Poster Presentation Lorne Infection and Immunity 2023

Recall, breadth and longevity of humoral immunity following Omicron BA.1 and BA.2 breakthrough infection (#155)

Wen Shi Lee 1 , Hyon-Xhi Tan 1 , Arnold Reynaldi 2 , Robyn Esterbauer 1 , Marios Koutsakos 1 , Julie Nguyen 1 , Thakshila Amaresana 1 , Helen Kent 1 , George Taiaroa 3 , Paul Kinsella 3 , Kwee Chin Liew 3 , Deborah A Williamson 3 , David Khoury 2 , Miles P Davenport 2 , Jennifer A Juno 1 , Stephen J Kent 1 , Adam K Wheatley 1
  1. Peter Doherty Institute of Infection and Immunology, Melbourne, VIC, Australia
  2. Kirby Institute, University of New South Wales, Kensington, NSW, Australia
  3. Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia

Introduction:

SARS-CoV-2 breakthrough infections of fully vaccinated individuals are becoming increasingly common with the rise of highly transmissible and immune evasive Omicron variants. Upon antigen re-exposure, Spike-specific memory B cells (MBCs) are reactivated and differentiate into antibody-secreting cells to provide an anamnestic antibody response. It remains unclear how long immunity lasts following Omicron breakthrough infection and whether antibodies against neo-epitopes within Omicron spike are elicited.

 

Methods:

We recruited and longitudinally sampled 24 fully vaccinated individuals with PCR and whole genome sequence-confirmed Omicron infections (8 BA.1, 16 BA.2). We measured plasma neutralising activity using a live virus neutralisation assay and MBCs specific for ancestral and/or Omicron S using fluorescent S protein probes. We measured SARS-CoV-2 RNA levels within nasal swabs using RT-PCR.

 

Results:

In the early stages of infection (1-5 days post-symptom onset), plasma neutralising titres against BA.1 or BA.2 were low or undetectable, before rising from days 5-7 up to days 30-45. Importantly, the recall of antibody responses lagged behind nasal viral loads that peaked around 3-4 days post symptom onset. Neutralising antibody titres against the infecting strain were durable and dropped from a mean of 983.7 at 1 month to 498.4 at 7 months for BA.1 infected subjects and 1719.2 at 1 month to 1533.4 at 4 months for BA.2 infected subjects. Importantly, people who recovered from BA.1 and BA.2 infection gained neutralisation breadth against the more immune evasive BA.4 variant. Cross-reactive MBCs that recognised both ancestral and Omicron spike were robustly expanded and displayed an activated phenotype (CD21-CD27+) at early timepoints. In contrast, very low frequencies of MBCs that only recognised Omicron spike were detected. Consistent with this data, we did not detect a rise in neo-antibody responses against Omicron S that do not cross-react with ancestral S.

 

Conclusion:

We find that Omicron breakthrough infection primarily expands cross-reactive MBCs and antibodies, leading to the rapid rise and durable maintenance of Omicron neutralising antibodies. Understanding the breadth of antibodies and MBCs elicited by infection with distinct variants will be critical to informing vaccine design to maximise protection against future variants.