Serial infection with SARS-CoV-2 Omicron BA.1 and BA.2 following three-dose COVID-19 vaccination

Abstract

SARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have immunologically assessed serial Omicron infections. We characterized SARS-CoV-2 humoral responses in an individual who acquired laboratory-confirmed Omicron BA.1.15 ten weeks after a third dose of BNT162b2, and BA.2 thirteen weeks later. Responses were compared to 124 COVID-19-naive vaccinees. One month post-second and -third vaccine doses, the participant's wild-type and BA.1-specific IgG, ACE2-displacement and virus neutralization activities were average for a COVID-19-naive triple-vaccinated individual. BA.1 infection boosted the participant's responses to the cohort ≥95th percentile, but even this strong "hybrid" immunity failed to protect against BA.2. Reinfection increased BA.1 and BA.2-specific responses only modestly. Though vaccines clearly protect against severe disease, results highlight the continued importance of maintaining additional protective measures to counteract the immune-evasive Omicron variant, particularly as vaccine-induced immune responses naturally decline over time.

Keywords: COVID-19; Omicron variant; humoral immunity; reinfection; vaccine.

Figure 1

Case participant history and longitudinal humoral responses against wild-type and Omicron BA.1 SARS-CoV-2. Panel (A) Case participant timeline. Immunizations and SARS-CoV-2 Omicron infection history are shown at the top. Longitudinal SARS-CoV-2 anti-N serology results are shown in small green (anti-N negative) or orange (anti-N positive) circles. Large black circles denote time points where additional humoral functions, shown in panels below, were measured. Panel (B) Longitudinal anti-S-RBD IgG concentrations, expressed in log₁₀ BAU/mL, in the case participant (large circles) versus the comparison group of SARS-CoV-2-naive individuals (small circles) at various time points following two- and three-dose COVID-19 vaccination. Wild-type (WT) specific anti-S-RBD responses are shown in red; Omicron BA.1-specific ones are shown in blue. Matching solid lines connect the participant’s longitudinal values, while dotted lines connect the median values for the comparison group. Approximate times of BA.1 and BA.2 infections are shown with arrows. Total Ns are shown at the bottom of the plot. Later time points have smaller Ns because some control participants were censored due to post-vaccination SARS-CoV-2 infection or had not yet completed the visit. Panel (C) same as (B), but for longitudinal ACE2% displacement function from wild-type (red) and BA.1 (blue) S-RBDs. Panel (D) same as (B), but for longitudinal live virus neutralization function against wild-type (red) and BA.1 (blue) strains. ULOQ/LLOQ: upper/lower limit of quantification.

Figure 2

Longitudinal humoral responses against wild-type, BA.1 and BA.2 Spike antigens. Panel (A) Anti-Spike IgG concentrations, expressed in log₁₀ BAU/mL, in the case participant (large circles) versus a subset of the comparison group of SARS-CoV-2-naive individuals (small circles) at one, three and six months following three-dose COVID-19 vaccination. Wild-type-specific (WT) anti-Spike responses are in red; BA.1-specific ones are in blue; BA.2-specific ones are in black. Matching solid lines connect the participant’s longitudinal values; dotted lines connect the median values for the comparison group. Approximate times of BA.1 and BA.2 infections are shown with arrows. Total Ns are shown at the bottom of the plot; the final time point has a smaller N because some control participants were censored due to post-vaccination SARS-CoV-2 infection or had not yet completed the visit. Panel (B) same as (A), but for longitudinal ACE2% displacement function from wild-type (red), BA.1 (blue) and BA.2 (black) Spike protein.