Protection of Newborn Macaques by Plant-Derived HIV Broadly Neutralizing Antibodies: a Model for Passive Immunotherapy during Breastfeeding

Abstract

Preventing HIV infection in newborns by vertical transmission remains an important unmet medical need in resource poor areas where ART is not available and mothers and infants cannot be treated pre-partum or during the breastfeeding period. In the present study, the protective efficacy of the potent HIV neutralizing antibodies PGT121 and VRC07-523, both produced in plants, were assessed in a multiple SHIV challenge breastfeeding macaque model. Newborn macaques received either six weekly SC injections with PGT121 alone or as a cocktail of PGT121-LS+VRC07-523-LS injected three times every two weeks. Viral challenge with SHIV SF162P3 was twice weekly over 5.5 weeks using 11 exposures. Despite the transient presence of plasma viral RNA either immediately after the first challenge or as single-point blips, the antibodies prevented a productive infection in all babies with no sustained plasma viremia, compared to viral loads ranging from 10 3 to 5x10 8 in four untreated controls. No virus was detected in PBMCs and only 3/159 tissue samples were weakly positive in the treated babies. Newborn macaques proved to be immunocompetent, producing transient anti-Env antibodies and anti-drug antibody (ADA) that were maintained in the circulation after passive bnAbs clearance. ADA responses were directed to the IgG1 Fc CH2-CH3 domains, which has not been observed to date in adult monkeys passively treated with PGT121 or VRC01. In addition, high levels of VRC07-523 anti-idiotypic antibodies in the circulation of one newborn was concomitant with the rapid elimination of VRC07. Plant-expressed antibodies show promise as passive immunoprophylaxis in a breastfeeding model in newborns. Importance Plant-produced human neutralizing antibody prophylaxis is highly effective in preventing infection in newborn monkeys during repeated oral exposure, modeling virus in breastmilk, and offers advantages in cost of production and safety. These findings raise the possibility that anti-Env antibodies may contribute to the control of viral replication in this newborn model and the observed immune responsiveness may be driven by the long-lived presence of immune complexes.

Evidence for the Role of a Second Fc-Binding Receptor in Placental IgG Transfer in Nonhuman Primates

“…Primate antibody studies utilized a macaque model involving subcutaneous (s.c.) passive administration of N. benthamiana plant-derived (denoted by the prefix “p” in the antibody name) or mammal-derived (denoted by the prefix “m” in the antibody name) human HIV envelope glycoprotein-directed bNAbs, and one monoclonal antibody (Mab) with only modest neutralizing activity. These antibodies had been previously shown to modulate or to prevent SHIV infection in macaques ( 29 , 31 – 33 ). The bNAbs had either unmodified or engineered Fc domains with either YTE ( 34 ) or LS ( 35 ) amino acid point mutations, which exhibit enhanced binding to FcRn at low but not neutral pH.…”

“…To this end, despite the significant anatomical and immunologic differences between mice and primates, comparative analysis of placental IgG transfer between species has been limited, and observations from the mouse model have generally been presumed to extend to humans. Here, HIV envelope glycoprotein-specific broadly neutralizing human IgG1 antibodies (bNAbs) PGT121 ( 26 ) and VRC07-523 ( 27 ), including variants with Fc domain mutations designed to improve FcRn affinity ( 28 , 29 ), were produced using the Nicotiana benthamiana p19 plant expression system. The placental transfer efficiency of these and mammalian cell-expressed counterparts, along with a modestly neutralizing antibody, 830A ( 30 ), were then compared in rhesus macaques and mice to assess whether IgG glycan profiles and receptor interactions beyond FcRn may play a prominent role in placental IgG transport.…”

Infant feeding: emerging concepts to prevent HIV transmission

“…Passive infant immunisation with bNAbs has prevented transmission in nonhuman primates, including during breastfeeding [ 40 ] and early human safety and pharmacokinetic data is encouraging [ 41 ]. The bNAb VRC01 (subcutaneous day 5 then monthly) and its long-acting formulation VRC01LS (subcutaneous day 5 then 12 weekly) given to breastfed infants was well tolerated with protective levels persisting for 8 weeks in the majority [ 42 , 43 ].…”

Cost‐effectiveness of broadly neutralizing antibody prophylaxis for HIV‐exposed infants in sub‐Saharan African settings

“…Infant prophylaxis with long-acting, injectable broadly neutralizing anti-HIV antibodies (bNAbs) could provide supplemental protection from vertical HIV transmission throughout breastfeeding [2]. BNAbs have demonstrated excellent efficacy as postnatal prophylaxis in non-human primates, including efficacy against intrapartum transmission if given within 24-30 hours after birth [2][3][4][5]. In the only human efficacy study published to date, one bNAb, VRC01, did not prevent overall HIV acquisition among at-risk adults; however, it demonstrated 75% efficacy against the acquisition of VRC01sensitive virus [6].…”