Comparison of Neutralizing Antibody Responses Elicited from Highly Diverse Polyvalent Heterotrimeric HIV-1 gp140 Cocktail Immunogens versus a Monovalent Counterpart in Rhesus Macaques

Bowles, Emma J.; Schiffner, Torben; Rosario, Maximillian; Needham, Gemma A.; Ramaswamy, Meghna; McGouran, Joanna F.; Kessler, Benedikt M.; LaBranche, Celia C.; McMichael, Andrew J.; Montefiori, David C.; Sattentau, Quentin J.; Hanke, Tomáš; Stewart‐Jones, Guillaume

doi:10.1371/journal.pone.0114709

Cited by 12 publications

(12 citation statements)

References 75 publications

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“…We have previously demonstrated that Carbopol elicits strong Th1-type T and B-cell responses in mice, mediating protection from otherwise lethal influenza infection, and anti-tumor responses [22] . We observed that Carbopol did not have obvious toxicity in mice [22] or non-human primates [23] , and propose that this type of polymer might have utility as a human vaccine adjuvant.…”

Section: Introductionmentioning

confidence: 73%

Sterile inflammation induced by Carbopol elicits robust adaptive immune responses in the absence of pathogen-associated molecular patterns

Gartlan

Krashias

Wegmann

et al. 2016

Vaccine

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Section: Introductionmentioning

confidence: 73%

Sterile inflammation induced by Carbopol elicits robust adaptive immune responses in the absence of pathogen-associated molecular patterns

Gartlan

Krashias

Wegmann

et al. 2016

Vaccine

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“…Despite many attempts (12)(13)(14)(78)(79)(80), generation of bNAb against tier 2 HIV-1 primary isolates by vaccination remains an unmet goal. Several recent studies have succeeded in demonstrating vaccine-induced NAb against autologous tier 2 virus or a panel of mutated tier 2 isolates with increased CD4 or V3 epitope exposure (12)(13)(14)21).…”

Section: Discussionmentioning

confidence: 99%

Induction of Heterologous Tier 2 HIV-1-Neutralizing and Cross-Reactive V1/V2-Specific Antibodies in Rabbits by Prime-Boost Immunization

Townsley

Mohamed²,

Guo

et al. 2016

J Virol

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Poxvirus prime-protein boost used in the RV144 trial remains the only immunization strategy shown to elicit a modest level of protection against HIV-1 acquisition in humans. Although neutralizing antibodies (NAb) were generated, they were against sensitive viruses, not the more resistant "tier 2" isolates that dominate circulating strains. Instead, risk reduction correlated with antibodies recognizing epitopes in the V1/V2 region of HIV-1 envelope glycoprotein (Env). Here, we examined whether tier 2 virus NAb and V1/V2-specific non-NAb could be elicited by a poxvirus prime-gp120 boost strategy in a rabbit model. We studied two clade B Envs that differ in multiple parameters, including tissue origin, neutralization sensitivity, and presence of the N197 (N7) glycan that was previously shown to modulate the exposure of conserved epitopes on Env. We demonstrate that immunized rabbits generated cross-reactive neutralizing activities against >50% of the tier 2 global HIV-1 isolates tested. Some of these activities were directed against the CD4 binding site (CD4bs). These rabbits also generated antibodies that recognized protein scaffolds bearing V1/V2 sequences from diverse HIV-1 isolates and mediated antibody-dependent cellular cytotoxicity. However, there are subtle differences in the specificities and the response rates of V1/V2-specific antibodies between animals immunized with different Envs, with or without the N7 glycan. These findings demonstrate that antibody responses that have been correlated with protection against HIV-1 acquisition in humans can be elicited in a preclinical model by a poxvirus prime-gp120 boost strategy and that improvements may be achievable by optimizing the nature of the priming and boosting immunogens. IMPORTANCEThe only vaccine approach shown to elicit any protective efficacy against HIV-1 acquisition is based on a poxvirus prime-protein boost regimen (RV144 Thai trial). Reduction of risk was associated with nonneutralizing antibodies targeting the V1/V2 loops of the envelope protein gp120. However, the modest efficacy (31.2%) achieved in this trial highlights the need to examine approaches and factors that may improve vaccine-induced responses, including cross-reactive neutralizing activities. We show here that rabbits immunized with a novel recombinant vaccinia virus prime-gp120 protein boost regimen generated antibodies that recognize protein scaffolds bearing V1/V2 sequences from diverse HIV-1 isolates and mediated antibody-dependent cellular cytotoxicity. Importantly, immunized rabbits also showed neutralizing activities against heterologous tier 2 HIV-1 isolates. These findings may inform the design of prime-boost immunization approaches and help improve the protective efficacy of candidate HIV-1 vaccines.

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“…Antibodies b12 ( 28 ), NIH45-46 ( 29 ), VRC01, VRC03 ( 30 ), 412D ( 31 ), A32 ( 32 ), C11 ( 33 ), CH01 ( 34 ), PGT145 ( 29 ), 2G12 ( 35 ), PGT121 ( 29 ), PGT128 ( 29 ), PGT135 ( 29 ), 14E, 19b, 39F ( 36 ), 35O22 ( 37 ), 3BC176, 3BC315 ( 38 ), PGT151 ( 39 ), CAP256-VRC26.08 ( 40 ), PDGM1400 ( 41 ), and 7B2 ( 42 ) were expressed in freestyle 293F cells under serum-free conditions and purified by protein A chromatography as previously described ( 43 ). Soluble CD4 (sCD4) ( 44 ), CD4-IgG2 ( 45 ), 15e, F105, 17b ( 46 ), PG16 ( 47 ), and b6 ( 28 ) were from the IAVI Neutralizing Antibody Consortium.…”

Section: Methodsmentioning

confidence: 99%

Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens

Schiffner

Val

Russell

et al. 2016

J Virol

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Major neutralizing antibody immune evasion strategies of the HIV-1 envelope glycoprotein (Env) trimer include conformational and structural instability. Stabilized soluble trimers such as BG505 SOSIP.664 mimic the structure of virion-associated Env but nevertheless sample different conformational states. Here we demonstrate that treating BG505 SOSIP.664 trimers with glutaraldehyde or a heterobifunctional cross-linker introduces additional stability with relatively modest effects on antigenicity. Thus, most broadly neutralizing antibody (bNAb) epitopes were preserved after cross-linking, whereas the binding of most weakly or nonneutralizing antibodies (non-NAb) was reduced. Cross-linking stabilized all Env conformers present within a mixed population, and individual conformers could be isolated by bNAb affinity chromatography. Both positive selection of cross-linked conformers using the quaternary epitope-specific bNAbs PGT145, PGT151, and 3BC315 and negative selection with non-NAbs against the V3 region enriched for trimer populations with improved antigenicity for bNAbs. Similar results were obtained using the clade B B41 SOSIP.664 trimer. The cross-linking method may, therefore, be useful for countering the natural conformational heterogeneity of some HIV-1 Env proteins and, by extrapolation, also vaccine immunogens from other pathogens.IMPORTANCE The development of a vaccine to induce protective antibodies against HIV-1 is of primary public health importance. Recent advances in immunogen design have provided soluble recombinant envelope glycoprotein trimers with near-native morphology and antigenicity. However, these trimers are conformationally flexible, potentially reducing B-cell recognition of neutralizing antibody epitopes. Here we show that chemical cross-linking increases trimer stability, reducing binding of nonneutralizing antibodies while largely maintaining neutralizing antibody binding. Cross-linking followed by positive or negative antibody affinity selection of individual stable conformational variants further improved the antigenic and morphological characteristics of the trimers. This approach may be generally applicable to HIV-1 Env and also to other conformationally flexible pathogen antigens.

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Comparison of Neutralizing Antibody Responses Elicited from Highly Diverse Polyvalent Heterotrimeric HIV-1 gp140 Cocktail Immunogens versus a Monovalent Counterpart in Rhesus Macaques

Cited by 12 publications

References 75 publications

Sterile inflammation induced by Carbopol elicits robust adaptive immune responses in the absence of pathogen-associated molecular patterns

Sterile inflammation induced by Carbopol elicits robust adaptive immune responses in the absence of pathogen-associated molecular patterns

Induction of Heterologous Tier 2 HIV-1-Neutralizing and Cross-Reactive V1/V2-Specific Antibodies in Rabbits by Prime-Boost Immunization

Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens

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