Passive Immunization in the Prevention and Treatment of Viral Infections

Abstract

The basic concepts of passive immunization and the potential of antibody therapy to confer immunity against infectious diseases were introduced already in the late 19th century. This approach was also later implemented to extensively treat and prevent infections, but with the development of effective vaccines, it became restricted to only a few medical conditions such as snake bites, neutralization of toxins, and prevention of rabies infection. This has dramatically changed in the last decade, as antibodies have been widely used in the clinic for the treatment of COVID-19 and the prevention of respiratory syncytial virus (RSV) infections. A stepping-stone for the progress in monoclonal antibody generation was the development of single-cell antibody cloning techniques that made it possible to develop effective neutralizing antibodies against highly mutable viruses such as influenza virus and HIV-1. Here, we review the use of passive immunotherapy in the clinic for treating and controlling SARS-CoV-2 and RSV infections. We further discuss key developments that have made it possible to use monoclonal antibodies against the highly mutable HIV-1 and influenza virus and advanced clinical trials designed to evaluate the efficacy of such an approach. Finally, we present recent findings that demonstrate that passive immunization can elicit long-term immunity in the host.

Keywords: antibodies; passive immunization; viral immunity; viruses.

FIGURE 1

Key antibody developments for ART‐free control of HIV‐1 viremia. (A) The use of bNAbs combinations. The HIV‐1 envelope trimer, with major epitopes targeted by the bNAbs combination in ongoing clinical trials, is shown. The epitope regions are highlighted as follows: the CD4 binding site in green, the V2 apex in magenta, and the V3 glycan supersite in orange. The bNAbs cocktails currently in clinical trials are listed in the grey box, with each bNAb color‐coded according to the specific target site it addresses in the study. (B) Modification of the antibody Fc domain for extended antibody half‐life. Depiction of Fc‐engineered bNAbs. LS and YTE mutants are Fc‐engineered antibodies with mutations (M428L/N434S for LS, M252Y/S254T/T256E for YTE) that significantly extend the half‐life of bNAbs. (C) Novel methods to target the HIV‐1 latent reservoir with bNAbs. A conceptual overview demonstrating the combined effects of Toll‐like receptor (TLR) agonists and bNAbs. TLR agonists and bNAbs‐antigen complexes engage plasmacytoid dendritic cells (pDCs), leading to enhanced viral antigen presentation to naïve CD8⁺ T cells and to increased cytokine release for activation of these cells. This process enhances the stimulation of HIV‐1 specific CTL mediated immunity. Additionally, TLR agonists activate the innate immune system by triggering pDCs, which in turn increases the proportion of activated cytotoxic NK cells. These primed NK cells bind to bNAb‐antigen complexes via Fcγ receptors, inducing antibody‐dependent cellular cytotoxicity (ADCC) to kill HIV‐1 infected CD4+ T cells. Finally, TLR agonists might increase the reactivation of the latent HIV‐1 provirus by cytokine release or cell‐to‐cell‐mediated activation.

FIGURE 2

Monoclonal antibodies against influenza NA glycoprotein and RSV F glycoprotein. (A, Left) NA protein from H1N1 subtype A/California/04/2009 in grey (PDB ID: 6Q23) showing the epitope of 1G01 Fab in green, 1E01 Fab in yellow, 1G04 Fab in pink, and common conserved active site epitopes between the antibodies are highlighted in red. (A, Right) NA protein from Influenza B/Beijing/1/87 in grey (PDB ID: 1NSC), in complex with 1G05 Fab in light blue and 2E01 Fab in Orange. (B) The RSV prefusion F trimer in grey with surface epitopes of nirsevimab at antigenic site Ø (red) and palivizumab at antigenic site II (purple). The 3D structures are created using the MolStar graphic tool.

FIGURE 3

Possible mechanisms for antibody‐mediated vaccinal effect. On the right, immune complexes formed by infused antibodies and circulating viruses act as strong immunogens to interact with Fcγ receptors on dendritic cells promoting phagolysosome fusion, maturation, and increased antigen uptake. This enhances antigen processing and presentation to CD8⁺ and CD4⁺ T cells and strengthens cellular antiviral responses. Alternatively (on the left), the administrated antibody could lead to an enhanced humoral response by inducing antigenic changes in the targeted virus. These viral antigenic changes will lead to the stimulation of new B‐cell lineages and the elicitation of antibodies with improved neutralization capacity.