Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions

Caniels, Tom G.; Medina-Ramírez, Max; Zhang, Jinsong; Sarkar, Achyut; Kumar, Sonu; LaBranche, Alex; Derking, Ronald; Allen, Joel D.; Snitselaar, Jonne L.; Capella-Pujol, Joan; Sánchez, Iván Del Moral; Yasmeen, Anila; Diaz, Marilyn; Aldon, Yoann; Bijl, Tom P. L.; Venkatayogi, Sravani; Beem, Joshua S. Martin; Newman, Amanda; Jiang, Chuancang; Lee, Wen-Hsin; Pater, Maarten; Burger, Judith A.; Breemen, Mariëlle J. van; Taeye, Steven W. de; Rantalainen, Kimmo; LaBranche, Celia C.; Saunders, Kevin O.; Montefiori, David C.; Ozorowski, Gabriel; Ward, Andrew B.; Crispin, Max; Moore, John P.; Klasse, Per Johan; Haynes, Barton F.; Wilson, Ian A.; Wiehe, Kevin; Verkoczy, Laurent; Sanders, Rogier W.

doi:10.1016/j.xcrm.2023.101003

Cited by 11 publications

(11 citation statements)

References 91 publications

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“…Results from such immunization studies confirmed that HIV-1 Env-based germline-targeting antigens could activate naïve bNAb-precursor B cells, which could gain selected bNAb features by switching the initial immunogens to heterologous, more native-like Env antigens, in subsequent boosts [20][21][22][23][24][25][26][27] . The HIV-1 germline-targeting antigen eOD-GT8, engineered to activate naïve B cells consisting of the VH1-2*02/03 germline gene of the VRC01-like family of bNAbs 18,20 , has in addition shown potential in activating the desired precursor B cells in humans 28 .…”

Section: Introductionmentioning

confidence: 81%

Antigen affinity and site of immunization dictate B cell recall responses

Termote,

Marques,

Hyllner

et al. 2024

Preprint

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Protective antibodies against HIV-1 require unusually high levels of somatic hypermutations (SHMs) introduced in germinal centers (GCs). To achieve this, a sequential vaccination approach was proposed. Using HIV-1 antibody knock-in mice with fate-mapping genes, we examined if antigen affinity affects the outcome of the B cell recall response. Compared to high affinity boost, low affinity boost resulted in decreased numbers of memory-derived B cells in secondary GCs, but with higher average SHM, indicating an affinity threshold for memory B cells to enter secondary GCs. Upon boosting local LNs, numbers of residual GC B cells increased independent on antigen affinity, while average SHM decreased. Our results demonstrate that antigen affinity and location of the boost affect the outcome of the B cell recall response. These results can help guide the design of vaccine immunogens aiming to selectively engage specific B cell clones for further SHM diversification.

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Section: Introductionmentioning

confidence: 81%

Antigen affinity and site of immunization dictate B cell recall responses

Termote,

Marques,

Hyllner

et al. 2024

Preprint

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“…(Design scenario II) At intermediate stages of the design process, the vaccine designer has developed an initial set of immunogens in a vaccine regimen and has evaluated the B cell response to this partial regimen by sequencing the antibody repertoire of immunized bnAb UCA knock-in mice [5,8,[12][13][14]. By measuring the frequency of occurrence of targeted mutations in immunized knock-in mice, the vaccine designer can determine which of the mutations necessary for broad neutralization are induced by immunization with the regimen.…”

Section: Challenges In Sequential Prime Boost Vaccine Designmentioning

confidence: 99%

“…Current experimental approaches to develop sequential prime boost vaccine regimens are highly labor- and time-intensive, relying on cycles of immunogen design, immunization of animal models, and B cell receptor repertoire sequencing to assess whether desired mutations were elicited [5, 8, 12]. An alternative approach, which we adopt here, is the use of computational models to accelerate the design process.…”

Section: Introductionmentioning

confidence: 99%

Computing the inducibility of B cell lineages under a context-dependent model of affinity maturation: Applications to sequential vaccine design

Mathews,

Van Itallie,

Wiehe

et al. 2023

Preprint

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A key challenge in B cell lineage-based vaccine design is understanding the inducibility of target neutralizing antibodies. We approach this problem through the use of detailed stochastic modeling of the somatic hypermutation process that occurs during affinity maturation. Under such a model, sequence mutation rates are context-dependent, rendering standard probability calculations for sequence evolution intractable. We develop an algorithmic approach to rapid, accurate approximation of key marginal sequence likelihoods required to inform modern sequential vaccine design strategies. These calculated probabilities are used to define an inducibility index for selecting among potential targets for immunogen design. We apply this approach to the problem of choosing targets for the design of boosting immunogens aimed at elicitation of the HIV broadly-neutralizing antibody DH270min11.

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“…Because of these challenges, preclinical vaccine NAbs tend to vary in potency and saturation, usually with limited breadth [14–17]. Notably, increasing the size of the glycan hole at the CD4 receptor binding site by depleting the glycan fence improves NAb induction against pseudoviruses (PVs) that lack these glycans, but not against the parent [15, 17–19].…”

Section: Introductionmentioning

confidence: 99%

Impact of Glycan Depletion, Glycan Debranching and Increased Glycan Charge on HIV-1 Neutralization Sensitivity and Immunogenicity

D’Addabbo,

Tong,

Crooks

et al. 2024

Preprint

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Modifying HIV-1’s envelope glycoprotein glycans can impact its neutralization sensitivity. The use of the knock out cell line GnT1-prevents the elaboration of complex-type glycans, and opens up the glycan shield, increasing bNAb vulnerability. Some bNAb precursors can bind to GnT1-trimers, supporting their use in vaccine priming. However, GnT1-trimers express poorly and exhibit very low infectious counts. Here, we describe two other potentially vaccine-relevant glycoengineered trimers, 1) To truncate complex glycans, we used of a cocktail of glycosidases, termed “NGAF3” (Neuraminidase, β-Galactosidase, N-Acetylglucosaminidase and endoglycosidaseF3). Like GnT1-trimers, NGAF3 reduced glycan clashes and increased bNAb potency while retaining a closed trimer conformation; 2) Modified by β-1,4-galactosyltransferase 1 (B4GalT1) and β-galactoside α-2,6 sialyltransferase 1 (ST6Gal1) during Env biosynthesis. Glycan mass spectrometry revealed that NGAF3 removed glycan heads of 3 of 7 positions on the trimer that are largely occupied by complex glycans. It also revealed a novel B4GalT1 activity to favor glycan precursor conversion to hybrid glycans rather than complex glycans. A comparison to monomeric gp120 revealed that B4GalT1’s new activity depends on tight glycan spacing. B4GalT1 affected more glycans than NGAF3 (6 out of 7 glycans), perhaps due to greater accessibilityduringEnv folding rather thanafterfolding. Surprisingly, the N611 glycan was unaffected by either modification. B4GalT1 and ST6Gal1 cooperatively increased the abundance of hybrid glycans and α-2,6 hypersialylated termini. This occurred largely by amplifying the abundance of a limited number of hybrid glycan structures that are also present on unmodified trimers. In rabbit vaccinations, B4GalT1+ST6GalT1-modified virus-like particles reduced the frequency and titers of serum NAbs that showed a modest preference for modified glycans. Conversely, chronically HIV-1-infected donor plasma neutralizing antibody titers were 1.7- to 10.8- fold higher against B4GalT1+ST6GalT1-modified pseudovirus. Overall, our data provide tools for heterologous prime, boost and polishing vaccine regimens using modified glycans.AUTHOR SUMMARYAn HIV-1 vaccine remains one of the most significant biomedical challenges today. Vaccines often work by triggering virus fighting antibodies to stave off infection. For HIV-1, this has been exceedingly difficult because the target, called the HIV-1 envelope glycoprotein (Env) is extremely variable and carries a thick sugar coat, protecting it from all but a few rare broadly reactive antibodies (termed bNAbs) that sometimes develop during natural HIV-1 infection. Given these challenges, it is reasonable to propose that any successful vaccine will need to be rationally designed to trigger the rare bNAbs. To meet this goal might require more 3 different vaccine components. First, a vaccine “prime” to trigger rare bNAb proliferation, followed by heterologous “boosts” and “polishing” immunogens to select for bNAbs. In this study, we evaluated two potential immunogens. In one approach, we used cocktails of enzymes to strip Env’s sugar coat, in the hope of reducing the barrier to stimulate bNAb precursors. In another, we used excess enzymes to build particular structures on Env’s coat. We checked how well these two Env variants were recognized by antibodies. We also checked in fine detail how the sugars were changed at the molecular level. Finally, we immunized rabbits. Our data enrich the number of strategies available to further explore the concept of priming, boosting and polishing vaccine shots.

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Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions

Cited by 11 publications

References 91 publications

Antigen affinity and site of immunization dictate B cell recall responses

Antigen affinity and site of immunization dictate B cell recall responses

Computing the inducibility of B cell lineages under a context-dependent model of affinity maturation: Applications to sequential vaccine design

Impact of Glycan Depletion, Glycan Debranching and Increased Glycan Charge on HIV-1 Neutralization Sensitivity and Immunogenicity

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