New Strategy Targets Rare B Cells for Effective HIV Vaccine Development
A recent study published in Nature Immunology has shown promising results using germline-targeting epitope scaffold nanoparticles to elicit rare broadly neutralizing antibody (bnAb) precursors against HIV.
Background
To achieve broad vaccination protection against diverse viruses like HIV, beta coronaviruses, hepatitis C, and influenza, bnAbs targeting conserved epitopes on variable membrane glycoproteins are essential. Although monoclonal bnAbs have been identified, strategies to elicit bnAbs with specific binding and genetic features are still needed.
Germline-targeting vaccine design aims to prime immunogens that stimulate responses from rare bnAb-precursor B cells with the necessary genetic features for bnAb development. Sequential boosting with immunogens similar to native glycoproteins can then guide B cell maturation to produce bnAbs targeting the desired epitope.
This approach has been demonstrated with VRC01-class bnAbs for the HIV envelope CD4-binding site in humans. However, most VRC01-class bnAbs interact dominantly through the heavy chain complementarity determining region 3 (HCDR3).
HCDR3-dominant bnAbs targeting the HIV envelope protein’s membrane-proximal external region (MPER) are crucial due to their high neutralization breadth, exemplified by bnAbs like DH511, LN01, and 10E8.
Study and Findings
In this study, researchers developed germline-targeting epitope scaffold nanoparticles to induce 10E8-class HCDR3-dominant bnAb-precursor responses. Initially, they optimized the epitope scaffold T117v2 in MPER for better performance.
Although T117v2 robustly bound to mature 10E8, it failed to bind other 10E8-class precursors identified through next-generation sequencing (NGS). To address this, the researchers developed immunogens based on T117v2, focusing on:
- Affinity towards 10E8 unmutated common ancestor (UCA) and NGS precursors,
- An affinity gradient for 10E8-class antibodies,
- Multivalent display on self-assembling nanoparticles,
- N-linked glycosylation sites to mitigate off-target responses.
Iterative optimization of T117v2 binding to 10E8 inferred germline, NGS precursors, and UCA resulted in a series of immunogens (10E8-GTs). These scaffolds were multimerized via fusion with self-assembling nanoparticles from hyper-thermophilic bacteria and included N-linked glycosylation sites to stabilize MPER in the 10E8-bound conformation.
Next, the researchers assessed the ability of a naïve B cell receptor (BCR) repertoire to respond to 10E8-GT immunogens. They found that 10E8-GT12, 10E8-GT10.1, and 10E8-GT9.2 bound to 0.7%, 0.8%, and 0.05% of naïve B cells from HIV-seronegative donors, respectively. A significant majority of these epitope scaffold-binding cells did not bind to 10E8 epitope-knockout versions of the constructs and were identified as epitope-specific BCRs.
BCR sequencing showed that epitope-specific BCRs were enriched for long HCDR3s and the YxFW binding motif in HCDR3, compared to control datasets. 10E8-GT scaffolds were found to selectively engage with naïve BCRs featuring 10E8-class HCDR3s, binding them with affinities suitable for efficient B cell activation in vivo.
The researchers then tested whether 10E8-GT immunogens could elicit 10E8-class responses in mice with diverse 10E8-class precursors. Using hD3-3/JH6 mice, they found that all immunogens except the control induced 10E8-class HCDR3s, enriched for the YxFw motif and long HCDR3s.
Rhesus macaques immunized with 10E8-GT10.2 12mer and saponin/mono-phosphoryl lipid nanoparticles also showed promising results.
Conclusion
The study demonstrates a successful strategy to elicit rare bnAb precursors through germline-targeting epitope scaffold nanoparticles, marking a significant step towards an effective HIV vaccine. This approach has the potential to be applied to other viruses, advancing the development of broad-spectrum vaccines.
