Conference report Innovative approaches to track lymph node germinal center responses to evaluate development of broadly neutralizing antibodies in human HIV vaccine trials M. Patricia D’Souza a,⇑ , Mary A. Allen a , Jane A.G. Baumblatt a , Cesar Boggiano a , Shane Crotty c , Christine Grady b , Colin Havenar-Daughton c , Antje Heit d , Dale J. Hu a , Nina Kunwar a , M. Juliana McElrath d , Lymph Node Webinar Contributors 1 a Division of AIDS, NIAID, Bethesda, MD, USA c Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA b Department of Bioethics, NIH, Bethesda, MD, USA d Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, USA article info Article history: Received 23 March 2018 Received in revised form 16 July 2018 Accepted 28 July 2018 Available online xxxx Keywords: HIV vaccines Lymph node biopsies Clinical immune monitoring abstract Phase 1 clinical studies will soon evaluate novel HIV-1 envelope immunogens targeting distinct ‘germ- line’ and memory B cell receptors to ultimately elicit HIV-1 broadly neutralizing antibodies (bNAbs). The National Institute of Allergy and Infectious Diseases (NIAID) recently convened a panel of US- based expert scientists, clinicians, sponsors and ethicists to discuss the role of sampling draining lymph nodes within preventive HIV vaccine trials. The meeting addressed the importance of evaluating germinal center (GC) responses following immunization to predict bNAb potency and breadth, and reviewed key aspects of this procedure within the clinical research setting, including informed consent, adverse event monitoring, study participant acceptability, medical expertise and training. We review highlights from the meeting and discuss the advantages and disadvantages of sampling lymph nodes by excisional biopsies compared to fine needle aspirations (FNA) in the context of prophylactic HIV vaccine trials. 1. Introduction Most currently licensed vaccines have relatively simple regi- mens which elicit the timely production of antibodies that inacti- vate or neutralize the target pathogen [1]. However, most of these pathogens either exhibit limited antigenic variability or have accessible immunodominant epitopes. On the other hand, HIV, with extensive genetic variability, has evolved strategies to mini- mize and evade effective antibody responses [2]. To address these challenges, current HIV vaccine research has employed a number of novel approaches to the field of vaccinology [3]. These include efforts to improve the potency and durability of non-neutralizing antibodies similar to those elicited in the RV144 clinical trial [4], which was the first and only HIV vaccine clinical trial to demon- strate modest efficacy. An alternative goal is to elicit potent broad neutralizing antibodies (bNAbs) which target conserved, vulnera- ble epitope sites on the native HIV-1 Env trimer and can potently neutralize a majority of circulating HIV-1 strains [5,6]. Passive transfer of bNAbs has been shown to prevent SIV trans- mission in animal models [7–9] and is a promising preventive strategy. Studies have identified multiple bNAbs that exhibit potent activity against a majority of HIV-1 strains [10–13]. One such bNAb, VRC01, is targeted to the CD4 binding site and neutral- izes approximately 90% of a broad panel of HIV-1 envelope pseudo- typed viruses [14,15]. VRC01 is currently being evaluated in two proof-of-concept clinical trials called ‘‘Antibody Mediated Preven- tion” (AMP) to test the effectiveness of passive immunization in preventing HIV infection. These trials afford a unique opportunity to determine the important parameters associated with protective efficacy and provide an impetus for developing appropriate immunogens to elicit bNAbs like VRC01 that can effectively pre- vent HIV acquisition. Generation of HIV-1 bNAbs is a complicated and challenging process due to the complex interplay of HIV genetic diversity and host immune responses. Specific examples of these challenges include the dense glycosylation [16] and the conformational flexi- bility of the HIV-1 Env glycoprotein [17] as well as the adaptive molecular mimicry of host antigens [18]. Despite these obstacles, up to 25% of HIV-1 infected individuals develop bNAbs detected https://doi.org/10.1016/j.vaccine.2018.07.071 0264-410X/ ⇑ Corresponding author. 1 See Appendix for List. Vaccine xxx (2018) xxx–xxx Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine Please cite this article in press as: Patricia D’Souza M et al. Innovative approaches to track lymph node germinal center responses to evaluate development of broadly neutralizing antibodies in human HIV vaccine trials. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.07.071