Evaluating the Epidemiological Consequences of Broadly Protective Immunity to Influenza A/H5N1 in the Event of a Pandemic

Abstract

Avian H5N1 influenza, especially clade 2.3.4.4b viruses, is an increasing public health threat in recent years, responsible for global, widespread deaths in birds, cattle, and other mammals. Though this virus is not yet transmissible between humans, an A/H5N1 virus with human-to-human transmission potential could have severe ramifications since humans have not been previously exposed to this influenza subtype. Reasons for the absence of human-to-human transmission remain unclear but likely include a combination of the lack of replication of H5N1 in the upper respiratory airways and broadly cross-protective pre-existing immunity. Recent serological data support the existence of pre-existing Hemagglutinin (HA) H5 Stem antibodies in the population, from shared epitopes with circulating seasonal influenza A viruses. This project aims to model the potential transmission dynamics and health burden of an A/H5N1 virus in the background of prior immunity to the H5 stem; we hope to understand the current and future immune landscape as well as the optimal age groups for vaccination to mitigate pandemic spread. By analyzing publicly available serological data, we show that prior immunity to the H5 stem depends on both birth year via the first influenza exposure in childhood (H1N1 HA stem imprinting) and age through repeat lifelong exposures to influenza. Next, we integrate this information on pre-existing immunity into a mathematical transmission model to anticipate the impact of an H5N1 outbreak until 2050, accounting for cohort aging and future imprinting patterns. We find that fluctuations in prior immunity due to birth cohort imprinting in 45 – 64-year-olds and the loss of prior immunity in 65+ year-olds suggest that the highest attack rates for an A/H5N1 pandemic would occur in 2025, followed by 2050, and then 2015. Based on this immune landscape and contact patterns, modeling suggests that the 6 – 12-year-old age group would have the highest attack rate in a potential H5N1 pandemic, and prioritizing vaccination for this age group would be optimal to reduce attack rates and hospitalizations through direct and indirect protection.