Monday, May 24, 2021

HIV mRNA Vaccines-Progress and Future Paths

Review
Zekun Mu et al. Vaccines (Basel). .
Free PMC article
doi: 10.3390/vaccines9020134.

Authors

Affiliations

  • 1 Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • 2 Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.

Abstract

The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host's cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.

Keywords: HIV; messenger RNA; vaccine.

Conflict of interest statement

B.F.H. has patent applications on some of the concepts discussed in this review.

Figures

Figure 1

Figure 1

Eliciting humoral and cellular responses…

Figure 1

Eliciting humoral and cellular responses through vaccination. Vaccine immunogens prompt antigen-specific responses from…

Figure 1
Eliciting humoral and cellular responses through vaccination. Vaccine immunogens prompt antigen-specific responses from B cells and T cells in draining lymph nodes. B cells are blue, CD8+ T cells are gold and CD4+ T cells are green. Some of the key molecular interactions between different cell types that are needed for optimal humoral and cellular defense are shown in boxes. For optimal humoral responses, antigen-specific B cells must interact with pre-TFH cells (“pTFH”) to initiate germinal center reactions. Within germinal centers, B cells proliferate and undergo somatic mutation, in which mutations are introduced into the genes encoding the B cell receptor, thereby enhancing or diminishing affinity for antigen. B cells bearing receptors that have acquired affinity through mutation interact with TFH cells to receive survival signals and re-enter the cycle of proliferation and mutation. Germinal centers produce long-lived plasma cells, which secrete high affinity antibody and memory B cells, which differentiate into plasma cells upon re-encounter of antigen. For protection from HIV, the goal of vaccination is to induce broadly neutralizing antibodies (“bnAb”), which serve as a first layer of defense by preventing HIV virions from infecting cells. For optimal induction of cellular immune responses, CD8+ T cells, dendritic cells and CD4+ helper cells are required. CD4+ T cells “license” dendritic cells to activate peptide-specific naïve CD8+ T cells, which receive co-stimulatory signals from both dendritic cells and CD4+ T cells to proliferate and differentiate into Cytotoxic T Lymphocytes (CTLs). For protection from HIV, a second goal of vaccination is to elicit a pool of HIV-specific memory CTLs to serve as a secondary layer of defense, killing host cells that become infected by virions that escape neutralization by bnAbs. Abbreviations: Ag: antigen; CTL: Cytotoxic T Lymphocyte; DC: Dendritic cell; FDC: Follicular Dendritic cell; GC TFH: Germinal Center T follicular Helper cell; pTFH: Pre-T Follicular Helper cell; TFR: T Follicular Regulatory cell.
Figure 2

Figure 2

Delivery methods for HIV mRNA…

Figure 2

Delivery methods for HIV mRNA vaccine. ( A ) Electroporation; ( B )…

Figure 2
Delivery methods for HIV mRNA vaccine. (A) Electroporation; (B) Cationic micelles composed of stearic acid (yellow) and Polyethylenimine (PEI) (blue); (C) Cationic nanoemulsion (CNE); The yellow core shows squalene. Surfactant such as Tween 80 and Span 85 are shown in blue and purple. Cationic lipid DOTAP (Dioleoyl-3-trimethylammonium propane) is shown with red ‘+’ mark; (D) poly(lactic acid) (PLA) nanoparticle (blue core) with cell penetrating peptide (CPP) (shown in red); (E) Cationic lipid nanoparticle (LNP); figure shows a lipid bilayer with other components that can be included, such as Polyethylene glycol (PEG), cholesterol or phospholipid; (F) Ex vivo loading of dendritic cell (DC). The table below summarizes the HIV mRNA vaccines that have been tested, detailing the delivery method, the type of mRNA, the in vitro and in vivo system used for testing, the mRNA-encoded immunogen and a short note on the results.

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