Use of broadly neutralizing antibodies for HIV‐1 prevention

Abstract

Summary Antibodies have a long history in antiviral therapy, but until recently they have not been actively pursued for HIV-1 due to modest potency and breadth of early human monoclonal antibodies (MAbs) and perceived insurmountable technical, financial, and logistical hurdles. Recent advances in the identification and characterization of MAbs with the ability to potently neutralize diverse HIV-1 isolates has reinvigorated discussion and testing of these products in humans, since new broadly neutralizing MAbs (bnMAbs) are more likely to be effective against worldwide strains of HIV-1. In animal models, there is abundant evidence that bnMAbs can block infection in a dose dependent manner, and the more potent bnMAbs will allow clinical testing at infusion doses that are practically achievable. Moreover, recent advances in antibody engineering are providing further improvements in MAb potency, breadth and half-life. This review summarizes the current state of the field of bnMAb protection in animal models as well as a review of variables that are critical for antiviral activity. Several bnMAbs are currently in clinical testing, and we offer perspectives on their use as pre-exposure prophylaxis (PrEP), potential benefits beyond sterilizing immunity, and a discussion of future approaches to engineer novel molecules.

Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge

“…SHIV-AD8EO, SHIV-SF162P3, SHIV-BaL) (9–11). Average serum concentrations at the time of challenge necessary for protection were variable but higher than that reported here (31). The lowest serum antibody concentrations that conferred complete protection were with PGT121 at 15 and 22 μg/mL against SHIV-SF162P3 and SHIV-AD8EO challenges, respectively, and partial or no protection was seen at serum levels of 1.8 μg/mL (9, 10).…”

Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials

“…These estimates are obtained from a logistic regression model of the NHP challenge data 11,30 with S and V as main effect terms and assuming no interaction of S and V , with a per-exposure infection odds ratio of 0.14 (95% CI: 0.02, 0.81) per-log  e increase of s and a per-exposure infection odds ratio of 3.42 (95% CI: 0.92, 12.73) per-log  e increase of v (Figures S1– S3). Estimated for the 5-fold per-exposure PE model is shown in Figure 3, where the effect of V remains the same as the NHP model, but the per-exposure infection odds ratio per-log  e increase of s is 0.31, instead (Figure S4).…”

“…Two models are considered for the specification of : the non-human primate (NHP) model and the 5-fold model. Under the NHP model, this function is specified based on observed data from non-human primate challenges, 11,30 in which a total of 40 healthy male and female animals were challenged intra-rectally with a single 100% infectious SHIV inoculation two days after an infusion of VRC01 at various dosage levels. The infection status was recorded for eight animals challenged with SHIV-SF162P3, and 32 animals challenged with SHIV BaLP4, along with the animals’ VRC01 plasma level on the day of challenge.…”

“…VRC01 targets the conserved CD4 binding site of the HIV envelope 7,8 and has been demonstrated to prevent HIV infection in non-human primate (NHP) challenge studies. 11–13,30 Building on these NHP results, the first efficacy studies of VRC01 – termed the Antibody Mediated Prevention (AMP) trials – for HIV prevention were launched in 2016, with an estimated total study duration of 5 years including enrollment and follow up. 14 Together, the two AMP trials were designed to enroll and randomize 4200 HIV-negative volunteers in 1:1:1 allocation to receive a total of ten intravenous infusions (8-weekly) of VRC01 at a dose of 10 mg/kg, 30 mg/kg, or placebo.…”

“…Briefly, the prediction of PE is primarily based on two input functions: (1) bivariate per-exposure prevention efficacy as a function of the concentration of VRC01 in participants’ serum at the time of exposure, S = s , and of the in vitro 80% inhibition concentration (IC80) of the mAb against the exposing virus, V = v ; and (2) the joint probability distribution P ( s , v ) of ( S , V ) at HIV exposures for participants in a mAb group (Figure 1). For (1), estimated from NHP high dose intra-rectal challenge data for VRC01 11,30 is used as the basis for a range of per-exposure PE models, indexed by the “NHP model” that assumes the per-exposure efficacy derived from NHP is applicable to humans. Based loosely on human explant experiments that suggest that some human genital tissues require greater concentrations of VRC01 for protection against HIV challenge than others, 28,29 we also use a “5-fold model” that assumes that 5-fold greater mAb concentration would be needed to provide the same level of PE as seen in the NHP challenge data.…”