Sequence and vector shapes vaccine induced antibody effector functions in HIV vaccine trials

Stephanie Fischinger,Pierre-Alexandre Bart,Jonathan Fuchs,William O Hahn,Shannon P Grant,Galit Alter,Yeycy Donastorg,Gavin Churchyard,Nicole Frahm,Deniz Cizmeci,Julie Mcelrath,Davy Deng,Michael Keefer,Hendrik Streeck,Zoe Moodie,Nadine Rouphael,Giuseppe Pantaleo,Guido Silvestri

doi:10.1371/journal.ppat.1010016

Abstract

Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA/vector, vector/vector and DNA/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA/rAd5 and rAd35/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies.Trial registration: ClinicalTrials.gov NCT00801697, NCT00961883, NCT02207920, NCT00125970, NCT02852005).

Highlights

Despite the development of highly effective, long-active anti-retroviral therapy (ART) that can control the Human Immunodeficiency Virus (HIV) [1] and even prevent infection if taken prior to exposure [2], 1.8 million individuals are newly infected with HIV every year [3]
Previous HIV-1 vaccine trials, including the RV144 efficacy trial that resulted in moderate protection from infection, showed the importance of non-neutralizing antibody responses and their contribution to protection against the virus
We found that the combination of a DNA or rAd prime with a rAd boost resulted in strong IgG1 and IgG3 responses, which have been shown to be associated with reduced risk in RV144

Summary

Introduction

Despite the development of highly effective, long-active anti-retroviral therapy (ART) that can control the Human Immunodeficiency Virus (HIV) [1] and even prevent infection if taken prior to exposure [2], 1.8 million individuals are newly infected with HIV every year [3]. A prophylactic vaccine against HIV remains critical in the ultimate control and elimination of HIV [4]. Using a pox-viral prime (ALVAC) and protein boost (AIDSVAX), the RV144 vaccine trial showed a modest level of protection, with 31.2% reduced risk of infection among vaccinated Thai individuals by 42 months [5,6]. The follow-on HVTN702 trial, performed in South Africa using the same vector with a different insert, a different protein/adjuvant combination, and with an extended vaccine regimen, failed to confer any level of protection against

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