A measles and rubella vaccine microneedle patch in The Gambia: a phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial

Abstract

Background: Microneedle patches (MNPs) have been ranked as the highest global priority innovation for overcoming immunisation barriers in low-income and middle-income countries. This trial aimed to provide the first data on the tolerability, safety, and immunogenicity of a measles and rubella vaccine (MRV)-MNP in children.

Methods: This single-centre, phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial was conducted in The Gambia. To be eligible, all participants had to be healthy according to prespecified criteria, aged 18-40 years for the adult cohort, 15-18 months for toddlers, or 9-10 months for infants, and to be available for visits throughout the follow-up period. The three age cohorts were randomly assigned in a 2:1 ratio (adults) or 1:1 ratio (toddlers and infants) to receive either an MRV-MNP (Micron Biomedical, Atlanta, GA, USA) and a placebo (0·9% sodium chloride) subcutaneous injection, or a placebo-MNP and an MRV subcutaneous injection (MRV-SC; Serum Institute of India, Pune, India). Unmasked staff ransomly assigned the participants using an online application, and they prepared visually identical preparations of the MRV-MNP or placebo-MNP and MRV-SC or placebo-SC, but were not involved in collecting endpoint data. Staff administering the study interventions, participants, parents, and study staff assessing trial endpoints were masked to treatment allocation. The safety population consists of all vaccinated participants, and analysis was conducted according to route of MRV administration, irrespective of subsequent protocol deviations. The immunogenicity population consisted of all vaccinated participants who had a baseline and day 42 visit result available, and who had no protocol deviations considered to substantially affect the immunogenicity endpoints. Solicited local and systemic adverse events were collected for 14 days following vaccination. Unsolicited adverse events were collected to day 180. Age de-escalation between cohorts was based on the review of the safety data to day 14 by an independent data monitoring committee. Serum neutralising antibodies to measles and rubella were measured at baseline, day 42, and day 180. Analysis was descriptive and included safety events, seroprotection and seroconversion rates, and geometric mean antibody concentrations. The trial was registered with the Pan African Clinical Trials Registry PACTR202008836432905, and is complete.

Findings: Recruitment took place between May 18, 2021, and May 27, 2022. 45 adults, 120 toddlers, and 120 infants were randomly allocated and vaccinated. There were no safety concerns in the first 14 days following vaccination in either adults or toddlers, and age de-escalation proceeded accordingly. In infants, 93% (52/56; 95% CI 83·0-97·2) seroconverted to measles and 100% (58/58; 93·8-100) seroconverted to rubella following MRV-MNP administration, while 90% (52/58; 79·2-95·2) and 100% (59/59; 93·9-100) seroconverted to measles and rubella respectively, following MRV-SC. Induration at the MRV-MNP application site was the most frequent local reaction occurring in 46 (77%) of 60 toddlers and 39 (65%) of 60 infants. Related unsolicited adverse events, most commonly discolouration at the application site, were reported in 35 (58%) of 60 toddlers and 57 (95%) of 60 infants that had received the MRV-MNP. All local reactions were mild. There were no related severe or serious adverse events.

Interpretation: The safety and immunogenicity data support the accelerated development of the MRV-MNP.

Funding: Bill & Melinda Gates Foundation.

Figure 1

Trial profile—toddler and infant cohorts (A) Toddler cohort (B) Infant cohort. MNP=microneedle patch. MRV=measles and rubella vaccine. SC=subcutaneous. *Defined as weight-for-length Z score of <2 SDs below the mean. †In the toddler MRV-MNP group the baseline immunogenicity sample was analysed for the toddler who received a non-study vaccine between baseline and day 42, thus 60 baseline sample results were available. ‡One infant in the MRV-MNP group and one infant in the MRV-SC group were withdrawn between baseline and day 42. The baseline samples for these two infants were not analysed, hence 59 infants were included in the immunogenicity population at baseline as well as day 42.

Figure 2

Local solicited adverse events—toddler and infant cohorts (A) Toddler cohort (B) Infant cohort. Numbers represent the absolute number of participants, from among the 60 in each randomisation group and cohort, affected on each day. All local reactions were mild in severity. In addition, one toddler had mild tenderness on day 8 following MRV-MNP and one toddler had mild tenderness on day 1 following placebo-MNP (data not shown graphically). MNP=microneedle patch. MRV=measles and rubella vaccine. SC=subcutaneous.

Figure 3

Unsolicited adverse events—toddler and infant cohorts (A) Toddler cohort (B) Infant cohort. Incidence or incidence difference and 95% CIs are shown. Only events which occurred in at least three participants in a given age cohort are included in the figure. MNP=microneedle patch. MRV=measles and rubella vaccine. SC=subcutaneous. *Percentage prevalence in MRV-MNP group minus percentage prevalence in placebo-MNP group. †Preferred term based on the Medical Dictionary for Regulatory Affairs.

Figure 4

Serum neutralising antibody seroprotection levels, geometric mean antibody concentrations, and reverse cumulative distribution curves—toddler and infant cohorts Toddler cohort (A) and infant cohort (B) measles and rubella serum neutralising antibody seroprotection rates (solid bars) and 95% CIs. Seroprotection rates are defined as the percentage of evaluable participants with an antibody concentration higher than 200 mIU/mL for measles and higher than 10 IU/mL for rubella. Toddler cohort (C) and infant cohort (D) measles and rubella serum neutralising antibody baseline and day 42 reverse cumulative distributions curves. MNP=microneedle patch. MRV=measles and rubella vaccine. SC=subcutaneous. IU=international unit. *Measles geometric mean concentrations are measured in mIU/mL. Rubella geometric mean concentrations are reported in IU/mL