CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

Abstract

SummaryHuman immunodeficiency virus-1 (HIV-1) canarypox vaccines are safe but poorly immunogenic. CD40 ligand (CD40L), a member of the tumor necrosis factor superfamily (TNFSF), is a pivotal co-stimulatory molecule for immune responses. To explore whether CD40L can be used as an adjuvant for HIV-1 canarypox vaccine, we constructed recombinant canarypox viruses expressing CD40L. Co-immunization of mice with CD40L expressing canarypox and the canarypox vaccine expressing HIV-1 proteins, vCP1452, augmented HIV-1 specific cytotoxic T lymphocyte (CTL) responses in terms of frequency, polyfunctionality and interleukin (IL)-7 receptor α chain (IL-7Rα, CD127) expression. In addition, CD40L expressed from canarypox virus could significantly augment CD4 + T cell responses against HIV-1 in mice. CD40L expressed from canarypox virus matured human monocyte-derived dendritic cells (MDDCs) in a tumor necrosis factor α (TNF-α) independent manner, which underwent less apoptosis, and could expand ex vivo Epstein-Barr virus (EBV)-specific CTL responses from healthy human individuals and ex vivo HIV-1-specific CTL responses from HIV-1-infected individuals in the presence or absence of CD4 + T cells. Taken together, our results suggest that CD40L incorporation into poxvirus vectors could be used as a strategy to enhance their immunogenicity.

Selection of Adjuvants for Enhanced Vaccine Potency

“…It is believed that the adjuvant effect is mediated at least in part through enhanced antigen presentation by specific B cells [373]. Such immune enhancement activity of CD40 antibody is similar to that of CD40 ligand, which has been shown to enhance cellular immune activity in mice [374]. Conjugation of anti-CD-40 to antigen (HSV glycoprotein D) enhanced the immunogenicity of the antigen [375].…”

Partial protection against SIV challenge by vaccination of adenovirus and MVA vectors in rhesus monkeys

“…Considerable research has been conducted using DNA vaccines (individually or with proteins and/or cytokines), 25 Ad-based vaccines (replication competent or replication deficient), vaccinia virus-based vaccines (MVA, canarypox virus (ALVAC) and attenuated vaccinia (NYVAC)), [31][32][33][34][35][36] and other vectors 37,38 alone or in combination to induce antigen-specific anti-retroviral responses in animals. Administration of a recombinant viral vector can induce strong humoral and cellmediated immune responses against both transgene and viral vectors.…”

Development of TNFSF as molecular adjuvants for ALVAC HIV-1 vaccines

“…We first tested this hypothesis in mouse model. We constructed recombinant ALVAC viruses that can express various murine TNFSF molecules, including CD40L, OX40L and others 4,5 (and Liu J, et al unpublished data). For CD40L, we constructed ALVAC vectors expressing either membrane CD40L (vCPmCD40L) or soluble multimeric CD40L (vCPmSP-D-CD40L), since a previous study reported that the fusion protein of surfactant protein D (SP-D) and CD40L, SP-D-CD40L, could promote CD40L to form soluble multimer, which was superior to membrane CD40L in augmenting immunogenicity elicited by an HIV-1 DNA vaccine in mice.…”

“…Using mouse model, we found some TNFSF molecules could augment cellular immune responses elicited by an ALVAC HIV-1 vaccine, vCP1452. 4,5 In this commentary, we will describe our experience in using TNFSF molecules as adjuvants for vCP1452 in mice, and briefly discuss challenges and prospects of using TNFSF molecules as adjuvants for ALVAC HIV-1 vaccines in clinical trials.…”