Comparative Immunogenicity of HIV-1 gp140 Vaccine Delivered by Parenteral, and Mucosal Routes in Female Volunteers; MUCOVAC2, A Randomized Two Centre Study

Abstract

BackgroundDefining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses.MethodsIn this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel.ResultsThree IM immunizations of CN54 gp140 at either 20 or 100 μg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization.ConclusionsThese data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming.Clinical Trials RegistrationEudraCT 2010-019103-27 and the UK Clinical Research Network (UKCRN) Number 11679

Native‐like Env trimers as a platform for HIV‐1 vaccine design

“…Tier-2 NAbs, even to autologous viruses, were rarely induced, exceptions being a study in which macaques were co-immunized with a DNA plasmid expressing gp160 and a gp140 pseudotrimer (72), and a study in which macaques were immunized 7 times with a gp140 pseudotrimer (73). When pseudotrimers have been tested in humans, the NAb responses were weak and limited to Tier-1 viruses (74–78). …”

“…73 When pseudotrimers had been tested in humans, the NAb responses were weak and limited to Tier-1 viruses. [74][75][76][77][78] The limitations of these uncleaved gp140 constructs only became understood more than a decade after they were first developed, when new analytical techniques and reagents became available over the period of a few years. 26,[54][55][56]58,71,[79][80][81] A new generation of bNAbs to trimer-dependent or -influenced epitopes served as important guides for the antigenic properties of trimer-mimicking Env proteins.…”

Optimized Mucosal MVA Prime/ Soluble gp120 Boost Vaccination Regimen Induces Similar Antibody Responses as an Intramuscular Regimen

“…Higher antigen doses are likely required for intranasal immunization to induce circulating antibody responses similar to those induced by injected vaccines (9). Therefore, we tested IN vaccination with 100, 200, and 300 µg of gp120 adjuvanted with the M7 peptide to determine what dose of gp120 administered IN was required to achieve serum anti-gp120 IgG titers similar to those induced by IM vaccination with 100 µg of HIV-1 gp120 adjuvanted with Addavax, a squalene-based oil-in-water emulsion (see experiments IN 1-3 in Table 1 ).…”

“…HIV-1 vaccine regimens utilizing a mucosal route of vaccination have been described in the literature but evaluating the potency of a mucosally-administered vaccine by comparison to a similar vaccine delivered parenterally is often not discussed. For example, mucosal immunization often fails to induce antigen-specific serum IgG responses comparable to those induced by parenteral immunization with the same antigen(8, 9). For example, our previous study that compared IM MVA priming with IM gp120 boosting (IM/IM) to IM MVA priming with IN gp120 boosting (IM/IN) demonstrated unique immune responses dependent on the route of immunization used(8).…”

“…While the IM/IM and IM/IN vaccine regimens both induced similar levels of anti-HIV binding antibodies, the IM/IN vaccine regimen enhanced the induction of breast milk anti-HIV IgA responses while it did induce HIV-1 neutralizing antibody responses comparable to those induced by the IM/IM vaccine regimen, indicating that IM/IM systemic immunization was more effective than IM/IN mucosal vaccination at eliciting functional systemic antibody responses. Others have reported that IN immunization of humans with 100 µg of HIV-1 gp140 was not immunogenic while IM immunization with 20 or 100 µg of the same antigen induced elevated serum anti-gp140 IgG responses(9). This observation highlights the difficulty in comparing the immunogenicity of the same HIV-1 antigen dose delivered parenterally vs mucosally.…”