vaccine manufacturers and healthcare providers to consider this approach for the vaccination of infants and children in routine immunisation programmes. Therefore, we plan to disseminate the review through a peer-reviewed journal publication and will also provide data that cannot be included in the published version to anyone upon reasonable request.

Systematic review registration
PROSPERO CRD42020213608