SARS-CoV-2 Anti-Spike IgG Antibody and ACE2 Receptor Binding Inhibition Levels among Breakthrough Stage Veteran Patients

Abstract

SARS-CoV-2 mRNA vaccines have been critical to curbing pandemic COVID-19; however, a major shortcoming has been the inability to assess levels of protection after vaccination. This study assessed serologic status of breakthrough infections in vaccinated patients at a Veterans Administration medical center from June through December 2021 during a SARS-CoV-2 delta variant wave. Breakthrough occurred mostly beyond 150 days after two-dose vaccination with a mean of 239 days. Anti-SARS-CoV-2 spike (S) IgG levels were low at 0 to 2 days postsymptoms but increased in subjects presenting thereafter. Population measurements of anti-S IgG and angiotensin converting enzyme-2 receptor (ACE2-R) binding inhibition among uninfected, vaccinated patients suggested immune decay occurred after 150 days with 62% having anti-S IgG levels at or below 1,000 AU comparable with breakthrough patients at 0 to 2 days postsymptom onset. In contrast, vaccination after resolved infection conferred robust enduring anti-S IgG levels (5,000 to >50,000 AU) with >90% ACE2-R binding inhibition. However, monoclonal antibody (MAb)-treated patients did not benefit from their prior infection suggesting impaired establishment of B cell memory. Analysis of boosted patients confirmed the benefit of a third vaccine dose with most having anti-S IgG levels above 5,000 AU with >90% ACE2-R binding inhibition, but a subset had levels <5,000 AU. Anti-S IgG levels >5,000 AU were associated with >90% ACE2-R binding inhibition and no documented breakthrough infections, whereas levels falling below 5,000 AU and approaching 1,000 AU were associated with breakthrough infections. Thus, quantitative antibody measurements may provide a means to guide vaccination intervals for the individual. IMPORTANCE Currently, clinicians have no guidance for the serologic assessment of SARS-Cov-2 postvaccination status regarding protection and risk of infection. Vaccination and boosters are administered blindly without evaluation of need or outcome at the individual level. The recent development of automated quantitative assays for anti-SARS-CoV-2 spike protein IgG antibodies permits accurate measurement of humoral immunity in standardized units. Clinical studies, such as reported here, will help establish protective antibody levels allowing identification and targeted management of poor vaccine responders and vaccinated subjects undergoing immune decay.

Keywords: ACE2 receptor; COVID-19; SARS-CoV-2; antibody assay; breakthrough infection; immunization; serology.

FIG 1

Numbers of documented breakthrough infections as related to months since completing two-dose SARS-CoV-2 vaccination. Data represent veterans presenting to the VA Ann Arbor Healthcare System during 2021.

FIG 2

SARS-CoV-2 anti-spike (S) and antinucleocapsid (N) IgG antibody levels among infected vaccinated and unvaccinated subjects evaluated at different days after initial symptom onset. (A) Anti-S (RBD) IgG, (Siemens semiquantitative assay). (B) Anti-N IgG (Abbott semiquantitative assay). Dashed and dotted lines show third order polynomial trendline fits for vaccinated and unvaccinated subjects, respectively.

FIG 3

Quantitative SARS-CoV-2 anti-S (RBD) IgG and ACE2 receptor binding inhibition among vaccinated subjects after two-dose vaccination. (A) anti-S (RBD) IgG. (B) ACE2-R binding inhibition. Solid circles are Pfizer and Moderna vaccinated subjects (N = 85) with no documented prior or current viral infection. Diamond enclosed circles are seven individuals who developed breakthrough infections after sampling. Open squares and triangles are respectively monoclonal antibody (MAb) untreated (N = 10) and treated (N = 12) subjects vaccinated after documented resolved infection.

FIG 4

Quantitative SARS-CoV-2 anti-S (RBD) IgG and ACE2 receptor binding inhibition among vaccinated subjects after third booster vaccination. (A) anti-S (RBD) IgG. (B) ACE2-R binding inhibition. Solid circles are Pfizer and Moderna vaccinated subjects (N = 74) with no documented prior or current viral infection. Open squares and triangles are respectively monoclonal antibody (MAb) untreated (N = 12) and treated (N = 4) subjects vaccinated after documented resolved infection.

FIG 5

Relationship of ACE2-receptor binding inhibition to anti-S (RBD) IgG level. Hatched area shows range where ACE-2R binding inhibition is at 50% or below. The steep slope between 800 and 5,000 AU indicates that virus neutralizing capacity may decline rapidly with modest degrees of immune decay in this region.