A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults

IntroductionThere is an urgent need for a new and effective tuberculosis vaccine because BCG does not sufficiently prevent pulmonary disease. IMX313 is a novel carrier protein designed to improve cellular and humoral immunity. MVA85A-IMX313 is a novel vaccine candidate designed to boost immunity primed by bacillus Calmette-Guérin (BCG) that has been immunogenic in pre-clinical studies. This is the first evaluation of IMX313 delivered as MVA85A-IMX313 in humans.MethodsIn this phase 1, open-label first-in-human trial, 30 healthy previously BCG-vaccinated adults were enrolled into three treatment groups and vaccinated with low dose MVA85A-IMX313 (group A), standard dose MVA85A-IMX313 (group B), or MVA85A (group C). Volunteers were followed up for 6 months for safety and immunogenicity assessment.ResultsThe majority of adverse events were mild and there were no vaccine-related serious AEs. Both MVA85A-IMX313 and MVA85A induced a significant increase in IFN-γ ELISpot responses. There were no significant differences between the Ag85A ELISpot and intracellular cytokine responses between the two study groups B (MVA85A-IMX313) and C (MVA85A) at any time point post-vaccination.ConclusionMVA85A-IMX313 was well tolerated and immunogenic. There was no significant difference in the number of vaccine-related, local or systemic adverse reactions between MVA85A and MVA85A-IMX313 groups. The mycobacteria-specific cellular immune responses induced by MVA85A-IMX313 were not significantly different to those detected in the MVA85A group. In light of this encouraging safety data, further work to improve the potency of molecular adjuvants like IMX313 is merited.This trial was registered on clinicatrials.gov ref. NCT01879163.     

Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults

Purpose

A non-randomised, open-label, Phase I safety and immunogenicity dose-finding study to assess the safety and immunogenicity of the candidate TB vaccine Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) from Mycobacterium tuberculosis (MTB) in healthy adult volunteers previously vaccinated with BCG.

Methods

Healthy BCG-vaccinated volunteers were vaccinated with either 1 × 10⁷ or 1 × 10⁸ PFU of MVA85A. All adverse events were documented and antigen specific T cell responses were measured using an ex vivo IFN-γ ELISPOT assay. Safety and immunogenicity were compared between the 2 dose groups and with a previous trial in which a dose of 5 × 10⁷ PFU MVA85A had been administered.

Results

There were no serious adverse events recorded following administration of either 1 × 10⁷ or 1 × 10⁸ PFU of MVA85A. Systemic adverse events were more frequently reported following administration of 1 × 10⁸ PFU of MVA85A when compared to either 5 × 10⁷ or 1 × 10⁷ PFU of MVA85A but were mild or moderate in severity and resolved completely within 7 days of immunisation. Antigen specific T cell responses as measured by the IFN-γ ELISPOT were significantly higher following immunisation in adults receiving 1 × 10⁸ PFU compared to the 5 × 10⁷ and 1 × 10⁷ doses. Additionally, a broader range of Ag85A epitopes are detected following 1 × 10⁸ PFU of MVA85A.

Conclusion

A higher dose of 1 × 10⁸ PFU of MVA85A is well-tolerated, increases the frequency of IFN-γ secreting T cells detected following immunisation and broadens the range of Ag85A epitopes detected.     

A randomized control trial comparing immunogenicity, safety, and preference for self- versus nurse-administered intradermal influenza vaccine

Background

Intradermally administered influenza vaccine is as immunogenic as intramuscular vaccine at a lower unit dose. New microinjection systems could allow self-administration of vaccine, potentially reducing the cost and inconvenience.

Objective

To compare the immunogenicity, reactogenicity, success rate, and acceptability of self- versus nurse-administered intradermal trivalent seasonal influenza vaccine.

Methods

Adults (18–59 years old) were randomized to either self- or nurse-administered intradermal vaccine. Prior to vaccination, participants completed a questionnaire and had blood drawn for hemagglutination inhibition titres. Participants in the nurse-administered group were vaccinated by study personnel. The self-administered group were given an instruction sheet and administered their own vaccine. All participants completed a questionnaire and adverse event diaries for 21 days post vaccination, at which time blood was again collected.

Results

Of the 228 participants, 115 were randomized to self-administration and 113 to nurse administration. Groups did not differ by sex, age, or levels of seroprotection at baseline. Of the 114 who completed self-administration, 106 (93%) were successful on the first attempt. There were no group differences in measures of immunogenicity for any of the strains. Self-administering participants reported a lower mean pain rating at vaccination but had larger areas of redness post-vaccination. Seventy percent of all participants said they would prefer intradermal over intramuscular vaccinations in the future, if given the choice.

Conclusion

Compared to nurse-administered intradermal influenza vaccine, self-administered vaccine was immunologically non-inferior and reached all EMA immunogenicity criteria for the A strains, was highly successful and well-accepted by study participants. Together, these data provide preliminary evidence of feasibility for this method of influenza vaccine administration, which may improve vaccine uptake in adults and increase efficiency of vaccine delivery during outbreaks.     

Immune efficacy of a candidate porcine reproductive and respiratory syndrome vaccine rHN-NP49 administered by a Needle-free intradermal delivery system in comparison with intramuscular injection

Porcine reproductive and respiratory syndrome (PRRS) is one of the major drivers of economic loss in the swine industry worldwide. In commercial pig production, vaccination is the first option in an attempt to control infectious diseases. Pigs are therefore often immunized with different vaccines, and almost all of them are delivered via the intramuscular (IM) route. However, the IM injection may result in physical damage, stress reactions, and is labor demanding. An alternative route is urgently needed to reduce the disadvantages of conventional vaccination. In this study, a needle-free intradermal (ID) delivery system was evaluated for delivering a live PRRS vaccine as compared with the traditional needle-syringe method. Fifty-two 4-week-old piglets were divided into six groups: piglets in groups A-C were immunized using ID delivery system with 10⁴, 10⁵ and 10⁶ TCID₅₀ of PRRS candidate vaccine strain rHN-NP49, respectively; piglets in group D were immunized IM with 10⁵ TCID₅₀ of rHN-NP49; and group E and F were used as challenge and control groups, respectively. At 28 days post vaccination, piglets in group A to E were challenged with a lethal dose of highly-pathogenic PRRSV. Similar results were found in viremia and antibody response among the ID and IM groups during the immunization stage. After challenge, similar results were found in average body weight gain, viral shedding, serum viral load, and clinical score among the immunization groups, with a higher protection ratio in the ID group compared with IM group with the same immunization dose. These results demonstrated that the ID delivery system could provide similar or even better protection compared with IM route, and could be an effective route for PRRS vaccination.     

Immunogenicity and safety of intradermal delivery of hepatitis B booster vaccine using the novel drug delivery device VAX-ID™

Background

Although intramuscular (IM) injection is still the most preferred method for vaccination, intradermal (ID) delivery may have several advantages over intramuscular and subcutaneous (SC), including an improved immune response and antigen dose sparing effect. However it is currently limited due to the difficulty in standardizing the injection technique often based on the Mantoux technique. Difficulties encountered using the Mantoux technique could be overcome by the use of alternative ID delivery systems that confer more uniform and standardized procedures.The aim of this study was to evaluate the performance of a newly developed intradermal injection device, VAX-ID?, via a proof-of-concept to assess the immunogenicity of a commercially available hepatitis B booster vaccination in healthy hepatitis B pre-immunised subjects. Additionally, device safety and tolerability was evaluated.

A preliminary study of chemo- and cytokine responses in rabies vaccine recipients of intradermal and intramuscular regimens

Plasma from 10 patients who had received rabies vaccine either intradermally (ID) or intramuscularly (IM) was examined for 20 chemo- and cytokines. Plasma samples were withdrawn on days 0, 3 and 7 after vaccination. These chemo- and cytokines and sampling days were chosen based on data collected from a protein array analysis of 122 cytokines conducted on one recipient of vaccine administered IM and one recipient of vaccine administered ID. Although eotaxin, interleukin (IL)-5 in the ID and IL-1 beta in the IM group were the only chemo- and cytokines that reached statistical significance (p < 0.05), the overall trends may suggest bias on Th1 or Th2 according to vaccination routes. IL-1 alpha, -2, and -6, hemofiltrate cysteine–cysteine chemokine (HCC-4), glucocorticoid induced tumor necrosis factor receptor (GITR), tumor necrosis factor (TNF) related apoptosis inducing ligand-receptor (TRAIL-R3) had some degree of elevation in the ID group. TNF-alpha, gamma-interferon, granulocytes/macrophages – colony stimulating factor (GM-CSF), transforming growth factor (TGF)-beta, lymphotactin and pulmonary and activation-regulated chemokine (PARC) were elevated, although not to a significant level, in the IM group. IL-12, interferon-inducible T cell alpha chemoattractrant (I-TAC) and sertoli cell factor (SCF) were not significantly elevated in both groups whereas IL-4 and -10 were unchanged. Further studies are required to determine whether the presence of specific chemokines, such as eotaxin, is responsible for the production of high levels of rabies virus neutralizing antibody after administration of the dose-sparing ID regimen.     

A new TB vaccine, MVA85A, induces durable antigen-specific responses 14 months after vaccination in African infants

This study aimed to evaluate the durability of the immunogenicity of MVA85A beyond infancy. Participants in an immunogenicity study of MVA85A administered at age of 4 months had additional evaluation 14 months after initial vaccination for IFN-γ ELISPOT responses to Ag85A peptide and ESAT6/CFP-10 and tuberculin skin test (TST). 112 children participated in this study. The anthropometry, biochemical and haematological safety profile were similar between the MVA85A recipients and controls. MVA85A recipients still had significantly higher immune responses to Ag85A compared to the controls. The majority of these children had negative responses to the TST as well as the ESAT6/CFP-10 antigens. In summary, MVA85A-vaccinated children had a persistently higher Ag85A immune response 14 months following vaccination than controls. All the children had negligible evidence of latent infection with M. tuberculosis (Mtb), suggesting that deploying a prophylactic vaccine against Mtb infection at this age could still be effective in this setting.     

Cost-effectiveness of an influenza vaccination program offering intramuscular and intradermal vaccines versus intramuscular vaccine alone for elderly

BackgroundIntradermal (ID) injection is an alternative route for influenza vaccine administration in elderly with potential improvement of vaccine coverage. This study aimed to investigate the cost-effectiveness of an influenza vaccination program offering ID vaccine to elderly who had declined intramuscular (IM) vaccine from the perspective of Hong Kong public healthcare provider.MethodsA decision analytic model was used to simulate outcomes of two programs: IM vaccine alone (IM program), and IM or ID vaccine (IM/ID program) in a hypothetic cohort of elderly aged 65 years. Outcome measures included influenza-related direct medical cost, infection rate, mortality rate, quality-adjusted life years (QALYs) loss, and incremental cost per QALY saved (ICER). Model inputs were derived from literature. Sensitivity analyses evaluated the impact of uncertainty of model variables.ResultsIn base-case analysis, the IM/ID program was more costly (USD52.82 versus USD47.59 per individual to whom vaccine was offered) with lower influenza infection rate (8.71% versus 9.65%), mortality rate (0.021% versus 0.024%) and QALYs loss (0.00336 versus 0.00372) than the IM program. ICER of IM/ID program was USD14,528 per QALY saved. One-way sensitivity analysis found ICER of IM/ID program to exceed willingness-to-pay threshold (USD39,933) when probability of influenza infection in unvaccinated elderly decreased from 10.6% to 5.4%. In 10,000 Monte Carlo simulations of elderly populations of Hong Kong, the IM/ID program was the preferred option in 94.7% of time.ConclusionsAn influenza vaccination program offering ID vaccine to elderly who had declined IM vaccine appears to be a highly cost-effective option.     

Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting

BackgroundVaccination that prevents tuberculosis (TB) disease, particularly in adolescents, would have the greatest impact on the global TB epidemic. Safety, reactogenicity and immunogenicity of the vaccine candidate M72/AS01_E was evaluated in healthy, HIV-negative adolescents in a TB endemic region, regardless of Mycobacterium tuberculosis (M.tb) infection status.MethodsIn a phase II, double-blind randomized, controlled study (NCT00950612), two doses of M72/AS01_E or placebo were administered intramuscularly, one month apart. Participants were followed-up post-vaccination, for 6 months. M72-specific immunogenicity was evaluated by intracellular cytokine staining analysis of T cells and NK cells by flow cytometry.ResultsNo serious adverse events were recorded. M72/AS01_E induced robust T cell and antibody responses, including antigen-dependent NK cell IFN-γ production. CD4 and CD8 T cell responses were sustained at 6 months post vaccination. Irrespective of M.tb infection status, vaccination induced a high frequency of M72-specific CD4 T cells expressing multiple combinations of Th1 cytokines, and low level IL-17. We observed rapid boosting of immune responses in M.tb-infected participants, suggesting natural infection acts as a prime to vaccination.ConclusionsThe clinically acceptable safety and immunogenicity profile of M72/AS01_E in adolescents living in an area with high TB burden support the move to efficacy trials.     

Enhanced immunogenicity and protective efficacy of a tetravalent dengue DNA vaccine using electroporation and intradermal delivery

Phase 1 clinical trials with a DNA vaccine for dengue demonstrated that the vaccine is safe and well tolerated, however it produced less than optimal humoral immune responses. To determine if the immunogenicity of the tetravalent dengue DNA vaccine could be enhanced, we explored alternate, yet to be tested, methods of vaccine administration in non-human primates. Animals were vaccinated on days 0, 28 and 91 with either a low (1 mg) or high (5 mg) dose of vaccine by the intradermal or intramuscular route, using either needle-free injection or electroporation devices. Neutralizing antibody, IFN-γ T cell and memory B cell responses were compared to a high dose group vaccinated with a needle-free intramuscular injection delivery device similar to what had been used in previous preclinical and clinical studies. All previously untested vaccination methodologies elicited improved immune responses compared to the high dose needle-free intramuscular injection delivery group. The highest neutralizing antibody responses were observed in the group that was vaccinated with the high dose formulation via intradermal electroporation. The highest IFN-γ T cell responses were also observed in the high dose intradermal electroporation group and the CD8⁺ T cells were the dominant contributors for the IFNγ response. Memory B cells were detected for all four serotypes. More than a year after vaccination, groups were challenged with dengue-1 virus. Both the low and high dose intradermal electroporation groups had significantly fewer days of dengue-1 virus RNAemia compared to the control group. The results from this study demonstrate that using either an electroporation device and/or the intradermal route of delivery increases the immune response generated by this vaccine in non-human primates and should be explored in humans.     

A Phase 1 clinical trial of a DNA vaccine for Venezuelan equine encephalitis delivered by intramuscular or intradermal electroporation

Venezuelan equine encephalitis virus (VEEV), a mosquito-borne alphavirus, causes periodic epizootics in equines and is a recognized biological defense threat for humans. There are currently no FDA-licensed vaccines against VEEV. We developed a candidate DNA vaccine expressing the E3-E2-6K-E1 genes of VEEV (pWRG/VEE) and performed a Phase 1 clinical study to assess the vaccine's safety, reactogenicity, tolerability, and immunogenicity when administered by intramuscular (IM) or intradermal (ID) electroporation (EP) using the Ichor Medical Systems TriGrid™ Delivery System. Subjects in IM-EP groups received 0.5 mg (N = 8) or 2.0 mg (N = 9) of pWRG/VEE or a saline placebo (N = 4) in a 1.0 ml injection. Subjects in ID-EP groups received 0.08 mg (N = 8) or 0.3 mg (N = 8) of DNA or a saline placebo (N = 4) in a 0.15 ml injection. Subjects were monitored for a total period of 360 days. No vaccine- or device-related serious adverse events were reported. Based on the results of a subject questionnaire, the IM- and ID-EP procedures were both considered to be generally acceptable for prophylactic vaccine administration, with the acute tolerability of ID EP delivery judged to be greater than that of IM-EP delivery. All subjects (100%) in the high and low dose IM-EP groups developed detectable VEEV-neutralizing antibodies after two or three administrations of pWRG/VEE, respectively. VEEV-neutralizing antibody responses were detected in seven of eight subjects (87.5%) in the high dose and five of eight subjects (62.5%) in the low dose ID-EP groups after three vaccine administrations. There was a correlation between the DNA dose and the magnitude of the resulting VEEV-neutralizing antibody responses for both IM and ID EP delivery. These results indicate that pWRG/VEE delivered by either IM- or ID-EP is safe, tolerable, and immunogenic in humans at the evaluated dose levels.Clinicaltrials.gov registry number NCT01984983.     

TcVac1 vaccine delivery by intradermal electroporation enhances vaccine induced immune protection against Trypanosoma cruzi infection in mice

The efforts for the development and testing of vaccines against Trypanosoma cruzi infection have increased during the past years. We have designed a TcVac series of vaccines composed of T. cruzi derived, GPI-anchored membrane antigens. The TcVac vaccines have been shown to elicit humoral and cellular mediated immune responses and provide significant (but not complete) control of experimental infection in mice and dogs. Herein, we aimed to test two immunization protocols for the delivery of DNA-prime/DNA-boost vaccine (TcVac1) composed of TcG2 and TcG4 antigens in a BALB/c mouse model. Mice were immunized with TcVac1 through intradermal/electroporation (IDE) or intramuscular (IM) routes, challenged with T. cruzi, and evaluated during acute phase of infection. The humoral immune response was evaluated through the assessment of anti-TcG2 and anti-TcG4 IgG subtypes by using an ELISA. Cellular immune response was assessed through a lymphocyte proliferation assay. Finally, clinical and morphopathological aspects were evaluated for all experimental animals. Our results demonstrated that when comparing TcVac1 IDE delivery vs IM delivery, the former induced significantly higher level of antigen-specific antibody response (IgG2a?+?IgG2b?>?IgG1) and lymphocyte proliferation, which expanded in response to challenge infection. Histological evaluation after challenge infection showed infiltration of inflammatory cells (macrophages and lymphocytes) in the heart and skeletal tissue of all infected mice. However, the largest increase in inflammatory infiltrate was observed in TcVac1_IDE/Tc mice when compared with TcVac1_IM/Tc or non-vaccinated/infected mice. The extent of tissue inflammatory infiltrate was directly associated with the control of tissue amastigote nests in vaccinated/infected (vs. non-vaccinated/infected) mice. Our results suggest that IDE delivery improves the protective efficacy of TcVac1 vaccine against T. cruzi infection in mice when compared with IM delivery of the vaccine.     

Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system

The advantages of intradermal (ID) vaccine administration have been well documented but difficulties in performing ID vaccination using existing techniques and equipment have limited it's clinical application. In the present study, a new ID injection technique and associated microinjection system is described and evaluated in a swine and Human models. Clinical investigation models included: injection site imaging (X-ray and 3D ultrasound echography), histological examination of injection sites, fluid injection volume accuracy measurement, subject’ perceived pain and local skin reactivity were specifically developed. These evaluations showed that microinjection system can make the practice of ID vaccination easy to perform, reliable and safe, thus setting the stage for broader clinical application of ID vaccine delivery.     

A phase I evaluation of inactivated influenza A/H5N1 vaccine administered by the intradermal or the intramuscular route

In a phase I clinical trial, one hundred healthy young adults were randomized to receive two doses 28 days apart of an inactivated, subvirion vaccine containing 15 or 45 μg of influenza A/H5N1 hemagglutinin (HA) by the intramuscular (IM) route, or 3 or 9 μg of H5 HA by the intradermal(ID) route. Seventy-seven subjects received a third dose. All regimens were safe and well tolerated. Antibody responses after two or three doses were low (≤20% or ≤38%, respectively) and similar in groups given 3 or 9 μg ID or 15 μg IM, and were significantly lower than those given 45 μg IM. Higher dosages of H5 HA and/or inclusion of adjuvant will be required to enhance immunogenicity by the ID route.     

Laser-assisted intradermal delivery of a microparticle vaccine for respiratory syncytial virus induces a robust immune response

Respiratory syncytial virus (RSV) is an infectious disease that poses a significant public health risk in young children. Vaccine studies conducted in the 1960s using an intramuscular injection of formalin-inactivated respiratory syncytial virus (Fi-RSV) resulted in an enhanced respiratory disease and led to the failure of the vaccine. Thus, the virus-like particles (VLP) of the RSV fusion (F) protein was used as the vaccine antigen in this study. The F-VLP was encapsulated in a microparticle (MP) matrix composed of cross-linked bovine serum albumin (BSA) to enhance the antigen presentation and uptake. Moreover, a painless vaccination method would be desirable for an infectious disease that mainly affects young children. Thus, an ablative laser device, Precise Laser Epidermal System (P.L.E.A.S.E), was utilized to create micropores on the skin for vaccine delivery. We observed enhanced antigen presentation of the vaccine microparticles (F-VLP MP) with and without the adjuvant monophosphoryl lipid A (MPL-A) MP in dendritic cells. Consequently, Swiss Webster mice were immunized with the adjuvanted vaccine microparticles using the P.L.E.A.S.E laser to study the in vivo immunogenicity. The immunized mice had high serum immunoglobulin (IgG, IgG2a) levels, indicating a Th1 response. Subsequent analysis of lung homogenates post- RSV challenge revealed high IgA, indicating generation of a mucosal immune response upon intradermal immunization. Flowcytometry analysis showed high CD8+, and CD4+ expression in the lymph node and spleen of the adjuvanted vaccine microparticle immunized mice. Increased expression of interferon gamma (IFN-γ) in the spleen cells further proved Th1 polarized immune response. Finally, an immune plaque assay indicated significantly low lung viral titer in the mice immunized with intradermal adjuvanted vaccine microparticles. Thus, ablative laser-assisted immunization with the F-VLP based adjuvanted vaccine microparticles could be a promising vaccine candidate for RSV.     

A phase 1 study of safety and immunogenicity following intradermal administration of a tetravalent dengue vaccine candidate

BackgroundAs part of the ongoing search for an effective dengue vaccine, Takeda performed a phase 1b study to investigate the safety and immunogenicity of an early low-dose tetravalent dengue vaccine candidate formulation (LD-TDV), based on an attenuated serotype 2 backbone, when administered intradermally with an injector device (PharmaJet®), or needle-syringe.MethodsThe study was performed in two centers in the US, in healthy 18–45 year old subjects with no history of dengue vaccination or disease. One or two vaccine doses were given on Day 0, and another dose or placebo on Day 90. Neutralizing antibodies were measured up to Day 270; safety was assessed as laboratory measurements and solicited and unsolicited adverse events on diary cards.ResultsChanges in World Health Organization prequalification guidance for new vaccines concerning storage conditions favored the use of lyophilized preparations, and led to the early cessation of enrolment, but not before 67 subjects were enrolled in four treatment groups. Sixty-five subjects completed the planned schedule. There were no safety signals or serious adverse events. All vaccination regimens elicited neutralizing antibodies. Titers of neutralizing antibodies against serotypes 1 and 2 were higher than those against serotypes 3 and 4. There were no consistent increases in responses with two doses given either concomitantly or 90 days apart.ConclusionsSimultaneous injection of two LD-TDV doses was shown to have the potential to improve seroconversion rates to serotypes 1 and 2, and to increase serotype 2 antibody titers. A primary dose of LD-TDV administered by PharmaJet was shown to induce more rapid seroconversion to serotypes 1, 2, and 3 compared with administration by needle-syringe (ClinicalTrials.gov: NCT01765426).     

Comparative immunogenicity of trivalent influenza vaccine administered by intradermal or intramuscular route in healthy adults

The present study was undertaken with controls using equal doses ID and IM plus the standard full dose IM to assess the role of route of vaccine in immunogenicity of inactivated influenza vaccine. The study was a prospective, randomized, active-controlled, open label clinical trial conducted in healthy young adult outpatients to compare the effect of route (IM versus ID) on antibody responses to influenza vaccine. Volunteers received 3, 6 or 9 microg of vaccine by ID or IM route; 15 microg IM was also studied. Low doses of vaccine given by either route were almost as immunogenic as the standard 15 microg IM dose of influenza vaccine. ID route was not superior to IM vaccine at inducing antibodies. ID vaccine induced significantly more local inflammatory response than IM vaccine.     

Immunogenicity comparison of the intradermal or endobronchial boosting of BCG vaccinates with Ad5-85A

Experiments in small animal models have indicated that intranasal vaccination confers a greater degree of protection against TB than other routes such as intradermal (i.d.) or intramuscular. In this work, using a prime-boost vaccination strategy, we have compared in cattle vaccinated with BCG as a priming vaccine the boosting capabilities of Ad5-85A delivered either via the endobronchial (e.b.) or i.d. route. We show that Ad5-85A delivered through either route induced comparable peripheral blood antigen specific responses, and that both i.d. and e.b. routes induced bronchioalveolar lavage cells (BALC) that produced antigen-specific IFNgamma. We also show that, regardless of the route of boosting, the kinetics of peripheral blood and BALC responses, as assessed by antigen specific IFNgamma production, are different with systemic responses being detectable earlier than mucosal responses. These results contribute to our understanding on how different vaccination strategies may affect different compartments of the immune response and in turn to the development of safer and more effective vaccines.     

Acceptability of an inactivated influenza vaccine delivered by microneedle patch: Results from a phase I clinical trial of safety,reactogenicity, and immunogenicity

ObjectiveThis study sought to evaluate the acceptability of inactivated influenza vaccine delivered by microneedle patch (MNP) in comparison to inactivated influenza vaccine (IIV) delivered by hypodermic needle.Design, Setting, and Participants.From the general population of Atlanta, Georgia, we screened 112 and enrolled 100 healthy adult subjects ages 18 to 49 years.Main Outcome(s) and Measure(s).Our participants were randomized to 4 groups of 25 per arm: (1) IIV by MNP administered by healthcare worker (HCW), (2) IIV by MNP self-administered by study participants, (3) IIV by intramuscular (IM) injection administered by HCW or (4) placebo by MNP administered by HCW. We administered four questionnaires: at Day 0 before and after study product delivery, and at Days 8 and 28.ResultsAt baseline, 98.6% of participants receiving MNP vaccination reported an overall positive experience with MNPs, compared to 86.4% for participants receiving IM vaccination. For future influenza vaccination, study participants (N = 99) preferred MNP (n = 65, 69.9%) to injections or nasal spray (n = 20, 21.5%), and the preference for MNP increased from Day 0 to Day 28. Factor analyses resulted in two scaled measures including MNP Use Perceptions (a = 0.799, n = 5 items) and MNP Perceived Convenience (a = 0.844, n = 4 items) that were included in longitudinal assessments; while findings reflect significant differences across treatment groups on mean scores for ease of use, MNP perceived protection, MNP reliability, and MNP selection knowledge, all groups reported their belief that influenza vaccination by MNP would be reliable and protective, as well as easy-to-use and convenient.Conclusions and RelevanceMost participants were accepting of IIV vaccination by MNP and preferred it to injection. Delivery of IIV by MNP may help increase vaccination coverage.     

A randomized,double-blind,dose-finding Phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE

IMVAMUNE^® is a Modified Vaccinia Ankara (MVA)-based virus that is being developed as a safer 3rd generation smallpox vaccine. In order to determine the optimal dose for further development, a double-blind, randomized Phase II trial was performed testing three different doses of IMVAMUNE^® in 164 healthy volunteers. All three IMVAMUNE^® doses displayed a favourable safety profile, with local reactions as the most frequent observation. The 1 × 10⁸ TCID₅₀ IMVAMUNE^® dose induced a total antibody response in 94% of the subjects following the first vaccination and the highest peak seroconversion rates by ELISA (100%) and PRNT (71%). This IMVAMUNE^® dose was considered to be optimal for the further clinical development of this highly attenuated poxvirus as a safer smallpox vaccine.