James L. Goodson

Background: The Measles–Rubella Microarray Patch (MR-MAP) is an important technology that is expected to reduce coverage and equity gaps for measles-containing vaccines (MCVs), reach zero-dose children, and contribute to elimination of measles and rubella. MR-MAPs are anticipated to be easier to deploy programmatically and could be delivered by lesser-trained health workers, thereby increasing immunization coverage. The most advanced MR-MAP has reached clinical proof-of-concept through a Phase I/II trial in the target population of infants and young children. The World Health Organization (WHO) and partners have developed the Phase III clinical trial framework for MR-MAPs presented in this article. Objectives and Methods: The purpose of such framework is to inform the considerations, design and approach for the pivotal clinical trial design, while considering the anticipated data requirements to inform regulatory approval, WHO prequalification, and policy decision. Results: The proposed Phase III trial would compare the immunogenicity and safety of an MR-MAP with MR vaccine delivered subcutaneously in 9- to 10-month-old infants. An analysis of non-inferiority (NI) of immunogenicity would occur six weeks after the first dose. Should regulatory agencies or policy makers require, a proportion of infants could receive a second dose of either the same or alternate MR vaccine presentation six months after the first dose, with those children returning six weeks after the second dose for a descriptive assessment of immunogenicity, and then followed up six months after the second dose for evaluation of safety and immunogenicity. It is anticipated that this proposed pivotal Phase III trial framework would generate the required clinical data for regulatory licensure and WHO prequalification (PQ) of MR-MAPs. However, the trial design would need to be reviewed and confirmed by a national regulatory authority (NRA) that will assess the product for regulatory licensure and the WHO PQ team. Additional research will likely be required to generate data on concomitant vaccine delivery, the safety and immunogenicity of MR-MAPs in other age groups such as children 1–5 years and infants younger than 9 months of age, and the impact of MR-MAPs on coverage and equity. Such studies could be conducted during or after clinical MR-MAP development.

Introduction: The WHO Measles and Rubella Strategic Framework 2021–2030 within the Immunization Agenda 2030 includes both measles and rubella elimination goals and provides guidance to countries for planning and implementing the measles and rubella elimination strategies. Namibia has been implementing measles elimination strategies since 1997. Methods: We reviewed and described the implementation of measles and rubella elimination strategies and the programmatic and epidemiological situation in Namibia during 2000–2023. Namibia introduced a rubella-containing vaccine (RCV) in 2016 as a combined measles–rubella (MR) vaccine using a MR catch-up campaign, targeting a wide age range based on detailed analysis and triangulation of multiple key data sources including MR vaccination coverage, MR case-based surveillance, detailed measles outbreak investigations, and serosurveys. Results: In 2020, estimated MCV1 coverage in Namibia reached 90% and has been sustained at 91% in 2021 and 2022. MCV2 was introduced in 2016, and the estimated MCV2 coverage has steadily increased to 79% in 2022. Following the MCV2 introduction and the implementation of the wide age range MR catch-up campaign in 2016, annual measles and rubella incidence decreased substantially. During 2017–2023, the period following the implementation of the catch-up MR vaccination SIA in 2016, average annual measles incidence per million population in Namibia decreased by 97% from the average during 2010–2016. Similarly, the average annual rubella incidence decreased by 95% from 2010–2016 to 2017–2023. Discussion: Successful implementation of the 2016 wide age range campaign and maintaining high routine immunization coverage likely led to the significant reduction in measles and rubella incidence in Namibia. To sustain the reduction in measles and rubella incidence and attain the elimination targets, Namibia needs to attain and maintain high routine immunization coverage with both doses of the MR vaccine and implement timely and high-quality periodic MR follow-up SIAs. High-quality elimination-standard measles and rubella surveillance will help guide strategies and serve as the basis for the eventual verification of measles and rubella elimination in Namibia according to the WHO-recommended framework.

Measles is a highly contagious disease and remains a major cause of child mortality worldwide. While measles vaccine is highly effective, high levels of population immunity are needed to prevent outbreaks. Simple but accurate tools are needed to estimate the profile of population measles immunity by age to identify and fill immunity gaps caused by low levels of vaccination coverage. The measles immunity profile estimates and visualizes the percentage of each birth cohort immune or susceptible to measles based on measles vaccination coverage. Several tools that employed this approach have been developed in the past, including informal unpublished versions. However, these tools used varying assumptions and produced inconsistent results. We updated the measles population immunity profile methodology to standardize and better document the assumptions and methods; provide timely estimates of measles population immunity; and facilitate prompt actions to close immunity gaps and prevent outbreaks. We recommend assuming that the second dose of the measles-containing vaccine (MCV2) and doses given during supplementary immunization activities (SIAs) first reach children who have been previously vaccinated against measles, so that previously unvaccinated children are reached only when the coverage of MCV2 or SIA is higher than the coverage achieved by all previous measles vaccination opportunities. This updated method provides a conservative estimate of immunization program impact to assess measles outbreak risk and to facilitate early planning of timely preventive SIAs to close population immunity gaps.

Efforts to control and eliminate measles and rubella are aided by high-quality surveillance data—supported by laboratory confirmation—to guide decision-making on routine immunization strategies and locations for conducting preventive supplementary immunization activities (SIAs) and outbreak response. Important developments in rapid diagnostic tests (RDTs) for measles and rubella present new opportunities for the global measles and rubella surveillance program to greatly improve the ability to rapidly detect and respond to outbreaks. Here, we review the status of RDTs for measles and rubella Immunoglobulin M (IgM) testing, as well as ongoing questions and challenges regarding the operational use and deployment of RDTs as part of global measles and rubella surveillance. Efforts to develop IgM RDTs that can be produced at scale are underway. Once validated RDTs are available, clear information on the benefits, challenges, and costs of their implementation will be critical for shaping deployment guidance and informing country plans for sustainably deploying such tests. The wide availability of RDTs could provide new programmatic options for measles and rubella elimination efforts, potentially enabling improvements and flexibility for testing, surveillance, and vaccination.

Mongolia experienced a nationwide measles outbreak during 1 March 2015–31 December 2016, with 49,077 cases reported to the WHO; many were among vaccinated young adults, suggesting a possible role of vaccine failure. Advanced laboratory methods, coupled with detailed epidemiological investigations, can help classify cases as vaccine failure, failure to vaccinate, or both. In this report, we conducted a study of cases to identify risk factors for breakthrough infection for a subset of laboratory-confirmed measles cases. Of the 193 cases analyzed, only 19 (9.8%) reported measles vaccination history, and 170 (88%) were uncertain. Measles-specific IgG avidity testing classified 120 (62%) cases as low IgG avidity, indicating no prior exposure to measles. Ten of these cases with low IgG avidity had a history of measles vaccination, indicating primary vaccine failure. Overall, sixty cases (31%) had high IgG avidity, indicating breakthrough infection after prior exposure to measles antigen through vaccination or natural infection, but the IgG avidity results were highly age-dependent. This study found that among young children aged 9 months–5 years, breakthrough infection was rare (4/82, 5%); however, among young adults aged 15–25 years, breakthrough infection due to secondary vaccine failure (SVF) occurred on a large scale during this outbreak, accounting for the majority of cases (42/69 cases, 61%). The study found that large-scale secondary vaccine failure occurred in Mongolia, which highlights the potential for sustained outbreaks in post-elimination settings due to “hidden” cohorts of young adults who may have experienced waning immunity. This phenomenon may have implications for the sustainability of measles elimination in countries that remain vulnerable to the importation of the virus from areas where it is still endemic. Until global measles elimination is achieved, enhanced surveillance and preparedness for future outbreaks in post- or peri-elimination countries may be required.

Background: New strategies to increase measles and rubella vaccine coverage, particularly in low- and middle-income countries, are needed if elimination goals are to be achieved. With this regard, measles and rubella vaccine microneedle patches (MRV-MNP), in which the vaccine is embedded in dissolving microneedles, offer several potential advantages over subcutaneous delivery. These include ease of administration, increased thermostability, an absence of sharps waste, reduced overall costs and pain-free administration. This trial will provide the first clinical trial data on MRV-MNP use and the first clinical vaccine trial of MNP technology in children and infants. Methods: This is a phase 1/2, randomized, active-controlled, double-blind, double-dummy, age de-escalation trial. Based on the defined eligibility criteria for the trial, including screening laboratory investigations, 45 adults [18–40 years] followed by 120 toddlers [15–18 months] and 120 infants [9–10 months] will be enrolled in series. To allow double-blinding, participants will receive either the MRV-MNP and a placebo (0.9% sodium chloride) subcutaneous (SC) injection or a placebo MNP and the MRV by SC injection (MRV-SC). Local and systemic adverse event data will be collected for 14 days following study product administration. Safety laboratories will be repeated on day 7 and, in the adult cohort alone, on day 14. Unsolicited adverse events including serious adverse events will be collected until the final study visit for each participant on day 180. Measles and rubella serum neutralizing antibodies will be measured at baseline, on day 42 and on day 180. Cohort progression will be dependent on review of the unblinded safety data by an independent data monitoring committee. Discussion: This trial will provide the first clinical data on the use of a MNP to deliver the MRV and the first data on the use of MNPs in a paediatric population. It will guide future product development decisions for what may be a key technology for future measles and rubella elimination. Trial registration: Pan-African Clinical Trials Registry 202008836432905. ClinicalTrials.gov NCT04394689

Disease eradication and elimination programs drive innovations based on progress toward measurable objectives, evaluations of new strategies and methods, programmatic experiences, and lessons learned from the field. Following progress toward global measles elimination, reducing measles mortality, and increasing introductions of measles and rubella vaccines to national programs, the measles and rubella immunization program has faced setbacks in recent years. Currently available vaccine delivery methods have complicated logistics and drawbacks that create barriers to vaccination; innovations for easier, more efficient, and safer vaccine delivery are needed. Progress can be accelerated by new technologies like microarray patches (MAPs) that are now widely recognized as a potential new tool for enhancing global immunizations efforts. Clinical trials of measles-rubella vaccine MAPs have begun, and several other vaccine MAPs are in the pre-clinical development pathway. MAPs could significantly contribute to Immunization Agenda 2030 priorities, including reaching zero-dose children; increasing vaccine access, demand, coverage, and equity; and achieving measles and rubella elimination. With strong partnerships between public health agencies and biotechnology companies, translational novel vaccine delivery systems can be developed to help solve public health problems and achieve global health priorities.

The number of children in the Eastern Mediterranean Region receiving 2 doses of measles vaccine increased during 2013–2018, but vaccination coverage remains below levels (≥95%) that the World Health Organization recommend for measles elimination.

The recent setbacks in efforts to achieve measles elimination goals are alarming. To reverse the current trends, it is imperative that the global health community urgently intensify efforts and make resource commitments to implement evidence-based elimination strategies fully, including supporting research and innovations. The Immunization Agenda 2030: A Global Strategy to Leave No One Behind (IA2030) is the new global guidance document that builds on lessons learned and progress made toward the GVAP goals, includes research and innovation as a core strategic priority, and identifies measles as a