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A mutation in VRC01, a broadly neutralizing, HIV-1-specific antibody, confers enhanced binding to the neonatal Fc receptor, increasing the antibody half-life in the serum and localization in mucosal tissues, where it provides superior protection against rectal simian HIV-1 infection in macaques. Enhanced anti-HIV activity in mutant VRC01 antibody The recent discovery of broad and potent anti-HIV-1 antibodies has renewed interest in their use for passive protection against human immunodeficiency virus-1 in humans. This paper describes a mutation in the HIV-specific broadly neutralizing antibody VRC01 that confers enhanced binding to the neonatal Fc receptor and increases the antibody half-life in serum and mucosal tissues. It conferred superior protection in a rectal simian-HIV challenge model in macaques when compared to wild-type VRC01. To protect against human immunodeficiency virus (HIV-1) infection, broadly neutralizing antibodies (bnAbs) must be active at the portals of viral entry in the gastrointestinal or cervicovaginal tracts. The localization and persistence of antibodies at these sites is influenced by the neonatal Fc receptor (FcRn).sup.1,2, whose role in protecting against infection in vivo has not been defined. Here, we show that a bnAb with enhanced FcRn binding has increased gut mucosal tissue localization, which improves protection against lentiviral infection in non-human primates. A bnAb directed to the CD4-binding site of the HIV-1 envelope (Env) protein (denoted VRC01).sup.3 was modified by site-directed mutagenesis to increase its binding affinity for FcRn. This enhanced FcRn-binding mutant bnAb, denoted VRC01-LS, displayed increased transcytosis across human FcRn-expressing cellular monolayers in vitro while retaining Fc[gamma]RIIIa binding and function, including antibody-dependent cell-mediated cytotoxicity (ADCC) activity, at levels similar to VRC01 (the wild type). VRC01-LS had a threefold longer serum half-life than VRC01 in non-human primates and persisted in the rectal mucosa even when it was no longer detectable in the serum. Notably, VRC01-LS mediated protection superior to that afforded by VRC01 against intrarectal infection with simian-human immunodeficiency virus (SHIV). These findings suggest that modification of FcRn binding provides a mechanism not only to increase serum half-life but also to enhance mucosal localization that confers immune protection. Mutations that enhance FcRn function could therefore increase the potency and durability of passive immunization strategies to prevent HIV-1 infection., Author(s): Sung-Youl Ko [sup.1] , Amarendra Pegu [sup.1] , Rebecca S. Rudicell [sup.1] [sup.6] , Zhi-yong Yang [sup.1] [sup.6] , M. Gordon Joyce [sup.1] , Xuejun Chen [sup.1] , Keyun [...]

Vaccine-induced immunity to Ebola virus infection in nonhuman primates (NHPs) is marked by potent antigen-specific cellular and humoral immune responses (1,2); however, the immune mechanism of protection remains unknown. Here we define the immune basis of protection conferred by a highly protective recombinant adenovirus virus serotype 5 (rAd5) encoding Ebola virus glycoprotein (GP) (1,3) in NHPs. Passive transfer of high-titer polyclonal antibodies from vaccinated Ebola virus-immune cynomolgus macaques to naive macaques failed to confer protection against disease, suggesting a limited role of humoral immunity. In contrast, depletion of [CD3.sup.+] T cells in vivo after vaccination and immediately before challenge eliminated immunity in two vaccinated macaques, indicating a crucial requirement for T cells in this setting. The protective effect was mediated largely by [CD8.sup.+] cells, as depletion of [CD8.sup.+] cells in vivo using the cM-T807 monoclonal antibody (mAb), which does not affect [CD4.sup.+] T cell or humoral immune responses, abrogated protection in four out of five subjects. These findings indicate that [CD8.sup.+] cells have a major role in rAd5-GP-induced immune protection against Ebola virus infection in NHPs. Understanding the immunologic mechanism of Ebola virus protection will facilitate the development of vaccines for Ebola and related hemorrhagic fever viruses in humans., Viral vector vaccines have shown efficacy for the delivery of Ebola virus genes and immune protection against infection in NHPs, but the mechanism of immune protection has not been defined [...]

SARS-CoV-2 has the capacity to evolve mutations to escape vaccine-and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool. Here, we challenged rhesus macaques with SARS-CoV-2 Delta and simultaneously treated them with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment gave equivalent protection in upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 did not block the development of memory responses to Delta and did not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Despite several published methods of inducing surgical anesthesia in guinea pigs, viable methods of anesthesia for blood collection from the vena cava are inadequate. We compared 5 anesthesia regimens and their efficacy in inducing anesthesia for blood sampling in guinea pigs: ketamine-xylazine (30 and 2.5 mg/kg) administered subcutaneously, intramuscularly, or intraperitoneally; pentobarbital (37 mg/kg) administered intraperitoneally; and medetomidine (0.5 mg/kg) administered intramuscularly. Parameters measured included time to onset of anesthesia, time to recovery from anesthesia, and complete blood count (CBC) and serum chemistry values. CBC values did not differ among the 5 regimens, but serum glucose, BUN, phosphorous, and creatine phosphokinase levels varied among groups. Based on our data, intraperitoneal ketamine-xylazine appears to emerge as a preferable injectable anesthetic regimen in guinea pigs for blood collection from the anterior vena cava.