Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability

Dubrovskaya, Viktoriya; Tran, Karen; Ozorowski, Gabriel; Guenaga, Javier; Wilson, Richard F.; Bale, Shridhar; Cottrell, Christopher A.; Turner, Hannah L.; Seabright, Gemma E.; O’Dell, Sijy; Torres, Jonathan L.; Yang, Lifei; Feng, Yanghe; Leaman, Daniel P.; Bernat, Néstor Vázquez; Liban, Tyler; Louder, Mark K.; McKee, Krisha; Bailer, Robert T.; Movsesyan, Arlette; Doria‐Rose, Nicole A.; Pancera, Marie; Hedestam, Gunilla B. Karlsson; Zwick, Michael B.; Crispin, Max; Mascola, John R.; Ward, Andrew B.; Wyatt, Richard T.

doi:10.1016/j.immuni.2019.10.008

Cited by 126 publications

(138 citation statements)

References 66 publications

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“…Many different multivalent display strategies have been employed. They include synthetic nanoparticles [26,27], liposomes [28], micelles [29], and polymers [30]. But one of the most common is to display antigens on platforms based on virus-like particles (VLPs).…”

Section: Immune Responses Elicited By Multivalent Vaccinesmentioning

confidence: 99%

Factors That Govern the Induction of Long-Lived Antibody Responses

Chackerian

Peabody

2020

Viruses

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The induction of long-lasting, high-titer antibody responses is critical to the efficacy of many vaccines. The ability to produce durable antibody responses is governed by the generation of the terminally differentiated antibody-secreting B cells known as long-lived plasma cells (LLPCs). Once induced, LLPCs likely persist for decades, providing long-term protection against infection. The factors that control the generation of this important class of B cells are beginning to emerge. In particular, antigens with highly dense, multivalent structures are especially effective. Here we describe some pathogens for which the induction of long-lived antibodies is particularly important, and discuss the basis for the extraordinary ability of multivalent antigens to drive differentiation of naïve B cells to LLPCs.

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Section: Immune Responses Elicited By Multivalent Vaccinesmentioning

confidence: 99%

Factors That Govern the Induction of Long-Lived Antibody Responses

Chackerian

Peabody

2020

Viruses

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“…The particles from the 2D classes do not reconstruct into an interpretable 3D density when provided a closed and ligand-free trimer as the initial model, which is likely a result of trimer dissociation (classes represent free protomers with several Fabs bound), trimer opening, or a combination of both. At least two broadly-neutralizing antibodies have been reported that induce trimer dissociation by targeting gp41, 3BC315 (derived from natural human infection) (47), and 1C2 (derived from rabbit immunization with engineered Env) (48). It has also been reported that antibodies directed against the CD4 binding site, V3 loop and the MPER can induce gp120 shedding (49).…”

Section: Evidence Of Destabilization Of Sosip Trimer Conformation By mentioning

confidence: 99%

Elicitation of potent serum neutralizing antibody responses in rabbits by immunization with an HIV-1 clade C trimeric Env derived from an Indian elite neutralizer

Kumar

Deshpande

Sewall

et al. 2020

Preprint

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Evaluating the structure-function relationship of viral envelope (Env) evolution and the development of broadly cross-neutralizing antibodies (bnAbs) in natural infection can inform rational immunogen design. In the present study, we examined the magnitude and specificity of autologous neutralizing antibodies induced in rabbits by a novel HIV-1 clade C Env protein (1PGE-THIVC) vis-à-vis those developed in an elite neutralizer from whom the env sequence was obtained that was used to prepare the soluble Env protein. The thermostable 1PGE-THIVC Env displayed a native like pre-fusion closed conformation in solution as determined by small angle X-ray scattering (SAXS) and negative stain electron microscopy (EM). This closed spike conformation of 1PGE-THIVC Env trimers was correlated with weak or undetectable binding of non-neutralizing monoclonal antibodies (mAbs) compared to neutralizing mAbs. Furthermore, 1PGE-THIVC SOSIP induced potent neutralizing antibodies in rabbits to autologous virus variants. The autologous neutralizing antibody specificity induced in rabbits by 1PGE-THIVC was mapped to the C3/V4 region (T362/P401) of viral Env. This observation agreed with electron microscopy polyclonal epitope mapping (EMPEM) of the Env trimer complexed with IgG Fab prepared from the immunized rabbit sera. While the specificity of antibodies elicited in rabbits associated with neutralizing autologous viruses were distinct to those developed in the elite neutralizer, EMPEM analysis demonstrated significant changes to Env conformations when incubated with polyclonal antibody sera from the elite neutralizer, suggesting these antibodies lead to the destabilization of Env trimers. Our study not only shows distinct mechanisms associated with potent neutralization of sequence matched and unmatched autologous viruses by antibodies induced in rabbits and in the elite neutralizer, but also highlights how neutralizing antibodies developed during the course of natural infection can impact viral Env conformations.Author SummaryThe interplay between circulating virus variants and broadly cross neutralizing polyclonal antibodies developed in a subset of elite neutralizers is widely believed to provide strategies for rational immunogen design. In the present study, we studied the structural, antigenic and immunogenic properties of a thermostable soluble trimeric protein with near native pre-fusion conformation prepared using the primary sequence of an HIV-1 clade C env isolated from the broadly cross neutralizing plasma of an elite neutralizer. This novel SOSIP Env trimer demonstrated comparable antigenic, structural and immunogenic properties that favoured several ongoing subunit vaccine design efforts. The novel clade C SOSIP induced polyclonal neutralizing antibody response developed in rabbits not only differed in its epitope specificity compared to that elicited in natural infection in presence of pool of viral quasispecies but also showed how they differ in their ability to influence Env structure and conformation. A better understanding of how vaccine-induced polyclonal neutralizing antibody responses compares to responses that developed in natural infection will improve our knowledge in designing better vaccine design strategies.

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“…Vaccine efforts against different targets from the erythrocytic stage of P. falciparum and also from gametocytes for transmission-blocking purpose are also being actively investigated [3]. Alternatively, delivery of antigens via attachment to liposomes is also being pursued for multivalent display of, for example, HIV-1 envelop trimers, where ease of production and ability to attach different antigens make these flexible platforms for antigen delivery, representing strategies yet to be explored for malaria [4][5][6][7]. Currently, the most advanced vaccine candidate is a recombinant protein based on the central NANP repeats and C-terminal region of the Pf circumsporozoite protein (GlaxoS-mithKline RTS,S/AS01 vaccine) [8].…”

Section: Introductionmentioning

confidence: 99%

Structure and mechanism of monoclonal antibody binding to the junctional epitope of Plasmodium falciparum circumsporozoite protein

et al. 2020

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Lasting protection has long been a goal for malaria vaccines. The major surface antigen on Plasmodium falciparum sporozoites, the circumsporozoite protein (PfCSP), has been an attractive target for vaccine development and most protective antibodies studied to date interact with the central NANP repeat region of PfCSP. However, it remains unclear what structural and functional characteristics correlate with better protection by one antibody over another. Binding to the junctional region between the N-terminal domain and central NANP repeats has been proposed to result in superior protection: this region initiates with the only NPDP sequence followed immediately by NANP. Here, we isolated antibodies in Kymab mice immunized with full-length recombinant PfCSP and two protective antibodies were selected for further study with reactivity against the junctional region. X-ray and EM structures of two monoclonal antibodies, mAb667 and mAb668, shed light on their differential affinity and specificity for the junctional region. Importantly, these antibodies also bind to the NANP repeat region with equal or better affinity. A comparison with an NANP-only binding antibody (mAb317) revealed roughly similar but statistically distinct levels of protection against sporozoite challenge in mouse liver burden models, suggesting that junctional antibody protection might relate to the ability to also cross-react with the NANP repeat region. Our findings indicate that additional efforts are necessary to isolate a true junctional antibody with no or much reduced affinity to the NANP region to elucidate the role of the junctional epitope in protection. PLOS PATHOGENSPLOS Pathogens | https://doi.org/10.The circumsporozoite protein (CSP) of Plasmodium falciparum malaria has been the foundation for the design of transmission blocking malaria vaccines. To date, the most promising CSP-based vaccine candidate is RTS,S, which consists of the central repeating NANP amino-acid sequence and the C-terminal domain of CSP fused to hepatitis B surface antigen that assembles into virus-like particles. Potential shortcomings of RTS,S includes the lack of other potential CSP epitopes such as the junctional epitope, which is located between the N-terminal domain of CSP and the start of the NANP repeat region. Here, we elicited antibodies against full-length CSP and screened for junctional epitope binding. We then used an array of biophysical techniques to elucidate the nature of the binding and tested the level of two protective antibodies in a mouse challenge model. Although the antibodies were able to bind both junctional and NANP epitopes, the in vivo data showed distinct levels of protection between themselves and also to an NANPonly binder. Our data suggest that their protection ability may be related to the strong cross-reactivity with NANP epitopes. Since all reported junctional antibodies to date have dual-specificity, we suggest that a true junctional binder with no or very low NANP affinity, if one can be found, is essential to evaluate the cont...

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Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability

Cited by 126 publications

References 66 publications

Factors That Govern the Induction of Long-Lived Antibody Responses

Factors That Govern the Induction of Long-Lived Antibody Responses

Elicitation of potent serum neutralizing antibody responses in rabbits by immunization with an HIV-1 clade C trimeric Env derived from an Indian elite neutralizer

Structure and mechanism of monoclonal antibody binding to the junctional epitope of Plasmodium falciparum circumsporozoite protein

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