Marilyn Kelly

 A rapid immunization strategy with a live-attenuated tetravalent dengue vaccine elicits protective neutralizing antibody responses in non-human primates
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.

 Early priming with inactivated poliovirus vaccine (IPV) and intradermal fractional dose IPV administered by a microneedle device: A randomized controlled trial
Inactivated poliovirus vaccine (IPV) introduction and phased oral poliovirus vaccine (OPV) cessation are essential for eradication of polio.
Healthy 6-week old infants in Bangladesh were randomized to one of five study arms: receipt of trivalent OPV (tOPV) or bivalent OPV (bOPV) at ages 6, 10 and 14 weeks, intramuscular IPV or intradermal one-fifth fractional dose IPV (f-IPV) at ages 6 and 14 weeks, or f-IPV at ages 6 and 14 weeks with bOPV at age 10 weeks (f-IPV/bOPV). All participants received tOPV at age 18 weeks.
Of 975 infants randomized, 95% (922) completed follow-up. Type 1 seroconversion after 3 doses at 6, 10 and 14 weeks was higher with bOPV compared with tOPV (99% vs 94%, p = 0.019). Seroconversions to types 1 and 3 after 2 IPV doses at ages 6 and 14 weeks were no different than after 3 doses of tOPV or bOPV at ages 6, 10 and 14 weeks. A priming response, seroconversion 1 week after IPV at 14 weeks among those who did not seroconvert after IPV at 6 weeks, was observed against poliovirus types 1, 2 and 3 in 91%, 84% and 97%, respectively. Compared with IPV, f-IPV failed non-inferiority tests for seroconversion with 1 or 2 doses and priming after 1 dose.
The findings demonstrate considerable priming with IPV at age 6 weeks, comparable immunogenicity of tOPV and bOPV, and inferior immunogenicity of one-fifth f-IPV compared with IPV. If IPV induced priming at age 6 weeks is similar to that at age 14 weeks, IPV could be administered at a younger age and possibly with a higher coverage.

 The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial
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.

 Vial usage, device dead space, vaccine wastage, and dose accuracy of intradermal delivery devices for inactivated poliovirus vaccine (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.

 Immune responses after fractional doses of inactivated poliovirus vaccine using newly developed intradermal jet injectors: A randomized controlled trial in Cuba
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.

 An economic model assessing the value of microneedle patch delivery of the seasonal influenza vaccine
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.

 Effect of jet injection on infectivity of measles, mumps, and rubella vaccine in a bench model
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.

 Randomized clinical trial in adults and newborns in South Africa to compare the safety and immunogenicity of bacille Calmette-Guérin (BCG) vaccine administration via a disposable-syringe jet injector to conventional technique with needle and syringe
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.

 Opportunities and challenges in delivering influenza vaccine by microneedle patch
Simple and efficacious delivery methods for influenza vaccines are needed to improve health outcomes and manage possible pandemics both in the United States and globally. One approach to meeting these needs is the microneedle patch (MNP), a small array of micron-scale needles that is applied to the skin like a bandage.
To inform additional technical developments and the eventual introduction of MNPs for influenza vaccination, we interviewed key opinion leaders in the United States for insights into the opportunities and challenges associated with this technology, particularly its potential for self-administration.
All interviewees expressed high support for administration of influenza vaccine in MNPs by health care providers and for self-administration in groups supervised by a provider. Self-administration via prescription and over-the-counter purchase of MNPs received lower levels of support. Interviewees also highlighted priorities that should be considered in the ongoing development of an influenza vaccine MNP, such as confirming efficacy and ensuring safety for self-administration. For patient and health care provider acceptability, important attributes are ease of use, short wear times, and an easily accessible application site.
Stakeholders agreed that using MNPs can help increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza. Another opportunity for this delivery method is the potential for self-administration. The prospect of reduced provider training requirements, increased thermostability, and high patient and provider acceptability makes it an attractive option for use in remote and low-resource settings worldwide. However, in addition to the technological challenges associated with producing the patch, developers must be mindful of cost considerations and key product attributes or requirements, such as usability, wear time, and proper disposal, that can affect how the product will be received in the marketplace.

 WHO Microarray Patch (MAP) Product Development Workshop
On 8 December 2015, the WHO Department for Immunization, Vaccines and Biologics convened patch developers, vaccine
manufacturers, regulators, funders and other key stakeholders to discuss WHO Microarray Patch (MAP) product development. This high level summary captures the major conclusions and recommendations; a more detailed paper on the
considerations for MAP product development will be forthcoming.