Journal Article

A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates

Allers, Carolina, Shen, Xiaoying, Crotty, Shane, Melo, Mariane, Rodrigues, Kristen A., Dufour, Jason P., Schiro, Faith, Lee, Wen-Hsin, Irvine, Darrell J., Grasperge, Brooke F., Ozorowski, Gabriel, Schief, William R., Groschel, Bettina, Phung, Ivy, Kubitz, Michael, Veazey, Ronald S., Pahar, Bapi, Georgeson, Erik, Kaczmarek Michaels, Katarzyna, Carnathan, Diane G., Bick, Michael, Burton, Dennis R., Eskandarzadeh, Saman, Kaur, Amitinder, Hangartner, Lars, Silvestri, Guido, Nedellec, Rebecca, Lopez, Paul G., Aye, Pyone P., Marina-Zárate, Ester, Montefiori, David C., Torres, Jonathan L., Ward, Andrew B., Maiorino, Laura, Fahlberg, Marissa, Gao, Hongmei

2023

Overview

Adjuvants and antigen delivery kinetics can profoundly influence B cell responses and should be critically considered in rational vaccine design, particularly for difficult neutralizing antibody targets such as human immunodeficiency virus (HIV). Antigen kinetics can change depending on the delivery method. To promote extended immunogen bioavailability and to present antigen in a multivalent form, native-HIV Env trimers are modified with short phosphoserine peptide linkers that promote tight binding to aluminum hydroxide (pSer:alum). Here we explore the use of a combined adjuvant approach that incorporates pSer:alum-mediated antigen delivery with potent adjuvants (SMNP, 3M-052) in an extensive head-to-head comparison study with conventional alum to assess germinal center (GC) and humoral immune responses. Priming with pSer:alum plus SMNP induces additive effects that enhance the magnitude and persistence of GCs, which correlate with better GC-T FH cell help. Autologous HIV-neutralizing antibody titers are improved in SMNP-immunized animals after two immunizations. Over 9 months after priming immunization of pSer:alum with either SMNP or 3M-052, robust Env-specific bone marrow plasma cells (BM B PC ) are observed. Furthermore, pSer-modification of Env trimer reduce targeting towards immunodominant non-neutralizing epitopes. The study shows that a combined adjuvant approach can augment humoral immunity by modulating immunodominance and shows promise for clinical translation. Protein antigens, such as HIV envelope protein, require adjuvants for high immunogenicity. Here the authors show that a combined adjuvant approach with slow antigen delivery and potent ISCOMs adjuvant primes robust germinal center activity and humoral immunity in non-human primates. pSer-modified antigen shifts immunodominance to allow subdominant epitope-targeting of rare B cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 13/1 / 13/31 / 38/91 / 631/250/2152/2153/1291 / 631/250/2152/2153/1982 / 631/250/590/2291 / 692/699/255/1901 / Adjuvants / Adjuvants, Immunologic - pharmacology / Alum / Aluminum / Aluminum hydroxide / Animals / Antibodies / Antibodies, Neutralizing / Antigens / Bioavailability / Bone marrow / env Gene Products, Human Immunodeficiency Virus / Env protein / Epitopes / Germinal Center / Germinal centers / HIV / HIV Antibodies / HIV Infections / Human immunodeficiency virus / Humanities and Social Sciences / Humoral immunity / Immune response (humoral) / Immunity / Immunity, Humoral / Immunization / Immunodominance / Immunogenicity / ISCOMS / Kinetics / Lymphocytes B / multidisciplinary / Neutralizing / Phosphoserine / Plasma cells / Primates / Priming / Proteins / Robustness / Science / Science (multidisciplinary) / Trimers / Viral envelope proteins