Safety and immunogenicity of an HIV-1 prefusion-stabilized envelope trimer (Trimer 4571) vaccine in healthy adults: A first-in-human open-label, randomized, dose-escalation, phase 1 clinical trial

Abstract

Background: Advances in therapeutic drugs have increased life-expectancies for HIV-infected individuals, but the need for an effective vaccine remains. We assessed safety and immunogenicity of HIV-1 vaccine, Trimer 4571 (BG505 DS-SOSIP.664) adjuvanted with aluminum hydroxide (alum), in HIV-negative adults.

Methods: We conducted a phase I, randomized, open-label, dose-escalation trial at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Eligible participants were HIV-negative, healthy adults between 18-50 years. Participants were randomized 1:1 to receive Trimer 4571 adjuvanted with 500 mcg alum by either the subcutaneous (SC) or intramuscular (IM) route at weeks 0, 8, and 20 in escalating doses of 100 mcg or 500 mcg. The primary objectives were to evaluate the safety and tolerability of Trimer 4571 with a secondary objective of evaluating vaccine-induced antibody responses. The primary and safety endpoints were evaluated in all participants who received at least one dose of Trimer 4571. Trial results were summarized using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03783130.

Findings: Between March 7 and September 11, 2019, 16 HIV-negative participants were enrolled, including six (38%) males and ten (62%) females. All participants received three doses of Trimer 4571. Solicited reactogenicity was mild to moderate in severity, with one isolated instance of severe injection site redness (6%) following a third 500 mcg SC administration. The most commonly reported solicited symptoms included mild injection site tenderness in 14 (88%) and mild myalgia in six (38%) participants. The most frequent unsolicited adverse event attributed to vaccination was mild injection site pruritus in six (38%) participants. Vaccine-induced seropositivity occurred in seven (44%) participants and resolved in all but one (6%). No serious adverse events occurred. Trimer 4571-specific binding antibodies were detected in all groups two weeks after regimen completion, primarily focused on the glycan-free trimer base. Neutralizing antibody activity was limited to the 500 mcg dose groups.

Interpretation: Trimer 4571 was safe, well tolerated, and immunogenic in this first-in-human trial. While this phase 1 trial is limited in size, our results inform and support further evaluation of prefusion-stabilized HIV-1 envelope trimers as a component of vaccine design strategies to generate broadly neutralizing antibodies against HIV-1.

Funding: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Keywords: BG505 DS-SOSIP.664; HIV-1; NIH; Phase 1 clinical trial; Trimer 4571; Vaccine.

Figure 1

Trial CONSORT diagram. Participants were enrolled according to dose-escalation protocol and randomized to receive three doses of adjuvanted Trimer 4571 at weeks 0, 8, and 20. All participants completed the protocol. IM denotes intramuscular, and SC subcutaneous route of vaccine administration. Participants who withdrew during enrollment did so because: time commitment for study procedures (10 participants, 19%), concern of potential risks of study procedures (28 participants, 52%), number of procedures/blood draws (2 participants, 4%), lost contact (5 participants, 9%), study closed to enrollment (7 participants, 13%), participants chose another study (1 participants, 2%) and other (29, 54%). Of the twenty-eight (28) participants that withdrew due to concern of potential risks, 23 (82%) had concerns with vaccine induced seropositivity (VISP). Participants could choose more than one withdrawal reason/category. * 500 mcg of alum was field mixed with Trimer 4571 for all study groups.

Figure 2

Maximum local and systemic reactogenicity reported within 7 days after receipt of each Trimer 4571 vaccination according to dose and route of administration. Percent of participants who reported a local or systemic symptom (y-axis) in the seven days following each vaccination. The severity of solicited adverse events was graded mild, moderate, and severe. Data are n (%). IM denotes intramuscular, and SC subcutaneous.

Figure 3

Vaccination with Trimer 4571 induces trimer-specific antibody responses by ELISA. Trimer 4571-specific antibody titers in serum were measured by ELISA at baseline and two weeks after each vaccination. HIV+ samples were used as positive controls. ELISA endpoint titer was defined as the reciprocal of the greatest dilution with an optical density value above 0·1. Geometric mean titers (GMTs) with 95% confidence intervals (CIs) are indicated by error bars. Horizontal dotted line indicates the assay negative cut off. IM denotes intramuscular, and SC subcutaneous. Significant differences from baseline to two weeks after regimen completion were observed for 100 mcg SC (p=0·029), 500 mcg IM (p=0·0052), and 500 mcg SC (p=0·0002) groups.

Figure 4

Vaccination with Trimer 4571 induces antibodies against trimer immunogen but not against other Env regions. Anti-Trimer 4571, V3 peptide, fusion peptide (FP), gp120, and gp41 responses at baseline and two weeks after regimen completion were assessed serologically by ELISA. HIV+ human sera were used as assay controls. Horizontal dotted lines indicate the assay negative cut offs. ELISA endpoint titer was defined as the reciprocal of the greatest dilution with an optical density value above 0·1. Significant increase in Trimer 4571 ELISA Endpoint titer was observed from baseline to two weeks after regimen completion across all study groups combined (p<0·0001). IM denotes intramuscular, and SC subcutaneous

Figure 5

Vaccination with Trimer 4571 elicits antibodies directed against glycan-free trimer base. A) ELISA base-binding endpoint antibody titers in serum were measured with or without trimer base-directed antibodies (RM19R) at two weeks after regimen completion. ELISA endpoint titer was defined as the reciprocal of the greatest dilution with an optical density value above 0·1. B) Ratios of responses directed to base epitopes were calculated as 1 - (endpoint titer with blocking/endpoint titer without blocking), so that the value is 1·00 when all responses are specific to the glycan-free base. IM denotes intramuscular, and SC subcutaneous

Figure 6

Electron Microscopy Polyclonal Epitope Mapping (EMPEM) of the antibody responses to Trimer 4571 distinguished three different antibody classes. A) Representative micrograph of negatively stained Trimer 4571 and Fab complexes (bar size: 100nm). B) Representative reference-free 2D classes of Fab bound to Trimer 4571 (bar size: 10 nm) C) 3D reconstruction of antibody classes detected at two weeks after regimen completion.