Randomized, Double-Blind Evaluation of Late Boost Strategies for HIV-Uninfected Vaccine Recipients in the RV144 HIV Vaccine Efficacy Trial

Rerks-Ngarm, Supachai; Pitisuttithum, Punnee; Excler, Jean–Louis; Nitayaphan, Sorachai; Kaewkungwal, Jaranit; Premsri, Nakorn; Kunasol, Prayura; Karasavvas, Nicos; Schuetz, Alexandra; Ngauy, Viseth; Sinangil, Faruk; Dawson, Peter; deCamp, Allan C.; Phogat, Sanjay; Garunathan, Sanjay; Tartaglia, James; DiazGranados, Carlos A.; Ratto‐Kim, Silvia; Pegu, Poonam; Eller, Michael A.; Karnasuta, Chitraporn; Montefiori, David C.; Sawant, Sheetal; Vandergrift, Nathan; Wills, Saintedym; Tomaras, Georgia D.; Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.; Vasan, Sandhya; O’Connell, Robert J.; Team, Rv Study

doi:10.1093/infdis/jix099

Cited by 58 publications

(71 citation statements)

References 30 publications

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“…Unfortunately, RV305 vaccinations did not improve the durability of Ab responses when compared with RV144. 105 IgG responses to HIV-1 gp120 and gp70V1V2 scaffolds were also induced in cervico-vaginal mucous and seminal plasma after boosting with AIDSVAX Ò B/E with/without ALVAC-HIV. IgG responses were not detectable in anogenital secretions from the group receiving ALVAC-HIV alone and were also not detectable in rectal secretion from any groups.…”

Section: Studies Building On Rv144mentioning

confidence: 96%

Progress in HIV vaccine development

Hsu

O’Connell

2017

Human Vaccines & Immunotherapeutics

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Section: Studies Building On Rv144mentioning

confidence: 96%

Progress in HIV vaccine development

Hsu

O’Connell

2017

Human Vaccines & Immunotherapeutics

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“…2B), a small fraction of the cells exhibited halos resulting from antibody-antigen precipitin bands that formed around the colonies secreting high levels of rgp120. The top 0.1% (44) of colonies selected based upon morphology and halo intensity were picked by the robot and expanded for further analysis (Fig. 2C).…”

Section: Resultsmentioning

confidence: 99%

“…(C) Relative mean exterior fluorescence of halo for more than 10,000 colonies imaged by the ClonePix2 plotted by rank. The top ranking 0.1% of colonies (44) were robotically picked and cultured. The six clones expressing 0.2-0.4 g/L at day 56 are shown in red.…”

Section: Resultsmentioning

confidence: 99%

Robotic selection for the rapid development of stable CHO cell lines for HIV vaccine for production

O’Rourke

Byrne

Tatsuno

et al. 2018

Preprint

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2 The production of envelope glycoproteins (Envs) for use as HIV vaccines is challenging.3 The yield of Envs expressed in stable Chinese Hamster Ovary (CHO) cell lines is 4 typically 10-100 fold lower than other glycoproteins of pharmaceutical interest.5 Moreover, Envs produced in CHO cells are typically enriched for sialic acid containing 6 glycans compared to virus associated Envs that possess mainly high-mannose 7 carbohydrates. This difference alters the net charge and biophysical properties of Envs 8 and impacts their antigenic structure. Here we employ a novel gene-edited CHO cell 9 line (MGAT1 -CHO) to address the problems of low expression, high sialic acid content, 10 and poor antigenic structure. We demonstrate that stable cell lines expressing high 11 levels of gp120, potentially suitable for biopharmaceutical production can be created 12 using the MGAT1 -CHO cell line. We also show that the efficiency of this process can be 13 greatly improved with robotic selection. Finally, we describe a MGAT1 -CHO cell line 14 expressing A244-rgp120 that exhibits improved binding of three major families of bN-15 mAbs compared to Envs produced in normal CHO cells. The new strategy described 16 has the potential to eliminate the bottleneck in HIV vaccine development that has limited 17 the field for more than 25 years. 18 3 19 1 Introduction 20The development of a safe, effective, and affordable HIV vaccine is a global 21 public health priority. After more than 30 years of HIV research, a vaccine with these 22properties has yet to be described. To date, the only clinical study to show that 23 vaccination can prevent HIV infection is the 16,000-person RV144 trial carried out in 24 Thailand between 2003 and 2009 (1). This study involved immunization with a 25 recombinant canarypox virus vector to induce cellular immunity (2-4) and a bivalent 26 recombinant gp120 vaccine designed to elicit protective antibody responses (5-7).27 Although statistically significant, the protective efficacy of this vaccination regimen was 28 low (31.2%, P=0.04). Several correlates of protection studies suggested that the 29 protection observed was primarily due to antibodies to rgp120 (8-10). Thus, there is 30 considerable interest in finding ways to improve the level of protection that can be 31 achieved with rgp120 vaccine regimens. Improving an existing vaccine such as RV144, 32 with an established record of safety, would be faster and more cost-effective than 33 developing a new vaccine concept from scratch. A roadmap to improve the rgp120 34 vaccine used in the RV144 trial has been provided by the recent studies of broadly 35 neutralizing monoclonal antibodies (bN-mAbs) to gp120 as well as studies of the 36 carbohydrate content of virion associated Env proteins. Beginning in 2009, studies of 37 bN-mAbs isolated from HIV infected subjects revealed that many recognized unusual 38 glycan dependent epitopes requiring high-mannose glycans that are early intermediates 39 in the N-linked glycosylation pathway (11)(12)(13)(14)(15)(16)(17)(18)(...

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“…The RV305 clinical trial (NCT01435135) was a boost given to 162 RV144 clinical trial participants (NCT00223080) six-eight years after the conclusion of RV144 [30]. Donors used in this study were from groups boosted either with AIDSVAX B/E + ALVAC-HIV (vCP1521) (Group I) or AIDSVAX B/E alone (Group II).…”

Section: Methodsmentioning

confidence: 99%

Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity

Easterhoff

Pollara

Luo

et al. 2019

Preprint

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Significance 26Over one million people become infected with HIV-1 each year making the development 27 of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human 28 HIV-1 vaccine-regimen is the only HIV-1 clinical trial to date to demonstrate vaccine- 29 efficacy. An area of focus has been on identifying ways by which to improve upon 30 RV144 vaccine-efficacy. The RV305 HIV-1 vaccine-regimen was a follow-up boost of 31 RV144 vaccine-recipients that occurred 6-8 years after the conclusion of RV144. Our 32 2 studies focused on the effect of delayed boosting in humans on the vaccine-induced 33 antibody repertoire. It was found that boosting with a HIV-1 Env vaccine increased 34 antibody-mediated effector function potency and breadth. 35Abstract 36 Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One 37 strategy is to induce non-neutralizing antibodies that kill virus-infected cells as these 38 antibody specificities have been implicated in slowing HIV-1 disease progression and in 39 protection. HIV-1 Env constant region 1 and 2 (C1C2) antibodies frequently contain 40 potent antibody dependent cellular cytotoxicity (ADCC) making them a vaccine target. 41Here we explore the effect of delayed and repetitive boosting of RV144 vaccinee 42 recipients with ALVAC/AIDSVAX B/E on the C1C2-specific antibody repertoire. It was 43 found that boosting increased clonal lineage specific ADCC breadth and potency. A 44 ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-45 specific antibody showed that it bound a highly conserved Env gp120 epitope. Thus, 46 rationally designed boosting strategies to affinity mature these type of IgG C1C2-47 specific antibody responses may be one method by which to make an improved HIV 48 vaccine with higher efficacy than seen in the RV144 trial. 49 INTRODUCTION 50CD4-inducible (CD4i) epitopes within HIV-1 envelope (Env) constant regions 1 and 51 2 (C1C2) are targets for antibodies that mediate antibody dependent cellular cytotoxicity 52 (ADCC) [1]. C1C2-specific antibody epitopes have been termed Cluster A [1] and defined 53 by two Env-targeted monoclonal antibodies (mAbs), A32 [2] and C11 [1]. Structural 54 analyses of antigen complexes formed by A32, A32-like [3-5] and C11-like antibodies [6] 55 3 indicate that these antibodies bind distinct Env epitopes. The A32 epitope involves a 56 discontinuous sequence within layers 1 and 2 of the inner domain [4, 5] while the C11 57 epitope maps to the inner domain eight-stranded β sandwich [6]. Importantly, both 58 antibodies are non-neutralizing for tier 2 HIV strains, but are capable of broad and potent 59 ADCC [1, 2]. 60 The secondary analysis of HIV-1 infection risk in RV114 (NCT00223080) 61 indicated that ADCC in the presence of low anti-Env IgA responses correlated with 62 decreased HIV-1 acquisition [7]. While antibodies representative of the Env variable 63 region 2 (V2) response inversely correlated with HIV-1 acquisition [7], we previously 64 demo...

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Randomized, Double-Blind Evaluation of Late Boost Strategies for HIV-Uninfected Vaccine Recipients in the RV144 HIV Vaccine Efficacy Trial

Abstract: NCT01435135.

Cited by 58 publications

References 30 publications

Progress in HIV vaccine development

Progress in HIV vaccine development

Robotic selection for the rapid development of stable CHO cell lines for HIV vaccine for production

Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity

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