A Rapid Review Contrasting the Evidence on Avian Influenza A(H5Nx) Clades 2.3.4.4b and 2.3.2.1c in Humans.

Avian influenza viruses (AIV) circulate in wild and domestic bird populations, posing an on-going risk for zoonotic transmission and virus adaptation to mammals and humans. The A(H5Nx) clades 2.3.2.1c and 2.3.4.4b currently circulating have caused sporadic infections in humans. A rapid review (RR) was conducted to contrast the evidence on infection from these clades in humans. Adhering to PRISMA guidelines, a protocol was developed a priori. The search was conducted in December 2023 for primary research articles (published and preprint) pertaining to AIV clades 2.3.4.4b or 2.3.2.1c in Scopus, PubMed and EuropePMC. Search verification and a grey literature search were also conducted in January 2024. Full-text relevance screening was conducted independently by two reviewers. Data extraction and risk of bias (ROB) assessment was conducted by one reviewer and verified by a senior reviewer. Results were reported narratively. Forty articles published between 2014 and 2023 were included in this RR. Studies found no discernible difference in the likely mode of exposure, transmission or the potential of AIV infection in humans between the two clades. Seropositivity, seroconversion and hospitalisation rates were also similar, while intensive care unit admission and fatalities were higher for A(H5Nx) clade 2.3.2.1c. Several markers of mammalian adaptation and mutations associated with increased viral replication, polymerase activity and virulence in mammals and/or mice were found in both clades. Most studies were considered to be at high ROB, while some well-designed cohort studies were at moderate ROB. This summary can be used to inform what is known about A(H5Nx) in humans for the two clades and suggests that there is on-going adaptation pressure from circulating AIVs that should be closely monitored. It is important to continue surveillance in birds, mammals and humans, conduct large epidemiological studies and develop mitigation strategies from a One Health perspective.