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Vaccine protection by virosome-induced IgG and IgA parallels the cooperation between systemically administered IgG1 and mucosally applied dimeric IgA2 monoclonal antibodies that as single-agents provided no/low protection – but when combined, prevented mucosal SHIV transmission in all passively immunized RMs.
Furthermore, subunit vaccine administration has often involved a single parenteral route (9–11) or sometimes by single mucosal administration (12, 13), but rarely involved combined mucosal and intramuscular (i.m.) immunizations as was done with virosomal vaccines (14, 15). Our team and others have postulated that an effective HIV/AIDS vaccine must be capable of eliciting both systemic and mucosal immune protection for maximal protection of different mucosal portals of entry. However, due to the compartmentalized mucosal and systemic immune systems, the induction of strong immune responses in various local and distant mucosal tissues and in the systemic compartment is challenging. The traditional parenteral immunization involving the i.m. or subcutaneous (s.c.) routes can elicit circulating B and T cells that generally remain mostly in the periphery.
The approach of an HIV vaccine immunization regimen combining the classical i.m. immunization route with mucosal boosting using the intranasal (i.n.) route was proposed as an alternative to induce systemic as well as mucosal anti-HIV immunity. This notably different vaccine strategy was evaluated with unadjuvanted influenza virus-based virosomes displaying HIV gp41 antigens; vaccine-induced systemic and mucosal antibody (Ab) responses were assessed in Chinese-origin rhesus macaques (RMs) that were immunized via two routes followed by intravaginal simian-human immunodeficiency virus (SHIV) challenges (14). The gp41 antigens were derived from Env regions highly conserved across multiple HIV clades and strains (Figure 1). These virosomes are lipid-based particles reconstituted in vitro from influenza viruses but devoid of nucleic acids and thus non-infectious (Figure 2). One population of virosomes was assembled to display on their surface Peptide 1 (P1), an extended version of the Membrane Proximal External Region (MPER) of HIV gp41, to generate virosome-P1. Another virosome population displayed recombinant, truncated gp41 (virosome-rgp41); rgp41 is devoid of the immunodominant region that contains the KLIC motif as well as other domains homologous to human host proteins. The combined vaccine preparation that consists of virosome-P1 plus virosome-rgp41, is termed MYM-V201 (Figure 2).
The initial study in Chinese-origin RMs evaluated only the combination of virosome-P1 plus virosome-rgp41 (but not single-agent virosomes). Control RMs received placebo virosomes devoid of HIV gp41 antigens (14), and two groups of vaccinees were given either four i.m. immunizations or two i.m. immunizations followed by two i.n. boosts, respectively. All animals were challenged intravaginally by repeated low-dose exposures to SHIVSF162P3, an R5-tropic, tier 2, clade B strain; the challenge SHIV encoded a heterologous gp41 sequence compared to that in the immunogens. Priming via the i.m. route followed by i.n. boosting was remarkably effective: 100% of the animals were protected and did not seroconvert to SIV Gag, a viral protein absent in the vaccine. However, protection was not sterile as some animals had low-level viral RNA blips just at the limit of detection (14).
Here we report a repeat study performed in Indian-origin RMs conducted at a different animal facility with the combination of unadjuvanted virosomes-P1 plus virosomes-rgp41, termed MYM-V201, using repeat low-dose intravaginal challenges. We included an additional group to evaluate animals vaccinated with the single-agent unadjuvanted virosomes-P1. The rationale for including the latter group is the successful conclusion of a Phase 1 clinical study with virosomes-P1 in low-risk women (15), where this vaccine was safe and immunogenic. However, no efficacy data existed from NHP studies regarding virosome-P1 as single immunogen.
The current study demonstrated significant protection for the combination of virosomes-P1 plus virosomes-rgp41 that – depending on the read-out – ranged from 78% to 87% during the first SHIV challenge phase, i.e., challenges #1 to #7, up to the day of but not including challenge #8 (termed Challenge Phase I). However, when the SHIV inoculum was increased by 50% as in the earlier study in Chinese RMs (14), protection was lost. Single-agent virosomes-P1 showed no efficacy throughout both SHIV challenge phases. We conclude that the combination of the two HIV gp41 virosomes, virosomes-P1 plus virosomes-rgp41, was safe, immunogenic, and effective as long as the intravaginal SHIV inoculum was within a 100-fold excess over the HIV RNA levels found in the semen of acutely infected men (16), or within a 70,000-fold excess of the median semen viral RNA content men who were part of HIV discordant heterosexual couples (17).
However, by Fc array analysis, protection in Group L was significantly associated with increased Fc?R2/3(A/B) across several time points compared to control Group M; iii) protection in Group L was lost in Challenge Phase II when the virus inoculum was increased by 50%; iv) estimates of the SHIV challenge inoculum in comparison with vRNA levels founds in the semen of men with acute HIV infection indicated protection against intravaginal challenge in the Indian RMs was at a high level as long as the SHIV inoculum did not exceed HIV RNA levels in semen of men with acute HIV infection by >100 fold (16); and v) single-agent virosomes-P1 provided no protection throughout Challenge Phases I and II and thus cannot be considered for clinical development. Importantly – during Challenge Phase I – we have confirmed that the combination of virosomes-P1 plus virosomes-rgp41 protects significantly against intravaginal SHIV challenges. Thus, the safety and efficacy of the gp41 virosomal platform, described earlier for Chinese-origin RMs, has been confirmed in Indian macaques.
Thus the Morgane reads I first posted & the Catalnet patent ref
P1 Rgp41
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