A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes

Abstract

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen.

Combined Skin and Muscle DNA Priming Provides Enhanced Humoral Responses to a Human Immunodeficency Virus Type 1 Clade C Envelope Vaccine

“…In all groups, homologous, group M consensus, clade C, F, and D binding vaccine-induced antibodies were detected by the dimeric FcγRIIIa and FcγRIIa, while vaccine-induced antibodies specific to clade B were low or absent, and clade A did not bind to dimeric FcγRIIIa and FcγRIIa. Low levels of neutralizing antibody were observed at week 22 against the closely matched clade C tier 1 isolate 93MW965, in line with previous observations using this envelope construct 28 , 29 , 33 ( Fig. 2I ).…”

“…boost with recombinant CN54 gp140 in the absence of adjuvant was similar to that previously observed following two immunizations with the same recombinant protein (CN54 gp140) delivered with the TLR adjuvant GLA-AF 28 or following different DNA-MVA priming regimes. 33 The different DNA prime-protein boost regimes in this study induced a predominant IgG1 response with lower levels of IgG3. IgG2 responses were less evident than in previous studies using recombinant CN54 gp140 adjuvanted in GLA-AF, 28 suggesting the DNA priming phase promoted a more Th1 dominant response.…”

“…In line with previous studies CN54 gp140 induced low neutralizing antibody responses against a closely matched clade C tier 1 isolate MW965 with minimal reactivity against clade B MN and SF162 and clade A/E recombinant TH023. 28 , 29 , 33 However, vaccine-induced serum antibodies were seen to interact with dimeric Fc receptors FcγRIIIa and/or FcγRIIa, surrogates of both ADCC and ADCP, respectively. 30 , 31 In particular clade C, F, and D binding vaccine-induced antibodies were detected by the dimeric FcγRIIIa and FcγRIIa.…”

Immunoglobulin G1 Allotype Influences Antibody Subclass Distribution in Response to HIV gp140 Vaccination

“…The IgG1 allotype abundance mirrors previously reported most frequent alleles representative of Caucasian population enrolled in this study (G1m3; G1m 17, 1; and G1m17,1,2), the concurring results demonstrate the interchangeability of the PCR and ELISA protocol for IgG1-allotyping. The clear cross-validation of both assays formats, allowed for the determination of the IgG1-allotype abundance in two additional clinical trials ( 23 , 30 ), from which only serum samples were available (Figure S3 in Supplementary Material).…”

A recombinant gp145 Env glycoprotein from HIV-1 expressed in two different cell lines: effects on glycosylation and antigenicity

“…These 'uncleaved trimers' consist of a single chain Env with a sequence that stops short of the 67 membrane-proximal region. Env glycoproteins developed in this category include the uncleaved 68 C97ZA012-gp140 [5], CN54gp140 [15], and CO6980v0c22 gp145 [16]. This family of immunogens 69 has been produced in large scale and tested in rodents and non-human primates.…”