Optimization of Mucosal Responses after Intramuscular Immunization with Integrase Defective Lentiviral Vector

Abstract

Many infectious agents infiltrate the host at the mucosal surfaces and then spread systemically. This implies that an ideal vaccine should induce protective immune responses both at systemic and mucosal sites to counteract invasive mucosal pathogens. We evaluated the in vivo systemic and mucosal antigen-specific immune response induced in mice by intramuscular administration of an integrase defective lentiviral vector (IDLV) carrying the ovalbumin (OVA) transgene as a model antigen (IDLV-OVA), either alone or in combination with sublingual adjuvanted OVA protein. Mice immunized intramuscularly with OVA and adjuvant were compared with IDLV-OVA immunization. Mice sublingually immunized only with OVA and adjuvant were used as a positive control of mucosal responses. A single intramuscular dose of IDLV-OVA induced functional antigen-specific CD8+ T cell responses in spleen, draining and distal lymph nodes and, importantly, in the lamina propria of the large intestine. These results were similar to those obtained in a prime-boost regimen including one IDLV immunization and two mucosal boosts with adjuvanted OVA or vice versa. Remarkably, only in groups vaccinated with IDLV-OVA, either alone or in prime-boost regimens, the mucosal CD8+ T cell response persisted up to several months from immunization. Importantly, following IDLV-OVA immunization, the mucosal boost with protein greatly increased the plasma IgG response and induced mucosal antigen-specific IgA in saliva and vaginal washes. Overall, intramuscular administration of IDLV followed by protein boosts using the sublingual route induced strong, persistent and complementary systemic and mucosal immune responses, and represents an appealing prime-boost strategy for immunization including IDLV as a delivery system.

Sublingual Immunization of Trivalent Human Papillomavirus DNA Vaccine in Baculovirus Nanovector for Protection against Vaginal Challenge

“…In the case of chimeric bovine papillomavirus virus-like particles incorporating sequence from human immunodeficiency virus-1 gp120, the vaginal IgA induction was higher following IM administration as compared to intravaginal administration [ 28 ]. Intramuscular administration of integrase-defective lentiviral vector carrying ovalbumin gene followed by sublingual ovalbumin administration was reported to induce persistent vaginal IgA immune responses [ 29 ]. A recent study reported that SL immunization of female human volunteers with Gardasil induced 38-fold lower serum IgG levels and 2-fold lower cervical/vaginal IgG levels than IM immunization [ 30 ], highlighting the importance of the delivery system for SL immunization.…”

Integrase-Deficient Lentiviral Vector as an All-in-One Platform for Highly Efficient CRISPR/Cas9-Mediated Gene Editing

“…have successfully employed IDLVs in mouse models as gene replacement therapies for degenerative retinal disease and hemophilia B, respectively. Furthermore, the efficacy of IDLVs in cancer immunotherapy and as a means of inducing protective immune responses to human pathogens has been characterized in different experimental settings 38, 39, 40. A growing body of literature describes IDLVs carrying zinc-finger nucleases as an effective means of gene editing for clinical and basic science applications28, 30, 31, 32.…”

Immunization with an SIV-based IDLV Expressing HIV-1 Env 1086 Clade C Elicits Durable Humoral and Cellular Responses in Rhesus Macaques

“…18 Mice immunized intranasally with IDLV expressing the influenza virus nucleoprotein (Flu-NP) were protected against Influenza virus challenge 19 and therapeutic vaccination with IDLV expressing the human papillomavirus 16 E7 protein (HPV-E7) as a tumor antigen resulted in the eradication of TC-1-derived tumor in tumor-bearing mice. 20 Antigen presentation persists for at least 30 days following IDLV immunization, 21 suggesting that IDLV provides prolonged expression of the encoded antigen, a desirable feature for any vaccine to achieve sustained protection over time.…”