A new pandemic

In 1963, the H3N8 (A/equine/2/Miami/63) subtype created an epidemic of equine influenza in Miami and subsequently spread throughout North and South America and Europe, creating massive outbreaks during 1964 and 1965. Since 1963, the H3N8 virus has drifted along a single lineage at a rate of 0.8 amino acid substitutions per year. Between 1978 and 1981, there were widespread epidemics of the A/equine/2 strain throughout the US and Europe despite the development of vaccines. Since the late 1980s, evolution of the H3N8 virus has diverged into two families: an "American-like" lineage and a "European-like" lineage.^[6] A 1997 study found H3N8 was responsible for over one quarter of the influenza infections in wild ducks.^[7]

H3N8 has been suggested as a possible cause of the 1889–1890 pandemic in humans, and also another epidemic in 1898–1900.^[8][9] Before the identification of H3N8 as a possible cause of the 1889 pandemic, the H2N2 subtype was suggested.^[10][11][12] At this point, it is not possible to identify the virus for either the 1889 or 1900 outbreak with certainty.^[13]

Abstract

XEC and KP.3.1.1 have surpassed KP.3 to become the globally dominant lineages due to their unique NTD mutations. However, several emerging JN.1 sublineages, such as LF.7.2.1, MC.10.1, NP.1, and, especially, LP.8.1, have demonstrated superior growth advantages compared to XEC. It is critical to access the virological and antigenic characteristics of these emerging SARS-CoV-2 variants. Here, we found that LF.7.2.1 is significantly more immune invasive than XEC, primarily due to the A475V mutation, which enabled the evasion of Class 1 neutralizing antibodies. However, LF.7.2.1's weak ACE2 binding affinity substantially impaired its fitness. Likewise, MC.10.1 and NP.1 exhibited strong antibody immune evasion due to the A435S mutation, but their limited ACE2 engagement efficiency restricted their growth advantage, suggesting that A435S may regulate the Spike conformation, similar to the NTD glycosylation mutations found in KP.3.1.1 and XEC. Most importantly, we found that LP.8.1 showed comparable humoral immune evasion to XEC but demonstrated much increased ACE2 engagement efficiency, supporting its rapid growth. These findings highlight the trade-off between immune evasion and ACE2 engagement efficiency in SARS-CoV-2 evolution, and underscore the importance of monitoring LP.8.1 These findings highlight the trade-off between immune evasion and ACE2 engagement efficiency in SARS-CoV-2 evolution, and underscore the importance of monitoring LP.8.1 and its descend lineages.