Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

Abstract

Background-In the last few years the HIV vaccine field has moved forward a number of promising vaccine candidates into human clinical trials.Objective-In this review we briefly discuss the advances made in vaccine development and HIV pathogenesis and give an overview of the body of work our lab has generated in multiple animal models on replication-competent Ad recombinant vaccines.Methods-Emphasis is placed on comparative examination of vaccine components, routes of immunization and challenge models using replicating Ad vectors.Results/conclusion-The overall findings make the case that replicating Ad vectors are superior in priming multiple arms of the immune system, and in conjunction with protein boosting, have resulted in dramatic protective efficacy leading to their advancement to phase 1 trials. Implications of the recent halting of the Merck Ad5-HIV phase 2b clinical trial for our vaccine approach and other vectored vaccines are discussed.

Replicating Adenovirus-Simian Immunodeficiency Virus (SIV) Recombinant Priming and Envelope Protein Boosting Elicits Localized, Mucosal IgA Immunity in Rhesus Macaques Correlated with Delayed Acquisition following a Repeated Low-Dose Rectal SIV mac251 Challenge

“…We have been pursuing a replicating Ad-HIV/simian immunodeficiency virus (SIV) recombinant prime/envelope protein boost approach (16,41) which elicits broad cellular immunity and functional, envelope-specific serum and mucosal antibodies that correlate with protection from HIV, SIV, and simian/human immunodeficiency virus (SHIV) challenges in rhesus macaque and chimpanzee models (3,9,18,30,31,40,47,53,55). Vaccine-induced, SIV-specific IgG and IgA memory B cells have also been shown to correlate with functional antibody responses and reduced viremia (4).…”

Multiple Vaccine-Elicited Nonneutralizing Antienvelope Antibody Activities Contribute to Protective Efficacy by Reducing both Acute and Chronic Viremia following Simian/Human Immunodeficiency Virus SHIV89.6PChallenge in Rhesus Macaques

“…We have been pursuing a replicating adenovirus (Ad)-HIV/ SIV prime/protein subunit boost AIDS vaccine approach (30,51), which has elicited strong, durable protection against HIV, SIV, and SHIV challenges (11,18,41,42,50). An underlying goal of these studies has been elucidation of immune responses that correlate with protective efficacy.…”

Replicating Adenovirus-Simian Immunodeficiency Virus (SIV) Vectors Efficiently Prime SIV-Specific Systemic and Mucosal Immune Responses by Targeting Myeloid Dendritic Cells and Persisting in Rectal Macrophages, Regardless of Immunization Route

“…This replicating Ad recombinant prime-boost approach elicits potent T cell immunity (35) and functional systemic and mucosal antibodies mediating neutralization (2,43), antibodydependent cellular cytotoxicity, antibody-dependent cell-mediated viral inhibition, and transcytosis inhibition (13,15,16,20,40). Memory B cells that recall functional antibody activity develop (3) along with increased antibody avidity (40), indicative of maturation.…”