Separate Injection Sites Research Articles

Efficacy and tolerability Aripiprazole once-monthly long-acting injectable in schizophrenia. Two-injection start regimen

IntroductionAripiprazole once-monthly is a long-acting intramuscular injectable formulation of aripiprazole. The starting dose can be administered by following one of two regimens: • One injection start: On the day of initiation, administer one injection of 400 mg Aripiprazole once monthly and continue treatment with 10 mg to 20 mg oral aripiprazole per day for 14 consecutive days • Two injection start (New regimen): On the day of initiation, administer two separate injections of 400 mg Aripiprazole once monthly at separate injection sites, along with one 20 mg dose of oral aripiprazole.ObjectivesTo assess the effectiveness and tolerability of Aripiprazole long-acting injectable (ALAI) in patients with schizophrenia. The starting dose was administered following the two injection start regimenMethodsSample:10 patients with schizophrenia (DSM 5 criteria) who started treatment with ALAI. The starting dose was administered following the two injection start regimen. On a tri-monthly basis, the following evaluations were performed during a follow-up period of 6 months: The Clinical Global Impression-Schizophrenia scale (CGI-SCH), treatment adherence, the number of hospitalizations and Side effects reportedResultsMean variations from baseline scores at 6 months was (-1.1 ±0.89) on the GCI-SCH. The percentage of patients who remained free of admissions at the end of the 6 months was 90%. The rate of adherence to treatment after 6 months was 80%. The most frequent side effect was transient mild insomnia (20%) .ConclusionsAripiprazole long-acting injectable (The starting dose was administered following the two injection start regimen) is effective, safe and well tolerated in clinical practice conditionsDisclosureNo significant relationships.

Botulinum Toxin for Chronic Lateral Epicondylitis (LE).

Lateral epicondylitis is a common disease in orthopaedic practice. Although the majority of cases do not become chronic, patients who do not respond to the initial treatment may suffer from pain in the long term and effective treatment is challenging. The off-label use of botulinum toxin is one of the common potential indications for the substance in orthopaedics and traumatology. In a literature review of 2000 - 2019, eight EBM ≥ level 3 studies evaluating the use of botulinum toxin in lateral epicondylitis were found. Five of these studies evaluated botulinum toxin versus placebo in chronic cases; two other studies compared botulinum toxin with corticosteroids in acute cases and classic Hohmann surgery in chronic cases; the eighth study compared botulinum toxin in two different injection sites and corticosteroids by classic injection. Our findings suggest that the use of this substance may be a treatment option in refractory chronic cases before surgery is indicated. The working group on botulinum toxin in O & T of the International Musculoskeletal Pain Society (IMPS/IGOST) introduced an alternative injection schedule, which combines findings from the recent clinical literature with practical experience in order to reduce the risk of side effects while ensuring treatment effectiveness. Using 2 simple tests of function and, if necessary, sonographic verification, 2 separate injection sites in the extensor carpi radialis or the extensor digitorum can be identified by palpation. The tendon level on the lateral epicondyle acts as the third injection site. With optimal use of the ampoule content, the 3 injection sites can be infiltrated individually, depending on the muscle status. On the one hand, this enables treatment to take place after a dual therapy approach and, on the other hand, the risk of overdose in a muscle with subsequent unnecessary muscle weakening can be reduced.

The Potency of an Anti-MERS Coronavirus Subunit Vaccine Depends on a Unique Combinatorial Adjuvant Formulation.

Vaccination is one of the most successful strategies to prevent human infectious diseases. Combinatorial adjuvants have gained increasing interest as they can stimulate multiple immune pathways and enhance the vaccine efficacy of subunit vaccines. We investigated the adjuvanticity of Aluminum (alum) in combination with rASP-1, a protein adjuvant, using the Middle East respiratory syndrome coronavirus MERS-CoV receptor-binding-domain (RBD) vaccine antigen. A highly enhanced anti-MERS-CoV neutralizing antibody response was induced when mice were immunized with rASP-1 and the alum-adjuvanted RBD vaccine in two separate injection sites as compared to mice immunized with RBD + rASP-1 + alum formulated into a single inoculum. The antibodies produced also significantly inhibited the binding of RBD to its cell-associated receptor. Moreover, immunization with rASP-1 co-administered with the alum-adjuvanted RBD vaccine in separate sites resulted in an enhanced frequency of TfH and GC B cells within the draining lymph nodes, both of which were positively associated with the titers of the neutralizing antibody response related to anti-MERS-CoV protective immunity. Our findings not only indicate that this unique combinatorial adjuvanted RBD vaccine regimen improved the immunogenicity of RBD, but also point to the importance of utilizing combinatorial adjuvants for the induction of synergistic protective immune responses.

Clinical efficacy of clodronic acid in horses diagnosed with navicular syndrome: A field study using objective and subjective lameness evaluation

Navicular syndrome, a common cause of equine forelimb lameness, is associated with pathological changes in the navicular bone. Consequently, administration of bisphosphonates (BPs) has been advocated in order to modify the rate of bone turnover. The present study aimed to assess the clinical efficacy of intramuscularly administered clodronic acid for the treatment of 11 horses with clinical and radiographic findings compatible with navicular syndrome. Magnetic resonance imaging was performed in 5 of the 11 horses. The animals were treated with an intramuscular dose of clodronic acid of 765 mg/horse, administered over three separate injection sites. Before and at 7, 30 and 90 days after treatment, horses were subjected to lameness and accelerometric evaluations. A clinical improvement was observed in 6 of the 11 horses. These 6 horses showed a mean reduction of two degrees in lameness score. Accelerometry in these horses revealed increased velocity, stride length, stride regularity and dorsoventral displacement of the gravity of centre together with a reduction in stride frequency, suggesting a gait improvement. This study demonstrates that intramuscular clodronic acid can be useful for lameness reduction in some horses with navicular syndrome.

Effect of Mesenchymal Stem Cells and Chicken Embryo Extract on Flap Viability and Mast Cells in Rat Skin Flaps

ABSTRACTStudy Objective: We investigated the effect of bone marrow mesenchymal stem cells (BMMSCs) and chicken embryo extract (CEE), alone and in combination, on tissue viability of skin flaps, and mast cells (MCs), in an experimental random skin flap (RSF) rat model. Materials and Methods: A 30 mm × 80 mm RSF was made on the dorsum of each of the forty rats, which were then divided into four groups. One group did not receive any treatment and served as the control, the second group received BMMSCs, the third group received CEE + BMMSCs, and the fourth group received CEE. For BMMSC treatment, 6 × 109 BMMSCs were injected into twelve separate injection sites of each flap. Seven days after RSF surgery, the remaining viable part of each flap was measured and examined to determine the number of blood vessels, MCs, and degranulated MCs. Results: The CEE, CEE + BMMSC, and BMMSC groups displayed significantly higher levels of flap viability (ANOVA test: p = 0.000; LSD test for all groups: p = 0.000), and a greater number of vessels (ANOVA test: p = 0.000; LSD test: p = 0.000, 0.002, and 0.012, respectively), compared with the control group. The flap viability was poorer in the BMMSC group than in the CEE and CEE + BMMSC groups. The BMMSC group also had a greater number of degranulated and total MCs, compared with the CEE and CEE + BMMSC groups. Conclusions: We observed biostimulatory effects of BMMSCs, CEE, and CEE + BMMSCs on flap viability and vessel numbers, compared to the control group. MCs produced in response to BMMSC treatment have an inhibitory effect on the RSFs survival in an ischemic tissue model.

Immunogenicity and safety of zoster vaccine live administered with quadrivalent influenza virus vaccine

ObjectivesRandomized, blinded, placebo-controlled trial to evaluate the safety and immunogenicity of ZOSTAVAX™ (ZV) administered concomitantly with quadrivalent inactivated influenza vaccine (IIV4) in adults≥50years of age (NCT02519855). MethodsOverall, 440 participants were randomized into the Concomitant Group (CG) and 442 into the Sequential Group (SG). The CG received ZV and IIV4 at separate injection sites on Day 1 and matching placebo at Week 4. The SG received placebo and IIV4 (2015–2016 influenza season) at separate injection sites on Day 1 and ZV at Week 4. Immunogenicity endpointsVaricella-zoster virus (VZV) antibody geometric mean titer (GMT) and geometric mean fold-rise (GMFR) from baseline to 4weeks postvaccination, measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and adjusted for age and prevaccination titer. Influenza strain-specific GMT at baseline and 4weeks postvaccination was measured by hemagglutination inhibition (HAI) assay. Safety endpointsInjection-site and systemic adverse experiences (AEs) within 28days following any vaccination and serious AEs throughout the study. ResultsThe adjusted VZV antibody GMT ratio (CG/SG) was 0.87 (95%CI: 0.80, 0.95), meeting the prespecified noninferiority criterion. The VZV antibody GMFR in the CG was 1.9 (95%CI: 1.76, 2.05), meeting the acceptability criterion. Influenza antibody GMT ratios for A/H1N1, A/H3N2, B/Yamagata and B/Victoria were 1.02 (95%CI: 0.88, 1.18), 1.10 (95%CI: 0.94, 1.29), 1.00 (95%CI: 0.88, 1.14), and 0.99 (95%CI: 0.87, 1.13), respectively. The frequency of vaccine-related injection-site and systemic AEs was comparable between groups. No vaccine-related serious AE was observed. ConclusionThe concomitant administration of ZV and IIV4 to adults≥50years of age induced VZV-specific and influenza-specific antibody responses that were comparable to those following administration of either vaccine alone, and was generally well tolerated.

Botulinum Toxin Type A Injections for the Treatment of Continent Catheterizable Ileal-colic Urinary Diversion Muscularis Overactivity

Continent catheterizable diversions can exhibit long-term complications such as high pressures and involuntary unit contractions within the urinary reservoir, rendering them similar to neurogenic bladders. Given the similarity of these issues to neurogenic detrusor overactivity, the use of Botox injections is a logical treatment option to explore. A patient with a contracted Indiana pouch continent catheterizable diversion was treated with intra-pouch Botox injections after failing maximal doses of oral anticholinergic medications. This patient underwent four consecutive percutaneous Botox pouch injections every 11-12 months under general anesthesia. Flexible cystoscope via the catch stoma was attempted first on the first two surgeries, but the scope could not reach the majority of the pouch. Thus, percutaneous access was obtained under fluoroscopic guidance, and the injections were performed through a suprapubic tube access sheath. Two hundred to four hundred units of Botox (stained with methylene blue) were visually injected in 20-40 separate injection sites. Of note, the initial dose used was 200 units and was increased to 300 units then 400 units on subsequent treatments to improve results and durability. After each round of Botox injections, the patient noted resolution of her symptoms. Postinjection urodynamic studies showed normal filling with no evidence of muscularis overactivity, even at high volumes of 600 cc. Botox injections may be an excellent long-term treatment option for contracted continent catheterizable diversions, or at least used as a temporizing measure before surgical augmentation. Further studies are needed to verify the durability, complications, and long-term outcomes of this procedure.

450. A Single Immunization With Optimized DNA Vaccines Protects Against Lethal Ebola Virus Challenge in Mice and Induces Seroconversion in Non-Human Primates Following a DNA Prime–DNA Boost Approach

Ebola is a hemorrhagic fever virus that is responsible for the severe, ongoing outbreak in West Africa, with over 21000 confirmed cases and a mortality rate of >39%. Control of the outbreak has been a considerable challenge as there are no approved vaccines or therapies. Recent reports suggest that the outbreak is more severe than previously thought and investigating alternative immunization approaches would be of great benefit. We generated 3 DNA vector vaccine candidates expressing the Zaire ebolavirus (EBOV) glycoprotein (GP): 2 vaccines designed based on consensus sequences of EBOV GPs (1976-2014) and a 3rd matched construct to a 2014 Guinea strain. Immunogenicity and protection was first evaluated in mice, followed by studies in non-human primates (NHP). BALB/c mice received a single immunization of each DNA vaccine (40mg), delivered by intramuscular injection followed by electroporation (IM-EP). We also co-administered 2 or 3 construct formulations of DNA vaccines as an alternative strategy to broaden efficacy against antigenically distant EBOV strains. All 3 single and all co-formulated vaccines generated strong T cell responses, including GP-specific polyfunctional CD4+ and CD8+ T cells secreting IFNγ, TNFα, and IL2. BALB/c mice (n=10/group) were challenged with a lethal dose of a heterologous mouse-adapted Mayinga 1976 EBOV strain. The two consensus DNA vaccines and 2 and 3 vaccine combinations were 100% protective in mice. The matched vaccine afforded 90% protection. Total GP-specific IgG levels were high in all surviving mice and low in unprotected animals suggesting that titers may correlate with therapeutic efficacy. As all 3 DNA vaccines were immunogenic and no antigen interference was observed, we next investigated immunogenicity of the 3 DNA vaccines in rhesus macaques following a DNA-DNA prime-boost immunization regimen. Macaques (n=5/group) received by IM-EP delivery:1) matched vaccine (4mg), 2) 3-construct formulation administered at a single injection site (2mg/vaccine), 3) 3-construct formulation delivered at separate injection sites (2mg/vaccine), or 4) 3-construct formulation combined with IL12 adjuvant (2mg/vaccine). Each immunization was followed by 3 subsequent DNA boosts at 1 month intervals. All groups had high GP-specific total IgG titers post-1st boost immunization that continued to increase over subsequent boosts and detectable T-cell responses. Overall, these studies demonstrate that a DNA-DNA prime-boost regimen can effectively induce seroconversion in NHPs and further studies will serve to evaluate protective immunogenicity. This approach not only serves as a tool to better understand the immune responses associated with protection against EBOV infection, but also has potential for translation towards human applications.

Short conserved sequences of HIV-1 are highly immunogenic and shift immunodominance.

Cellular immunity is pivotal in HIV-1 pathogenesis but is hampered by viral sequence diversity. An approach to minimize this diversity is to focus immunity on conserved proteome sequences; therefore, we selected four relatively conserved regions (Gag amino acids 148 to 214 and 250 to 335, Env amino acids 521 to 606, and Nef amino acids 106 to 148), each created in three mosaics, to provide better coverage of M-group HIV-1 sequences. A conserved-region vaccine (CRV) delivering genes for these four regions as equal mixtures of three mosaics each (each region at a separate injection site) was compared to a whole-protein vaccine (WPV) delivering equimolar amounts of genes for whole Gag, Env, and Nef as clade B consensus sequences (separate injection sites). Three rhesus macaques were vaccinated via three DNA primes and a recombinant adenovirus type 5 boost (weeks 0, 4, 8, and 24, respectively). Although CRV inserts were about one-fifth that of WPV, the CRV generated comparable-magnitude blood CD4+ and CD8+ T lymphocyte responses against Gag, Env, and Nef. WPV responses preferentially targeted proteome areas outside the selected conserved regions in direct proportion to sequence lengths, indicating similar immunogenicities for the conserved regions and the outside regions. The CRV yielded a conserved-region targeting density that was approximately 5-fold higher than that of the WPV. A similar pattern was seen for bronchoalveolar lymphocytes, but with quadruple the magnitudes seen in blood. Overall, these findings demonstrate that the selected conserved regions are highly immunogenic and that anatomically isolated vaccinations with these regions focus immunodominance compared to the case for full-length protein vaccination. HIV-1 sequence diversity is a major barrier limiting the capability of cellular immunity to contain infection and the ability of vaccines to match circulating viral sequences. To date, vaccines tested in humans have delivered whole proteins or genes for whole proteins, and it is unclear whether including only conserved sequences would yield sufficient cellular immunogenicity. We tested a vaccine delivering genes for four small conserved HIV-1 regions compared to a control vaccine with genes for whole Gag, Env, and Nef. Although the conserved regions ranged from 43 to 86 amino acids and comprised less than one-fifth of the whole Gag/Env/Nef sequence, the vaccines elicited equivalent total magnitudes of both CD4+ and CD8+ T lymphocyte responses. These data demonstrate the immunogenicity of these small conserved regions and the potential for a vaccine to steer immunodominance toward conserved epitopes.

Immunologic responses of beef calves to concurrent application of modified-live viral vaccine (intranasal and systemic administration) and systemically administered Mannheimia haemolytica bacterin-leukotoxoid.

A study was conducted to assess the immunological response to a Mannheimia haemolytica bacterin-leukotoxoid, given separately or concurrently with a multivalent intranasally administered modified-live viral vaccine to range beef calves. Initially 202 spring-born calves were screened for infectious bovine rhinotracheitis (IBR), bovine respiratory syncytial virus (BRSV), and M. haemolytica leukotoxin antibody titers on day-30. A total of 154 calves with day 0 geometric mean IBR titers of <1:6 were accepted into the study. Fifty-one calves were assigned to treatment group T1 (M. haemolytica bacterin-leukotoxoid only; One Shot®, Pfizer Animal Health, New York, NY) and 51 calves were assigned to group T2 (intranasal modified-live virus (MLV) bovine herpesvirus-1 (BHV-1) and parainfluenza-3 (PI3) vaccine; TSV-2®, Pfizer Animal Health) and M. haemolytica bacterin-leukotoxoid (One Shot®). Fifty-two calves were assigned to group T3 intranasal MLV BHV-1, PI3, and BRSV vaccine (INFORCETM 3, Pfizer Animal Health) and M. haemolytica bacterin-leukotoxoid (One Shot®). On day 0, all study calves were administered their assigned vaccine. On day 91, all calves in the study were administered a pentavalent MLV vaccine containing BHV-1, BVD types 1 and 2, BRSV, and PI3 antigens (Bovi-Shield GOLD® 5, Pfizer Animal Health) and M. haemolytica bacterin-leukotoxoid (One Shot®) at separate injection sites. On days 0, 14, 28, 91, and 112, blood samples were collected, serum separated, and held frozen until completion of the study, at which time samples were evaluated for IBR and BRSV serum neutralization antibody titers and M. haemolytica leukotoxin antibody concentrations. Results demonstrated concurrent administration of the intranasal vaccines and the M. haemolytica bacterin-leukotoxoid did not affect the bacterin-leukotoxoid serological response. Calves vaccinated with intranasal BRSV vaccine had a significant (P less than 0.05) increase in BRSV antibody response when revaccinated systemically with injectable 5-way MLV vaccine 90 days later. Vaccination with M. haemolytica bacterin-leukotoxoid at approximately eight weeks of age resulted in a statistically significant (P less than 0.05) anamnestic response following revaccination 90 days later.

Immunogenicity, Reactogenicity and Safety of a Combined DTPa-IPV Vaccine Compared with Separate DTPa and IPV Vaccines in Healthy Korean Infants

Purpose : To compare immunogenicity and reactogenicity of a combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (DTPa-IPV, IPV, GlaxoSmithKline Biologicals) with co-administration of commercially available DTPa and IPV vaccines at separate injection sites (DTPa+IPV). Methods : A total of 458 infants aged 8-12 weeks were randomized to receive three-ose primary vaccination at 2, 4 and 6 months with DTPa-IPV or DTPa+IPV. Blood samples were collected pre and post vaccination for measurement of immune responses. Reactogenicity was assessed following each dose using diary cards. Results : One month post-dose 3, seroprotection rates for anti-diphtheria, anti-tetanus and anti-poliovirus types 1, 2 and 3 were and vaccine response rates to pertussis antigens were at least 98.6% in both DTPa-IPV and DTPa + IPV groups. Non-inferiority between the groups was demonstrated based on pre-defined statistical criteria. Incidences of both local and systemic symptoms were within the same range across both groups with grade 3 symptoms reported following no more than 4.3% of DTPa-IPV doses and 4.5% of DTPa + IPV doses. Two serious adverse events (both pyrexia) after DTPa-IPV administration were considered vaccine-related. Both infants recovered fully. Conclusion : Combined DTPa-IPV vaccine was immunogenic and well tolerated when used as a three-dose primary vaccination course in Korean infants. DTPa-IPV could be incorporated into the Korean vaccination schedule, reducing the number of injections required to complete primary immunization.

Immunogenicity and safety of concomitant administration of a measles, mumps and rubella vaccine (M-M-RvaxPro®) and a varicella vaccine (VARIVAX®) by intramuscular or subcutaneous routes at separate injection sites: a randomised clinical trial

BackgroundWhen this trial was initiated, the combined measles, mumps and rubella (MMR) vaccine was licensed for subcutaneous administration in all European countries and for intramuscular administration in some countries, whereas varicella vaccine was licensed only for subcutaneous administration. This study evaluated the intramuscular administration of an MMR vaccine (M-M-RvaxPro®) and a varicella vaccine (VARIVAX®) compared with the subcutaneous route.MethodsAn open-label randomised trial was performed in France and Germany. Healthy children, aged 12 to18 months, received single injections of M-M-RvaxPro and VARIVAX concomitantly at separate injection sites. Both vaccines were administered either intramuscularly (IM group, n = 374) or subcutaneously (SC group, n = 378). Immunogenicity was assessed before vaccination and 42 days after vaccination. Injection-site erythema, swelling and pain were recorded from days 0 to 4 after vaccination. Body temperature was monitored daily between 0 and 42 days after vaccination. Other adverse events were recorded up to 42 days after vaccination and serious adverse events until the second study visit.ResultsAntibody response rates at day 42 in the per-protocol set of children initially seronegative to measles, mumps, rubella or varicella were similar between the IM and SC groups for all four antigens. Response rates were 94 to 96% for measles, 98% for both mumps and rubella and 86 to 88% for varicella. For children initially seronegative to varicella, 99% achieved the seroconversion threshold (antibody concentrations of ≥ 1.25 gpELISA units/ml). Erythema and swelling were the most frequently reported injection-site reactions for both vaccines. Most injection-site reactions were of mild intensity or small size (≤ 2.5 cm). There was a trend for lower rates of injection-site erythema and swelling in the IM group. The incidence and nature of systemic adverse events were comparable for the two routes of administration, except varicella-like rashes, which were less frequent in the IM group.ConclusionThe immunogenicities of M-M-RvaxPro and VARIVAX administered by the intramuscular route were comparable with those following subcutaneous administration, and the tolerability of the two vaccines was comparable regardless of administration route. Integration of both administration routes in the current European indications for the two vaccines will now allow physicians in Europe to choose their preferred administration route in routine clinical practice.Trial registrationClinicalTrials.gov NCT00432523

IMMUNOGENICITY AND SAFETY OF CONCOMITANT ADMINISTRATION OF MEASLES-MUMPS-RUBELLA VACCINE AND VARICELLA VACCINE BY THE INTRAMUSCULAR OR SUBCUTANEOUS ROUTE

INTRODUCTION: In Europe, recommended administration route for vaccines and physicians' preferences vary. OBJECTIVE: The aim of this study was to compare the immunogenicity and safety profile (injection-site and systemic adverse events) of a measles-mumps-rubella vaccine (M-M-RvaxPRO) and a varicella vaccine (Varivax) when given by intramuscular or subcutaneous route. METHODS: A total of 752 healthy children who were 12 to 18 months of age were randomly assigned to receive concomitantly at 2 separate injection sites 1 dose of both vaccines by the same route, either intramuscular or subcutaneous. RESULTS: Six weeks after vaccination, response rates in patients who were initially seronegative were similar for all antigens (intramuscular noninferior to subcutaneous), and geometric mean titers were comparable irrespective of the administration route (Table 1). Similar numbers and types of systemic adverse events were observed in both groups, excepted for varicella/varicella-like rashes, which were less frequent in the intramuscular group. Injection-site reactions were also less frequent for both vaccines in the intramuscular group compared with the subcutaneous group (15.8% and 25.8% of patients for M-M-RvaxPRO and 20.9% and 34.3% for Varivax, respectively), but the safety pattern was comparable between groups. CONCLUSIONS: These results support both intramuscular and subcutaneous administration routes for M-M-RvaxPRO and Varivax. TABLE 1.Response Rates and Geometric Mean Titers of the Measles-Mumps-Rubella and Varicella Vaccines When Given by Different RoutesPer-Protocol AnalysisIntramuscularSubcutaneous n Relative Risk, %GMTs n Relative Risk, %GMTsMeasles, ≥255 mIU/mL34994.32396.436396.12560.6Mumps, ≥10 ELISA Ab U/mL34997.786.436398.189.8Rubella, ≥10 IU/mL32198.197.231898.194.4Varicella ≥5 gpELISA U/mL33688.49.834585.59.2 ≥1.25 gpELISA U/mL33698.59.834599.49.2

Safety and Immunogenicity Profile of the Concomitant Administration of ZOSTAVAX and Inactivated Influenza Vaccine in Adults Aged 50 and Older

To evaluate the safety and immunogenicity of ZOSTAVAX administered concomitantly with inactivated influenza vaccine or sequentially in adults aged 50 and older. Randomized, blinded, placebo-controlled study. Thirteen U.S. and seven European study sites. Three hundred eighty-two concomitantly, 380 sequentially vaccinated subjects. The concomitant vaccination group received influenza vaccine and ZOSTAVAX at separate injection sites on Day 1 and placebo at Week 4. The nonconcomitant vaccination group received influenza vaccine and placebo at separate injection sites on Day 1 and ZOSTAVAX at Week 4. Primary safety endpoints: vaccine-related serious adverse experiences (AEs) within 28 days postvaccination (PV); and diary card-prompted local and systemic AEs. Primary immunogenicity endpoints: geometric mean titer (GMT) and geometric mean fold rise (GMFR) from baseline of varicella-zoster virus (VZV) antibody (Ab) at 4 weeks PV according to glycoprotein enzyme-linked immunosorbent assay (gpELISA) and GMT of influenza Ab for the three vaccine strains (2005-2006 influenza season) at 4 weeks PV according to hemagglutination inhibition assay. Secondary immunogenicity endpoint: influenza seroconversion rates (SCRs). No serious AEs related to ZOSTAVAX were observed during the study. VZV Ab GMTs 4 weeks PV for the concomitant and sequential groups were 554 and 597 gpELISA U/mL, respectively. The estimated VZV Ab GMT ratio was 0.9 (95% confidence interval (CI)=0.8-1.0), indicating noninferior (P<.001 for the null hypothesis of GMT ratio <0.67) responses. Estimated VZV Ab GMFR from baseline in the concomitant group was 2.1 (95% CI=2.0-2.3), indicating acceptable fold rise. Estimated GMT ratios (concomitant/sequential) for influenza strains A(H1N1), A(H3N2), and B were 0.9 (95% CI=0.8-1.1), 1.1 (95% CI=0.9-1.3), and 0.9 (95% CI=0.8-1.1), respectively, and SCRs were comparable across both groups, with more than 85% achieving titers of 1:40 or greater, meeting regulatory criteria. ZOSTAVAX and influenza vaccine given concomitantly are generally well tolerated in adults aged 50 and older. Ab responses were similar whether ZOSTAVAX and influenza vaccine were given concomitantly or sequentially.

One-year post-primary antibody persistence and booster immune response to a fully liquid five-component acellular pertussis, diphtheria, tetanus, inactivated poliomyelitis, Haemophilus influenzae type b conjugate vaccine

To evaluate antibody persistence one year after three-dose primary vaccination and booster immune response during the second year of life for a fully liquid diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis-Haemophilus influenzae type b (DTaP-IPV-PRP approximately T) vaccine. Infants at 18-19 months of age were given a booster dose of either DTaP-IPV-PRP approximately T (group A) or DTaP-IPV plus PRP approximately T at separate injection sites (group B), after primary vaccination at two, four and six months of age, with the same vaccines. Antibody concentrations were measured pre- and post-booster. Reactogenicity and safety were evaluated from parent reports. Before the booster dose, 93.1% of group A and 95.1% of group B children still had anti-PRP antibody titers > or =0.15 microg/ml. All children had antibody levels believed to protect against tetanus, polio 1 (except one subject in group B), polio 2, polio 3, and diphtheria (except one subject in group A). At least 94% of children still had antibody concentrations > or =5 ELISA units (EU) to pertussis antigens (pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin (PRN), fimbriae 2 and 3 (FIM2+3)). One month after the booster dose, all subjects achieved antibody concentrations or titers believed to be protective for PRP (polyribose ribitol phosphate)(> or =1 microg/ml), diphtheria and tetanus (> or =0.1 IU/ml) and poliovirus types 1, 2, and 3 (> or =81/dil.), and at least 90.5% of subjects had four-fold increases in antibody concentrations to pertussis antigens following the booster. Anti-PRP geometric mean titers (GMTs) increased from 1.07 to 59.6 microg/ml and from 1.8 to 62.2 microg/ml in groups A and B, respectively. Both vaccine groups showed low reactogenicity rates. The fully liquid pentavalent DTaP-IPV-PRP approximately T vaccine is highly immunogenic, with good antibody persistence for each antigen approximately one year after primary vaccination and strong booster responses at 18-19 months of age. Because this combined vaccine is fully liquid, requiring no reconstitution of lyophilized PRP approximately T, the ease of use and proper administration are improved.

The Safety and Immunogenicity of a Quadrivalent Measles, Mumps, Rubella and Varicella Vaccine in Healthy Children

This clinical trial was conducted to demonstrate that each of 3 consistency lots of a combined measles, mumps, rubella and varicella vaccine (MMRV) would be well tolerated, induce clinically acceptable and similar immune responses to each antigen and induce immune responses similar to measles, mumps and rubella vaccine (MMR) administered concomitantly with varicella vaccine (V). An additional objective was to evaluate the persistence of antibodies 1 year postvaccination. Study participants 12 to 23 months of age received a single injection of either one of 3 consistency lots of MMRV or MMR + V administered at separate injection sites. A total of 3,928 healthy children were enrolled at study sites in the United States and Canada. Immune responses to measles, mumps, rubella and varicella in children immunized with each of 3 lots of MMRV were similar and the combined response to all 3 lots was comparable to that of the control group. The 1-year antibody persistence rates for measles, mumps, rubella and varicella viruses were each greater than 95% and comparable among the recipients of the 3 consistency lots of MMRV and the control group. All vaccines were generally well tolerated during the 42 days after vaccination and the overall incidence of adverse experiences was comparable between recipients of MMRV and MMR + V. Rates of fever (temperature >or=38.9 degrees C oral equivalent or tactile) were greater in recipients of MMRV than in recipients of MMR + V (39.1% versus 33.1%, P = 0.001). Fevers were transient and there was no difference in the incidence of febrile seizures. MMRV was generally well tolerated and had comparable immunogenicity and overall safety profiles to MMR + V administered concomitantly. Long-term persistence of antibodies after receipt of MMRV is expected based on similar antibody titers against all 4 antigens 1 year postvaccination compared with recipients of MMR and V.

Efficacy of vaccines against chlamydiosis and Q fever: Bringing-in the murine model

As chlamydiosis and Q fever can affect ovine and caprine flocks simultaneously or successively, mouse models were used to demonstrate that simultaneous vaccination with the live Chlamydophila abortus 1B vaccine and the killed phase-I- Coxiella vaccine, administrated in two separate injection sites had no effect on their efficacy against subsequent challenges with either C. abortus or Coxiella burnetii.

A Phase 1 Study of PAmAb, a Fully Human Monoclonal Antibody against Bacillus anthracis Protective Antigen, in Healthy Volunteers

Inhibition of the binding of Bacillus anthracis protective antigen (PA) to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin. A fully human monoclonal antibody against B. anthracis PA, PAmAb, was previously shown to provide a survival advantage in rabbit and monkey models of inhalational anthrax. A randomized, single-blind, placebo-controlled, dose-escalation study with 105 healthy volunteers was conducted to evaluate the safety, pharmacokinetics, and biological activity of PAmAb. Subjects received PAmAb or placebo as a single intramuscular injection (11 subjects/cohort) or intravenous infusion (10 subjects/cohort). Three intramuscular dose levels (0.3, 1.0, and 3.0 mg/kg) and 5 intravenous dose levels (1.0, 3.0, 10, 20, and 40 mg/kg) were studied. Two separate intramuscular injection sites (gluteus maximus and vastus lateralis) were evaluated in the cohorts (hereafter, the "IM-GM" and "IM-VL" cohorts, respectively). PAmAb was well tolerated, with no dose-limiting adverse events. All adverse events were transient and mild to moderate in incidence and/or severity. The pharmacokinetics of PAmAb were linear within each route and site of administration but were significantly different between the IM-GM and IM-VL cohorts. The mean terminal elimination half-life ranged from 15 to 19 days. The bioavailability of PAmAb is approximately 50% for IM-GM injection and 71%-85% for IM-VL injection. The biological activity of PAmAb in serum, assessed using a cyclic adenosine monophosphate assay, correlated with serum concentrations. PAmAb is safe, well tolerated, and bioavailable after a single intramuscular or intravenous dose, which supports further clinical development of PAmAb as a novel therapeutic agent for inhalational anthrax.

Immunogenicity and Reactogenicity of Four Doses of Diphtheria-Tetanus-Three-Component Acellular Pertussis-Hepatitis B-Inactivated Polio Virus-Haemophilus influenzae Type b Vaccine Coadministered with 7-Valent Pneumococcal Conjugate Vaccine

The 7-valent pneumococcal (7vPn) conjugate vaccine is licensed for primary and booster vaccination according to the same immunization schedules as routinely recommended diphtheria-tetanus-pertussis-based childhood vaccines and can be coadministered during the same vaccination visit. An open, randomized study evaluated the immunogenicity and safety of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine and a 7vPn conjugate vaccine when coadministered at 2, 3 and 4 months and 12-23 months of age, compared with the administration of the hexavalent DTPa-HBV-IPV/Hib vaccine given alone. Serum antibody titers were measured before and 1 month after the primary course and before and 1 month after the booster dose. Solicited local and general adverse events were recorded for 4 days and unsolicited adverse events were recorded for 30 days after each vaccine dose. A total of 345 subjects were enrolled for primary vaccination with the hexavalent vaccine (170 without and 175 with the 7vPn vaccine coadministered) and 266 returned for booster vaccination (122 without and 144 with coadministration of the 7vPn vaccine). After primary vaccination, antibody responses against the common antigens were similar in both groups, with seroprotection rates of 93.6-100% and with similar antibody decay before booster vaccination. The fourth dose induced a vigorous booster response, with seroprotection/vaccine response rates of 96.8-100%. Response to the 7vPn primary and booster vaccination was within previously reported ranges. Differences in reactogenicity resulted from higher incidences of symptoms after concomitant vaccination. Rectal temperature >39.5 degrees C was observed after 1.2% of the coadministered vaccine doses during primary vaccination and after 2.8% of the booster vaccine doses. Coadministration of the DTPa-HBV-IPV/Hib and 7vPn vaccines at separate injection sites during the same vaccination visit was effective and safe.

Immunogenicity and reactogenicity of diphtheria, tetanus and pertussis toxoids combined with inactivated polio vaccine, when administered concomitantly with or as a diluent for a Hib conjugate vaccine

In an open trial, 400 infants were randomized to vaccination with a combined diphtheria–tetanus–pertussis-inactivated polio vaccine (DTaP-IPV) either mixed with a Haemophilus influenzae type b (Hib) tetanus toxoid conjugate immediately before injection (DTaP-IPV/Hib (mix)) or given concurrently with the Hib conjugate at separate injection sites (DTaP-IPV+Hib (sep)). The pertussis component consisted of pertussis toxoid alone. The vaccines were given intramuscularly at 3, 5 and 12 months of age. No vaccine-related serious adverse events occurred. Local reactions were evaluated from diary cards completed by the parents. Infants who received DTaP-IPV/Hib (mix) experienced fewer local reactions. Sera were obtained 28–45 days after the second and third vaccinations. Total Hib capsular antibodies were similar in the two groups after the second injection but lower in the group receiving DTaP-IPV/Hib (mix) than in the group receiving DTaP-IPV+Hib (sep) after the third injection (geometric mean 6.1 vs 10.4 μg/ml). Mixing of the vaccines also led to somewhat lower diphtheria toxin antibodies (5.9 vs 7.7 IU/ml after the third injection) while tetanus antibodies were higher (3.9 vs 2.5 IU/ml after the third injection). Antibodies against pertussis toxin and the three polio virus types were similar in the two groups. The moderate impairment of the Hib antibody response caused by mixing of the Hib conjugate with aluminium adsorbed DTaP may be due to physicochemical interference but is probably of little clinical importance because of the ability of the Hib conjugates to induce an immunologic memory.