Induction Of Antibodies To Hiv-1 Envelope Using Simian Adenovirus Vaccines

Human immunodeficiency virus type 1 (HIV-1) has infected 76 million people since the beginning of the epidemic. The first evidence that an HIV-1 vaccine could prevent infection in humans was provided in the RV144 vaccine efficacy trial. RV144 demonstrated 31.2% efficacy and immune correlate analyses indicated that antibodies targeting the variable 2 (V2) region of HIV-1 envelope (Env) correlated with decreased risk of infection. However, significant improvements are needed to develop a globally effective vaccine against HIV-1. Several approaches can be employed to improve upon vaccination strategies: heterologous prime-boost regimens, immunogen design, and alternative adjuvants. To enhance Env-specific antibodies, I tested simian-derived adenovirus (SAdV) vectors expressing Env proteins and administered them in heterologous prime-boost regimens with recombinant Env in adjuvant. In the first study, I tested the SAdV vectors in prime-boost regimens with trimeric Env protein in aluminum salt. Priming with SAdV vector was advantageous over protein prime and inclusion of the trimeric protein induced neutralizing antibodies. It has been suggested that a vaccine designed to elicit greater V2-specific antibody responses than that seen in the RV144 trial may be more effective at preventing HIV-1 infection. The variable 1 and 2 (V1/V2) region of Env has been grafted onto a protein scaffold and shown to exhibit a native conformation. In the second study, I sought to enhance the V2-specific antibody response using SAdV vectors expressing scaffolded V1/V2. SAdV vectors expressing scaffolded V1/V2 elicited greater V2-specific antibodies only transiently. However, SAdV vectors expressing either HIV-1 gp140 or scaffolded V1/V2 induced sustained response rates of V2 conformational antibodies more than one year after vaccination. This contrasts with the RV144 trial, where V2-specific antibody responses declined quickly after vaccination. In the third study, I tested calcium phosphate (CaP) as an adjuvant to a recombinant Env protein compared to alum adjuvant. Alum, the most commonly used adjuvant, induces suboptimal immune responses. CaP has demonstrated preferential immune responses as an adjuvant in animals and humans. CaP did not elicit greater antibody responses in this study. These studies demonstrate SAdV vectors as advantageous vaccine vector platforms and that novel immunogen design can improve HIV-1 vaccines

Impact of school-entry vaccination requirement changes on clinical practice implementation and adolescent vaccination rates in metropolitan Philadelphia

In 2017, Pennsylvania amended school-entry vaccination requirements including reduction of the provisional period from eight months to the first five days of school and requirement of meningococcal-conjugate vaccine (MCV4) for students entering 12th grade. This cross-sectional study evaluates the impact of these new requirements on clinical practice and vaccination rates among requirement-eligible adolescents within a large pediatric network in metropolitan Philadelphia. We surveyed providers from 24 pediatric primary care facilities across five Southeastern Pennsylvania counties to assess strategies for timely vaccination of children, facilitators and barriers to implementation of these strategies, and attitudes toward the new school vaccine requirements. Vaccination rates post-five-day grace period among eligible 12–18-year-old adolescents were calculated using aggregate electronic health record data and compared pre- and post-policy implementation (2016 vs. 2017) using two-sample tests of proportion. Overall, providers were supportive of the new vaccination requirements and reported that their facilities were equipped to accommodate the increased demand for vaccination visits prior to the beginning of the school year. There were modest increases in Tdap and MCV4 vaccination rates among 12–13-year-old adolescents by mid-September and a significant increase for MCV4 among 17–18-year-old adolescents (p > .001) in all regions. There were also statistically significant increases (p > .001) in MenB and HPV vaccination rates in this older age group. Our results suggest that these amended school-entry vaccination requirements may help improve timely vaccination rates for both required and non-required vaccines, increasing protection among students at the beginning of the school year