Plasma neutralizing antibodies in an infant with interclade HIV-1 superinfection preferentially neutralize superinfecting HIV-1 strains

AbstractHIV-1 superinfection is defined as infection by an unrelated second strain of HIV-1 after seroconversion due to primary infecting strain and has been associated with development of breadth in the neutralizing antibody (nAb) response, altered disease progression and efficacy of antiretrovirals; though conflicting observations have also been reported. Superinfection has been reported in HIV-1 infected adults. Recently we observed that multivariant infection in infants was associated with early induction of plasma broadly neutralizing antibodies (bnAbs) targeting diverse autologous viruses, however, there is paucity of information on infants with HIV-1 superinfection. Furthermore, the mechanisms by which superinfection in an infant, after priming by an initial infection, potentiate the evolution of a bnAb response have not been evaluated. Herein, we performed a longitudinal analysis and observed evolution of nAb responses in an antiretroviral naïve perinatally HIV-1 infected infant, with interclade superinfection (clade C followed by a unique A1C recombinant). The nAb responses broadened rapidly after superinfection targeted an undefined glycan-dependent epitope on the superinfecting variant, while no enrichment of nAb response against the primary infecting strain occurred. Defining virological features in infants with sequential infection with highly divergent circulating viruses that improve nAb responses will contribute information that could be leveraged for optimization of multicomponent candidate vaccines.ImportanceHIV-1 infected infants develop bnAbs rapidly suggesting factors governing bnAb induction in infants are distinct from adults. HIV-1 superinfection is more common in adults whereas the stringent genetic bottleneck for transmission in infants often leads to infection by a single transmitted/founder HIV-1 strain. Longitudinal studies in infants with HIV-1 superinfection can provide key information on the viral factors that induce a bnAb response towards development of a polyvalent vaccine. Herein, we show that in infant who was sequentially infected with two HIV-1 strains from different clades, antibody responses were primarily generated against the superinfecting, second strain of HIV-1.These antibody responses were dependent on glycans, and targeted an undefined epitope in the C3V4 region of HIV-1 Env. A better understanding of how neutralizing antibody responses develop during natural HIV-1 superinfection in infants will provide information relevant to HIV Env vaccine development and evaluation.

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Antibody responses induced by SHIV infection are more focused than those induced by soluble native HIV-1 envelope trimers in non-human primates

PLoS Pathogens ◽

10.1371/journal.ppat.1009736 ◽

2021 ◽

Vol 17 (8) ◽

pp. e1009736

Author(s):

Jelle van Schooten ◽

Marlies M. van Haaren ◽

Hui Li ◽

Laura E. McCoy ◽

Colin Havenar-Daughton ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Natural Infection ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

Antibody Diversity ◽

Infected Infant ◽

Immunodeficiency Virus ◽

Shiv Infection ◽

Hiv 1

The development of an effective human immunodeficiency virus (HIV-1) vaccine is a high global health priority. Soluble native-like HIV-1 envelope glycoprotein trimers (Env), including those based on the SOSIP design, have shown promise as vaccine candidates by inducing neutralizing antibody responses against the autologous virus in animal models. However, to overcome HIV-1’s extreme diversity a vaccine needs to induce broadly neutralizing antibodies (bNAbs). Such bNAbs can protect non-human primates (NHPs) and humans from infection. The prototypic BG505 SOSIP.664 immunogen is based on the BG505 env sequence isolated from an HIV-1-infected infant from Kenya who developed a bNAb response. Studying bNAb development during natural HIV-1 infection can inform vaccine design, however, it is unclear to what extent vaccine-induced antibody responses to Env are comparable to those induced by natural infection. Here, we compared Env antibody responses in BG505 SOSIP-immunized NHPs with those in BG505 SHIV-infected NHPs, by analyzing monoclonal antibodies (mAbs). We observed three major differences between BG505 SOSIP immunization and BG505 SHIV infection. First, SHIV infection resulted in more clonal expansion and less antibody diversity compared to SOSIP immunization, likely because of higher and/or prolonged antigenic stimulation and increased antigen diversity during infection. Second, while we retrieved comparatively fewer neutralizing mAbs (NAbs) from SOSIP-immunized animals, these NAbs targeted more diverse epitopes compared to NAbs from SHIV-infected animals. However, none of the NAbs, either elicited by vaccination or infection, showed any breadth. Finally, SOSIP immunization elicited antibodies against the base of the trimer, while infection did not, consistent with the base being placed onto the virus membrane in the latter setting. Together these data provide new insights into the antibody response against BG505 Env during infection and immunization and limitations that need to be overcome to induce better responses after vaccination.

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Development of a Norovirus P Particle Platform for Eliciting Neutralizing Antibody Responses to the Membrane Proximal External Region of Human Immunodeficiency Virus Type 1 Envelope

Protein and Peptide Letters ◽

10.2174/0929866521666140616120955 ◽

2014 ◽

Vol 21 (12) ◽

pp. 1230-1239

Author(s):

Yang Zang ◽

Jinpeng Bi ◽

Dongchuan Du ◽

Xintao Liu ◽

Yan Zhang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

External Region ◽

Membrane Proximal External Region ◽

Immunodeficiency Virus ◽

Hiv 1

Eliciting efficient broadly neutralizing antibodies (BnAbs) is an important goal that has yet to be achieved for human immunodeficiency type 1 (HIV-1) vaccine development, although they are rarely produced in virus-infected individuals. In particular, inducing specific neutralizing antibodies to the gp41 membrane proximal external region (MPER) has proven a difficult task. In this study, we introduce Norovirus P particles as a new platform to display the MPER epitope of HIV-1 as a vaccine with the aim of enhancing immune responses. The results showed that HIV-1 chimeric P particles were capable of inducing MPER-specific antibody responses in immunized guinea pigs, although only weakly neutralizing activity could be detected. These findings are consistent with other previous studies which have also focused on the well-studied 2F5 and 4E10 BnAbs. Our findings provide an alternate strategy for design of vaccines against HIV-1. However, great challenges remain in the effort to develop vaccines that can induce efficient HIV-1 neutralizing antibodies.

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Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies

Vaccines ◽

10.3390/vaccines7030076 ◽

2019 ◽

Vol 7 (3) ◽

pp. 76 ◽

Cited By ~ 15

Author(s):

Mitch Brinkkemper ◽

Kwinten Sliepen

Keyword(s):

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Critical Role ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

Viral Membrane ◽

Immunodeficiency Virus ◽

Hiv 1

The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing antibodies (bNAbs) that are capable of neutralizing the majority of circulating HIV-1 strains. The envelope glycoprotein (Env) trimer on the viral membrane is the sole target of bNAbs and the key component of vaccination approaches aimed at eliciting bNAbs. Multimeric presentation of Env on nanoparticles often plays a critical role in these strategies. Here, we will discuss the different aspects of nanoparticles in Env vaccination, including recent insights in immunological processes underlying their perceived advantages, the different nanoparticle platforms and the various immunogenicity studies that employed nanoparticles to improve (neutralizing) antibody responses against Env.

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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

10.1101/2020.09.15.297697 ◽

2020 ◽

Author(s):

Rajesh Kumar ◽

Suprit Deshpande ◽

Leigh M. Sewall ◽

Gabriel Ozorowski ◽

Christopher A. Cottrell ◽

...

Keyword(s):

Electron Microscopy ◽

Neutralizing Antibodies ◽

Natural Infection ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Clade C ◽

Immunogen Design ◽

Env Protein ◽

Immunogenic Properties ◽

Hiv 1

AbstractEvaluating 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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Neutralizing Antibody Responses following Long-Term Vaccination with HIV-1 Env gp140 in Guinea Pigs

Journal of Virology ◽

10.1128/jvi.00369-18 ◽

2018 ◽

Vol 92 (13) ◽

pp. e00369-18 ◽

Cited By ~ 7

Author(s):

Christine A. Bricault ◽

James M. Kovacs ◽

Alexander Badamchi-Zadeh ◽

Krisha McKee ◽

Jennifer L. Shields ◽

...

Keyword(s):

Guinea Pigs ◽

Neutralizing Antibodies ◽

Antibody Responses ◽

Tier 2 ◽

Broadly Neutralizing Antibodies ◽

Vaccination Regimen ◽

Tier 1 ◽

Clade C ◽

Hiv 1

ABSTRACTA vaccination regimen capable of eliciting potent and broadly neutralizing antibodies (bNAbs) remains an unachieved goal of the HIV-1 vaccine field. Here, we report the immunogenicity of longitudinal prime/boost vaccination regimens with a panel of HIV-1 envelope (Env) gp140 protein immunogens over a period of 200 weeks in guinea pigs. We assessed vaccine regimens that included a monovalent clade C gp140 (C97ZA012 [C97]), a tetravalent regimen consisting of four clade C gp140s (C97ZA012, 459C, 405C, and 939C [4C]), and a tetravalent regimen consisting of clade A, B, C, and mosaic gp140s (92UG037, PVO.4, C97ZA012, and Mosaic 3.1, respectively [ABCM]). We found that the 4C and ABCM prime/boost regimens were capable of eliciting greater magnitude and breadth of binding antibody responses targeting variable loop 2 (V2) over time than the monovalent C97-only regimen. The longitudinal boosting regimen conducted over more than 2 years increased the magnitude of certain tier 1 NAb responses but did not increase the magnitude or breadth of heterologous tier 2 NAb responses. These data suggest that additional immunogen design strategies are needed to induce broad, high-titer tier 2 NAb responses.IMPORTANCEThe elicitation of potent, broadly neutralizing antibodies (bNAbs) remains an elusive goal for the HIV-1 vaccine field. In this study, we explored the use of a long-term vaccination regimen with different immunogens to determine if we could elicit bNAbs in guinea pigs. We found that longitudinal boosting over more than 2 years increased tier 1 NAb responses but did not increase the magnitude and breadth of tier 2 NAb responses. These data suggest that additional immunogen designs and vaccination strategies will be necessary to induce broad tier 2 NAb responses.

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Elicitation of Neutralizing Antibody Responses to HIV-1 Immunization with Nanoparticle Vaccine Platforms

Viruses ◽

10.3390/v13071296 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1296

Author(s):

Amyn A. Murji ◽

Juliana S. Qin ◽

Tandile Hermanus ◽

Lynn Morris ◽

Ivelin S. Georgiev

Keyword(s):

Guinea Pigs ◽

Neutralizing Antibodies ◽

Large Fraction ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Vaccine Platform ◽

Current Vaccine ◽

Single Antigen ◽

Clade C ◽

Hiv 1

A leading strategy for developing a prophylactic HIV-1 vaccine is the elicitation of antibodies that can neutralize a large fraction of circulating HIV-1 variants. However, a major challenge that has limited the effectiveness of current vaccine candidates is the extensive global diversity of the HIV-1 envelope protein (Env), the sole target for HIV-neutralizing antibodies. To address this challenge, various strategies incorporating Env diversity into the vaccine formulation have been proposed. Here, we assessed the potential of two such strategies that utilize a nanoparticle-based vaccine platform to elicit broadly neutralizing antibody responses. The nanoparticle immunogens developed here consisted of different formulations of Envs from strains BG505 (clade A) and CZA97 (clade C), attached to the N-termini of bacterial ferritin. Single—antigen nanoparticle cocktails, as well as mosaic nanoparticles bearing both Env trimers, elicited high antibody titers in mice and guinea pigs. Furthermore, serum from guinea pigs immunized with nanoparticle immunogens achieved autologous, and in some cases heterologous, tier 2 neutralization, although significant differences between mosaic and single—antigen nanoparticles were not observed. These results provide insights into the ability of different vaccine strategies for incorporating Env sequence diversity to elicit neutralizing antibodies, with implications for the development of broadly protective HIV-1 vaccines.

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Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers

Journal of Virology ◽

10.1128/jvi.01214-20 ◽

2020 ◽

Vol 94 (24) ◽

Author(s):

Anna Schorcht ◽

Tom L. G. M. van den Kerkhof ◽

Christopher A. Cottrell ◽

Joel D. Allen ◽

Jonathan L. Torres ◽

...

Keyword(s):

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

High Titer ◽

Vaccine Design ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Tier 2 ◽

Broadly Neutralizing Antibodies ◽

Subtype B ◽

Hiv 1

ABSTRACT The induction of broadly neutralizing antibodies (bNAbs) is a major goal in vaccine research. HIV-1-infected individuals that develop exceptionally strong bNAb responses, termed elite neutralizers, can inform vaccine design by providing blueprints for the induction of similar bNAb responses. We describe a new recombinant native-like envelope glycoprotein (Env) SOSIP trimer, termed AMC009, based on the viral founder sequences of an elite neutralizer. The subtype B AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bNAb epitopes. Overall, its structure at 4.3-Å resolution was similar to that of BG505 SOSIP.664. The AMC009 trimer resembled one from a second elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, the AMC009 trimers did not induce autologous neutralizing antibody (NAb) responses efficiently while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the NAb activity from the rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers. These results advance our understanding of how to use Env trimers in multivalent vaccination regimens and the immunogenicity of trimers derived from elite neutralizers. IMPORTANCE Elite neutralizers, i.e., individuals who developed unusually broad and potent neutralizing antibody responses, might serve as blueprints for HIV-1 vaccine design. Here, we studied the immunogenicity of native-like recombinant envelope glycoprotein (Env) trimers based on viral sequences from elite neutralizers. While immunization with single trimers from elite neutralization did not recapitulate the breadth and potency of neutralization observed in these infected individuals, a combination of three subtype B Env trimers from elite neutralizers resulted in some neutralization breadth within subtype B viruses. These results should guide future efforts to design vaccines to induce broadly neutralizing antibodies.

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Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope

Journal of Virology ◽

10.1128/jvi.00828-17 ◽

2017 ◽

Vol 91 (18) ◽

Cited By ~ 21

Author(s):

Colin Anthony ◽

Talita York ◽

Valerie Bekker ◽

David Matten ◽

Philippe Selhorst ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Prolonged Exposure ◽

Vaccine Development ◽

Viral Evolution ◽

Neutralizing Antibody ◽

Viral Escape ◽

Broadly Neutralizing Antibodies ◽

Immunogen Design ◽

Early Strain ◽

Hiv 1

ABSTRACT V3-glycan-targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep-sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan-directed bNAbs compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly via an N334-to-N332 glycan switch, which took just 7.5 weeks to reach >50% frequency. In contrast, escape from the bNAbs was mediated via multiple pathways and took longer, with escape first occurring through an increase in V1 loop length, which took 46 weeks to reach 50% frequency, followed by an N332-to-N334 reversion, which took 66 weeks. Importantly, bNAb escape was incomplete, with contemporaneous neutralization observed up to 3 years postinfection. Both the ssNAb response and the bNAb response were modulated by the presence/absence of the N332 glycan, indicating an overlap between the two epitopes. Thus, selective pressure by ssNAbs to maintain the N332 glycan may have constrained the bNAb escape pathway. This slower and incomplete viral escape resulted in prolonged exposure of the bNAb epitope, which may in turn have aided the maturation of the bNAb lineage. IMPORTANCE The development of an HIV-1 vaccine is of paramount importance, and broadly neutralizing antibodies are likely to be a key component of a protective vaccine. The V3-glycan-targeting bNAb responses are among the most promising vaccine targets, as they are commonly elicited during infection. Understanding the interplay between viral evolution and the development of these antibodies provides insights that may guide immunogen design. Our work contrasted the dynamics of the early strain-specific antibodies and the later broadly neutralizing responses to a common Env target (V3C3), showing slower and more complex escape from bNAbs. Constrained bNAb escape, together with evidence of contemporaneous autologous virus neutralization, supports the proposal that prolonged exposure of the bNAb epitope enabled the maturation of the bNAb lineage.

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Stepwise Conformational Stabilization of a HIV-1 Clade C Consensus Envelope Trimer Immunogen Impacts the Profile of Vaccine-Induced Antibody Responses

Vaccines ◽

10.3390/vaccines9070750 ◽

2021 ◽

Vol 9 (7) ◽

pp. 750

Author(s):

Alexandra Hauser ◽

George Carnell ◽

Kathrin Held ◽

Guidenn Sulbaran ◽

Nadine Tischbierek ◽

...

Keyword(s):

Thermal Stability ◽

Neutralizing Antibodies ◽

Structural Integrity ◽

Phase 1 ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Preventive Vaccine ◽

Clade C ◽

Research Consortium ◽

Hiv 1

Stabilization of the HIV-1 Envelope glycoprotein trimer (Env) in its native pre-fusion closed conformation is regarded as one of several requirements for the induction of neutralizing antibody (nAb) responses, which, in turn, will most likely be a prerequisite for the development of an efficacious preventive vaccine. Here, we systematically analyzed how the stepwise stabilization of a clade C consensus (ConC) Env immunogen impacts biochemical and biophysical protein traits such as antigenicity, thermal stability, structural integrity, and particle size distribution. The increasing degree of conformational rigidification positively correlates with favorable protein characteristics, leading to optimized homogeneity of the protein preparations, increased thermal stability, and an overall favorable binding profile of structure-dependent broadly neutralizing antibodies (bnAbs) and non-neutralizing antibodies (non-nAbs). We confirmed that increasing the structural integrity and stability of the Env trimers positively correlates with the quality of induced antibody responses by the immunogens. These and other data contribute to the selection of ConCv5 KIKO as novel Env immunogens for use within the European Union’s H2020 Research Consortium EHVA (European HIV Alliance) for further preclinical analysis and phase 1 clinical development.

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Immunogenicity in Rabbits of HIV-1 SOSIP Trimers from Clades A, B, and C, Given Individually, Sequentially, or in Combination

Journal of Virology ◽

10.1128/jvi.01957-17 ◽

2018 ◽

Vol 92 (8) ◽

Cited By ~ 28

Author(s):

Alba Torrents de la Peña ◽

Steven W. de Taeye ◽

Kwinten Sliepen ◽

Celia C. LaBranche ◽

Judith A. Burger ◽

...

Keyword(s):

Antibody Response ◽

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Broadly Neutralizing Antibodies ◽

Clade C ◽

Sequential Regimen ◽

Alternative Designs ◽

Hiv 1 ◽

Trimeric Envelope

ABSTRACT Recombinant soluble HIV-1 envelope glycoprotein (Env) SOSIP trimers are a design platform for inducing broadly neutralizing antibodies (bNAbs) by vaccination. To date, these and alternative designs of native-like trimers, given singly or in pairs, have not induced bNAbs in test animals such as rabbits or macaques. Here, we have evaluated whether trivalent and tetravalent combinations of SOSIP trimers from clades A, B, and C, delivered simultaneously or sequentially, induce better neutralizing antibody responses in rabbits than when given alone. None of the tested formulations led to the induction of bNAbs. We found that BG505 clade A trimers dominated the autologous NAb responses induced by combinations, which probably relates to the presence of immunodominant glycan holes on the BG505 trimer. Furthermore, autologous NAb responses to all individual trimers were reduced when they were delivered in combinations compared with when delivered alone, suggesting that immunogen interference had occurred. Finally, in a sequential regimen, a heterologous clade C trimer cross-boosted NAb responses that were primed by earlier immunizations with clade A and B trimers. Taken together, these findings should allow us to improve the design of immunization regimens based on native-like HIV-1 Env trimers. IMPORTANCE A successful HIV-1 vaccine most probably requires a trimeric envelope glycoprotein (Env) component, as Env is the only viral protein on the surface of the virus and therefore the only target for neutralizing antibodies. Native-like Env trimers can induce strain-specific neutralizing antibodies but not yet broadly neutralizing antibodies. To try to broaden the antibody response, we immunized rabbits with soluble native-like Env trimers from three different clades using monovalent, multivalent, and sequential regimens. We found that the neutralizing antibody response against each immunogen was reduced when the immunogens were delivered in combination or sequentially compared to the monovalent regimen. In contrast, when the Env trimers from different clades were delivered sequentially, the neutralizing antibody response could be cross-boosted. Although the combination of native-like Env trimers from different clades did not induce broadly neutralizing antibodies, the results provide clues on how to use native-like trimers in vaccination experiments.

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