Abstract
Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells (MBCs) to germinal centers (GCs) is inefficient and may be derailed by serum antibody-induced epitope masking, driving further B cell receptor (BCR) modification in GC-experienced B cells after boosting poses a challenge. Using humanized immunoglobulin knockin mice, we found that GT protein trimer immunogen N332-GT5 could prime inferred-germline precursors to the V3-glycan-targeted bnAb BG18 and that B cells primed by N332-GT5 were effectively boosted by either of two novel protein immunogens designed to have minimum cross-reactivity with the off-target V1-binding responses. The delivery of the prime and boost immunogens as messenger RNA lipid nanoparticles (mRNA-LNPs) generated long-lasting GCs, somatic hypermutation, and affinity maturation and may be an effective tool in HIV vaccine development.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, Non-U.S. Gov't
MeSH terms
-
AIDS Vaccines* / immunology
-
Animals
-
B-Lymphocytes / immunology
-
Broadly Neutralizing Antibodies* / immunology
-
Cross Reactions
-
Female
-
Gene Knock-In Techniques
-
Germinal Center* / immunology
-
HIV Antibodies* / immunology
-
HIV Envelope Protein gp120 / chemistry
-
HIV Envelope Protein gp120 / genetics
-
HIV Envelope Protein gp120 / immunology
-
HIV Infections / immunology
-
HIV Infections / prevention & control
-
HIV-1* / genetics
-
HIV-1* / immunology
-
Humans
-
Immunization, Secondary*
-
Liposomes
-
Memory B Cells / immunology
-
Mice
-
Mice, Inbred C57BL
-
Nanoparticles*
-
Receptors, Antigen, B-Cell / genetics
-
Receptors, Antigen, B-Cell / immunology
-
Somatic Hypermutation, Immunoglobulin
-
mRNA Vaccines* / immunology
Substances
-
AIDS Vaccines
-
Broadly Neutralizing Antibodies
-
HIV Antibodies
-
HIV Envelope Protein gp120
-
Lipid Nanoparticles
-
Liposomes
-
Receptors, Antigen, B-Cell
-
mRNA Vaccines