CROI 2016 Abstract eBook

Abstract Listing

Oral Abstracts

88 An Infant bNAbWith Low Somatic Hypermutation Contributes to Polyclonal Breadth Cassandra Simonich 1 ; KatherineWilliams 1 ;Theodore Gobillot 2 ; Hadega Aamer 3 ; Stephanie Rainwater 1 ; Ruth Nduati 4 ; Julie M. Overbaugh 1

1 Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA; 2 Univ of Washington, Seattle, WA, USA; 3 Seattle Children’s Rsr Inst, Seattle, WA, USA; 4 Univ of Nairobi, Nairobi, Kenya Background: Rapid development of plasma cross-clade neutralization breadth has been described in infants compared to adults. The characteristics of infant HIV-specific antibodies contributing to plasma neutralization breadth have not yet been studied, but may provide unique insights into the process of developing HIV-1-specific broadly neutralizing antibody (bNAb) responses. Methods: We isolated and characterized neutralizing antibodies (NAb) from an infant sample from 450 days of age (~15 months), an estimated 336 days (~11 months) post- infection – a time when cross-clade NAb breadth was detected in plasma. We used large-scale culture of memory B cells followed by high-throughput neutralization assays to identify HIV-specific B cells. The neutralization breadth of isolated infant-derived NAbs was defined using a diverse panel of envelope variants. The epitope target of the infant-derived antibody demonstrating the greatest neutralization breadth was defined by identifying mutations in known neutralizing epitope targets that confer neutralization resistance. Results: To date, 9 infant-derived HIV-1-specific neutralizing antibodies have been identified and all are produced from distinct lineages of B cells. The level of somatic hypermutation (SHM) of infant neutralizing antibodies is significantly lower than adult bNAbs and also NAbs from adults with Tier 1 neutralizing activity but limited cross-clade Tier 2 activity. Several infant NAbs demonstrate heterologous Tier 2 neutralization; one demonstrates cross-clade Tier 2 neutralization breadth against clades A, B and C, and neutralizes 7 of 12 viruses from a standardized panel of global reference viruses. For this antibody, neutralizing activity is dependent on the N332 residue in V3, a known site of vulnerability and target of adult bNAbs such as PGT121 and PGT128. However, the VH-gene usage of this antibody is not the same as known adult bNAbs that target this site, and SHM is 6.8% at the nucleotide level compared to 17% for PGT121 and 19% for PGT128. Conclusions: These data suggest that infant responses may be polyclonal and a component of the response includes antibodies targeting a glycan epitope. Furthermore, these data suggest that this infant’s response may target some similar epitopes as adults, but do so using distinct gene families and less SHM. 89LB Virus, Host, and Disease Factors Govern HIV-1 Broadly Neutralizing Antibody Induction Peter Rusert 1 ; Roger Kouyos 2 ; Claus Kadelka 1 ; Hanna Ebner 1 ; Merle Schanz 1 ; Michael Huber 1 ; Dominique L. Braun 2 ; Huldrych F. Günthard 2 ; Alexandra Trkola 3 ; for the Swiss HIV Cohort Study 1 Inst of Med Virology, Univ of Zurich, Zurich, Switzerland; 2 Univ Hosp Zurich, Zurich, Switzerland; 3 Univ of Zurich, Zurich, Switzerland Background: Development of an effective AIDS vaccine that elicits broadly neutralizing antibodies (bnAbs) urgently awaits the identification of parameters that steer their induction. Here we report on a systematic analysis of bnAb activity in 4484 HIV-1 infected individuals designed to explore and identify viral, host and disease factors that affect bnAb generation. Methods: Plasma neutralization activity was determined in a TZM-bl based pseudovirus neutralization assay against an 8 multi-clade virus panel. Top ranked neutralizers were further characterized in a 40 virus panel and the top 87 plasmas subjected to a bnAb fingerprinting analysis to delineate specificities. Results: By linking information on the obtained bnAb activity with comprehensive longitudinal patient and virus data available in our cohort, we confirmed using logistic regression that three parameters reflecting the exposure to antigen - namely the viral load, the length of untreated infection and viral diversity – independently of each other drive bnAb induction. Black ethnicity proved to be associated with significantly higher rates of bnAb induction than white ethnicity independently of all other probed variables including the infecting HIV-1 subtype. In total we identified 239 individuals with elite or broad neutralization activity. Neutralization finger print analysis of the bnAb specificity of the top 87 ranked plasmas identified a strong predisposition of individual HIV-1 subtypes to induce certain bnAb types. Subtype B infection induced CD4bs bnAbs more frequently than non-B infection (p= 0.02; Fisher’s exact test) whereas V2-glycan bnAbs were highly effectively stimulated by non-B but not subtype B viruses (p= 5*10 -6 , Fisher’s exact test). Conclusions: Our study provides a number of novel and exciting clues for vaccine design. Three parameters, viral load, diversity and length of infection, previously implicated in bnAb evolution proved to influence bnAb generation independently of each other and thus individually could have a potential to advance vaccine strategies. The advantage of black ethnicity in inducing bnAbs highlights the need to uncover host genome determinants in bnAb inducing individuals of all ethnicities to understand their importance and implications for vaccines. Lastly, the subtype dependence in bnAb type development strongly implies that distinct subtype specific structural features of the viral envelope trimer must exist, which need to be unraveled and harnessed for vaccine immunogen design. 90 Clinical Safety and Pharmacokinetics of IV and SC VRC01, a Broadly Neutralizing mAb Kenneth H. Mayer 1 ; Kelly Seaton 2 ;Yunda Huang 3 ; Nicole Grunenberg 3 ; John Hural 3 ; Julie Ledgerwood 4 ; Robert Bailer 4 ; Richard A. Koup 4 ; Mary Allen 5 ; Barney Graham 5 1 The Fenway Inst, Fenway Hlth, Boston, MA, USA; 2 Duke Univ, Durham, NC, USA; 3 Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA; 4 VRC, NIAID, NIH, Bethesda, MD, USA; 5 NIAID, NIH, Bethesda, MD, USA Background: VRC01 is a monoclonal antibody (mAb) directed at the CD-4 binding site that neutralized most HIV isolates that it was tested against in vitro, protected simians from retroviral challenges, decreased HIV plasma RNA in treatment-naïve HIV-infected participants (ppt), and offers the potential to prevent HIV transmission in humans. Methods: In HVTN 104, 88 low risk, healthy men (n=44) and women (n=44) were enrolled and assigned to receive either a 40 mg/kg IV loading dose, followed by 20 mg/kg IV every 4 weeks (Group 1), or 10, 30 or 40 mg/kg of VRC01 administered intravenously (IV) every 8 weeks (Groups 2, 4, or 5), or a 40 mg/kg IV loading dose, followed by 5 mg/ kg subcutaneously, every 2 weeks for 5.5 months (Group 3, which included a placebo arm). Safety and tolerability were evaluated by site clinicians and reviewed weekly by the protocol safety team. VRC01 drug levels in serumwere measured by a VRC01 anti-idiotype ELISA binding antibody assay. Safety data from all 5 groups and pharmacokinetic data from groups 1 to 3 are presented here. Results: The median age of enrollees was 27 yrs (range: 18-50); 46.5%were non-White; 11.4%were Hispanic. Infusions and injections were generally well-tolerated, with 28% of infusions and 14% of injections resulting in mild pain/tenderness reactions, and very few erythema/induration reactions. 57% of participants had a systemic reaction, and of the 3 that were severe, 2 had concurrent viral infections, and 1 had malaise lasting 1 day. Most participants (72.7%) reported at least 1 adverse event, 73.6% of these events were graded as mild; with only 6.2% deemed product-related, and all of those were mild. Study product was discontinued after AEs in 3 ppt, out of caution. As of Sept. 4, 2015, 226 infusions and 167 injections were completed. Median peak levels after a 40 mg/kg infusion generally exceeded 300 mcg/mL and median VRC01 levels at 112 days were ~30 mcg/mL whether VRC01 was administered at 20 mg/kg at 28 days, 40 mg/kg at 56 days, or 5 mg/kg SC every 2 weeks. Drug levels from the first 3 groups are depicted in the acompanying figure. Conclusions: VRC01 administered IV or SC was well-tolerated. Product-related AEs were generally transient and mild. After a 40 mg/kg IV loading dose, VRC01 levels could be maintained >30 mcg/mL for several months through either IV or SC administration. These findings support the rationale that VRC01 administered every 2 weeks SC or 2 months IV should be evaluated for HIV immunoprophylaxis

Oral Abstracts

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CROI 2016