In a recent study posted to the medRxiv* preprint server, researchers in the United States assessed the efficiency of protection mediated by antibodies against symptomatic coronavirus disease 2019 (COVID-19) at low serum-neutralizing titers.
Study: Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers. Image Credit: Lightspring / Shutterstock
All human correlates of protection (CoP) investigations conducted to date have been complicated by the existence of other types of immunity elicited by vaccination and natural infection. Since there are no standardized serological assays, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced neutralizing antibody (nAb) titers must be normalized to those noted after convalescence, enabling the determination of only relative protective titers instead of absolute ones. The high levels of serum neutralization provided by these treatments have prevented the determination of a protective neutralization threshold, despite clinical research showing that monoclonal antibodies transferred passively can protect against COVID-19 when there is no other type of protection present.
About the study
In the present study, the team performed a Phase 2/3 clinical investigation to assess the efficiency of a half-life extended human monoclonal antibody (adintrevimab) for preventing symptomatic COVID-19.
The team altered employed two amino acids (M428L/N434A or LA) to alter the Fc region of ADG2 to form ADG2-LA or adintrevimab to increase the binding affinity of ADG2 to the neonatal Fc receptor in the lysosome and extend in vivo serum half-life. Previous research has demonstrated that these two mutations enhance binding to human FcRn. In addition, research in rhesus macaques has demonstrated that the N484A variation considerably reduces clearance compared to the wild-type.
The team assessed the pharmacokinetics of adintrevimab in naive cynomolgus macaques after a single 10 mg/kg intramuscular (IM) injection or intravenous (IV) infusion to determine whether the increase in FcRn binding translated to a longer serum half-life in vivo. The effect of the LA alteration on binding to recombinant C1q, FcgRI, FcgRIIa, FcgRIIb, and FcgRIIIa. The team also used effector function assays in vitro to evaluate antibody-dependent cellular phagocytosis (ADCP) facilitated by monocytes and neutrophils (ADNP), antibody-mediated complement deposition (ADCD), and antibody-dependent natural killer cell activation and degranulation (ADNKA).
Adintrevimab was advanced into a Phase 1 study to evaluate its safety and pharmacokinetic properties. Additionally, a Phase 2/3 prevention study was performed with the pre-exposure prophylaxis (PrEP) cohort to determine whether a single 300 mg dose can suppress the progression of symptomatic COVID-19 in adults SARS-CoV-2-naive. All patients in the Phase 2/3 study who were baseline seronegative with a negative reverse transcription–polymerase chain reaction (RT-PCR) were included in the primary analysis cohort.
The study results showed limited clearance and an average half-life of 19.7 days after IV infusion compared to the eight to 10 days corresponding to non–Fc modified IgGs in NHPs. Following a single 10 mg/kg IM dosage, systemic exposure showed good relative bioavailability and a 22.2-day half-life. The LA alteration provided adintrevimab a longer half-life in NHPs as a result.
Comparable levels of ADCD, ADCP, ADNKA, and ADNP activity were induced in vitro by ADG2 and adintrevimab. Additionally, their binding affinities towards C1q and human Fcg receptors were similar. This suggested that the LA modification improved FcRn binding without significantly affecting Fc-mediated effector activities. Finally, the team demonstrated that in vitro tests for hydrophobicity, polyreactivity, and thermal stability showed that the LA modification had no appreciable impact on the molecule's biophysical characteristics.
Adintrevimab showed a relative risk decline of 71% against placebo in the pre-SARS-CoV-2 Omicron variant cohort concerning the primary outcome of the diagnosis of RT-PCR-confirmed COVID-19 through three months. An 84% relative risk decline compared to the placebo in RT-PCR-confirmed COVID-19 diagnosis through six months was found in a post-hoc analysis of a sample of pre-Omicron patients randomized before 15 June 2021. In addition, a higher percentage of events was observed in the placebo group than in the adintrevimab group throughout the third and sixth months compared to months zero through three, which caused improved effectiveness through day 180. The team also observed that the Omicron PrEP population's efficacy declined more quickly.
The normalized Delta serum neutralizing titers on days 90 and 180 were 1:3880 and 1:2454, and these values were linked to 71% and 84.4% lower risks of developing symptomatic Delta infection, respectively. Adintrevimab's median serum concentrations on days 28, 60, and 90 were 31.2, 27.1, and 23.28 mg/L, respectively. These values corresponded to serum neutralizing titers against Omicron BA.1 of 1:29, 1:25, and 1:21, respectively. This indicated that adintrevimab offered significant defense against symptomatic COVID-19 even at serum nAb titers as low as about 1:30.
Overall, the study findings showed that protection against symptomatic COVID-19 can be obtained at low serum nAb titers of the order of 1:30 with the use of both monoclonal antibodies and vaccines.
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.
- Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers, Pete Schmidt, Kristin Narayan, Yong Li, Chengzi Kaku, Michael Brown, Elizabeth Champney, James Geoghegan, Maximiliano Vasquez, Eric Krauland, Thomas Yockachonis, Shuangyi Bai, Bronwyn Gunn, Anthony Cammarata, Chris Rubino, Laura M Walker, medRxiv 2022.10.18.22281172, DOI: https://doi.org/10.1101/2022.10.18.22281172, https://www.medrxiv.org/content/10.1101/2022.10.18.22281172v1