Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody

Abstract

To guide vaccine design, we assessed whether human monoclonal antibodies (MAbs) b12 and b6 against the CD4 binding site (CD4bs) on HIV-1 gp120 and F240 against an immundominant epitope on gp41 could prevent vaginal transmission of simian HIV (SHIV)-162P4 to macaques. The two anti-gp120 MAbs have similar monomeric gp120-binding properties, measured in vitro, but b12 is strongly neutralizing and b6 is not. F240 is nonneutralizing. Applied vaginally at a high dose, the strongly neutralizing MAb b12 provided sterilizing immunity in seven of seven animals, b6 in zero of five animals, and F240 in two of five animals. Compared with control animals, the protection by b12 achieved statistical significance, whereas that caused by F240 did not. For two of three unprotected F240-treated animals there was a trend toward lowered viremia. The potential protective effect of F240 may relate to the relatively strong ability of this antibody to capture infectious virions. Additional passive transfer experiments also indicated that the ability of the administered anti-gp120 MAbs to neutralize the challenge virus was a critical influence on protection. Furthermore, when data from all of the experiments were combined, there was a significant increase in the number of founder viruses establishing infection in animals receiving MAb b6, compared with other nonprotected macaques. Thus, a gp120-binding, weakly neutralizing MAb to the CD4bs was, at best, completely ineffective at protection. A nonneutralizing antibody to gp41 may have a limited capacity to protect, but the results suggest that the central focus of HIV-1 vaccine research should be on the induction of potently neutralizing antibodies.

Les anticorps anti-VIH

“…Il est cependant à noter que l'importance des mécanismes d'inhibition dépendants des RFc a d'ores et déjà été confirmé dans des modèles animaux [11,18,19]. En effet, dans un modèle de primate non humain, l'étude du transfert passif de l'anticorps neutralisant b12 ou de l'anticorps b12 mutant (dénommé LALA et incapable de fixer le complément ou les RFcγ) a démontré une diminution de 50 % de l'efficacité de protection par l'anticorps LALA [11,18].…”

“…Plus récemment, une fonction de protection partielle et une activité sur la diminution de la charge virale ont été attribuées à des Ac non neutralisants inhibiteurs dans le modèle de primate non humain. Ces anticorps possèdent des fonctions inhibitrices dépendantes de leur région Fc et de l'expression des RFc [19,20]. Chez les patients infectés, des anticorps inhibiteurs sont fréquemment détectés très tôt après la phase aiguë de l'infection ( Figure 1, courbe rouge) [21,22].…”

On the benefits of sin

“…52 Additional support for this possibility comes from a recent study in the rhesus macaque SHIV model of HIV-infection. Burton et al 43 demonstrated that a non-neutralizing Ab clone directed against the gp41 component of the HIV Env can mediate limited protection against SHIV challenge in rhesus macaques.…”

“…40 These Abs are seen as ideal candidates for an effective HIV vaccine to induce, as upon passive transfer to rhesus macaques and vector-induced expression in humanized mice they protect from infection with SHIV and HIV, respectively. [41][42][43][44][45] Despite the attractiveness of these targets for vaccines and the considerable interest they have invoked, attempts to induce BnAbs through vaccination have failed. The impediment to stimulating BnAbs through vaccination is, at least in part, thought to be related to the extensive somatic hypermutation required to generate these Abs.…”

Efficient Single Tobamoviral Vector-Based Bioproduction of Broadly Neutralizing Anti-HIV-1 Monoclonal Antibody VRC01 in Nicotiana benthamiana Plants and Utility of VRC01 in Combination Microbicides

“…For example, potential conflicts of priorities between treatment and prevention may arise, and emergence of escape mutants could compromise available therapy options (6,7). Human anti-HIV-1 broadly neutralizing monoclonal antibodies (bnMAbs) may provide attractive options in this context, given their proven protective efficacy against infection upon pre-and/or postexposure uses in animal challenge models (8)(9)(10)(11)(12)(13)(14) and inherent general safety because of their human origin. A phase I randomized controlled clinical trial has been recently completed for a vaginal microbicide candidate containing three bnMAbs, 2F5, 4E10, and 2G12, showing that daily vaginal administration of the bnMAbs (50 mg each) to healthy women for 12 days was safe and well tolerated (15).…”