New vaccine compositions, formulations and combinations have greatly advanced in recent decades. Presently, vaccines are available against 25 diseases, and 12 vaccines are now included in the Expanded Programme on Immunization (EPI), as compared to the original four vaccines recommended when the EPI was established in 1974. The addition of new vaccines to the EPI schedule saves lives but also increases the cost and complexity of vaccine delivery, particularly in low-resource settings. Most vaccines require storage in the cold chain and are administered by a trained healthcare workers via conventional needle and syringe injection. This poses challenges, considering broader coverage targets and the emergence of new vaccines from the development pipeline. For example, the Global Alliance for Vaccines and Immunisation (GAVI) projects that by 2020 four times the cold chain capacity will be needed as compared to 2010.
Vaccination programmes require innovative approaches that simplify vaccine delivery by removing the need for a cold chain, minimizing the packaging footprint, easing administration and reducing waste. In addition, quantitative tools that model the potential health system benefits of these, innovations can describe the potential value proposition for novel technologies and effectively advocate for their development. Understanding the challenges of vaccination programmes helps define the needs of novel technologies and as such informs the development of products with attributes that are more likely to effectively impact coverage.
Co-chaired by WHO and PATH, the Delivery Technology Working Group (DT WG) reports directly to WHO’s Immunization Practices Advisory Committee (IPAC). Its mission is to maximize impact of immunization products for public-sector use, including stand-alone delivery technologies, novel primary containers, combination vaccine/device products and other alternative delivery technologies.
This page provides a list of resources related to vaccine delivery technologies, as well as materials developed by the DT WG. The aim is to inform industry and public-sector stakeholders; encourage a constructive dialogue on the presentation, packaging, and delivery of existing and new vaccine products; raise awareness; and harness the potential of new innovations.
Measles vaccination programs would benefit from delivery methods that decrease cost, simplify logistics, and increase safety. Conventional subcutaneous injection is limited by the need for skilled healthcare professionals to reconstitute and administer injections, and by the need for safe needle handling and disposal to reduce the risk of disease transmission through needle re-use and needlestick injury. Microneedles are micron-scale, solid needles coated with a dry formulation of vaccine that dissolves in the skin within minutes after patch application. By avoiding the use of hypodermic needles, vaccination using a microneedle patch could be carried out by minimally trained personnel with reduced risk of blood-borne disease transmission. The goal of this study was to evaluate measles vaccination using a microneedle patch to address some of the limitations of subcutaneous injection. Viability of vaccine virus dried onto a microneedle patch was stabilized by incorporation of the sugar, trehalose, and loss of viral titer was less than 1 log10(TCID50) after storage for at least 30 days at room temperature. Microneedle patches were then used to immunize cotton rats with the Edmonston-Zagreb measles vaccine strain. Vaccination using microneedles at doses equaling the standard human dose or one-fifth the human dose generated neutralizing antibody levels equivalent to those of a subcutaneous immunization at the same dose. These results show that measles vaccine can be stabilized on microneedles and that vaccine efficiently reconstitutes in vivo to generate a neutralizing antibody response equivalent to that generated by subcutaneous injection.
As micro-array patches (MAPs, also known as microneedle patches) continue to be developed, their potential advantages of thermal stability and improved ease-of-use, and immunogenicity make them a candidate for use with measles-rubella (MR) vaccines. They have particular advantages that could facilitate delivery and increase coverage for these two vaccines in both low and middle-income countries (LMICs) and high income countries. The following is a Target Product Profile (TPP) for a generic microarray patch (MAP) presentation) with a solid vaccine formulation of a live-attenuated measles-rubella (MR) vaccine (including both coated and dissolvable MAP formats, but not hollow microneedle arrays intended to deliver liquid or reconstituted vaccines). The process of deriving this MR MAP TPP is intended to help focus stakeholders to define acceptable and optimal product attributes, to guide product developers.
The phased replacement of oral polio vaccine (OPV) with inactivated polio vaccine (IPV) is expected to significantly complicate mass vaccination campaigns, which are an important component of the global polio eradication endgame strategy. To simplify mass vaccination with IPV, we developed microneedle patches that are easy to administer, have a small package size, generate no sharps waste and are inexpensive to manufacture. When administered to rhesus macaques, neutralizing antibody titers were equivalent among monkeys vaccinated using microneedle patches and conventional intramuscular injection for IPV types 1 and 2. Serologic response to IPV type 3 vaccination was weaker after microneedle patch vaccination compared to intramuscular injection; however, we suspect the administered type 3 dose was lower due to a flawed pre-production IPV type 3 analytical method. IPV vaccination using microneedle patches was well tolerated by the monkeys. We conclude that IPV vaccination using a microneedle patch is immunogenic in rhesus macaques and may offer a simpler method of IPV vaccination of people to facilitate polio eradication.
Transcutaneous immunization (TCI) is an attractive vaccination method compared with conventional injectable vaccines because it is easier to administer without pain. We developed a dissolving microneedle patch (MicroHyala, MH) made of hyaluronic acid and showed that transcutaneous vaccination using MH induced a strong immune response against various antigens in mice. In the present study, we investigated the clinical safety and efficacy of a novel transcutaneous influenza vaccine using MH (flu-MH), which contains trivalent influenza hemagglutinins (15 μg each). Subjects of the TCI group were treated transcutaneously with flu-MH, and were compared with subjects who received subcutaneous injections of a solution containing 15 μg of each influenza antigen (SCI group). No severe local or systemic adverse events were detected in either group and immune responses against A/H1N1 and A/H3N2 strains were induced equally in the TCI and SCI groups. Moreover, the efficacy of the vaccine against the B strain in the TCI group was stronger than that in the SCI group. Influenza vaccination using MH is promising for practical use as an easy and effective method to replace conventional injections systems.
Microneedle patches provide an alternative to conventional needle-and-syringe immunisation, and potentially offer improved immunogenicity, simplicity, cost-effectiveness, acceptability, and safety. We describe safety, immunogenicity, and acceptability of the first-in-man study on single, dissolvable microneedle patch vaccination against influenza.
Maternal and neonatal tetanus claim tens of thousands lives every year in developing countries, but could be prevented by hygienic practices and improved immunization of pregnant women. This study tested the hypothesis that skin vaccination can overcome the immunologically transformed state of pregnancy and enhance protective immunity to tetanus in mothers and their newborns. To achieve this goal, we developed microneedle patches (MNPs) that efficiently delivered unadjuvanted tetanus toxoid to skin of pregnant mice and demonstrated that this route induced superior immune responses in female mice conferring 100% survival to tetanus toxin challenge when compared to intramuscular vaccination. Mice born to MNP-vaccinated mothers showed detectable tetanus–specific IgG antibodies up to 12 weeks of age and complete protection to tetanus toxin challenge up at 6 weeks of age. In contrast, none of the 6-week old mice born to intramuscularly vaccinated mothers survived challenge. Although pregnant mice vaccinated with unadjuvanted tetanus toxoid had 30% lower IgG and IgG1 titers than mice vaccinated intramuscularly with Alum®-adjuvanted tetanus toxoid vaccine, IgG2a titers and antibody affinity maturation were similar between these groups. We conclude that skin immunization with MNPs containing unadjuvanted tetanus toxoid can confer potent protective efficacy to mothers and their offspring using a delivery method well suited for expanding vaccination coverage in developing countries.
MAPs cost analyses
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.
MAPs for developing countries
Millions of people die of infectious diseases each year, mostly in developing countries, which could largely be prevented by the use of vaccines. While immunization rates have risen since the introduction of the Expanded Program on Immunization (EPI), there remain major challenges to more effective vaccination in developing countries. As a possible solution, microneedle patches containing an array of micron-sized needles on an adhesive backing have been developed to be used for vaccine delivery to the skin. These microneedle patches can be easily and painlessly applied by pressing against the skin and, in some designs, do not leave behind sharps waste. The patches are single-dose, do not require reconstitution, are easy to administer, have reduced size to simplify storage, transportation and waste disposal, and offer the possibility of improved vaccine immunogenicity, dose sparing and thermostability. This review summarizes vaccination challenges in developing countries and discusses advantages that microneedle patches offer for vaccination to address these challenges. We conclude that microneedle patches offer a powerful new technology that can enable more effective vaccination in developing countries.
Fractional Dose IPV ID delivery devices
The World Health Organization recommends that, as part of the new polio endgame, a dose of inactivated poliovirus vaccine (IPV) be introduced by the end of 2015 in all countries using only oral poliovirus vaccine (OPV). Administration of fractional dose (1/5th of full dose) IPV (fIPV) intradermally may reduce costs, but its administration is cumbersome with BCG needle and syringe. We evaluated performance of two newly developed intradermal-only jet injectors and compared the immune response induced by fIPV with that induced by full-dose IPV.
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.
Intradermal immunization has become a forefront of vaccine improvement, both scientifically and commercially. Newer technologies are being developed to address the need to reduce the dose required for vaccination and to improve the reliability and ease of injection, which have been major hurdles in expanding the number of approved vaccines using this route of administration. In this review, 7 y of clinical experience with a novel intradermal delivery device, the MicronJet600, which is a registered hollow microneedle that simplifies the delivery of liquid vaccines, are summarized. This device has demonstrated both significant dose-sparing and superior immunogenicity in various vaccine categories, as well as in diverse subject populations and age groups. These studies have shown that intradermal delivery using this device is safe, effective, and preferred by the subjects. Comparison with other intradermal devices and potential new applications for intradermal delivery that could be pursued in the future are also discussed.
Oral vaccine containers
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.
BCG jet injection
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.
MMR jet injection
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.
Dengue jet injectors
Dengue viruses (DENVs) cause approximately 390 million cases of DENV infections annually and over 3 billion people worldwide are at risk of infection. No dengue vaccine is currently available nor is there an antiviral therapy for DENV infections. We have developed a tetravalent live-attenuated DENV vaccine tetravalent dengue vaccine (TDV) that consists of a molecularly characterized attenuated DENV-2 strain (TDV-2) and three chimeric viruses containing the pre-membrane and envelope genes of DENV-1, -3, and -4 expressed in the context of the TDV-2 genome. To impact dengue vaccine delivery in endemic areas and immunize travelers, a simple and rapid immunization strategy (RIS) is preferred. We investigated RIS consisting of two full vaccine doses being administered subcutaneously or intradermally on the initial vaccination visit (day 0) at two different anatomical locations with a needle-free disposable syringe jet injection delivery devices (PharmaJet) in non-human primates. This vaccination strategy resulted in efficient priming and induction of neutralizing antibody responses to all four DENV serotypes comparable to those elicited by the traditional prime and boost (2 months later) vaccination schedule. In addition, the vaccine induced CD4+ and CD8+ T cells producing IFN-γ, IL-2, and TNF-α, and targeting the DENV-2 NS1, NS3, and NS5 proteins. Moreover, vaccine-specific T cells were cross-reactive with the non-structural NS3 and NS5 proteins of DENV-4. When animals were challenged with DENV-2 they were protected with no detectable viremia, and exhibited sterilizing immunity (no increase of neutralizing titers post-challenge). RIS could decrease vaccination visits and provide quick immune response to all four DENV serotypes. This strategy could increase vaccination compliance and would be especially advantageous for travelers into endemic areas.
Skin Vaccination Summit meeting summary
Vaccination is an acknowledged powerful intervention toreduce mortality and morbidity caused by infectious diseases, pre-venting 2.5 million deaths each year as estimated by the WorldHealth Organization . Despite the impressive success of modernvaccine programs, there is still a need to improve the effectivenessand safety of the current vaccine strategy. Without doubt, the siteof the body where the vaccine is administered is of ultimate impor-tance and it may very well be that the traditional intramuscular (IM)or subcutaneous (SC) methods are suboptimal. These vaccinationroutes have empirically been selected in the past without scientiﬁcevidence showing that these locations are the best to use. However,because of the large historical evidence that protective immuniza-tion is reached via these routes, the global health community stillcontinues to use the muscle and subcutis as injection sites for thevast majority of present-day vaccines.
Intradermal adapter device technology minimizes the complexity of the Mantoux technique, thereby providing predictable, reproducible intradermal (ID) injections and removing the concerns regarding the ease and reliability of Mantoux technique when using conventional needle and syringe. The technology employs a simple device with geometry designed to gently deform the skin surface and the subcutaneous tissue, providing the ideal angle and depth of needle insertion for consistently successful intradermal injections. The results of this development were presented at the First, Second and Third Skin Vaccination Summits in 2011, 2013 and 2015 respectively , and . The current publication addresses the performance of intradermal adapters (IDA) evaluated in three preclinical studies. The evaluations were based on the assessment of bleb formation in a skin model, an accepted indicator of ID injection success. All evaluated devices share the same proprietary dermal interface technology. Devices instituting this design are easy to use, require minimal training, and employ conventionally molded parts and cannula. These studies evaluated IDAs of initial design integral with luer lock needles, IDAs for use with conventional syringes, and intradermal adapters for use with auto disable syringes (ADID adapters). The evaluated ID adapters were intended to consistently place the lancet of the needle at a depth of 0.75 mm from the skin’s surface. This placement depth addresses the variation in the skin thickness at immunization sites for the majority of patients independent of many other variables. Most participants preferred the intradermal adapter method over the traditional Mantoux and identified a need for the adapter at their workplace. Evaluation of IDAs by registered nurses indicated these devices increase success of bleb formation. The use of IDA increased the success of forming blebs by about 30%. Nurses felt the injections were much easier to perform, in particular by novices.
West Pharmaceutical Services, Inc. (NYSE: WST), a global leader in innovative solutions for injectable drug administration, today shared the results of a study highlighting the benefits of West's ID Adapter for improving the intradermal administration of polio vaccines. The study results were presented at the Fourth Skin Vaccination Summit in May 2017 by Dr. Ondrej Mach, Clinical Trials and Research Team Lead, Polio Department, World Health Organization (WHO), and recently published in the journal Vaccine.