Clinical study of safety and immunogenicity of pentavalent DTP-HB-Hib vaccine administered by disposable-syringe jet injector in India.

INTRODUCTION: We conducted a randomized, observer-blind, non-inferiority, parallel-group clinical study of diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae type b conjugate (pentavalent) vaccination of infants in India. Goals were to determine whether the seropositivity rate after vaccination via disposable-syringe jet injector (DSJI) was non-inferior to that via needle and syringe (N-S), and to compare the safety of vaccination by the two methods. METHODS: Healthy children received a three-dose series of vaccine intramuscularly by DSJI or N-S beginning at 6-8 weeks of age. Immunoglobulin G antibody levels were measured by ELISA at 4-6 weeks after the third dose. The main secondary endpoint was safety, measured as injection site and systemic reactions. DISCUSSION: The study was stopped early out of caution beyond that specified in the protocol stopping criteria, after the Data Safety Committee noted a higher frequency of injection site reactions, especially moderate and severe, in the DSJI group. As a result, 128 subjects-DSJI group 61; N-S group 67-completed the study, rather than the 340 planned, and the study was not sufficiently powered to compare immunogenicity endpoints for the groups. Descriptive statistics indicate that seropositivity induced by vaccination with the DSJI was similar to that of N-S for all five antigens. Pentavalent vaccine includes whole-cell pertussis vaccine and an aluminum adjuvant, which may have contributed to the higher number of local reactions with the DSJI. The reactions caused no serious or long-term sequelae, and may be more acceptable in other populations or circumstances.US National Institutes of Health clinical trials identifier: NCT02409095.

Affordable Care Act Impact on Community Health Center Staffing and Enrollment: A Cross-Sectional Study.

Over 500 000 Washingtonians gained health insurance under the Affordable Care Act (ACA). As more patients gain insurance, community health centers (CHCs) expect to see an increase in demand for their services. This article studies the CHCs in Washington State to examine how the increase in patients has been impacting their workload and staffing. We found a reported mean increase of 11.7% and 5.4% in new Medicaid and Exchange patients, respectively. Half of the CHCs experienced large or dramatic workload impact from the ACA. Our findings suggest that CHCs need further workforce support to meet the expanding patient demand.

Needle-free jet injector intradermal delivery of fractional dose inactivated poliovirus vaccine: Association between injection quality and immunogenicity.

INTRODUCTION: The World Health Organization recommends that as part of the polio end-game strategy a dose of inactivated poliovirus vaccine (IPV) be introduced by the end of 2015 in all countries currently using only oral poliovirus vaccine (OPV). Administration of fractional dose (1/5 of full dose) IPV (fIPV) by intradermal (ID) injection may reduce costs, but its conventional administration is with Bacillus Calmette-Guerin (BCG) needle and syringe (NS), which is time consuming and technically challenging. We compared injection quality achieved with BCG NS and three needle-free jet injectors and assessed ergonomic features of the injectors. METHODS: Children between 12 and 20 months of age who had previously received OPV were enrolled in the Camaguey, Cuba study. Subjects received a single fIPV dose administered intradermally with BCG NS or one of three needle-free injector devices: Bioject Biojector 2000® (B2000), Bioject ID Pen® (ID Pen), or PharmaJet Tropis® (Tropis). We measured bleb diameter and vaccine loss as indicators of ID injection quality, with desirable injection quality defined as bleb diameter ≥5mm and vaccine loss <10%. We surveyed vaccinators to evaluate ergonomic features of the injectors. We further assessed the injection quality indicators as predictors of immune response, measured by increase in poliovirus neutralizing antibodies in blood between day 0 (pre-IPV) and 21 (post-vaccination). RESULTS: Delivery by BCG NS and Tropis resulted in the highest proportion of subjects with desirable injection quality; health workers ranked Biojector2000 and Tropis highest for ergonomic features. We observed that vaccine loss and desirable injection quality were associated with an immune response for poliovirus type 2 (P=0.02, P=0.01, respectively). CONCLUSIONS: Our study demonstrated the feasibility of fIPV delivery using needle-free injector devices with high acceptability among health workers. We did not observe the indicators of injection quality to be uniformly associated with immune response.

Clinical performance and safety of adapters for intradermal delivery with conventional and autodisable syringes.

Although the number of vaccines and diagnostic tests currently delivered intradermally is limited, this route of administration offers potential advantages due to the high concentration of antigen-presenting cells in the skin. One factor which may in part be limiting development and use of intradermal (ID) administration is concern about the ease and reliability of the needle and syringe-based Mantoux technique. A phase I clinical study was conducted to evaluate two ID adapters that have been developed as injection-delivery aids to increase the safety, simplicity, and reliability of ID injection: a prototype autodisable, intradermal (ADID) adapter for autodisable (AD) syringes, and a marketed side-merge adapter (SMA). Thirty healthy adult volunteers each received six injections of 0.1 mL of sterile saline solution. Each adapter was used to give injections into the upper deltoid, forearm, and suprascapular regions of each volunteer. The needle-bevel orientation during injection was random. Injection performance was determined by measuring wheal size and fluid leakage. Wheals were similar in size for the ADID adapter (mean 9.9 ± 0.17 mm) and SMA (mean 9.8 ± 0.15 mm). In all of the injections completed with the SMA, and 98% of those completed with the ADID, fluid leakage was less than 10% of the intended injection volume. Minor skin abrasions were the only adverse events. Based on self-reporting of pain, injections were well tolerated (mean pain score of 2 on a 0-10 scale). ID delivery using the SMA and ADID adapters appears safe and effective.

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

INTRODUCTION: Intradermal bacille Calmette-Guérin (BCG) vaccination by needle-free, disposable-syringe jet injectors (DSJI) is an alternative to the Mantoux method using needle and syringe (NS). We compared the safety and immunogenicity of BCG administration via the DSJI and NS techniques in adults and newborn infants at the South African Tuberculosis Vaccine Initiative (SATVI) research site in South Africa. METHOD: Thirty adults and 66 newborn infants were randomized 1:1 to receive intradermal BCG vaccine (0.1 mL in adults; 0.05 mL in infants) via DSJI or NS. Wheal diameter (mm) and skin fluid deposition at the site of injection (SOI) were measured immediately post-vaccination. Adverse events and SOI reactogenicity data were collected 30 min and 1, 2, 4, and 12 weeks after vaccination for adults and at 30 min and 4, 10, and 14 weeks for infants. Blood was collected in infants at 10 and 14 weeks to assess BCG-specific T-cell immune responses. RESULTS: More infant BCG vaccinations by DSJI deposited >5 µL fluid on the skin surface, compared to NS (49% versus 9%, p=0.001). However, all 12 infant vaccinations that did not produce any SOI wheal occurred in the NS group (36%, p<0.001). Median wheal diameter, in participants for which an SOI wheal formed, did not differ significantly between groups in infants (combined 3.0mm IQR 2.0 to 4.0, p=0.59) or in adults (combined 9.0mm IQR 7.0 to 10.0, p=0.13). Adverse events were similar between study arms. Proportion of participants with BCG scars after three months did not differ in adults (combined 97%, p=0.67) or infants (combined 62%, p=0.13). Frequencies of BCG-specific clusters of differentiation 4 (CD4) and clusters of differentiation 8 (CD8) T-cells co-expressing IFN-γ, TNF-α, IL-2, and/or IL-17 were not different in the DSJI and NS groups. CONCLUSION: BCG vaccination of newborn infants via DSJI was more likely to deliver an appropriate intradermal wheal at the SOI as compared to NS, despite leaving more fluid on the surface of the skin. Safety, reactogenicity, and antigen-specific T-cell immune responses did not differ between DSJI and NS techniques.

Immunogenicity and safety of measles-mumps-rubella vaccine delivered by disposable-syringe jet injector in healthy Brazilian infants: a randomized non-inferiority study.

This study aimed to determine if immunogenicity to measles-mumps-rubella vaccine delivered to infants via a disposable-syringe jet injector (DSJI) was non-inferior to that administered by needle and syringe (NS). Vaccination safety was evaluated, as were the use, performance, and acceptability of each delivery method. The DSJI was the PharmaJet 2009 generation-1 device (G1) and the vaccine was measles-mumps-rubella vaccine from Bio-Manguinhos. Five hundred eighty-two healthy Brazilian infants were randomized to receive vaccine via G1 or NS. Seroconversion rates against measles and mumps viruses in the G1 treatment group did not meet non-inferiority criteria when compared with the NS group; however, responses in the G1 group to rubella virus were non-inferior to those of NS vaccinees. Most adverse events were mild or moderate. Crying after injection was more frequent in the NS group, and local skin reactions were more common in the G1 group. Five serious adverse events were judged causally unrelated to treatment and all resolved. Parents/guardians expressed a strong preference for G1 over NS for their children. Vaccinators found the G1 easy to use but noted incomplete vaccine delivery in some cases. Although the G1 has been superseded by an updated device, our results are important for the continued improvement and evaluation of DSJIs, which have the potential to overcome many of the challenges and risks associated with needle-based injections worldwide. Recommendations for future DSJI clinical studies include rigorous training of vaccinators, quantitative measurement of wetness on the skin following injection, and regular monitoring of device and vaccinator performance.

Comparing Measures of Late HIV Diagnosis in Washington State.

As more US HIV surveillance programs routinely use late HIV diagnosis to monitor and characterize HIV testing patterns, there is an increasing need to standardize how late HIV diagnosis is measured. In this study, we compared two measures of late HIV diagnosis, one based on time between HIV and AIDS, the other based on initial CD4(+) results. Using data from Washington's HIV/AIDS Reporting System, we used multivariate logistic regression to identify predictors of late HIV diagnosis. We also conducted tests for trend to determine whether the proportion of cases diagnosed late has changed over time. Both measures lead us to similar conclusions about late HIV diagnosis, suggesting that being male, older, foreign-born, or heterosexual increase the likelihood of late HIV diagnosis. Our findings reaffirm the validity of a time-based definition of late HIV diagnosis, while at the same time demonstrating the potential value of a lab-based measure.

Pretargeted radioimmunotherapy using anti-CD45 monoclonal antibodies to deliver radiation to murine hematolymphoid tissues and human myeloid leukemia.

Radioimmunotherapy (RIT) for treatment of hematologic malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted (P)RIT studies to augment the efficacy in mice of therapy using a pretargeted anti-human (h)CD45 antibody (Ab)-streptavidin (SA) conjugate followed by a biotinylated clearing agent and radiolabeled 1,4,7,10-tetraazacylodode cane N,N',N",N'''-tetraacetic (DOTA)-biotin. Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and <1:1 with conventional RIT. In vivo imaging studies confirmed that the PRIT approach provided high-contrast tumor images with minimal blood-pool activity, whereas directly labeled anti-hCD45 Ab produced distinct tumor images but the blood pool retained a large amount of labeled Ab for a prolonged time. Therapy experiments showed that (90)Y-DOTA-biotin significantly prolonged survival of mice treated with pretargeted anti-hCD45 Ab-SA compared with mice treated with conventional RIT using (90)Y-labeled anti-hCD45 Ab at 200 muCi. Because human CD45 antigens are confined to xenograft tumor cells in this model, and all murine tissues are devoid of hCD45 and will not bind anti-hCD45 Ab, we also compared one-step and PRIT using an anti-murine (m)CD45 Ab where the target antigen is present on normal hematopoietic tissues. After 24 h, 27.3% +/- 2.8% of the injected dose of activity was delivered per gram (% ID/g) of lymph node using (131)I-A20-Ab compared with 40.0 +/- 5.4% ID/g for pretargeted (111)In-DOTA-biotin. These data suggest that pretargeted methods for delivering RIT may be superior to conventional RIT when targeting CD45 for the treatment of leukemia and may allow for the intensification of therapy, while minimizing toxicities.

Evaluation of CD20, CD22, and HLA-DR targeting for radioimmunotherapy of B-cell lymphomas.

Despite the promise of radioimmunotherapy using anti-CD20 antibodies (Ab) for the treatment of relapsed patients with indolent non-Hodgkin lymphoma (NHL), most patients treated with conventional doses of (131)I-tositumomab or (90)Y-ibritumomab eventually relapse. We did comparative assessments using conventional radioimmunotherapy targeting CD20, CD22, and HLA-DR on human Ramos, Raji, and FL-18 lymphoma xenografts in athymic mice to assess the potential for improving the efficacy of radioimmunotherapy by targeting other NHL cell surface antigens. Results of biodistribution studies showed significant differences in tumor localization consistent with variable antigenic expression on the different lymphoma cell lines. Interestingly, the radioimmunoconjugate that yielded the best tumor-to-normal organ ratios differed in each tumor model. We also explored administering all three (111)In-1,4,7,10-tetra-azacylododecane N,N',N'',N'''-tetraacetic acid antibodies in combination, but discovered, surprisingly, that this approach did not augment the localization of radioactivity to tumors compared with the administration of the best single radiolabeled Ab alone. These data suggest that conventional radioimmunotherapy using anti-CD20, anti-HLA-DR, or anti-CD22 Abs is effective when used singly and provides targeted uptake of radiolabel into the tumor that is dependent on the levels of antigen expression. Improvements in tumor-to-normal organ ratios of radioactivity cannot be achieved using directly labeled Abs in combination but may be afforded by novel pretargeting methods.

Comparative biodistributions of pretargeted radioimmunoconjugates targeting CD20, CD22, and DR molecules on human B-cell lymphomas.

Pretargeted radioimmunotherapy (PRIT) using streptavidin (SA)-conjugated antibodies (Abs), followed by clearing agent and radiolabeled biotin is a promising method that can increase the effectiveness of RIT, while decreasing the toxicities associated with directly labeled Abs. Although CD20 has been the traditional target antigen for RIT of non-Hodgkin lymphoma (NHL), studies targeting HLA DR and CD22 have yielded promising results. Targeting all 3 antigens at once may further augment the effect of PRIT. This study compares the targeting of Ramos, Raji, and FL-18 lymphoma xenografts with either anti-CD20 Ab/SA (1F5/SA), anti-HLA DR Ab/SA (Lym-1/SA), anti-CD22 Ab/SA (HD39/SA), or all 3 conjugates in combination, followed 24 hours later by a biotin-N-acetyl-galactosamine clearing agent, and 3 hours after that by (111)In-DOTA-biotin. The Ab/SA conjugate yielding the best tumor uptake and tumor-to-normal organ ratios of radioactivity varied depending on the target antigen expression on the cell line used, with 1F5/SA and Lym-1/SA yielding the most promising results overall. Also, the best tumor-to-normal organ ratios of absorbed radioactivity were obtained using single conjugates optimized for target tumor antigen expression rather than the combination therapy. This study highlights the importance of screening the antigenic expression on lymphomas to select the optimal reagent for PRIT.