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Microneedle array patch (MAP) technology is a promising new delivery technology for vaccines and pharmaceuticals, yet due to several differing and novel production methods, barriers to full-scale manufacturing exist. PATH conducted a manufacturing readiness assessment and follow-up interviews to identify both the current manufacturing readiness of the industry as well as how readiness varies by developer type and MAP type. Follow-up interviews identified barriers the industry faces in reaching full manufacturing readiness, including the perceived regulatory and investment risk of manufacturing MAPs at scale due to quality requirements and control methods, uncertain sterility requirements, lack of standard production methods (especially around dissolvable MAP drying methods), and the lack of available contract manufacturing organizations with MAP manufacturing capabilities. A Regulatory Working Group has been established to identify and address critical quality issues specific to MAP manufacturing with the aim of providing developers insight into what will be expected for MAP product approvals. Standardizing MAP production equipment and automatic, visual quality control could reduce the overall investment risk to developers and contract manufacturing organizations in pursuing pilot-scale manufacturing capabilities and ultimately lower barriers to the scale-up of full medical MAP product lines. Graphical abstract

Purpose Whilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectable nanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user. To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA and CAB LA via self-disabling dissolving microarray patches (MAPs). Methods Dissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, with various nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robust and were capable of penetrating ex vivo skin with intradermal ARV deposition. Results In a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profiles, with therapeutically relevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study, repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout the duration of the study. Conclusions These results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPV and CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one that is capable of being painlessly administered in the comfort of the patient’s own home on a biweekly or less frequent basis. Graphical abstract

BackgroundProgress towards measles and rubella (MR) elimination has stagnated as countries are unable to reach the required 95% vaccine coverage. Microarray patches (MAPs) are anticipated to offer significant programmatic advantages to needle and syringe (N/S) presentation and increase MR vaccination coverage. A demand forecast analysis of the programmatic doses required (PDR) could accelerate MR-MAP development by informing the size and return of the investment required to manufacture MAPs.MethodsUnconstrained global MR-MAP demand for 2030-2040 was estimated for three scenarios, for groups of countries with similar characteristics (archetypes), and four types of uses of MR-MAPs (use cases). The base scenario 1 assumed that MR-MAPs would replace a share of MR doses delivered by N/S, and that MAPs can reach a proportion of previously unimmunised populations. Scenario 2 assumed that MR-MAPs would be piloted in selected countries in each region of the World Health Organization (WHO); and scenario 3 explored introduction of MR-MAPs earlier in countries with the lowest measles vaccine coverage and highest MR disease burden.ResultsFor the base scenario (1), the estimated global PDR for MR-MAPs was forecasted at 30 million doses in 2030 and increased to 220 million doses by 2040. Compared to scenario 1, scenario 2 resulted in an overall decrease in PDR of 18%, and scenario 3 resulted in a 21% increase in PDR between 2030-2040.ConclusionsSignificant demand is expected for MR-MAPs between 2030-2040, however, efforts are required to address remaining data quality, uncertainties and gaps that underpin the assumptions in this analysis.Key pointsthe delivery of measles and rubella vaccines with microarray patches (MR-MAPs) could disrupt the immunization landscape. We estimated the demand for MR-MAPs between 2030-2040 at 4.05 billion doses. This analysis will inform the size of investment required to manufacture MR-MAPs.

Whilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectable nanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user. To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA and CAB LA via self-disabling dissolving microarray patches (MAPs).Dissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, with various nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robust and were capable of penetrating ex vivo skin with intradermal ARV deposition.In a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profiles, with therapeutically relevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study, repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout the duration of the study.These results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPV and CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one that is capable of being painlessly administered in the comfort of the patient's own home on a biweekly or less frequent basis.

Highlights • A compelling public health need based on evidence is the foundation for product innovation. • Reaching the unreached with product innovations will require substantial investment. • Aligned partnership and sustained resources accelerates innovation development. • Strategies that de-risk investment by developers incentivizes development and uptake. • Overcoming barriers to innovation needs integrated, strategic stakeholder collaboration., Vaccine-product innovations that address barriers to immunization are urgently needed to achieve equitable vaccine coverage, as articulated in the new Immunization Agenda 2030 and the Gavi 5.0 strategy. In 2020, the Vaccine Innovation Prioritisation Strategy (VIPS) prioritized three innovations, namely microarray patches (MAPs), heat-stable and controlled-temperature chain (CTC) enabled liquid vaccine formulations and barcodes on primary packaging. These innovations were prioritized based on the priority immunization barriers that they may help overcome in resource constrained contexts, as well as by considering their potential impact on health, coverage and equity, safety, economic costs and their technical readiness and commercial feasibility. VIPS is now working to accelerate the development and lay the foundation for future uptake of the three priority vaccine-product innovations, with the long term-goal to ensure equitable vaccine coverage and increased impact of vaccines in low- and middle- income countries. To inform our strategic planning, we analyzed four commercially available vaccine product-innovations and conducted interviews with individuals from 17 immunization organizations, and/or independent immunization experts. The findings are synthesized into an ‘innovation conundrum’ that describes the challenges encountered in developing vaccine-product innovations and a vaccine-product innovation ‘theory of change’, which highlights actions that should be undertaken in parallel to product development to incentivize sustainable investment and prepare the pathway for uptake and impact.

Measles and rubella microarray patches (MR-MAPs) are critical in achieving measles and rubella eradication, a goal highly unlikely to meet with current vaccines presentations. With low commercial incentive to MAP developers, limited and uncertain funding, the need for investment in a novel manufacturing facility, and remaining questions about the source of antigen, product demand, and regulatory pathway, MR-MAPs are unlikely to be prequalified by WHO and ready for use before 2033. This article describes the current progress of MR-MAPs, highlights challenges and opportunities pertinent to MR-MAPs manufacturing, regulatory approval, creating demand, and timelines to licensure. It also describes activities that are being undertaken by multiple partners to incentivise investment in and accelerate the development of MR-MAPs.

Microarray patch (MAP) technology is a promising new delivery technology for vaccines and pharmaceuticals. Yet due to several differing and novel production methods, barriers to full-scale manufacturing exist. PATH conducted a manufacturing readiness assessment and follow-up interviews to identify both the current manufacturing readiness of the industry as well as how readiness varies by developer type and MAP type. Follow-up interviews identified barriers the industry faces in reaching full manufacturing readiness, including the perceived regulatory and investment risk of manufacturing MAPs at scale due to quality requirements and control methods, uncertain sterility requirements, lack of standard production methods (especially around dissolvable MAP drying methods), and the lack of available contract manufacturing organizations with MAP manufacturing capabilities. A Regulatory Working Group has been established to identify and address critical quality issues specific to MAP manufacturing with the aim of providing developers insight into what will be expected for MAP product approvals. Standardizing MAP production equipment and automatic, visual quality control could reduce the overall risk to developers and contract manufacturing organizations in pursuing pilot-scale manufacturing capabilities and ultimately lower barriers to the scale-up of full medical MAP product lines.

Microarray patches (MAPs), also referred to as microneedle patches, are a novel methodology that have the potential to overcome barriers to vaccine delivery in low- and middle-income countries (LMICs), and transform the way that vaccines are delivered within immunization programs. The World Health Organization’s Initiative for Vaccine Research and its partners are working to understand how MAPs could ease vaccine delivery and increase equitable access to vaccines in LMICs. Global stakeholders have been engaged to evaluate technical, economic, and programmatic challenges; to validate assumptions where possible; and to propose areas of focus to facilitate future vaccine-MAP product development. This report summarizes those learnings.

In 2016, the World Health Organization (WHO) announced a global shortage of inactivated poliovirus vaccine that was expected to last until 2020 at least. In response, WHO's Strategic Advisory Group of Experts on Immunization recommended that countries consider a strategic shift to fractional-dose inactivated poliovirus vaccine, which involves a new dosing schedule (i.e. administered at 6 and 14 weeks of age) and has a different mode of delivery than full-dose inactivated poliovirus vaccine (i.e. intradermal rather than intramuscular). Introduction of fractional-dosing requires careful planning and management to ensure adequate vaccine supplies, to prevent wastage, to provide training for health workers, and to ensure accurate record-keeping. In early 2016, given the global vaccine shortage and a limited supply from domestic manufacturers, India's Expert Advisory Group on polio recommended the staggered introduction of fractional-dosing. India was the first country to introduce fractional-dose inactivated poliovirus vaccine into routine immunization, initially in eight states in 2016. Following a rapid assessment of its initial implementation, fractional-dosing was extended and, by June 2017, all Indian states were covered. Here we summarize India's experience with the introduction, discuss the challenges faced and the strategies used to address them, and report on the outcomes achieved. We also describe the lessons learnt, especially managing vaccine supplies and wastage, monitoring and supervision, and training needs. As the use of fractional-dose inactivated poliovirus vaccine is dose-sparing and reduces the cost of the immunization programme, it will remain an important part of India's long-term strategy for polio vaccination.En 2016, l’Organisation mondiale de la Santé (OMS) a annoncé une pénurie mondiale du vaccin antipoliomyélitique inactivé, prévue pour durer jusqu'à 2020 au minimum. Face à cette situation, le Groupe stratégique consultatif d’experts sur la vaccination a recommandé aux pays d'envisager un changement de stratégie afin de privilégier l’utilisation du vaccin antipoliomyélitique inactivé en doses fractionnées, ce qui implique un nouveau calendrier de vaccination (administration du vaccin à l'âge de 6 et de 14 semaines) et un mode d’administration différent de celui du vaccin antipoliomyélitique inactivé en dose complète (par voie intradermique et non pas par voie intramusculaire). L’introduction d'une vaccination en doses fractionnées exige de la rigueur en matière de planification et de gestion, afin de garantir des stocks de vaccins suffisants, d’éviter les gaspillages, de former les agents de santé et d’assurer une tenue précise des dossiers médicaux. Début 2016, du fait de la pénurie mondiale du vaccin et d’un approvisionnement limité par les fabricants nationaux, le Groupe consultatif d’experts de l’Inde sur l’éradication de la poliomyélite a recommandé d’introduire progressivement les doses fractionnées. Si bien que l’Inde est le premier pays à avoir introduit le vaccin antipoliomyélitique inactivé en doses fractionnées dans le calendrier de vaccination systématique, d’abord dans huit États en 2016. Après une rapide évaluation de cette mise en œuvre initiale, l’utilisation des doses fractionnées s’est étendue, pour finalement être effective dans tous les États indiens en juin 2017. Dans cet article, nous récapitulons l’expérience de l’Inde à ce sujet, nous évoquons les défis rencontrés et les stratégies employées pour les surmonter ainsi que les résultats obtenus. Nous décrivons également les enseignements tirés de cette expérience, notamment en matière de gestion des stocks de vaccins, de prévention des gaspillages, de suivi et de supervision, mais aussi concernant les besoins en formation. Étant donné que l'utilisation de doses fractionnées du vaccin antipoliomyélitique inactivé permet d’économiser des doses vaccinales et de réduire le coût du programme de vaccination, cela restera un élément essentiel dans la stratégie à long terme de l’Inde en matière de vaccination contre la poliomyélite.En 2016, la Organización Mundial de la Salud (OMS) anunció una escasez mundial de vacunas inactivadas del poliovirus que se esperaba que se prolongara al menos hasta 2020. En respuesta, el Grupo de asesoramiento estratégico de expertos en inmunización de la OMS recomendó que los países consideraran la posibilidad de un cambio estratégico hacia una vacuna inactivada del poliovirus de dosis fraccionada, que incluye un nuevo esquema de dosificación (es decir, administrada a las seis y a las catorce semanas de edad) y que tiene un modo de administración diferente al de la vacuna inactivada del poliovirus de dosis completa (es decir, intradérmica y no intramuscular). La introducción de la dosis fraccionada requiere una planificación y una gestión minuciosas para garantizar el suministro adecuado de las vacunas, evitar el despilfarro, formar a los trabajadores sanitarios y garantizar el mantenimiento de registros precisos. A principios de 2016, dada la escasez mundial de vacunas y el limitado suministro de los fabricantes nacionales, el Grupo de asesoramiento experto sobre la polio de la India recomendó la introducción escalonada de dosis fraccionadas. La India fue el primer país en introducir la vacuna inactivada del poliovirus de dosis fraccionada en la inmunización sistemática, inicialmente en ocho estados en 2016. Tras una rápida evaluación de la aplicación inicial, se amplió la dosificación fraccionada y, para junio de 2017, se cubrieron todos los estados de la India. En este documento se resume la experiencia de la India con la introducción, se examinan los problemas encontrados y las estrategias utilizadas para resolverlos y se informa sobre los resultados alcanzados. También se describen las lecciones aprendidas, especialmente en lo que se refiere a la gestión de los suministros de vacunas y el desperdicio, el seguimiento y la supervisión, y las necesidades de formación. Dado que el uso de la vacuna inactivada del poliovirus de dosis fraccionada ahorra dosis y reduce el coste del programa de inmunización, seguirá siendo una parte importante de la estrategia a largo plazo de la India para la vacunación contra la polio.في عام 2016، أعلنت منظمة الصحة العالمية (2016 年，世界卫生组织 (WHO) 宣布灭活脊髓灰质炎疫苗面临全球范围内的短缺，此情况预计将至少持续至 2020 年。为了应对此情况，世卫组织免疫接种战略咨询专家组建议各国将分剂量灭活脊髓灰质炎疫苗的战略性转变纳入考量，这涉及新的给药方案（即在 6 和 14 周时给药）并具有不同于全剂量灭活脊髓灰质炎疫苗的注射方式（即皮内注射而非肌肉注射）。引入分剂量注射方式需要细致规划和管理，从而保证疫苗供应充足、避免损耗，对医务工作者进行培训，确保精准记录。2016 年初，鉴于全球疫苗短缺以及国内疫苗制造商供应不足，印度脊髓灰质炎专家咨询小组建议错开分剂量灭活脊髓灰质炎疫苗的接种时间。印度是第一个将分剂量灭活脊髓灰质炎疫苗纳入常规免疫接种的国家，并于 2016 年开始在 8 个邦实施接种。对首次实施分剂量疫苗接种进行快速评估后，印度迅速扩大了分剂量灭活脊髓灰质炎疫苗的接种范围。截至 2017 年 6 月，印度各邦均已覆盖。本文归纳总结了印度在接种分剂量疫苗方面的经验，对其面临的挑战以及应对策略予以讨论并汇报了所取得的成果。我们还对以往的经验教训进行了回顾总结，尤其是在疫苗的供应、损耗管理方面、监测与监督方面以及培训需求方面。由于分剂量灭活脊髓灰质炎疫苗的使用可以节省剂量并降低免疫计划的成本，因此它将成为印度脊髓灰质炎疫苗接种长期战略计划的重要组成部分。.В 2016 году Всемирная организация здравоохранения (ВОЗ) объявила о глобальной нехватке инактивированной полиовакцины, которая может продлиться как минимум до 2020 года. В ответ на это Стратегическая консультативная группа экспертов ВОЗ по иммунизации рекомендовала странам рассмотреть стратегию перехода на частичную дозировку инактивированной полиовакцины, что подразумевает новый режим дозирования (в 6 и 14 недель после рождения) и иной способ введения (внутрикожно, а не внутримышечно, как это делалось в случае введения полноценной дозы инактивированной полиовакцины). Переход на частичную дозировку требует тщательного планирования и отслеживания, чтобы обеспечить достаточные поставки вакцины, предотвратить потери, обучить медицинских работников, а также гарантировать точное ведение документации. В начале 2016 года, ввиду глобальной нехватки вакцины и ограниченных поставок от отечественных производителей, Консультативная группа экспертов Индии по полиомиелиту рекомендовала поэтапный переход на частичную дозировку. Индия стала первой страной, внедрившей инактивированную полиовакцину в частичной дозировке в график плановых мероприятий по иммунизации изначально в восьми штатах в 2016 году. На основании оперативной оценки начального этапа перехода было принято решение расширить использование частичной дозировки, и к июню 2017 года все штаты Индии перешли на использование новой схемы. В статье приведен краткий обзор опыта Индии по переходу на новую схему, обсуждаются возникшие проблемы и стратегии, используемые для их решения, а также представлен отчет о достигнутых результатах. Авторы описывают полученный опыт, в частности мероприятия по управлению поставками вакцины и предотвращению потерь, мониторингу и надзору, а также потребности в области профессиональной подготовки. Поскольку использование инактивированной полиовакцины в частичной дозировке позволяет экономить дозы и сокращает стоимость программы иммунизации, данный подход станет неотъемлемой частью долговременной программы Индии по вакцинации от полиомиелита.

Despite the existence of a variety of contraceptive products for women, as well as decades of research into the prevention and treatment of human immunodeficiency virus (HIV), there is still a globally unmet need for easily accessible, acceptable, and affordable products to protect women's sexual and reproductive health. Microarray patches (MAPs) are a novel platform being developed for the delivery of hormonal contraception and antiretroviral drugs. MAPs provide enhanced drug delivery to the systemic circulation via the transdermal route when compared to transdermal patches, oral and injectable formulations. These minimally invasive patches can be self-administered by the user, reducing the burden on health care personnel. Since MAPs represent needle-free drug delivery, no sharps waste is generated after application, thereby eliminating possible MAP reuse and risk of needle-stick injuries. This review discusses the administration of contraceptive and antiretroviral drugs using MAPs, their acceptability by end-users, and the future perspective of the field.

Injectable long-acting cabotegravir (CAB LA) is effective and safe for pre-exposure HIV prophylaxis. It is recently approved for clinical use in those at high risk of contracting HIV. However, injections are invasive and access to trained healthcare personnel to administer CAB LA can be limited, especially in low-income countries (LICs). Herein, for the first time, the development of a bilayer microarray patch (MAP) with unique design and novel formulation as a potential alternative self-administrated intradermal delivery system for CAB is reported. The novel MAP has a high drug load (≈3 mg/0.5 cm2 of CAB LA or its micronized sodium salt) and fast-dissolving tips (

A fractional dose of inactivated poliovirus vaccine (fIPV) administered by the intradermal route delivers one fifth of the full vaccine dose administered by the intramuscular route and offers a potential dose-sparing strategy to stretch the limited global IPV supply while further improving population immunity. Multiple studies have assessed immunogenicity of intradermal fIPV compared with the full intramuscular dose and demonstrated encouraging results. Novel intradermal devices, including intradermal adapters and disposable-syringe jet injectors, have also been developed and evaluated as alternatives to traditional Bacillus Calmette–Guérin needles and syringes for the administration of fIPV. Initial experience in India, Pakistan, and Sri Lanka suggests that it is operationally feasible to implement fIPV vaccination on a large scale. Given the available scientific data and operational feasibility shown in early-adopter countries, countries are encouraged to consider introducing a fIPV strategy into their routine immunization and supplementary immunization activities.

A variety of vaccine packaging and delivery technologies may benefit the immunization supply chain. These include alternative primary packaging, such as blow-fill-seal polymer containers, and novel delivery technologies, such intradermal delivery devices, microarray patches, and sublingual formulations of vaccines, and others in development. The potential timeline to availability of these technologies varies and depends on their stage of development and the type of data necessary to achieve licensure. Some new delivery devices are anticipated to be introduced in 2017, such as intradermal devices for delivery of inactivated poliovirus vaccine to stretch vaccine supplies due to a supply limitation. Other new technologies requiring vaccine reformulation, such as microarray patches and sublingual vaccines, may become available in the long term (2021 and beyond). Development of many new technologies requires partnership between vaccine and technology manufacturers and identification of the applicable regulatory pathway. Interaction with public-sector stakeholders early on (through engagement with forums such as the World Health Organization's Immunization Practices Advisory Committee Delivery Technologies Working Group) is important to ensure suitability for immunization program use. Key considerations for programmatic suitability of a new vaccine, packaging, and delivery device include cold chain volume, costs, and health impact.

Oral administration of vaccines is simpler and more acceptable than injection via needle and syringe, particularly for infants (Fig. 1) This route is promising for new vaccines in development against enterotoxigenic Escherichia coli (ETEC) and Shigella that cause childhood diarrhea with devastating consequences in low-resource countries. However, vaccine antigens and adjuvants given orally need buffering against the degradative effects of low stomach pH, and the type and volume of antacid buffer require special attention for infants. In addition, container/closure systems must be compatible with vaccine formulations, protect against water and gas transfer, and have minimal impact on the cold chain. Health care workers in demanding low-resource settings need an administration device that is easy to use, yet will accurately measure and safely deliver the correct vaccine dose. Developers must consider manufacturing capabilities, and immunization program managers want affordable vaccines. As new combination enteric vaccine candidates advance into clinical evaluation, features of the final vaccine presentation—liquid or dry format, diluent, buffer, primary and secondary packaging, and administration device—should be taken into account early in product development to achieve the greatest possible impact for the vaccine.

Antiretroviral (ARV) drugs have, for many years, been studied and administered in the prevention and treatment of human immunodeficiency virus (HIV). Intramuscular (IM) injection of long acting (LA) ARVs are in clinical development, but injectable formulations require regular access to healthcare facilities and disposal facilities for sharps. The development of a discrete, self-administered, and self-disabling vehicle to deliver ARVs could obviate these issues. This study describes the formulation, mechanical characterization, and in vivo evaluation of dissolving microarray patches (MAPs) containing a LA nanosuspension of the ARV, rilpivirine (RPV, RPV LA), for vaginal delivery. This is the first study to apply MAPs into vaginal tissue. The RPV LA MAPs penetrate ex vivo skin and a synthetic vaginal skin model and withstand the effects of potential dragging motion across synthetic vaginal epithelium. In in vivo studies, the mean plasma concentration of RPV in rats at the 56 day endpoint (116.5 ng mL

Rotavirus infection, which can be prevented by vaccination, is responsible for a high burden of acute gastroenteritis disease in children, especially in low-income countries. An appropriate formulation, packaging, and delivery device for oral rotavirus vaccine has the potential to reduce the manufacturing cost of the vaccine and the logistical impact associated with introduction of a new vaccine, simplify the vaccination procedure, and ensure that the vaccine is safely and accurately delivered to children. Single-dose prefilled presentations can be easy to use; however, they are typically more expensive, can be a bottleneck during production, and occupy a greater volume per dose vis-à-vis supply chain storage and medical waste disposal, which is a challenge in low-resource settings. Multi-dose presentations used thus far have other issues, including increased wastage of vaccine and the need for separate delivery devices. In this study, the goals were to evaluate both the technical feasibility of using preservatives to develop a liquid multi-dose formulation and the primary packaging alternatives for orally delivered, liquid rotavirus vaccines. The feasibility evaluation included evaluation of commonly used preservatives for compatibility with rotavirus vaccines and stability testing of rotavirus vaccine in various primary containers, including Lameplast's plastic tubes, BD's oral dispenser version of Uniject™ (Uniject DP), rommelag's blow-fill-seal containers, and MEDInstill's multi-dose vial and pouch. These presentations were compared to a standard glass vial. The results showed that none of the preservatives tested were compatible with a live attenuated rotavirus vaccine because they had a detrimental effect on the viability of the virus. In the presence of preservatives, vaccine virus titers declined to undetectable levels within 1 month. The vaccine formulation without preservatives maintained a stability profile over 12 months in all primary containers that was similar to its profile in standard glass vials. This study demonstrates that there are multiple options for the primary container for rotavirus vaccines intended for oral delivery. Selection of an optimal primary container should take into consideration additional factors, including stability as well as cold chain volume, usability, cost, and manufacturing feasibility.

Shortages of vaccines such as inactivated poliovirus and yellow fever vaccines have been addressed by administering reduced—or fractional—doses, as recommended by the World Health Organization Strategic Advisory Group of Experts on Immunization, to expand population coverage in countries at risk. We evaluated 3 kinds of vaccine vial stoppers to assess their performance after increased piercing from repeated withdrawal of doses needed when using fractional doses (0.1 mL) from presentations intended for full-dose (0.5 mL) delivery. Self-sealing capacity and fragmentation of the stopper were assessed via modified versions of international standard protocols. All stoppers maintained self-sealing capacity after 100 punctures. The damage to stoppers measured as the fragmentation rate was within the target of ≤ 10% of punctures resulting in a fragment after as many as 50 punctures. We concluded that stopper failure is not likely to be a concern if existing vaccine vials containing up to 10 regular doses are used up to 50 times for fractional dose delivery.

One means of combating the spread of human immunodeficiency virus (HIV) is through the delivery of long-acting, antiretroviral (ARV) drugs for prevention and treatment. The development of a discreet, self-administered and self-disabling delivery vehicle to deliver such ARV drugs could obviate compliance issues with daily oral regimens. Alternatives in development, such as long-acting intramuscular (IM) injections, require regular access to health care facilities and disposal facilities for sharps. Consequently, this proof of concept study was developed to evaluate the use of dissolving microarray patches (MAPs) containing a long-acting (LA) nanosuspension of the candidate ARV drug, rilpivirine (RPV). MAPs were mechanically strong and penetrated skin in vitro, delivering RPV intradermally. In in vivo studies, the mean plasma concentration of RPV in rats (431 ng/ml at the Day 7 time point) was approximately ten-fold greater than the trough concentration observed after a single-dose in previous clinical studies. These results are the first to indicate, by the determination of relative exposures between IM and MAP administration, that larger multi-array dissolving MAPs could potentially be used to effectively deliver human doses of RPV LA. Importantly, RPV was also detected in the lymph nodes, indicating the potential to deliver this ARV agent into one of the primary sites of HIV replication over extended durations. These MAPs could potentially improve patient acceptability and adherence to HIV prevention and treatment regimens and combat instances of needle-stick injury and the transmission of blood-borne diseases, which would have far-reaching benefits, particularly to those in the developing world., Graphical abstract Unlabelled Image

Background The purpose of this research was to develop a microarray patch (MAP; also known as a microneedle patch) for delivery of long-acting cabotegravir (CAB LA) for HIV pre-exposure prophylaxis (PrEP) and co-delivery of long-acting CAB LA and a hormonal contraceptive to enable a future multi-purpose prevention technology. This abstract presents preclinical pharmacokinetic results of MAP delivery of CAB LA. Methods MAPs are an alternative delivery technology in clinical development for intradermal delivery of vaccines and pharmaceuticals. A MAP consists of an array of micron-scale projections ( Results We successfully formulated and optimized MAP projection geometry to accommodate high drug-loading requirements of CAB LA (5.86 mg CAB LA per 1 cm2 MAP), a hydrophobic drug. The MAPs are stable for 6 months under accelerated aging conditions in foil packaging, readily pierce the skin, and rapidly dissolve. In rats, plasma concentration levels of CAB LA were maintained above therapeutic targets of 4xPA-IC90 for 28 days; however, bioavailability was lower than IM or ID injection controls. Photos: QUB. MAPs dissolving over time in phosphate-buffered solution; MAP projections fully dissolved within 25 minutes. Conclusion Additional development work is warranted, including optimizing bioavailability, evaluating MAPs as a maintenance dose in vivo, conducting cost of manufacturing and cost of delivery analyses, and assessing potential end-user acceptability. Disclosures Bill Spreen, PharmD, ViiV Healthcare (Employee), Trevor Scott, RPh, PhD, ViiV Healthcare (Employee). Others Authors: No reported disclosures.

Background New vaccine technologies may improve the acceptability, delivery (potentially enabling self-administration), and product efficacy of influenza vaccines. One such technology is the microneedle patch (MNP), a skin delivery technology currently in development. Although MNPs hold promise in preclinical studies, their potential economic and epidemiologic impacts have not yet been evaluated. Methods We utilized a susceptible-exposed-infectious-recovered (SEIR) transmission model linked to an economic influenza outcomes model to assess the economic value of introducing the MNP into the current influenza vaccine market in the United States from the third-party payer and societal perspectives. We also explored the impact of different vaccination settings, self-administration, the MNP price, vaccine efficacy, compliance, and MNP market share. Outcomes included costs, quality-adjusted life years (QALYs), cases, and incremental cost-effectiveness ratios (ICERs; cost/QALY). Results With healthcare provider administration, MNP introduction would be cost-effective (ICERs ≤$23,347/QALY) at all MNP price points ($9.50–$30) and market shares (10–60%) assessed, except when compliance and efficacy were assumed to be the same as existing vaccines and the MNP occupied a 10% market share. If MNP self-administration were available (assuming the same efficacy as current technologies), MNP compliance or its efficacy would need to increase by ≥3% in order to be cost-effective (ICERs ≤$1401/QALY), assuming a 2% reduction in administration success with unsupervised self-administration. Under these conditions, MNP introduction would be cost-effective for all price points and market shares assessed. Conclusions When healthcare providers administered the MNP, its introduction would be cost-effective or dominant (i.e., less costly and more effective) in the majority of scenarios assessed. If self-administration were available, MNP introduction would be cost-effective if it increased compliance enough to overcome any decrease in self-administration success or if the MNP presentation afforded an increase in efficacy over current delivery methods for influenza vaccines.

The immunogenicity of fractional (one-fifth, 0.1 mL) intradermal doses of the inactivated poliovirus vaccine (ID fIPV) is positively correlated with the size of the intradermal fluid bleb. Training of vaccinators for campaign and routine ID fIPV administration should focus on generating an 8- to 10-mm bleb with each injection. Clinical Trials Registration NCT01847872

Despite limitations of glass packaging for vaccines, the industry has been slow to implement alternative formats. Polymer containers may address many of these limitations, such as breakage and delamination. However, the ability of polymer containers to achieve cost of goods sold (COGS) and total cost of delivery (TCOD) competitive with that of glass containers is unclear, especially for cost-sensitive low- and lower-middle-income countries. COGS and TCOD models for oral and parenteral vaccine packaging formats were developed based on information from subject matter experts, published literature, and Kenya’s comprehensive multiyear plan for immunization. Rotavirus and inactivated poliovirus vaccines (IPV) were used as representative examples of oral and parenteral vaccines, respectively. Packaging technologies evaluated included glass vials, blow-fill-seal (BFS) containers, preformed polymer containers, and compact prefilled auto-disable (CPAD) devices in both BFS and preformed formats. For oral vaccine packaging, BFS multi-monodose (MMD) ampoules were the least expensive format, with a COGS of $0.12 per dose. In comparison, oral single-dose glass vials had a COGS of $0.40. BFS MMD ampoules had the lowest TCOD of oral vaccine containers at $1.19 per dose delivered, and ten-dose glass vials had a TCOD of $1.61 per dose delivered. For parenteral vaccines, the lowest COGS was achieved with ten-dose glass vials at $0.22 per dose. In contrast, preformed CPAD devices had the highest COGS at $0.60 per dose. Ten-dose glass vials achieved the lowest TCOD of the parenteral vaccine formats at $1.56 per dose delivered. Of the polymer containers for parenteral vaccines, BFS MMD ampoules achieved the lowest TCOD at $1.89 per dose delivered, whereas preformed CPAD devices remained the most expensive format, at $2.25 per dose delivered. Given their potential to address the limitations of glass and reduce COGS and TCOD, polymer containers deserve further consideration as alternative approaches for vaccine packaging.

Highlights • We compared MMR vaccine administration by disposable-syringe jet injector (DSJI) and needle and syringe (N-S). • The study was conducted in 340 toddlers who had received a measles vaccine at 9 months. • On day 35, seropositivity for all three viruses was more than 97% in both the groups. • Reactogenicity by both methods was comparable. • MMR vaccination via DSJI is as immunogenic and safe as vaccination by N-S., Background We conducted a randomized, non-inferiority, clinical study of MMR vaccine by a disposable-syringe jet injector (DSJI) in toddlers in India in comparison with the conventional administration. Methods MMR vaccine was administered subcutaneously by DSJI or needle-syringe (N-S) to toddlers (15–18 months) who had received a measles vaccine at 9 months. Seropositivity to measles, mumps, and rubella serum IgG antibodies was assessed 35 days after vaccination. Non-inferiority was concluded if the upper limit of the 95% CI for the difference in the percent of seropositive between groups was less than 10%. Solicited reactions were collected for 14 days after vaccination by using structured diaries. Results In each study group, 170 subjects received MMR vaccine. On day 35, seropositivity for measles was 97.5% [95% CI (93.8%, 99.3%)] in the DSJI group and 98.7% [95% CI (95.5%, 99.8%)] in the N-S group; for mumps, 98.8% [95% CI (95.6%, 99.8%)] and 98.7% [95% CI (95.5%, 99.8%)]; and for rubella, 98.8% [95% CI (95.6%, 99.8%)] and 100% [95% CI (97.7%, 100.0%)]; none of the differences were significant. The day 35 post-vaccination GMTs in DSJI and N-S groups were measles: 5.48 IU/ml [95% CI (3.71, 8.11)] and 5.94 IU/ml [95% CI (3.92, 9.01)], mumps: 3.83 ISR [95% CI (3.53, 4.14)] and 3.66 ISR [95% CI (3.39, 3.95)] and rubella: 95.27 IU/ml [95% CI (70.39, 128.95)] and 107.06 IU/ml [95% CI (79.02, 145.06)]; none of the differences were significant. The DSJI group reported 173 solicited local reactions and the N-S group reported 112; most were mild grade. Of the total of 156 solicited systemic adverse events, most were mild, and incidence between the two groups was similar. Conclusions MMR vaccination via DSJI is as immunogenic as vaccination by N-S. Safety profile of DSJI method is similar to N-S except for injection site reactions which are more with DSJI and are well-tolerated. Registration US National Institutes of Health clinical trials identifier – NCT02253407. Clinical trial registry of India identifier – CTRI/2013/05/003702

Immunization program delivery strategies that enable high vaccine coverage, particularly in inaccessible and remote areas, are critical to achieving optimal vaccine impact. In addition to demonstration of safety and efficacy, there are many factors that influence whether a newly licensed vaccine will be introduced into a country's national immunization program, particularly in resource-constrained environments. This paper describes three case studies of novel approaches that represent the potential for improved programmatic impact by increasing vaccine accessibility in different ways. However, the pathway to regulatory approval, policy recommendation, and program introduction in low- and middle-income countries is complex, requiring engagement with multiple, diverse stakeholders. Consideration of aspects that affect uptake in low- and middle-income countries, during the product development stage, will help better position new or second-generation vaccine products for successful implementation to achieve public health impact.

Introduction Intradermal delivery of a fractional dose of inactivated poliovirus vaccine (IPV) offers potential benefits compared to intramuscular (IM) delivery, including possible cost reductions and easing of IPV supply shortages. Objectives of this study were to assess intradermal delivery devices for dead space, wastage generated by the filling process, dose accuracy, and total number of doses that can be delivered per vial. Methods Devices tested included syringes with staked (fixed) needles (autodisable syringes and syringes used with intradermal adapters), a luer-slip needle and syringe, a mini-needle syringe, a hollow microneedle device, and disposable-syringe jet injectors with their associated filling adapters. Each device was used to withdraw 0.1-mL fractional doses from single-dose IM glass vials which were then ejected into a beaker. Both vial and device were weighed before and after filling and again after expulsion of liquid to record change in volume at each stage of the process. Data were used to calculate the number of doses that could potentially be obtained from multidose vials. Results Results show wide variability in dead space, dose accuracy, overall wastage, and total number of doses that can be obtained per vial among intradermal delivery devices. Syringes with staked needles had relatively low dead space and low overall wastage, and could achieve a greater number of doses per vial compared to syringes with a detachable luer-slip needle. Of the disposable-syringe jet injectors tested, one was comparable to syringes with staked needles. Discussion If intradermal delivery of IPV is introduced, selection of an intradermal delivery device can have a substantial impact on vaccine wasted during administration, and thus on the required quantity of vaccine that needs to be purchased. An ideal intradermal delivery device should be not only safe, reliable, accurate, and acceptable to users and vaccine recipients, but should also have low dead space, high dose accuracy, and low overall wastage to maximize the potential number of doses that can be withdrawn and delivered.

Several vaccines, diagnostic tests, and medications are currently delivered intradermally, and it is likely that this route of administration will grow in importance. A phase I clinical study was conducted to evaluate the intradermal (ID) adapter, a prototype intradermal delivery aid, for safety and precision of injection. Healthy adult volunteers received two injections each of 0.1 mL of sterile saline solution in the upper deltoid region of the arm using the ID adapter. Injection performance was determined by the proportion of injections delivered to the dermal layer by measuring wheals and fluid leakage, and through ultrasound imaging. Of the 40 study injections, 100% were determined to be successful intradermal injections. Leakage of liquid at the injection site was negligible. Performance was similar with the bevel orientation both upward and downward. Minor bleeding and skin abrasions were the only reported adverse events. Injections were well tolerated based on self-reporting of pain of injection. Based on these results, the ID adapter appears to be safe and effective as an alternative to the Mantoux method of ID delivery for future use in clinical evaluations of ID delivery of vaccines, skin tests, and other drugs.

The World Health Organization recommends that as part of the polio end-game strategy a dose of inactivated poliovirus vaccine (IPV) be introduced by the end of 2015 in all countries currently using only oral poliovirus vaccine (OPV). Administration of fractional dose (1/5 of full dose) IPV (fIPV) by intradermal (ID) injection may reduce costs, but its conventional administration is with Bacillus Calmette-Guerin (BCG) needle and syringe (NS), which is time consuming and technically challenging. We compared injection quality achieved with BCG NS and three needle-free jet injectors and assessed ergonomic features of the injectors.Children between 12 and 20 months of age who had previously received OPV were enrolled in the Camaguey, Cuba study. Subjects received a single fIPV dose administered intradermally with BCG NS or one of three needle-free injector devices: Bioject Biojector 2000® (B2000), Bioject ID Pen® (ID Pen), or PharmaJet Tropis® (Tropis). We measured bleb diameter and vaccine loss as indicators of ID injection quality, with desirable injection quality defined as bleb diameter ≥5mm and vaccine loss10%. We surveyed vaccinators to evaluate ergonomic features of the injectors. We further assessed the injection quality indicators as predictors of immune response, measured by increase in poliovirus neutralizing antibodies in blood between day 0 (pre-IPV) and 21 (post-vaccination).Delivery by BCG NS and Tropis resulted in the highest proportion of subjects with desirable injection quality; health workers ranked Biojector2000 and Tropis highest for ergonomic features. We observed that vaccine loss and desirable injection quality were associated with an immune response for poliovirus type 2 (P=0.02, P=0.01, respectively).Our study demonstrated the feasibility of fIPV delivery using needle-free injector devices with high acceptability among health workers. We did not observe the indicators of injection quality to be uniformly associated with immune response.

We compared the ability of three intradermal delivery devices to administer an intended dose to pig skin in vivo and target that dose to the dermal rather than subcutaneous layers. The three devices were a standard hypodermic needle and syringe for the Mantoux technique, an adapter designed to facilitate proper hypodermic needle and syringe use, and a hollow microneedle. Reliability was determined as the percentage of the administered dose that entered the skin, as opposed to remaining in the device or on the skin surface. The intradermal adapter (97.6 ± 1.5 % delivered, mean ± standard deviation), Mantoux technique (95.4 ± 4.9 %), and hollow microneedle (94.9 ± 0.3 %) exhibited similar reliability. Accuracy was determined as the percentage of the dose that entered the skin that localized in the dermis. All three devices achieved similar accuracy: hollow microneedle (99 ± 12 % delivered to the dermis, median ± standard deviation), Mantoux technique (97 ± 16 %), and intradermal adapter (92 ± 21 %). We conclude that intradermal injection by all three methods studied provided reliable delivery to the skin and provided accurate localization of delivery within the dermis. Next-generation designs of these devices have now received clearance from the FDA and are used as medical products and/or in clinical trials.

Disposable-syringe jet injectors (DSJIs) with single-use, auto disable, needle-free syringes offer the opportunity to avoid hazards associated with injection using a needle and syringe. Clinical studies have evaluated DSJIs for vaccine delivery, but most studies have focused on inactivated, subunit, or DNA vaccines. Questions have been raised about possible damage to live attenuated viral vaccines by forces generated during the jet injection process. This study examines the effect of jet injection on the integrity of measles, mumps, and rubella vaccine (MMR), measured by viral RNA content and infectivity. Three models of DSJIs were evaluated, each generating a different ejection force. Following jet injection, the RNA content for each of the vaccine components was measured using RT-qPCR immediately after injection and following passage in Vero cells. Jet injection was performed with and without pig skin as a simulation of human skin. There was little to no reduction of RNA content immediately following jet injection with any of the three DSJIs. Samples passaged in Vero cells showed no loss in infectivity of the measles vaccine following jet injection. Mumps vaccine consistently showed increased replication following jet injection. Rubella vaccine showed no loss after jet injection alone but some infectivity loss following injection through pig skin with two of the devices. Overall, these data demonstrated that forces exerted on a live attenuated MMR vaccine did not compromise vaccine infectivity. The bench model and protocol used in this study can be applied to evaluate the impact of jet injection on other live virus vaccines.

Introduction Intradermal bacille Calmette-Guérin (BCG) vaccination by needle-free, disposable-syringe jet injectors (DSJI) is an alternative to the Mantoux method using needle and syringe (NS). We compared the safety and immunogenicity of BCG administration via the DSJI and NS techniques in adults and newborn infants at the South African Tuberculosis Vaccine Initiative (SATVI) research site in South Africa. Method Thirty adults and 66 newborn infants were randomized 1:1 to receive intradermal BCG vaccine (0.1 mL in adults; 0.05 mL in infants) via DSJI or NS. Wheal diameter (mm) and skin fluid deposition at the site of injection (SOI) were measured immediately post-vaccination. Adverse events and SOI reactogenicity data were collected 30 min and 1, 2, 4, and 12 weeks after vaccination for adults and at 30 min and 4, 10, and 14 weeks for infants. Blood was collected in infants at 10 and 14 weeks to assess BCG-specific T-cell immune responses. Results More infant BCG vaccinations by DSJI deposited >5 μL fluid on the skin surface, compared to NS (49% versus 9%, p = 0.001). However, all 12 infant vaccinations that did not produce any SOI wheal occurred in the NS group (36%, p

Although the number of vaccines and diagnostic tests currently delivered intradermally is limited, this route of administration offers potential advantages due to the high concentration of antigen-presenting cells in the skin. One factor which may in part be limiting development and use of intradermal (ID) administration is concern about the ease and reliability of the needle and syringe-based Mantoux technique. A phase I clinical study was conducted to evaluate two ID adapters that have been developed as injection-delivery aids to increase the safety, simplicity, and reliability of ID injection: a prototype autodisable, intradermal (ADID) adapter for autodisable (AD) syringes, and a marketed side-merge adapter (SMA). Thirty healthy adult volunteers each received six injections of 0.1 mL of sterile saline solution. Each adapter was used to give injections into the upper deltoid, forearm, and suprascapular regions of each volunteer. The needle-bevel orientation during injection was random. Injection performance was determined by measuring wheal size and fluid leakage. Wheals were similar in size for the ADID adapter (mean 9.9 ± 0.17 mm) and SMA (mean 9.8 ± 0.15 mm). In all of the injections completed with the SMA, and 98% of those completed with the ADID, fluid leakage was less than 10% of the intended injection volume. Minor skin abrasions were the only adverse events. Based on self-reporting of pain, injections were well tolerated (mean pain score of 2 on a 0–10 scale). ID delivery using the SMA and ADID adapters appears safe and effective.