Intrastructural Help: Harnessing T Helper Cells Induced by Licensed Vaccines for Improvement of HIV Env Antibody Responses to Virus-Like Particle Vaccines.

Hassan Elsayed,Andres M. Salazar,Johnson Mak,Ghulam Nabi,Keith K. Khoo,Matthias Tenbusch,William J. McKinstry,Klaus Überla,Vladimir Temchura,Frank Kirchhoff

doi:10.1128/jvi.00141-18

Abstract

ABSTRACTInduction of persistent antibody responses by vaccination is generally thought to depend on efficient help by T follicular helper cells. Since the T helper cell response to HIV Env may not be optimal, we explored the possibility of improving the HIV Env antibody response to virus-like particle (VLP) vaccines by recruiting T helper cells induced by commonly used licensed vaccines to provide help for Env-specific B cells. B cells specific for the surface protein of a VLP can internalize the entire VLP and thus present peptides derived from the surface and core proteins on their major histocompatibility complex class II (MHC-II) molecules. This allows T helper cells specific for the core protein to provide intrastructural help for B cells recognizing the surface protein. Consistently, priming mice with an adjuvanted Gag protein vaccine enhanced the HIV Env antibody response to subsequent booster immunizations with HIV VLPs. To harness T helper cells induced by the licensed Tetanolpur vaccines, HIV VLPs that contained T helper cell epitopes of tetanus toxoid were generated. Tetanol-immunized mice raised stronger antibody responses to immunizations with VLPs containing tetanus toxoid T helper cell epitopes but not to VLPs lacking these epitopes. Depending on the priming immunization, the IgG subtype response to HIV Env after the VLP immunization could also be modified. Thus, harnessing T helper cells induced by other vaccines appears to be a promising approach to improve the HIV Env antibody response to VLP vaccines.IMPORTANCE Induction of HIV Env antibodies at sufficient levels with optimal Fc effector functions for durable protection remains a challenge. Efficient T cell help may be essential to induce such a desirable antibody response. Here, we provide proof of concept that T helper cells induced by a licensed vaccine can be harnessed to provide help for HIV Env-specific B cells and to modulate the Env-specific IgG subtype response.

Highlights

IMPORTANCE Induction of HIV Env antibodies at sufficient levels with optimal Fc effector functions for durable protection remains a challenge
We previously observed that T helper cells induced by DNA or adenoviral vector vaccines encoding Gag or GagPol provided intrastructural help for Env antibody responses after Virus-like particle (VLP) booster immunizations in mice [8, 9]
To explore whether an adjuvanted protein vaccine could modulate the HIV Env antibody response by intrastructural help, mice were first immunized with recombinant Gag protein adjuvanted with poly(ICLC), a Toll-like receptor 3 (TLR3) and MDA-5 ligand [14]

Summary

Introduction

IMPORTANCE Induction of HIV Env antibodies at sufficient levels with optimal Fc effector functions for durable protection remains a challenge. This intrastructural help [10,11,12,13] can be explained by uptake of entire VLPs by Envspecific B cells and subsequent presentation of Gag- and Env-derived T helper cell epitopes on major histocompatibility complex class II (MHC-II) molecules of the Envspecific B cells (Fig. 1) We extend these observations to adjuvanted protein vaccines and provide proof of concept that T helper cells induced by a commonly used licensed protein vaccine can be harnessed to deliver help for Env antibody responses. Recruitment of preexisting T helper cells induced by licensed vaccines seems to be a promising novel strategy to optimize antibody responses to surface proteins of VLP vaccines

Methods

Results

Conclusion