Bubble dynamics and speed of jets for needle-free injections produced by thermocavitation.

Significance: The number of injections administered has increased dramatically worldwide due to vaccination campaigns following the COVID-19 pandemic, creating a problem of disposing of syringes and needles. Accidental needle sticks occur among medical and cleaning staff, exposing them to highly contagious diseases, such as hepatitis and human immunodeficiency virus. In addition, needle phobia may prevent adequate treatment. To overcome these problems, we propose a needle-free injector based on thermocavitation. Aim: Experimentally study the dynamics of vapor bubbles produced by thermocavitation inside a fully buried 3D fused silica chamber and the resulting high-speed jets emerging through a small nozzle made at the top of it. The injected volume can range from ∼0.1 to 2 µL per shot. We also demonstrate that these jets have the ability to penetrate agar skin phantoms and ex-vivo porcine skin. Approach: Through the use of a high-speed camera, the dynamics of liquid jets ejected from a microfluidic device were studied. Thermocavitation bubbles are generated by a continuous wave laser (1064 nm). The 3D chamber was fabricated by ultra-short pulse laser-assisted chemical etching. Penetration tests are conducted using agar gels (1%, 1.25%, 1.5%, 1.75%, and 2% concentrations) and porcine tissue as a model for human skin. Result: High-speed camera video analysis showed that the average maximum bubble wall speed is about 10 to 25 m/s for almost any combination of pump laser parameters; however, a clever design of the chamber and nozzle enables one to obtain jets with an average speed of ∼70 m/s. The expelled volume per shot (0.1 to 2 µl) can be controlled by the pump laser intensity. Our injector can deliver up to 20 shots before chamber refill. Penetration of jets into agar of different concentrations and ex-vivo porcine skin is demonstrated. Conclusions: The needle-free injectors based on thermocavitation may hold promise for commercial development, due to their cost and compactness.

InjectMeAI-Software Module of an Autonomous Injection Humanoid.

The recent pandemic outbreak proved social distancing effective in helping curb the spread of SARS-CoV-2 variants along with the wearing of masks and hand gloves in hospitals and assisted living environments. Health delivery personnel having undergone training regarding the handling of patients suffering from Corona infection have been stretched. Administering injections involves unavoidable person to person contact. In this circumstance, the spread of bodily fluids and consequently the Coronavirus become eminent, leading to an upsurge of infection rates among nurses and doctors. This makes enforced home office practices and telepresence through humanoid robots a viable alternative. In providing assistance to further reduce contact with patients during vaccinations, a software module has been designed, developed, and implemented on a Pepper robot that estimates the pose of a patient, identifies an injection spot, and raises an arm to deliver the vaccine dose on a bare shoulder. Implementation was done using the QiSDK in an android integrated development environment with a custom Python wrapper. Tests carried out yielded positive results in under 60 s with an 80% success rate, and exposed some ambient lighting discrepancies. These discrepancies can be solved in the near future, paving a new way for humans to get vaccinated.

Manufacturing a chimpanzee adenovirus-vectored SARS-CoV-2 vaccine to meet global needs.

Manufacturing has been the key factor limiting rollout of vaccination during the COVID-19 pandemic, requiring rapid development and large-scale implementation of novel manufacturing technologies. ChAdOx1 nCoV-19 (AZD1222, Vaxzevria) is an efficacious vaccine against SARS-CoV-2, based upon an adenovirus vector. We describe the development of a process for the production of this vaccine and others based upon the same platform, including novel features to facilitate very large-scale production. We discuss the process economics and the "distributed manufacturing" approach we have taken to provide the vaccine at globally-relevant scale and with international security of supply. Together, these approaches have enabled the largest viral vector manufacturing campaign to date, providing a substantial proportion of global COVID-19 vaccine supply at low cost.

An ultra-low-cost electroporator with microneedle electrodes (ePatch) for SARS-CoV-2 vaccination.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other pathogens with pandemic potential requires safe, protective, inexpensive, and easily accessible vaccines that can be developed and manufactured rapidly at a large scale. DNA vaccines can achieve these criteria, but induction of strong immune responses has often required bulky, expensive electroporation devices. Here, we report an ultra-low-cost (<1 USD), handheld (<50 g) electroporation system utilizing a microneedle electrode array ("ePatch") for DNA vaccination against SARS-CoV-2. The low cost and small size are achieved by combining a thumb-operated piezoelectric pulser derived from a common household stove lighter that emits microsecond, bipolar, oscillatory electric pulses and a microneedle electrode array that targets delivery of high electric field strength pulses to the skin's epidermis. Antibody responses against SARS-CoV-2 induced by this electroporation system in mice were strong and enabled at least 10-fold dose sparing compared to conventional intramuscular or intradermal injection of the DNA vaccine. Vaccination was well tolerated with mild, transient effects on the skin. This ePatch system is easily portable, without any battery or other power source supply, offering an attractive, inexpensive approach for rapid and accessible DNA vaccination to combat COVID-19, as well as other epidemics.

Use of lay vaccinators in animal vaccination programmes: A scoping review.

BACKGROUND: The human resource gap in veterinary sectors, particularly in low-income countries, imposes limitations on the delivery of animal healthcare in hard-to-reach populations. Lay animal health workers have been deployed in these settings to fill the gap though there are mixed views about the benefits of doing this and whether they can deliver services safely. We mapped evidence on the nature and extent of roles assigned to lay animal vaccinators, and identified lessons useful for their future deployment. METHODOLOGY/PRINCIPAL FINDINGS: Following the PRISMA Extension for Scoping Reviews guidelines, we searched seven bibliographic databases for articles published between 1980 and 2021, with the search terms lay OR community-based OR volunteer AND "animal health worker" OR vaccinator*, and applied an a priori exclusion criteria to select studies. From 30 identified studies, lay vaccinators were used by non-government developmental (n = 12, 40%), research (n = 10, 33%) and government (n = 5, 17%) programmes to vaccinate domestic animals. The main reason for using lay vaccinators was to provide access to animal vaccination in the absence of professional veterinarians (n = 12, 40%). Reported positive outcomes of programmes included increased flock and herd sizes and farmer knowledge of best practice (n = 13, 43%); decreased disease transmission, outbreaks and mortality (n = 11, 37%); higher vaccination coverage (10, 33%); non-inferior seroconversion and birth rates among vaccinated herds (n = 3, 10%). The most frequently reported facilitating factor of lay vaccinator programmes was community participation (n = 14, 47%), whilst opposition from professional veterinarians (n = 8, 27%), stakeholders seeking financial gains to detriment of programmes goals (n = 8, 27%) and programming issues (n = 8, 27%) were the most frequently reported barriers. No study reported on cost-effectiveness and we found no record from a low and middle-income country of lay vaccinator programmes being integrated into national veterinary services. CONCLUSION: Although the majority of included studies reported more benefits and positive perceptions of lay vaccinator programmes than problems and challenges, regularization will ensure the programmes can be designed and implemented to meet the needs of all stakeholders.

Formulation Approach that Enables the Coating of a Stable Influenza Vaccine on a Transdermal Microneedle Patch.

A trivalent influenza split vaccine was formulated at high concentration for coating on the transdermal microneedle system. Monovalent vaccine bulks of three influenza strains, two influenza A strains, and one B strain were diafiltrated, concentrated, and lyophilized. The lyophilized powder of each vaccine strain was separately reconstituted and subsequently combined into a coating formulation of high concentration trivalent vaccine. The formulation process converted the monovalent vaccine bulks with low hemagglutinin (HA) concentrations 0.1 mg/mL into a viscous, emulsion containing HA at ~50 mg/mL. This physically stable emulsion demonstrated viscosity 1 poise and 30° contact angle for effective, homogeneous coating on each microneedle. Evaluation of the vaccine antigen HA by SRID and SDS-PAGE/Western blot showed that HA remained stable throughout the vaccine transdermal microneedle system manufacturing process and 1-year ambient storage (25°C). Anti-influenza antibody responses were evaluated by ELISA and hemagglutination inhibition (HAI) assay after primary and booster immunization with the vaccine-coated transdermal microneedle systems at either 25-µg or 40-µg total HA. The results showed the induction of serum anti-influenza IgG and anti-HA neutralizing antibodies after primary immunization and significant titer rises after booster immunization for both doses, indicating the dry-coated trivalent vaccine delivered by transdermal microneedle system elicited both primary and recall antibody responses against all three antigen strains. The study demonstrates that the transdermal microneedle system provides an attractive alternative for influenza vaccine delivery with key advantages such as preservative-free and room-temperature storage.

In vitro evaluation of novel (nanoparticle) oral delivery systems allow selection of gut immunomodulatory formulations.

Oral delivery is the most convenient way to vaccinate cultured fish, however it is still problematic, primarily due to a lack of a commercially valid vaccine vehicle to protect the antigen against gastric degradation and ensure its uptake from the intestine. With the goal of advancing the potential to vaccinate orally, this study evaluates a novel silicon nanoparticle-based vehicle (VacSaf carrier). Aeromonas salmonicida antigens were formulated with the VacSaf carrier using different preparation methods to generate dry powder and liquid formulations. Twelve formulations were first subjected to an in vitro evaluation where the A. salmonicida bacterin conjugated to VacSaf carriers were found superior at inducing pro-inflammatory cytokine expression in primary leucocyte cultures and the macrophage/monocyte cell line RTS-11 compared with A. salmonicida bacterin alone. This was especially apparent after exposure to acid conditions to mimic stomach processing. One formulation (FD1) was taken forward to oral delivery using two doses and two administration schedules (5 days vs 10 days, the latter 5 days on, 5 days off, 5 days on), and the transcript changes of immune genes in the intestine (pyloric caeca, midgut and hindgut) and spleen were evaluated by qPCR and serum IgM was measured by ELISA. The VacSaf carrier alone was shown to be safe for use in vivo, in that no side-effects were seen, but it did induce expression of some cytokines, and may have value as an oral adjuvant candidate. The FD1 bacterin formulation was effective at inducing a range of cytokines associated with innate and adaptive immunity, mainly in the pyloric caeca, compared to A. salmonicida bacterin alone (which had almost no effect), and confirms the immune competence of this gut region following appropriate oral vaccination. These results reveal that in vitro screening of formulations for oral delivery has value and can be used to assess the most promising formulations to test further.

A spraying applicator device is not required for efficacy of a live intranasal respiratory vaccine in young calves, which improves user convenience.

Almost all bovine intranasal respiratory vaccines require a spraying device, but there are no published reports which prove the necessity of this. The objective of this investigation was to compare the efficacy of the Bovilis® INtranasal RSP™ Live vaccine when applied with or without an (intra)nasal spraying device. This vaccine contains live, attenuated strains of bovine respiratory syncytial virus (BRSV) and bovine parainfluenza virus type 3 (BPI3V) and is licensed to protect young cattle against respiratory infections with wild-type field isolates of these viruses. Two efficacy studies, for BRSV and BPI3V respectively, were performed in which the vaccine was administered using a spraying device or directly from the tip of a syringe as a liquid stream. Both BRSV-vaccinated groups showed a reduction of nasal shedding, BRSV titres in lung washings and clinical symptoms. The BPI3V vaccinated groups showed a significant reduction of nasal shedding and a non-significant reduction of clinical symptoms. Overall, in both studies, the groups in which vaccine was administered without the spraying device performed better than the groups with the spraying device, although this difference was not statistically significant. In conclusion, a spraying device to administer Bovilis® INtranasal RSP™ Live was not required and both application methods induced a protective immune response. This makes application more convenient and flexible for future users and animals.

Influenza Vaccines toward Universality through Nanoplatforms and Given by Microneedle Patches.

Influenza is one of the top threats to public health. The best strategy to prevent influenza is vaccination. Because of the antigenic changes in the major surface antigens of influenza viruses, current seasonal influenza vaccines need to be updated every year to match the circulating strains and are suboptimal for protection. Furthermore, seasonal vaccines do not protect against potential influenza pandemics. A universal influenza vaccine will eliminate the threat of both influenza epidemics and pandemics. Due to the massive challenge in realizing influenza vaccine universality, a single vaccine strategy cannot meet the need. A comprehensive approach that integrates advances in immunogen designs, vaccine and adjuvant nanoplatforms, and vaccine delivery and controlled release has the potential to achieve an effective universal influenza vaccine. This review will summarize the advances in the research and development of an affordable universal influenza vaccine.

Informe especial: Coberturas de vacunación en residentes de la CABA en contexto Covid-19: 2 de octubre de 2020 / Special report: Vaccination coverage in CABA residents in context of Covid19

La vacunación es considerada una actividad esencial durante la pandemia de COVID-19 y se han desarrollado diferentes estrategias para el sostenimiento de la vacunación en el contexto actual, facilitar el acceso a través de la adaptación y reorganización de los servicios de salud, el no requerimiento de permisos de circulación para la vacunación, vacunación en instituciones fuera de salud, así como la elaboración de recomendaciones para realizar la vacunación de manera segura protegiendo tanto al vacunador como la persona a vacunar, entre otros. Con el objetivo de realizar la medición del impacto en las actividades de vacunación, se realiza el análisis comparativo de las vacunas aplicadas durante el primer semestre de los años 2018-2020, con la información recibida en el nivel central del Programa de Inmunizaciones. Se excluye del presente análisis la información referida a la vacuna antigripal ya que tiene una modalidad diferente de aplicación. (AU)

A microneedle patch for measles and rubella vaccination: a game changer for achieving elimination.

While morbidity and mortality associated with measles and rubella (MR) have dramatically decreased, there are still >100000 estimated deaths due to measles and an estimated 100000 infants born with congenital rubella syndrome annually. Given highly effective MR vaccines, the primary barrier to global elimination of these diseases is low vaccination coverage, especially among the most underserved populations in resource-limited settings. In contrast to conventional MR vaccination by hypodermic injection, microneedle patches are being developed to enable MR vaccination by minimally trained personnel. Simplified supply chain, reduced need for cold chain storage, elimination of vaccine reconstitution, no sharps waste, reduced vaccine wastage, and reduced total system cost of vaccination are advantages of this approach. Preclinical work to develop a MR vaccine patch has proceeded through successful immunization studies in rodents and non-human primates. On-going programs seek to make MR vaccine patches available to support MR elimination efforts around the world.

The origins and genomic diversity of American Civil War Era smallpox vaccine strains.

Vaccination has transformed public health, most notably including the eradication of smallpox. Despite its profound historical importance, little is known of the origins and diversity of the viruses used in smallpox vaccination. Prior to the twentieth century, the method, source and origin of smallpox vaccinations remained unstandardised and opaque. We reconstruct and analyse viral vaccine genomes associated with smallpox vaccination from historical artefacts. Significantly, we recover viral molecules through non-destructive sampling of historical materials lacking signs of biological residues. We use the authenticated ancient genomes to reveal the evolutionary relationships of smallpox vaccination viruses within the poxviruses as a whole.

Diphtheria toxoid dissolving microneedle vaccination: Adjuvant screening and effect of repeated-fractional dose administration.

In this study the effect of repeated-fractional intradermal administration of diphtheria toxoid (DT) compared to a single administration in the presence or absence of adjuvants formulated in dissolving microneedles (dMNs) was investigated. Based on an adjuvant screening with a hollow microneedle (hMN) system, poly(I:C) and gibbsite, a nanoparticulate aluminum salt, were selected for further studies: they were co-encapsulated with DT in dMNs with either a full or fractional DT-adjuvant dose. Sharp dMNs were prepared regardless the composition and were capable to penetrate the skin, dissolve within 20 min and deposit the intended antigen-adjuvant dose, which remained in the skin for at least 5 h. Dermal immunization with hMN in repeated-fractional dosing (RFrD) resulted in a higher immune response than a single-full dose (SFD) administration. Vaccination by dMNs led overall to higher responses than hMN but did not show an enhanced response after RFrD compared to a SFD administration. Co-encapsulation of the adjuvant in dMNs did not increase the immune response further. Immunization by dMNs without adjuvant gave a comparable response to subcutaneously injected DT-AlPO4 in a 15 times higher dose of DT, as well as subcutaneous injected DT-poly(I:C) in a similar DT dose. Summarizing, adjuvant-free dMNs showed to be a promising delivery tool for vaccination performed in SFD administration.

Needle-free injectors for mass administration of fractional dose inactivated poliovirus vaccine in Karachi, Pakistan: A survey of caregiver and vaccinator acceptability.

The first large-scale vaccination campaign using needle-free jet injectors to administer fractional doses of inactivated poliovirus vaccine (fIPV) was conducted in Karachi, Pakistan, in February 2019. Data on acceptability of jet injectors were collected from 610 vaccinators and 4898 caregivers during the first four days of the campaign. Of those with prior needle and syringe experience, both vaccinators and caregivers expressed a strong preference for jet injectors (578/592 [97.6%] and 4792/4813 [99.6%], respectively), citing ease of use, appearance, and child's response to vaccination. Among caregivers, 4638 (94.7%) stated they would be more likely to bring their child for vaccination in a future campaign that used jet injectors. Mean vaccine coverage among towns administering fIPV was 98.7% - an increase by 18.4% over the preceding campaign involving full-dose IPV. Our findings demonstrate the strong acceptability of fIPV jet injectors and highlight the potential value of this method in future mass campaigns.

The Falconi's needle against anti-vaccination: A minimally invasive tool in the nineteenth century.

The history of Giovanni Falconi's career and his vaccination campaigns is two hundred years old. It is however very relevant today because of the widespread negative social opinion against vaccination at that time, opinions which seem to have re-emerged even in the current century. In his very important role of "Vaccine Conservator" (a sort of national supervisor for the quality of vaccinations), he clashed with the prejudice of the people and with the anti-scientific attitudes of some of his illustrious colleagues. He investigated how to simplify the procedure with a smallpox needle that became known as "Falconi's Needle" or "Falconian Needle". Falconi also made several experiments on smallpox vaccine preparation and was a supporter of the use of "animal" and "humanized" formulas despite the prejudice regarding the latter. Due to his profound anatomical knowledge and the strength of mind that characterized him, he was able to follow evidence-based scientific principles in his methods. Thanks to this he managed to convince people not to oppose vaccinations. He also succeeded in bringing the number of vaccinated people to exceed the number of newborns, a great achievement that led to remarkable progress in Italy and the rescue of thousands of lives throughout Europe. Unfortunately, it was not possible to find a copy of this instrument, which required the author to have the needle reconstructed.

Evaluation of digital vaccine card in nursing practice in vaccination room.

OBJECTIVE: develop and evaluate a vaccine application for mobile devices, with update integrated with the National Immunization Program Information System, for care in vaccination rooms. METHOD: methodological research based on the Pressman System Development Life Cycle theory developed in three stages: integrative literature review, computational development, and application evaluation. The product was evaluated as to satisfaction, using a validated questionnaire, and as to usability by the System Usability Scale. RESULTS: the application functionalities were based on the survey of technological Innovations on immunization, published in the scientific literature. It displays user vaccines directly from the National Immunization Program Information System, notifies about upcoming vaccines, and enables the inclusion of vaccine cards of dependents. The evaluation resulted in users' mean score of 90.5 ± 11.1 and health professionals' mean score of 84.2 ± 19.4. CONCLUSION: the application is a technological tool with potential to improve the work process in vaccination rooms and to reach the goals of vaccine coverage. It synchronizes data with the National Immunization Program Information System, thus enabling the maintenance of people's vaccination history.

A surface charge dependent enhanced Th1 antigen-specific immune response in lymph nodes by transfersome-based nanovaccine-loaded dissolving microneedle-assisted transdermal immunization.

The efficient delivery of vaccines to draining lymph nodes and the induction of robust local immune responses are crucial for immunotherapy. Transdermal administration has been evidenced to facilitate the delivery of ingredients to lymph nodes. In this study, transfersomes with opposite surface charges were applied for antigen encapsulation and these were integrated with dissolving microneedles to investigate their effects on immune responses via transdermal immunization. The microneedles were easily inserted into mouse skin and achieved the local release of nanovaccines into the dermis through dissolution. Although anionic nanovaccines promoted cellular uptake via DC2.4, cationic nanovaccines exhibited stronger escape capacities from endocytic compartments, facilitating antigen processing via an MHC-I presentation pathway, and formed larger accumulations in lymph nodes. Compared with their anionic counterparts, the cationic nanovaccines more efficiently activated DC maturation and induced Th1 immunity; this was suggested by the significantly increased IgG2a/IgG1 ratio and elevated cytokine secretion from Th1 cells, without an enhancement in the Th2 response. Such an enhanced Th1 antigen-specific immune response in lymph nodes via a transdermal vaccine delivery platform is beneficial for potential immunotherapy approaches.

Integration of needle-free jet injection with advanced electroporation delivery enhances the magnitude, kinetics, and persistence of engineered DNA vaccine induced immune responses.

The combination of optimized DNA constructs, improved formulations and advanced in vivo electroporation (EP) has been shown to generate potent and efficacious immune responses in the clinic. Needle-free jet injection has also been reported to improve DNA vaccine delivery over standard needle and syringe in clinical trials. Here we investigated the impact of combined jet injection and EP (Jet-EP) delivery on muscle transfection efficiency and DNA vaccine immunogenicity in rabbits and nonhuman primates (NHPs) compared to jet injection alone. Our results show that the addition of EP significantly enhanced in vivo DNA transfection efficiency of rabbit muscle over jet injection alone. Jet-EP delivery augmented the rate and magnitude of DNA vaccine induced humoral and cellular responses over jet injection alone in both rabbits and NHPs. Jet-EP delivery also resulted in higher proportions of polyfunctional antigen specific T cells producing IFNγ, IL-2, and/or TNFα. Elevated antibody levels were sustained nine months post immunization in NHPs immunized with a DNA vaccine using Jet-EP delivery, far outperforming jet delivery alone. Our results provide proof-of-concept that addition of advanced EP to needle-free jet injection delivery improves in vivo DNA transfection efficiency, increasing the magnitude, rate and duration of cellular and humoral immune responses to DNA vaccines. This combination likely has significant advantages in important vaccine and immunotherapy settings.

HIV-1 vaccination by needle-free oral injection induces strong mucosal immunity and protects against SHIV challenge.

The oral mucosa is an attractive site for mucosal vaccination, however the thick squamous epithelium limits antigen uptake. Here we utilize a modified needle-free injector to deliver immunizations to the sublingual and buccal (SL/B) tissue of rhesus macaques. Needle-free SL/B vaccination with modified vaccinia Ankara (MVA) and a recombinant trimeric gp120 protein generates strong vaccine-specific IgG responses in serum as well as vaginal, rectal and salivary secretions. Vaccine-induced IgG responses show a remarkable breadth against gp70-V1V2 sequences from multiple clades of HIV-1. In contrast, topical SL/B immunizations generates minimal IgG responses. Following six intrarectal pathogenic SHIV-SF162P3 challenges, needle-free but not topical immunization results in a significant delay of acquisition of infection. Delay of infection correlates with non-neutralizing antibody effector function, Env-specific CD4+ T-cell responses, and gp120 V2 loop specific antibodies. These results demonstrate needle-free MVA/gp120 oral vaccination as a practical and effective route to induce protective immunity against HIV-1.

Vaccination with influenza hemagglutinin-loaded ceramic nanoporous microneedle arrays induces protective immune responses.

Microneedle arrays (MNAs) are a promising mean to administer vaccines. Without the need of highly trained personnel, MNAs can be applied to deliver vaccines into the dermis, which is well equipped to initiate potent immune responses. While vaccination using dissolving microneedle arrays has been extensively investigated, the use of solid nanoporous MNAs (npMNAs) to deliver vaccines remained largely unexplored. In this report we investigated whether npMNAs with an average pore size of 80 nm, can be used for influenza vaccination based on recombinant hemagglutinin (HA) protein of the 2009 pandemic H1N1 (pH1N1) virus. Fluorescently labeled HA loaded in the npMNAs was effectively delivered into the skin of mouse ears, as a result of a diffusion-based process. Compared to intramuscular immunization, intradermal HA vaccination of mice using npMNAs elicited high levels of HA antigen specific antibodies, with pH1N1 hemagglutination inhibition and neutralization activity. Moreover, mice vaccinated with pH1N1 HA loaded npMNAs were completely protected against a potentially lethal challenge with mouse adapted pH1N1 virus. These results illustrate that intradermal subunit vaccine immunization using npMNAs is a promising approach to facilitate effective vaccination.