A couple of weeks ago, I gave a group meeting talk on my current research. Interestingly most of the questions I received were not directly related to my research methods, but rather, on the broader application of antibody-related therapies, as I used the example of convalescent sera as a potential ‘quick fix’ in the current COVID-19 pandemic, to motivate why antibody research is important! So I thought in this blog post, I would give a quick introduction to convalescent sera. (Disclaimer: This does not contain any clinical information.)
Background: As of now, we have not established a cure for SARS-CoV-2 [1]. In previous outbreaks, passive immunisation through transferring convalescent blood products from people who have recovered from the infection, was the only therapeutic option at the early stages before a drug or vaccine has been developed [2]. The Food and Drug Administration (FDA) has issued guidance and encourages such practice [3], while (controversial) evidence of applying such therapy for COVID-19 patients has been published [4].
What is convalescent sera/plasma? People who have recovered from an infection carry antibodies that can neutralise the target virus. Convalescent plasma from these people serve as a mean to transfer these antibodies to severe patients as a passive antibody therapy. This only provides immediate immunity, but will not elicit a full immune response and let your body ‘remember’ how to fight against the invaders.
What is the promise behind administering convalescent sera to patients?Neutralisation: It is believed to be the main mechanism for convalescent sera to work: by binding to the functional sites (e.g. receptors on the viral envelope) and neutralising the virus directly.
Antibody-dependent cellular cytotoxicity (ADCC): After IgG (or IgE) antibodies ‘mark’ the target protein on the viral envelope, Fc receptors, typically CD16, on the effector cell (e.g. natural killer cells, macrophages etc.) recognise the bound antibodies and triggers apoptosis of the target cell. See the blog post of [5] for a list of examples where passive immunity harnesses ADCC to fulfil its therapeutic utility, in flu, HIV and cancer.
How does that relate to structural biology?
Deep sequencing data enriched by structural annotation [6] enable us to compare the antibody repertoire before and after an infection [7]. Thus we look at designing the two key components of an antibody: the binding site and the framework. In an ideal world, based on the crystal structures of the key protein targets in SARS-CoV-2, if we are able to identify the complementary antibody binding site, we could then screen through large sequencing datasets such as those that become available after vaccination trials to look for potential leads. Simultaneously, we will consider the framework – to optimise for developability, immunogenicity, and how it interacts with effector cells. The promise of finding a potential antibody therapeutic from a human antibody sequencing dataset lies in the mitigation of these potential issues [8].
- https://www.jci.org/articles/view/138003
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781783/
- https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-encourages-recovered-patients-donate-plasma-development-blood
- https://www.pnas.org/content/early/2020/04/02/2004168117
- https://blog.quartzy.com/2017/04/14/antibody-dependent-cellular-cytotoxicity
- https://journals.plos.org/ploscompbiol/article/authors?id=10.1371/journal.pcbi.1007636
- https://www.biorxiv.org/content/10.1101/2020.03.17.993444v2
- https://www.tandfonline.com/doi/full/10.1080/19420862.2019.1633884
