Mucosal and Systemic Anti-HIV Responses in Rhesus Macaques following Combinations of Intranasal and Parenteral Immunizations

Abstract

There is an urgent need to develop vaccines that can elicit immunological memory responses against HIV. Using the rhesus macaque model and a combination of intranasal (IN) and parenteral immunizations with DNA or protein adsorbed to microparticles or mixed with mucosal adjuvants we sought to induce anti-HIV memory-type immune responses in both the mucosal and systemic compartments. Prime/boost immunizations were performed through five IN immunizations alone with HIV-env oligomeric gp140 (Ogp140) or HIV-gag-p24 mixed with Escherichia coli heat labile-derived mutant adjuvants or two parenteral immunizations with DNA encoding HIV-env or -gag adsorbed to microparticles followed by three IN immunizations with p24 gag protein and the mutant adjuvants. Both modes of immunizations induced anti-gp140 plasma and vaginal IgG and IgA as well as interferon (IFN)-gamma secreting peripheral blood mononuclear cells (PBMC) after HIV-env and -gag peptide restimulation. After a resting period of 4 months, when the levels of humoral and cellular responses had decreased, intramuscular (IM) booster immunizations with p55-gag protein adsorbed to microparticles and Ogp140 in MF59 oil in water emulsion significantly enhanced anti-HIV plasma and vaginal antibody, as well as peripheral blood IFN-gamma responses in all groups of vaccinated macaques. Importantly, plasma neutralization activity against both homologous and heterologous HIV strains was observed in all groups following the IM booster immunizations with protein. These findings show that IN priming alone or combinations of parenteral and IN immunizations followed by IM booster immunizations hold promise to significantly enhance mucosal and systemic memory-type immune responses against HIV-1 antigens.

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

“…Our preclinical study results also indicated that this combination vaccination approach, but not recombinant protein alone, was effective in eliciting NAbs against primary HIV isolates [19], a finding that has been confirmed subsequently by other independent studies [20][21][22][23][24][25][26]. Furthermore, when polyvalent primary Env antigen formulations were used, the DNA primeprotein boost approach was more effective than the monovalent primary Env antigen in eliciting rabbit NAbs against a wide range of selected primary viral isolates across subtypes A, B, C, D and E [27].…”

Induction of HIV-Blocking Anti-CCR5 IgA in Peyers's Patches without Histopathological Alterations

“…These results agreed with findings from immunizations performed in other animal models, also confirmed in recent clinical trials, where mucosal boosting after intramuscular immunization was superior to intramuscular immunization alone in providing full protective mucosal responses (36,37). In human immunization, mucosal boosting following systemic immunization was considered safe and was found effective, even in the absence of mucosal adjuvants (38,39).…”

Differential immunogenicity of vaccinia and HIV-1 components of a human recombinant vaccine in mucosal and blood compartments

“…Inducing mucosal immune responses has been the focus of many efforts over the past 5-10 years, including comparisons of different immunization routes, often alternating prime-boost strategies mucosally and systemically, as well as comparisons of different immunization sites, with subsequent evaluation of induced mucosal immune responses [7][8][9][10][11][12][13][14][15][16][17][18][19]. While this human, Phase 1 trial aimed to secondarily assess the differential impact on induced mucosal responses with two systemic immunization sites (deltoid and inguinal) [10], but was halted after enrollment of 8 subjects in favor of a larger trial to address the question using a canarypox vaccine.…”