Biology subjects

Merrick, B.

Publications and source records attributed to Merrick, B..

2 recordsLinked to original sources

bioRxiv2025

Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses

The rapid development of vaccines against SARS-CoV-2 during the COVID-19 pandemic proved vital in controlling viral spread and reducing mortality and morbidity. Both neutralising activity and effector function activity of Spike-specific antibodies have been shown to be important for their protective and therapeutic activity. However, several recent studies have reported that vaccination with mRNA based COVID-19 vaccines can lead to elevated levels of Spike-specific IgG4, an isotype which is often considered anti-inflammatory due to its reduced binding to Fc{gamma} receptors on immune cells. Here we show that the level of Spike-specific IgG4 produced following BNT162b2 vaccination is impacted by the interval between and frequency of vaccines boosts, prior SARS-CoV-2 infection (hybrid immunity), breakthrough infection and bivalent vaccine boosters. Despite the increase in Spike-specific IgG4 between the 2nd and 3rd BNT162b2 vaccine dose, neutralisation, ADCD and ADCP activity all increased. Through expression of SARS-CoV-2 monoclonal antibodies cloned as IgG1, IgG2, IgG3 and IgG4, we demonstrated that whilst Spike-specific IgG4 had reduced effector function activity, including ADCC, ADCD and ADCP, IgG4 was only inhibitory when directly competing with functional IgG subclasses binding to an overlapping epitope. In the context of polyclonal plasma, ADCC and ADCD activity could not be depleted by addition of high concentrations of a Spike-specific IgG4 mAb cocktail suggesting the non-stimulatory effect of Spike-specific IgG4 may be hidden in more complex scenarios, such as polyclonal mixes in serum.

immunology↗

bioRxiv2021

ADNKA overcomes SARS-CoV2-mediated NK cell inhibition through non-spike antibodies

The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This correlated with a reduction in NK cell activation, identifying a novel mechanism by which SARS-CoV2 antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.

immunology↗