Functional Antibody Response Against V1V2 and V3 of HIV gp120 in the VAX003 and VAX004 Vaccine Trials

Balasubramanian, Preetha; Williams, Constance; Shapiro, Mariya B.; Sinangil, Faruk; Higgins, Keith; Nádas, Arthur; Totrov, Maxim; Kong, Xiang‐Peng; Fioré-Gartland, Andrew; Haigwood, Nancy L.; Zolla‐Pazner, Susan; Hioe, Catarina E.

doi:10.1038/s41598-017-18863-0

Cited by 28 publications

(32 citation statements)

References 48 publications

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“…In RV144, the DNA prime protein-boosting strategy used was not sufficient to fully mature the vaccine-induced V2-specific antibody response. However, in other ALVAC and AIDSVAX studies, repetitive boosting led to a decline in V1V2-specific antibody responses after 4 immunizations and a skewing from the more functional IgG3 isotype to IgG4 (41,42). In contrast, the boost given to RV144 vaccinees occurred many years later in the RV305 clinical trial.…”

Section: Discussionmentioning

confidence: 90%

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

Easterhoff¹,

Pollara²,

Luo³

et al. 2020

JCI Insight

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Section: Discussionmentioning

confidence: 90%

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

Easterhoff¹,

Pollara²,

Luo³

et al. 2020

JCI Insight

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“…Thus, clonal lineages with fine epitope specificities capable of being matured to increased ADCC breadth and potency greatly benefited from the two AIDSVAX B/E boosts given in the RV305 clinical trial. It should be noted that in VAX003 and VAX004 clinical trials ADCC responses peaked at 3 to 4 immunizations and declined after 5 to 7 immunizations (20). Collectively these data indicate that while the RV144 clinical trial was underboosted, repetitive subsequent boosting beyond RV305 does not necessarily lead to continuously better functional antibody outcomes.…”

Section: Discussionmentioning

confidence: 90%

Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency

Easterhoff

Pollara

Luo

et al. 2020

J Virol

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Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One strategy is to induce nonneutralizing antibodies (NNAbs) that kill virus-infected cells, as these antibody specificities have been implicated in slowing HIV-1 disease progression and in protection. HIV-1 Env constant region 1 and 2 (C1C2) monoclonal antibodies (MAbs) frequently mediate potent antibody-dependent cellular cytotoxicity (ADCC), making them an important vaccine target. Here, we explore the effect of delayed and repetitive boosting of RV144 vaccine recipients with AIDSVAX B/E on the C1C2-specific MAb repertoire. It was found that boosting increased clonal lineage-specific ADCC breadth and potency. A ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-specific MAb showed that it bound a highly conserved Env gp120 epitope. Thus, boosting to affinity mature these types of IgG C1C2-specific antibody responses may be one method by which to make an improved HIV vaccine with higher efficacy than that seen in the RV144 trial. IMPORTANCE Over one million people become infected with HIV-1 each year, making the development of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human HIV-1 vaccine regimen is the only HIV-1 clinical trial to date to demonstrate vaccine efficacy. An area of focus has been on identifying ways by which to improve upon RV144 vaccine efficacy. The RV305 HIV-1 vaccine regimen was a follow-up boost of RV144 vaccine recipients that occurred 6 to 8 years after the conclusion of RV144. Our study focused on the effect of delayed boosting in humans on the vaccine-induced Env constant region 1 and 2 (C1C2)-specific antibody repertoire. It was found that boosting with an HIV-1 Env vaccine increased C1C2-specific antibody-dependent cellular cytotoxicity potency and breadth.

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“…A late boost 6–8 years after the initial vaccination greatly elevated anti-V1V2 Ab levels, albeit transiently ( 13 ). In the earlier VAX003 and VAX004 vaccine trials, which tested solely AIDSVAX Env gp120 proteins and showed no protective efficacy ( 14 , 15 ), vaccine recipients also generated serum Abs to V1V2 and V3, but these responses peaked after 3 to 4 immunizations and declined after 5 to 7 immunizations ( 16 ). Functional Ab responses measured by tier 1 virus neutralization and ADCC similarly were not sustained.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Antibody Responses to the V1V2 and V3 Regions of HIV-1 Envelope by Immune Complex Vaccines

et al. 2018

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Prophylactic HIV vaccines must elicit antibodies (Abs) against the virus envelope glycoproteins (Env) to effectively prevent HIV infection. We investigated a vaccine platform that utilizes immune complexes made of Env proteins gp120 and monoclonal Abs (mAbs) against different gp120 epitopes. We previously observed alterations in V3 antigenicity upon formation of certain gp120/mAb complexes and demonstrated the ability of these complexes to modulate the elicitation of V3 Ab responses. However, the effects on the V1V2 domain, an important target for Abs that correlate with vaccine-induced protection against HIV, have not been studied, nor have immune complex vaccines made with non-B subtype Env. This study compared subtypes B (JRFL) and CRF_01.AE (A244) Env gp120 proteins in complex with selected gp120-specific mAbs. Allosteric and antigenic changes were detected on these immune complexes, indicating that gp120/mAb interaction induces alterations on the Env surface that may modify the Env immunogenic properties. To evaluate this idea, mice were immunized with gp120/mAb complexes or their uncomplexed gp120 counterparts. The overall serum IgG titers elicited against gp120 were comparable, but a marked skewing toward V1V2 or V3 was evident and dependent on the gp120 strain and the specificity of the mAb used to form the complexes. Compared with uncomplexed gp120JRFL, gp120JRFL complexed with CD4bs or V1V2 mAbs, but not with C2 or V3 mAbs, elicited V3 Abs of greater titers and breadth, and Abs more capable of neutralizing tier 1 virus. Epitope mapping revealed a shift to a more conserved site in the V3 crown. However, the complexes did not enhance V1V2 Ab response, and the elicited V1V2 Abs were not cross-reactive. This profile contrasts with Ab responses to gp120A244/mAb complexes. Notably, gp120A244/mAb complexes induced higher levels of V1V2 Abs with some cross-reactivity, while also stimulating weak or strain-specific V3 Abs. Sera from gp120A244/mAb complex-immunized animals displayed no measurable virus neutralization but did mediate Ab-dependent cellular phagocytosis, albeit at levels similar to that induced by gp120A244 alone. These data indicate the potential utility of immune complexes as vaccines to shape Ab responses toward or away from Env sites of interest.

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Functional Antibody Response Against V1V2 and V3 of HIV gp120 in the VAX003 and VAX004 Vaccine Trials

Cited by 28 publications

References 48 publications

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency

Modulation of Antibody Responses to the V1V2 and V3 Regions of HIV-1 Envelope by Immune Complex Vaccines

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