Background: No immunogen to date has reliably elicited broadly neutralizing antibodies (bnAbs) to HIV in humans or animal models. Recent advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env) have improved the elicitation of potent isolate-specific Ab responses in rabbits and macaques, but so far failed to induce bnAbs. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target occluded conserved epitope regions on Env relative to exposed variable epitope regions. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach nearly 70 amino acids in length.
Methods: Here we show that immunization of cows with BG505 SOSIP results in the rapid elicitation of broad and potent serum antibody responses. Four cows were immunized in total. Serum were collected over the course of immunization and evaluated for neutralization breadth and potency. Single memory B cells were then antigen-sorted with BG505 SOSIP and heavy and light chain variable genes were amplified by PCR.
Results: All immunized cows developed broad and potent neutralizing serum responses. Longitudinal serum analysis for one cow showed the development of neutralization breadth (19%, n = 114 cross-clade isolates) in 42 days and peak breadth (100%, n = 12 global isolates panel) at 217 days. A monoclonal antibody was isolated from this cow which harbored an ultralong HCDR3 of 64 amino acids and was able to recapitulate 69% of neutralization breadth with a potent median IC50 of 0.03 µg/ml. The antibody epitope mapped to the CD4 binding site of HIV Env.
Conclusions: Despite the inherent difficulty of eliciting broad and potent responses to HIV in most test animals, immunization with a trimer mimic in cows was able to show rapid responses in only 42 days, supporting the notion that the frequency of long HCDR3s is a critical factor in the ability to elicit HIV bnAbs. The results further suggest that immunization of cows may provide an avenue to quickly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.