A new study published on the preprint server medRxiv* finds improved Fc cross-reactivity against certain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOCs). Moreover, the researchers found that VOCs differentially trigger Fc effector functions, thus providing important implications for vaccination.
The researchers in the study demonstrated that even while the Beta VOC partially evades Fc effector activity in individuals infected with the original variant, not all functions are equivalently affected. This is suggestive of differential targeting by antibodies mediating distinct Fc functions with significantly improved Fc cross-reactivity against SARS-CoV-2 VOCs.
Study: A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity. Image Credit: Immersion Imagery / Shuterstock.com
The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by the SARS-CoV-2. In the absence of adequate global SARS-CoV-2 vaccine coverage, VOCs continue to emerge. Several VOCs include the Alpha (B.1.1.7), Beta (B.1.351/501Y.V2), Gamma (P.1), and Delta (B.1.617.2) variants. These VOCs are generally able to evade neutralizing responses.
While VOCs robustly escape neutralization, several VOCs have been prone to T-cell function and spike antibody functions after both infection and vaccination. In addition to mediating neutralization, antibodies are important in driving several effector functions.
Antibodies are able to engage cellular receptors through their Fc portion. Some of the activities performed by the Fc portion of antibodies include antibody-dependent cellular cytotoxicity (ADCC), cellular phagocytosis (ADCP), cellular trogocytosis (ADCT), and cell membrane nibbling and complement deposition (ADCD).
Despite the potential lack in neutralizing efficacy of SARS-CoV-2 antibodies against newer variants, cross-reactivity with the preserved Fc effector function can still allow these antibodies to successfully target VOCs. For example, although infected individuals presented substantially reduced neutralization titers post-Ad26.COV.2S vaccination, they maintained efficacy against severe COVID-19 illness, even as the Beta variant emerged in South Africa.
Fc effector function is also associated with COVID-19 severity and mortality. Thus, the Fc effector function is highly important for disease outcomes.
However, the Fc effector functions in individuals infected with VOCs are not yet investigated. While the neutralizing antibodies triggered by VOCs show varying patterns of breadth against the SARS-CoV-2 spike protein of different genotypes, the present study looks at the Fc responses to VOCs.
The researchers conducted their study among individuals infected with the original Wuhan D614G SARS-CoV-2 strain in South Africa, where three distinct waves of COVID-19 have occurred since March 2020. The first wave peaked in mid-July 2020, the second in January 2021, and the third in August 2021.
Each wave was dominated by a different variant. Whereas the first wave was caused by the original SARS-CoV-2 strain, the second wave was driven by the Beta variant, and the third wave was almost exclusively Delta.
Using convalescent plasma from the infected individuals, the researchers determined the binding and neutralizing ability against the original (D614G) or Beta lineages from the first and second waves.
Comparison of the binding of antibodies from Wave 1 plasma to the original (D614G) or Beta spikes showed a significant decrease in binding to Beta. In contrast, the wave 2 plasma from Beta infections showed a significant increase in the antibody binding to Beta.
The researchers found similar observations in the neutralization titers. These findings, therefore, confirmed the ability of convalescent plasma to target epitopes beyond the neutralizing epitopes mutated in VOCs.
While the Fc effector function is elicited by the Ad26.COV.2.S vaccine appears to remain largely effective across all VOCs, it is not as cross-reactive as those elicited by the Beta variant. These results were suggestive of the possibility of epitope-specific functional responses.
Moreover, this study illustrated that the Fc effector VOC cross-reactivity is not due to the binding titer. The researchers found preserved Fc effector function but a loss in neutralization against the Beta strain in wave 1 samples. Thus, targeting by the Fc effector function appears to be distinct from that of neutralization.
Significantly, the researchers showed that the SARS-CoV-2 N-terminal domain (NTD) and receptor-binding domain (RBD) of the spike protein are targets of the Fc effector function responses (ADCC) in the convalescent plasma. However, mutations in these regions that allow for complete escape during neutralization in individuals infected with the original (D614G) variant only slightly affect ADCC.
The researchers also showed that the Beta-elicited ADCC enhances cross-reactivity against the SARS-CoV-2 Alpha, Beta, Gamma, and Delta as compared to those elicited by the original SARS-CoV-2 variant and Ad26.COV2.S vaccination.
The current study demonstrated that the Beta variant partially evades several Fc effector functions. However, individuals who were infected with the Beta variant developed Fc effector functions with good cross-reactivity against all VOCs. Vaccine-elicited Fc effector function also appears to be retained across VOCs, though it is not as cross-reactive as Beta-elicited.
Importantly, this study demonstrated that despite waning neutralization effects, Fc effector functions against emerging VOCs persist. The spike sequence of the priming immunogen is therefore the likely cause to determine unique Fc effector function profiles. This observation is key to potential modulation in future vaccine design for a more balanced and broad response.
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.