Cross-sectional and longitudinal genotype to phenotype surveillance of SARS-CoV-2 variants over the first four years of the COVID-19 pandemic
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Background
Continued phenotyping and ongoing surveillance are important in current and future monitoring of emerging SARS-CoV-2 lineages. Herein we developed pragmatic strategies to track the emergence, spread and phenotype of SARS-CoV-2 variants in Australia in an era of decreasing diagnostic PCR testing and focused cohort-based studies. This was aligned to longitudinal studies that span 4 years of the COVID-19 pandemic.
Methods
Throughout 2023, we partnered with diagnostic pathology providers and pathogen genomics teams to identify relevant emerging or circulating variants in the New South Wales (NSW) community. We monitored emerging variants through viral culture, growth algorithms, neutralization responses and change entry requirements defined by ACE2 and TMPRSS2 receptor use. To frame this in the context of the pandemic stage, we continued to longitudinally track neutralisation responses at the population level using using sequential batches of pooled Intravenous Immunoglobulins (IVIG) derived from in excess of 700,000 donations.
Findings
In antibodies derived from recent individual donations and thousands of donations pooled in IVIGs, we observed continued neutralization across prior and emerging variants with EG.5.1, HV.1, XCT and JN.1 ranked as the most evasive SARS-CoV-2 variants. Changes in the type I antibody site at Spike positions 452, 455 and 456 were associated with lowered neutralization responses in XBB lineages. In longitudinal tracking of population immunity spanning three years, we observed continued maturation of neutralization breadth to all SARS-CoV-2 variants over time. Whilst neutralization responses initially displayed high levels of imprinting towards Ancestral and early pre-Omicron lineages, this was slowly countered by increased cross reactive breadth to all variants. We predicted JN.1 to have a significant transmission advantage in late 2023 and this eventuated globally at the start of 2024. We could not attributed this advantage to neutralization resistance but rather propose that this growth advantage arises from the preferential utilization of TMPRSS2 cleavage-resistant ACE2.
Interpretation
The emergence of many SARS-CoV-2 lineages documented at the end of 2023 to be initially associated with lowered neutralization responses. This continued to be countered by the gradual maturation of cross reactive neutralization responses over time. The later appearance and dominance of the divergent JN.1 lineage cannot be attributed to a lack of neutralization responses alone, and we support its dominance to be the culmination of both lowered neutralization and changes in ACE2/TMPRSS2 entry preferences.
