An SHIV DNA/MVA Rectal Vaccination in Macaques Provides Systemic and Mucosal Virus-Specific Responses and Protection against AIDS

Abstract

We explored the use of a simian-human immunodeficiency virus (SHIV) DNA vaccine as an effective mucosal priming agent to stimulate a protective immune response for AIDS prevention. Rhesus macaques were vaccinated rectally with a DNA construct producing replication-defective SHIV particles, and boosted with either the same DNA construct or recombinant modified vaccinia virus Ankara (MVA) expressing SIV Gag, SIV Pol, and HIV Env (MVA-SHIV). Virus-specific mucosal and systemic humoral and cell-mediated immune responses could be stimulated by this approach but were present inconsistently among the vaccinated animals. Rectal vaccination with either SHIV DNA alone or SHIV DNA followed by MVA-SHIV induced SIV Gag/Pol- or HIV gp120-specific IgA in rectal secretions of four of seven animals. However, the gp120-specific rectal IgA antibody responses were not durable and had become undetectable in all but one animal shortly before rectal challenge with pathogenic SHIV 89.6P. Only the macaques primed with SHIV DNA and boosted with MVA-SHIV demonstrated SHIV-specific IgG in plasma. In addition, these animals developed more consistent antiviral cell-mediated responses and had better preservation of CD4 T cells following challenge with SHIV 89.6P. Our study demonstrates the utility of a rectal DNA/MVA vaccination protocol for the induction of diverse responses in different immunological compartments. In addition, the immunity achieved with this mucosal vaccination regimen is sufficient to delay progression to AIDS.

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

“…Further, a trimeric HIV gp140 protein delivered vaginally in a stabilizing polymeric gel to guinea pigs elicited genital tract IgG and IgA and serum IgG (10). IR priming of rhesus macaques with a simian-human immunodeficiency virus (SHIV) DNA followed by vector and envelope boosting elicited transient SIV-specific IgA in rectal secretions and systemic cellular and humoral immunity, although protection against SHIV 89.6P acquisition was not obtained (38).…”

Protection against simian/human immunodeficiency virus (SHIV) 89.6P in macaques after coimmunization with SHIV antigen and IL-15 plasmid

“…Accordingly, vaccines that induce HIV-specific cellular immunity are being pursued (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The exact nature of how the antigen-specific lymphocytes should be armed is still unknown.…”

HIV Envelope-Specific Antibody and Vaccine Efficacy

“…Several vaccine approaches have been evaluated in non-human primates for the ability to elicit viral-specific IgA antibodies at genital/rectal sites. These have included tonsillar immunizations with replication-defective SIV (Vagenas et al, 2009), administration of DNA vaccines intranasally or rectally, followed by boosting with MVA recombinants (Bertley et al, 2004;Wang et al, 2004), intradermal or intramuscular administrations of DNA vaccines together with GM-CSF DNA or CCL27 DNA as adjuvants (Lai et al, 2007;Kraynyak et al, 2010) vaginal delivery of trimeric HIV envelope together with Carbopol gel (Cranage et al, 2011), upper respiratory track immunization with replication-competent Ad-recombinants followed by intramuscular boosting with envelope protein (Florese et al, 2009;Hidajat et al, 2009;Xiao et al, 2010), and intramuscular plus intranasal immunization with a gp41 subunit vaccine delivered on virosomes (Bomsel et al, 2011). These have had varying degrees of success in consistently eliciting mucosal IgA antibodies.…”