How do BNT162b2 vaccine-induced neutralizing and non-neutralizing antibodies synergize to promote protection against SARS-CoV-2?

In a recent article posted to the medRxiv* preprint server, scientists explored the coronavirus disease 2019 (COVID-19) BNT162b2 vaccine triggered non-neutralizing and neutralizing antibody functions.

Study: BNT162b2 induced neutralizing and non-neutralizing antibody functions against SARS-CoV-2 diminish with age. Image Credit: Christoph Burgstedt/Shutterstock
Study: BNT162b2 induced neutralizing and non-neutralizing antibody functions against SARS-CoV-2 diminish with age. Image Credit: Christoph Burgstedt/Shutterstock

Background

Among the most crucial indicators of vaccine effectiveness in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are neutralizing antibody reactions. Every new SARS-CoV-2 variant raises concerns regarding the diminished vaccine efficacy due to their escape of vaccine-elicited neutralizing antibodies

Nevertheless, mounting epidemiological evidence demonstrates that while vaccination-based infection prevention differs, protection against severe illness and mortality is still high. Therefore, immune responses aside from neutralization may afford COVID-19 vaccine effectiveness.

The intricacy of polyclonal antibody reactions and their implications in COVID-19 remain little understood, despite being one of the essential elements of immune defense. Notably, polyclonal antibodies work via fragment antigen-binding (Fab) domains, which directly neutralize the virus, and fragment crystallizable (Fc) regions, which activate immune cells' Fc receptors to elicit non-neutralizing host responses. Therefore, antibody Fc effector activities might impact SARS-CoV-2 infection outcomes and vaccination protection.

About the study

The current research sought to comprehend how COVID-19 protection was promoted by the interaction of non-neutralizing and neutralizing actions brought on by vaccination. For this, the scientists used sera samples from 51 COVID-19-uninfected medical professionals who received two doses of the SARS-CoV-2 BNT162b2 messenger ribonucleic acid (mRNA) vaccination. They aimed to evaluate the connections between the Fc and Fab domain activities in polyclonal reactions to vaccination.

The vaccination timeframe of the study volunteers ranged from December 2020 to February 2021. Besides, the subjects were aged between 21 and 82 years. The period between the first and second vaccine doses (20 to 22 days, a difference of two days) and dose 2 and sample collection (14 to 15 days, a difference of one day), as well as the gender distribution, were carefully considered while choosing samples to reduce confounding factors. 

Further, the researchers conducted confirmatory screening to ensure no measurable SARS-CoV-2 nucleocapsid-selective antibodies were present to rule out the complicating element of hybrid immunity resulting from SARS-CoV-2 infection. They also excluded people with active SARS-CoV-2 symptoms or a history of prior COVID-19.

The team evaluated neutralization against the SARS-CoV-2 wildtype (WA.1) strain and five clinical variants: Beta (B.1.351), Alpha (B.1.1.7), Gamma (P.1), Omicron (BA.2), and Delta (B.1.617.2). Additionally, they assessed vaccine-selective antibody Fc traits of isotype, Fc effector activities, Fc receptor adhesion, and immunoglobulin G (IgG) glycosylation.

Results

The study results illustrated that the two doses of the COVID-19 BNT162b2 mRNA vaccine successfully stimulated both neutralizing and non-neutralizing antibody activities. The authors stated that the presence of vaccine-specific antibodies was critical. They also noted that quality and quantity affect how well non-neutralizing and neutralizing antibodies work. As a result, antibody titers were linked with neutralizing ability, and vaccine-triggered neutralizing reactions against live clinical isolates of SARS-CoV-2 WA.1 strain and five different variants became less potent with age.

The neutralization of SARS-CoV-2 was associated with the activation of natural killer cells by Fc gamma receptor IIIa (FcgRIIIa), also known as CD16a. In addition, FcgRIIIa-mediated natural killer cell activation results in cytotoxicity. However, it does not cause complement deposition or phagocytosis.

Indeed, FcgRIIIa interaction was linked to age-dependent sialylation and afucosylation of post-translational vaccine-selective IgG. The polyfunctionality of vaccine-induced antibodies was compromised in people aged 65 or older. They exhibited decreased neutralization breadth among variants, general Fc functional potency, and synchronization between non-neutralizing and neutralizing antibodies.

The study data depicted that the association between antibody concentrations and neutralizing potential was reduced among different SARS-CoV-2 variants. Furthermore, there was some overlap in the connections with non-neutralizing activities, particularly antibody-dependent NK cell activation (ADNKA).

The study results demonstrate that non-neutralizing antibody effector activities were immune determinants that could guide the ability of vaccinations to prevent disease, an increasingly important target given the ongoing emergence of novel SARS-CoV-2 variants that defy neutralization.

Conclusions

According to the study findings, the COVID-19 BNT162b2 vaccine induces Fc effector functions and antibodies that could neutralize clinical isolates of SARS-CoV-2 WA.1 and five variants, including the Omicron BA.2 variant. FcRIIIa activity exhibited connections to neutralizing ability and vaccine-selective antibodies afucosylation and sialylation following translation. Further, non-neutralizing and neutralizing functions decline with age, with restricted polyfunctional magnitude, breadth, and synchronization found in those aged 65 or older relative to those below 65.

The team mentioned that researching Fc activities and Fab-mediated neutralization offers more knowledge on vaccine effectiveness for at-risk populations, like the elderly, against SARS-CoV-2 and new variant strains.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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