IID Vaccine Evaluation and Development

Leidos Biomedical Research, Inc., Frederick MD

Investigators

Abstract

The VRC mission and scope includes development of vaccines for human diseases of high public health importance such as malaria, tuberculosis, and RSV. The overarching objectives of this task include activities to evaluate a candidate malaria vaccine and to develop and evaluate an RSV vaccine, with potential development of tuberculosis vaccines. OBJECTIVE 1: MALARIA VACCINE EVALUATION BACKGROUND Malaria infects 200-300 million people and is a leading cause of death in young children in Sub-Saharan Africa. A major scientific effort using the most advanced techniques has been initiated with the samples from studies with attenuated whole parasite vaccine (VRC 312) to define the immune mechanisms of protection. The samples from VRC 314 would substantially expand this effort most notably in understanding what is required for long-term protection. Identifying a vaccine approach to reduce morbidity and mortality in infants would be a major public health advance. VRC requests support to continue the scientific exploration to define immune correlates of protection and extend the ongoing clinical trial to determine whether IV administration confers durable protection against a heterologous challenge, and whether combining whole sporozoite priming with GSK?s RTS.S vaccine candidate would provide the critical proof-of- principle for advancing this concept to infants. PROJECT REQUIREMENTS The VRC provided the critical scientific findings to advance an attenuated whole parasite vaccine into a phase I clinical trial performed at the NIH (VRC 312). High-level protection was achieved in a dose-dependent manner following IV administration of the vaccine. To confirm and extend these findings, VRC 314 was initiated in Q4/2013 to determine how dose and interval affect durability of protection following IV administration and assess whether IM administration confers protection. VRC now requests support to: 1. Extend the correlates analysis on existing samples 2. Determine the level of protection against heterologous challenge 3. Manufacture clinical materials in order to evaluate the combination of IM delivery of irradiated sporozoites boosted with RTS,S in nonhuman primates and in a clinical trial OBJECTIVE 2: RSV VACCINE DEVELOPMENT BACKGROUND No vaccine is currently available to prevent RSV infection. Passive antibody is licensed for prophylaxis of infants at high risk for severe disease (~90,000 in U.S. annually). However, all children are infected by RSV by age 3 and at risk of lower respiratory tract disease, so the vaccine target population is the entire birth cohort (U.S. ~4 million; globally >100 million). In the U.S., RSV infection is the most common cause of bronchiolitis and pneumonia in children less than one year old, and the most common cause for hospitalization in children under five. Worldwide, it is estimated that RSV is responsible for nearly 7 percent of deaths in babies aged 1 month to 1 year of age, second only to malaria as cause of death from a single pathogen. The VRC requests support to determine whether the stabilized prefusion F protein will significantly boost serum neutralizing activity in adults, and to inform advanced development of a candidate RSV vaccine within 2 years for pregnant women, the elderly, and young children. The VRC has demonstrated preclinical proof-of-concept that stabilized prefusion RSV F is a promising vaccine candidate, and now proposes to undertake cGMP production, determine safety and immunogenicity in a Phase 1 clinical trial, and establish a partnership with industry for advanced development. PROJECT REQUIREMENTS The VRC has designed a vaccine antigen based on the structure of the native pre-triggered RSV F glycoprotein and has demonstrated high immunogenicity in preclinical studies. This included discovering a novel neutralization-sensitive antigenic site that is a key determinant for protective immunity. VRC requests support to produce the recombinant stabilized prefusion RSV F for evaluation as a vaccine candidate by completing the following: 1. Final selection of optimal stabilized prefusion trimeric RSV F protein to advance to clinical trials 2. Product development, formulation, GLP toxicity, and cGMP production of stabilized prefusion F 3. Manufacture clinical materials in order to evaluate stabilized prefusion F protein in Phase 1 clinical trials of the comparing unadjuvanted and alum-adjuvanted formulations in young adults