Efficacy of Messenger RNA-1273 Against Severe Acute Respiratory Syndrome Coronavirus 2 Acquisition in Young Adults From March to December 2021

BACKGROUND: The efficacy of messenger RNA (mRNA)-1273 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well defined, particularly among young adults. METHODS: Adults aged 18-29 years with no known history of SARS-CoV-2 infection or prior vaccination for coronavirus disease 2019 (COVID-19) were recruited from 44 US sites from 24 March to 13 September 2021 and randomized 1:1 to immediate vaccination (receipt of 2 doses of mRNA-1273 vaccine at months 0 and 1) or the standard of care (receipt of COVID-19 vaccine). Randomized participants were followed up for SARS-CoV-2 infection measured by nasal swab testing and symptomatic COVID-19 measured by nasal swab testing plus symptom assessment and assessed for the primary efficacy outcome. A vaccine-declined observational group was also recruited from 16 June to 8 November 2021 and followed up for SARS-CoV-2 infection as specified for the randomized participants. RESULTS: The study enrolled 1149 in the randomized arms and 311 in the vaccine-declined group and collected >122 000 nasal swab samples. Based on randomized participants, the efficacy of 2 doses of mRNA-1273 vaccine against SARS-CoV-2 infection was 52.6% (95% confidence interval, -14.1% to 80.3%), with the majority of infections due to the Delta variant. Vaccine efficacy against symptomatic COVID-19 was 71.0% (95% confidence interval, -9.5% to 92.3%). Precision was limited owing to curtailed study enrollment and off-study vaccination censoring. The incidence of SARS-CoV-2 infection in the vaccine-declined group was 1.8 times higher than in the standard-of-care group. CONCLUSIONS: mRNA-1273 vaccination reduced the incidence of SARS-CoV-2 infection from March to September 2021, but vaccination was only one factor influencing risk. CLINICAL TRIALS REGISTRATION: NCT04811664

Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition

BACKGROUND : Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. METHODS : We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC80) of acquired isolates was measured with the TZM-bl assay. RESULTS : Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/ HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], −11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, −45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC80 <1 μg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates. CONCLUSIONS : VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective.Supported by Public Health Service Grants (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Research Center [FHCRC]; UM1 AI068618, to HVTN Laboratory Center, FHCRC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, University of Washington) from the National Institute of Allergy and Infectious Diseases (NIAID) and by the Intramural Research Program of the NIAID.http://www.nejm.orgam2022School of Health Systems and Public Health (SHSPH

Antigenic characterization of the human immunodeficiency virus (HIV-1) envelope glycoprotein precursor incorporated into nanodiscs

The entry of human immunodeficiency virus (HIV-1) into host cells is mediated by the viral envelope glycoproteins (Envs), which are derived by the proteolytic cleavage of a trimeric gp160 Env precursor. The mature Env trimer is a major target for entry inhibitors and vaccine-induced neutralizing antibodies. Env interstrain variability, conformational flexibility and heavy glycosylation contribute to evasion of the host immune response, and create challenges for structural characterization and vaccine development. Here we investigate variables associated with reconstitution of the HIV-1 Env precursor into nanodiscs, nanoscale lipid bilayer discs enclosed by membrane scaffolding proteins. We identified detergents, as well as lipids similar in composition to the viral lipidome, that allowed efficient formation of Env-nanodiscs (Env-NDs). Env-NDs were created with the full-length Env precursor and with an Env precursor with the majority of the cytoplasmic tail intact. The self-association of Env-NDs was decreased by glutaraldehyde crosslinking. The Env-NDs exhibited an antigenic profile expected for the HIV-1 Env precursor. Env-NDs were recognized by broadly neutralizing antibodies. Of note, neutralizing antibody epitopes in the gp41 membrane-proximal external region and in the gp120:gp41 interface were well exposed on Env-NDs compared with Env expressed on cell surfaces. Most Env epitopes recognized by non-neutralizing antibodies were masked on the Env-NDs. This antigenic profile was stable for several days, exhibiting a considerably longer half-life than that of Env solubilized in detergents. Negative selection with weak neutralizing antibodies could be used to improve the antigenic profile of the Env-NDs. Finally, we show that lipid adjuvants can be incorporated into Env-NDs. These results indicate that Env-NDs represent a potentially useful platform for investigating the structural, functional and antigenic properties of the HIV-1 Env trimer in a membrane context

Negative selection of Env-NDs with the weak neutralizing antibody b6.

<p>(A) Schematic diagram of negative selection of Env-NDs with the weakly neutralizing b6 antibody. (B,C) The recognition of the HIV-1_JR-FL Env(-)Δ808-NDs and Env(-)-NDs captured on an ELISA plate by the indicated ligands is shown. The ligands are highlighted as described in the legend to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0170672#pone.0170672.g006" target="_blank">Fig 6</a>. * = p < 0.05, unpaired t-test.</p

Effect of a one-week room temperature incubation of HIV-1 Env in NDs, liposomes, detergent and in detergent-free conditions.

<p>(A-D) The binding of the indicated ligands to the HIV-1_JR-FL Env(-)Δ808 glycoprotein in NDs (glutaraldehyde-crosslinked), liposomes (crosslinked), in brain lipids/CHAPSO, in Cymal-6, or in detergent-free conditions was measured by ELISA. The ligands are highlighted as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0170672#pone.0170672.g006" target="_blank">Fig 6</a> legend. * = p < 0.05, unpaired t-test.</p

Antigenic characterization of the HIV-1_JR-FL Env(-)Δ808-NDs and glutaraldehyde-treated and untreated Env(-)Δ808 glycoproteins on the surface of expressing cells.

<p>(A) The epitopes on the HIV-1 Env trimer recognized by the monoclonal antibodies used in this study are shown. The HIV-1 Env structure shown in schematic is from reference 50. The potently neutralizing antibodies that are expected to bind the Env trimer efficiently are shown in green text. The weakly neutralizing antibodies that are not expected to bind the HIV-1 Env trimer efficiently are shown in red text. (B) Binding of the indicated ligands to the minimally frozen HIV-1_JR-FL Env(-)Δ808-NDs or the HIV-1_JR-FL Env(-)-NDs captured on an ELISA plate is compared with ligand binding to glutaraldehyde-treated or untreated Env(-)Δ808 glycoprotein in a cell-surface ELISA. * = p < 0.05, unpaired t-test.</p

Morphology and size of Env-NDs and empty NDs.

<p>(A) Negative-stain electron micrographs of HIV-1_JR-FL Env(-)Δ808-NDs and empty NDs. (B) Examples of individual particles in the preparations of Env(-)Δ808-NDs and empty NDs. (C) One hundred randomly chosen Env(-)Δ808-NDs and empty NDs were measured, and both the maximum and minimum dimensions were recorded and averaged. The Env(-)Δ808-ND particles that clearly consisted of aggregated individual NDs were excluded from the analysis. (D) The Env(-)Δ808-NDs and empty NDs were incubated with the 2G12 antibody and Protein A-5 nm gold conjugate. For the empty NDs, 244 particles were examined; for the Env(-)Δ808-NDs, 44 particles were examined. The percentage of labeled particles was calculated. The gold beads associated with large aggregates and with the randomly sampled non-particulate background were also scored. Statistical significance was evaluated by using a Student’s t-test.</p

Incorporation of the full-length HIV-1_JR-FL Env precursor into NDs.

<p>(A) The HIV-1_JR-FL Env(-) glycoprotein was purified and analyzed by SDS-PAGE (left panel) and Blue Native PAGE (right panel). Both gels were stained with Coomassie Blue. (B) A size-exclusion chromatograph (SEC) of the glutaraldehyde-crosslinked HIV-1_JR-FL Env(-)-NDs run on a Superdex 200 column is shown. (C) The high-molecular-weight SEC fractions (upper panel) and the low-molecular-weight SEC fractions (lower panel) were Western blotted and probed with a mixture of sera from HIV-1-infected individuals to detect Env (αEnv) and with an anti-ApoA1 antibody to detect MSP1E2. An anomaly in the gel caused some of the Env bands in the high-molecular-weight SEC fractions to appear artefactually as two bands. (D)The specificities of the anti-ApoA1 antibody and the serum mixture for MSP1E2 and Env(-), respectively, were demonstrated by probing Western blots. (E) Negative-stain electron micrograph of glutaraldehyde-crosslinked HIV-1_JR-FL Env(-)-NDs and selected particles. The white arrows indicate individual Env(-)-NDs; some aggregates of the Env(-)-NDs are evident as well.</p

Molecular weight and composition of the Env-NDs.

<p>(A) The HIV-1_JR-FL Env(-)Δ808-NDs were analyzed by Multi-Angle Light Scattering (MALS). (B) MALS analysis of the purified Env(-)Δ808 glycoprotein in Cymal-6 detergent. (C) Krypton staining of SDS-polyacrylamide gels of dilutions of the Env(-)Δ808-NDs, which were compared with Krypton-stained standards (known amounts of Env(-)Δ808 glycoprotein and MSP1E2). The densitometric quantification of the bands allowed an estimation of the average Env(-)Δ808: MSP1E2 ratio in the Env-NDs.</p