Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with &gt;50% breadth

Chen, Xuejun; Zhou, Tongqing; Schmidt, Stephen D.; Duan, Hongying; Cheng, Cheng; Chuang, Gwo-Yu; Gu, Ying; Louder, Mark K.; Lin, Bob C.; Shen, Chen‐Hsiang; Sheng, Zizhang; Zheng, Michelle; Doria‐Rose, Nicole A.; Joyce, Michael; Shapiro, Lawrence; Tian, Ming; Alt, Frederick W.; Kwong, Peter D.; Mascola, John R.

doi:10.1016/j.immuni.2020.12.014

Cited by 43 publications

(84 citation statements)

References 52 publications

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“…Epitope-based vaccine approaches, guided by knowledge of the major structural vulnerability supersites recognized by bNAbs, have been extensively explored 24,25 and recently yielded a partial success in inducing neutralization breadth by targeting the fusion peptide in glycoprotein (gp)41 (refs 26,27 ). Another major line of research, based on sequential modulation of B cell responses along specific bNAb lineages by initial priming with germline-engaging core antigens followed by stepwise immunization with increasingly antibody-shielded Env forms, holds promise of success in recruiting the appropriate precursor B cells [28][29][30] . Additional vaccine strategies, mostly based on prime-boost schemes, have yielded different VLPs after ultracentrifugation on a sucrose cushion.…”

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confidence: 99%

A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques

Zhang

Narayanan

Liu

et al. 2021

Nat Med

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112

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The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. Here, we show that a messenger RNA (mRNA) vaccine co-expressing membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins to generate virus-like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macaques. In mice, immunization with co-formulated env and gag mRNAs was superior to env mRNA alone in inducing neutralizing antibodies. Macaques were primed with a transmitted-founder clade-B env mRNA lacking the N276 glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous envs (clades A and C). This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4 + T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simian-human immunodeficiency virus (SHIV AD8). Thus, the multiclade env-gag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine. Nature MediciNedegrees of protection in non-human primate models [31][32][33][34][35] . Some approaches have used messenger RNA (mRNA) as a vector, resulting in the induction of polyfunctional antibody responses comparable to those induced by protein immunization, as well as efficient T cell responses [36][37][38] . Altogether, the evidence so far accumulated suggests that no individual factor will determine the ultimate success of a bNAb-inducing HIV-1 vaccine, which probably requires a combination of efficient precursor B cell priming, optimization of Env design and presentation, and sustained heterologous Env boosting. ResultsDesign of an env-gag VLP mRNA vaccine platform. Critical advancements in mRNA technology over the past two decades 39,40 have enabled the development of mRNA-based vaccine platforms, which have recently shown remarkable effectiveness against ). Taking advantage of the versatility of mRNA as an expression system, we designed a novel vaccine platform by combining a series of features that we postulated to be critical for the elicitation of protective antibody responses. These include, first, the use of mRNA as a vehicle in order to instruct host cells to endogenously express membrane-bound viral glycoproteins and decorate them with native N-linked glycosylation; second, the use of full-length or minimally truncated HIV-1 Envs that do not expose distractive immunodominant epitopes, unlike truncated soluble trimers; third, co-expression of Env with Gag in order to promote the in vivo production of virus-like particles (VLPs), which closely mimic native viral particles produced by HIV-1 infection; fourth, initial priming with an Env capable of engaging germline bNAb precursors; and last, intensive heterologous boosting with tier-2 Envs from different clades in order to selectively expan...

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confidence: 99%

A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques

Zhang

Narayanan

Liu

et al. 2021

Nat Med

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112

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“…A modified gp120 protein designed to engage VRC01 germline and intermediate antibodies referred to as 426C core has shown promise in expanding VRC01 precursor B cells in mice when combined with other immunogens [ 99 , 100 , 101 ]. Thus, 426C core is another candidate gp120 immunogen that will be tested in human clinical trials for inducing or maturing CD4bs bnAb lineages.…”

Section: Discussionmentioning

confidence: 99%

Strategies for induction of HIV‐1 envelope‐reactive broadly neutralizing antibodies

et al. 2021

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IntroductionA primary focus of HIV‐1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly affinity‐matured bnAbs. HIV‐1 envelope (Env) encodes epitopes for bnAbs of different specificities. Design of immunogens to induce bnAb precursors of different specificities and mature them into bnAb status is a goal for HIV‐1 vaccine development. We review vaccine strategies for bnAb lineages development and highlight the immunological barriers that these strategies must overcome to generate bnAbs.MethodsWe provide perspectives based on published research articles and reviews.DiscussionThe recent Antibody Mediated Protection (AMP) trial that tested the protective efficacy of one HIV‐1 Env bnAb specificity demonstrated that relatively high levels of long‐lasting serum titers of multiple specificities of bnAbs will be required for protection from HIV‐1 transmission. Current vaccine efforts for induction of bnAb lineages are focused on immunogens designed to expand naïve HIV‐1 bnAb precursor B cells following the recent success of vaccine‐induction of bnAb precursor B cells in macaques and humans. BnAb precursor B cells serve as templates for priming‐immunogen design. However, design of boosting immunogens for bnAb maturation requires knowledge of the optimal immunogen design and immunological environment for bnAb B cell lineage affinity maturation. BnAb lineages acquire rare genetic changes as mutations during B cell maturation. Moreover, the immunological environment that supports bnAb development during HIV‐1 infection is perturbed with an altered B cell repertoire and dysfunctional immunoregulatory controls, suggesting that in normal settings, bnAb development will be disfavoured. Thus, strategies for vaccine induction of bnAbs must circumvent immunological barriers for bnAb development that normally constrain bnAb B cell affinity maturation.ConclusionsA fully protective HIV‐1 vaccine needs to induce durable high titers of bnAbs that can be generated by a sequential set of Env immunogens for expansion and maturation of bnAb B cell lineages in a permitted immunological environment. Moreover, multiple specificities of bnAbs will be required to be sufficiently broad to prevent the escape of HIV‐1 strains during transmission.

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“…Recent advances have identified five CD4-mimic bnAbs [ 40 , 43 ] of which three fall within the VRC01 subclass, characterized by a V H 1-2-derived heavy chain and a short, 5-residue CDRL3 used to avoid clashes with the N276 glycan [ 40 , 43 ]. PGV19 is a VRC01-class bnAb that neutralized 70–75% of a 20-pseudovirus panel, and is the first structurally characterized VRC01 class bnAb with a lambda light chain [ 40 , 54 ].…”

Section: Hiv-1 Neutralizing Epitopesmentioning

confidence: 99%

“…For example, Chen and colleagues isolated VRC01 class bnAbs, 2411a and 2413a, from sequential immunizations of humanized mice expressing unmutated VRC01 class precursors. These bnAbs achieved moderate breadth and potency (2411a: 51% breadth, median IC 50 1.49 µg/mL; 2413a: 34% breadth, median IC 50 3.86 µg/mL) [ 43 ]. As another example, Dubrovskaya and colleagues isolated a gp120–gp41 interface bnAb, called 1C2, from sequential immunization of rabbits [ 50 ].…”

Section: Bnab Elicitation In Mice and Other Animalsmentioning

confidence: 99%

A Structural Update of Neutralizing Epitopes on the HIV Envelope, a Moving Target

Miller

Finkelstein

Erdman

et al. 2021

Viruses

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Antibodies that can neutralize diverse HIV-1 strains develop in ~10–20% of HIV-1 infected individuals, and their elicitation is a goal of vaccine design. Such antibodies can also serve as therapeutics for those who have already been infected with the virus. Structural characterizations of broadly reactive antibodies in complex with the HIV-1 spike indicate that there are a limited number of sites of vulnerability on the spike. Analysis of their structures can help reveal commonalities that would be useful in vaccine design and provide insights on combinations of antibodies that can be used to minimize the incidence of viral resistance mutations. In this review, we give an update on recent structures determined of the spike in complex with broadly neutralizing antibodies in the context of all epitopes on the HIV-1 spike identified to date.

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Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with >50% breadth

Cited by 43 publications

References 52 publications

A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques

A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques

Strategies for induction of HIV‐1 envelope‐reactive broadly neutralizing antibodies

A Structural Update of Neutralizing Epitopes on the HIV Envelope, a Moving Target

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