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No Monkey Business: Nonhuman Primate Models for HIV Prevention

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Date: 16 October 2017 (Monday)
Time: 1:00 – 2:30 PM EDT

“No Monkey Business: Nonhuman Primate Models for HIV Prevention” is a 1.5-hour webinar highlighting the latest research using nonhuman primate (NHP) models for HIV prevention, which will be held on Monday, 16 October 2017.

This mini-symposium co-chaired by Shelby O’Connor (University of Wisconsin) and Matt Reynolds (University of Wisconsin) will present a few pathbreaking studies using NHP models to test several active and passive immunization approaches for HIV prevention and discuss the latest developments in the field. This webinar is inspired by presentations at the “35th Annual Symposium on Nonhuman Primate Models for AIDS,” which took place in Madison, WI, in 2017 August, and will feature the following four short, 15 minute talks followed by a 30-minute panel discussion.

Ann Hessell, Oregon Health & Science University, Oregon National Primate Research CenterAnn Hessell, Oregon Health & Science University, Oregon National Primate Research Center
Targeting V1V2 in active and passive immunizations

Neutralization potency of a passively transferred antibody against the challenge virus has been shown to be the primary correlate of protection against mucosal SHIV challenges in macaques. A new report confirms that this is also true for V2-directed broadly neutralizing monoclonal antibodies (bNmAbs). However, much less is known about the mechanism associated with protection when neutralization is not the predominate mode of in vivo anti-viral activity leading to blunting viremia and clearance of virus-infected tissue reservoirs. Here, we present data from a passive protection study with monoclonal antibody (mAb) 830A that targets a conformational epitope within V2 overlapping the α4β7 integrin binding site. Subcutaneous delivery of 830A two days before six repeated intrarectal (IR) challenges resulted in a significant improvement in protection and reduction of viral reservoirs in lymphoid tissues compared to controls. The importance of the study is that the protection and viremia blunting in the presence of the 830A was not predominantly mediated by powerful neutralization of the challenge virus. Moreover, implications for immunogen design of vaccine strategies is presented here by data from active immunization studies using novel V1V2 scaffold immunogens. Although the potential for bNmAbs for prevention and immunotherapy applications against HIV infection is extremely encouraging, eliciting potent bNmAbs like those currently under study has not been possible. In contrast, our vaccine regimen using these constructs show that it is possible to elicit high titers of antibodies in macaques that specifically target conformational epitopes in V1V2 that also have neutralizing and Fc-mediated effector activity.

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Genevieve Fouda, Duke Human Vaccine InstituteGenevieve Fouda, Duke Human Vaccine Institute
Non-human primate models of HIV maternal and infant immunization

Despite global scale-up in antiretroviral-based prevention of mother-to-child transmission services, more than 150,000 infants become infected with HIV-1 yearly. Immune based interventions including maternal and/or infant immunization will likely be needed to eliminate pediatric HIV. Our group uses non-human primate models to study passive and active maternal and infant immunization strategies. We have investigated immune responses elicited in breast milk and plasma of hormone-induced lactating rhesus monkeys after vaccination with a MVA prime protein boost strategy administered either intramuscularly (IM) or intranasally (IN). While the systemic immunization induced functional IgG response in milk, the mucosal immunization induced robust IgA. Interestingly, combining mucosal and systemic immunization led to both functional IgG and IgA responses in breast milk. To determine if maternal immunization can protect infants from virus acquisition, we immunized pregnant rhesus macaques with a MVA prime/ IM+IN protein boost vaccine regimen, then orally challenged their infants starting at 6 weeks of age with a weekly oral low-dose of the clade C tier 2 SHIV1157ipd3N4. Maternal antibodies were adequately transferred across the placenta, but were not protective as there was no significant difference in the number of infected animals, number of challenges required to achieve viremia or the peak viral load between infants born to HIV vaccinated or placebo mothers. Nevertheless, it is important to note that in general maternal antibody levels were low as only two vaccine doses were administered before delivery and that the challenge and vaccine virus strains were different. We have also investigated if passive immunization of infant rhesus macaques with HIV envelope-specific antibodies isolated from breast milk of HIV-infected women can protect from a SHIV1157ipd3N4 oral challenge. Interestingly, we observed that administration of an antibody cocktail with neutralizing and ADCC activity led to partial protection with transmission of fewer transmitted/founder (T/F) virus variants compared to control mAb-treated infants. In future studies, it will be important to determine if boosting of maternal immune responses through optimal immunization with currently available products can impact infant virus acquisition.

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Jeffrey Schneider, Northwestern UniversityJeffrey Schneider, Northwestern University
Tracking fluorophore-conjugated VRC01 following intravenous injection in the rhesus macaque

Due to the success of passive infusion of broadly neutralizing antibodies (bNAbs) in SHIV challenged rhesus macaques to block systemic infection, a new trial was launched this past fall where at-risk individuals received an intravenous (IV) infusion of the bNAb, VRC01. However, there are still many questions as to how these specialized antibodies can provide sterilizing immunity, one of which is how long it takes for antibodies to achieve steady state levels in the tissue following IV injection. Current efforts to track antibodies utilize low resolution and sensitivity methods such as ELISA and indirect labeling imaging techniques. Here we demonstrate that it is possible to utilize the fluorophores Cy5 and Cy3 directly conjugated to VRC01‐LS for direct visualization and quantification of passively transferred antibodies in plasma, mucosal secretions, and tissue. In sequential vaginal biopsies acquired from the same animal from 24hr to 8wks post IV‐injection of VRC01‐LS‐Cy5, we found that antibody slowly built up and achieved steady state at 1wk. Similar to the findings in a single rhesus macaque, we found that levels of antibody grew steadily in the female reproductive tract (FRT) and at distal sites in sequentially necropsied animals achieving steady state levels at 1wk and decreasing around week 2. Through tracking antibody in the FRT and at distal sites we will be able to correlate virus replication and antibody levels in these tissues and more importantly identify sites of virus‐antibody interaction.

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Justin Greene, Vaccine and Gene Therapy Institute, Oregon Health & Science UniversityJustin Greene, Vaccine and Gene Therapy Institute, Oregon Health & Science University
CyCMV vaccination induces unconventional CD8 T cells in mauritian cynomolgus macaques

Rhesus macaques (RM) vaccinated with strain 68-1 rhesus CMV (RhCMV) vaccine vectors expressing SIV antigens demonstrate unprecedented protection against highly virulent SIVmac239 replication, with protected RM eventually clearing the virus. This protection is associated with unconventional CD8+ T cell responses that are either MHC-II or MHC-E restricted. These unconventional CD8+ T cell responses may be the result of the unique MHC complexity present in RM, or the result of conserved immunoregulatory mechanisms utilized by CMV. In order to parse out the importance of host immunogenetics from strain-specific CMV mechanisms, additional nonhuman primate models of CMV infection are needed. Mauritian-origin cynomolgus macaques (MCM) are a particularly attractive nonhuman primate model due to a significant population bottleneck 400 years ago that resulted in highly limited immunogenetics. We captured MCM CMV (CyCMV) as a BAC and subsequently developed an SIV Gag-expressing vector with deletions corresponding to those found in RhCMV 68-1. Vaccination of MCM with “strain 68-1 like” CyCMV induced unconventional CD8+ T cell responses including MHC-E and MHC-II restricted responses, including “supertope” responses that are present in every RhCMV strain 68-1 vaccinated RM. Interestingly, both RhCMV vaccinated RM and CyCMV vaccinated MCM target identical supertope peptides that are restricted by MHC-E. As CMV-vectors advance toward human clinical trials, these results suggest a similarly designed human CMV may induce unconventional CD8+ T cell responses in humans.

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If you have any questions about the meeting, please contact Bargavi Thyagarajan at bthyagarajan@vaccineenterprise.org

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