Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers

Abstract

Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against coronavirus disease 2019 (COVID-19). However, the induction of multiple layers of immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life–extended monoclonal antibody (adintrevimab) provides about 50% protection against symptomatic COVID-19 in SARS-CoV-2–naïve adults at serum nAb titers on the order of 1:30. Vaccine modeling results support a similar 50% protective nAb threshold, suggesting that low titers of serum nAbs protect in both passive antibody prophylaxis and vaccination settings. Extrapolation of adintrevimab pharmacokinetic data suggests that protection against susceptible variants could be maintained for about 3 years. The results provide a benchmark for the selection of next-generation vaccine candidates and support the use of broad, long-acting monoclonal antibodies as alternatives or supplements to vaccination in high-risk populations.

Examining protective effects of SARS-CoV-2 neutralizing antibodies after vaccination or monoclonal antibody administration

“…nAb titer measured shortly after the final dose of the SARS-CoV-2 vaccine series is strongly associated with protection against COVID-19 in vaccine trials 8 – 12 . Similarly, nAb titers are associated with protection in observational studies following natural infection, monoclonal antibody (mAb) prevention trials, and in non-human primate studies 5 , 13 , 14 . NAb titer has recently been accepted as a correlate of protection for emergency use authorization of SARS-CoV-2 variant vaccine booster vaccines without the additional requirement of new randomized trials to affirm clinical benefit 15 , 16 .…”

A generalized framework to identify SARS-CoV-2 broadly neutralizing antibodies

“…5c). Given serum neutralizing titers are an established correlate of protection against SARS-CoV-2 53–56 , we also evaluated the neutralizing activities of the mouse sera against XBB.1.5, HK.3.1, and JN.1 pseudoviruses. BD55-1205 achieved high geometric mean peak serum neutralizing titers of 4496 against XBB.1.5, 5138 against HK.3.1 and 4608 against JN.1 at 48 hours post administration, underscoring the antibody’s breadth (Fig.…”

“…To that end, we encoded BD55-1205 in mRNA and formulated it into lipid nanoparticles (LNPs) for in vivo delivery. We also introduced the “LA” modification (M428L/N434A) in the Fc region to enhance human FcRn binding at acidic pH, thereby improving the antibody half-life 56 . Formulated LNPs were delivered by intravenous injection to Tg32-SCID transgenic female mice that are homozygous for human fragment crystallizable neonatal receptor (FcRn) 57 .…”

Safety, Pharmacokinetics, Serum Neutralizing Titers, and Immunogenicity of Adintrevimab, a Monoclonal Antibody Targeting SARS-CoV-2: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Dose-escalation Study in Healthy Adults

“…Monoclonal antibodies targeting the receptor binding domain (RBD) of the spike protein have been shown to be safe and effective in volunteers and in participants diagnosed with or at high risk of COVID-19. There is also evidence that sVNA titers can be used as a correlate of protection against COVID-19 disease [ 7 ]. Adintrevimab demonstrated a strong correlation between pharmacokinetics and sVNA titers.…”

“…Adintrevimab prevents viral entry into host cells by binding to a highly conserved epitope on the receptor-binding domain of the SARS-CoV-2 spike protein [ 4 – 6 ]. In addition, the crystallizable fragment region of the heavy chain contains an LA modification (M428L/N434A) to provide an extended half-life [ 7 ]. Using a population pharmacokinetic (PK) model, a median half-life of 141–152 days was estimated following 300 mg intramuscular (IM) administration for prevention and treatment, respectively [ 8 ].…”