Influenza Virus: Dealing with a Drifting and Shifting Pathogen

Abstract

Numerous modern technological and scientific advances have changed the vaccine industry. However, nearly 70 years of influenza vaccine usage have passed without substantial changes in the underlying principles of the vaccine. The challenge of vaccinating against influenza lies in the constantly changing nature of the virus itself. Influenza viruses undergo antigenic evolution through antigenic drift and shift in their surface glycoproteins. This has forced frequent updates of vaccine antigens to ensure that the somewhat narrowly focused vaccine-induced immune responses defend against circulating strains. Few vaccine production systems have been developed that can entertain such constant changes. Although influenza virus infection induces long-lived immunologic memory to the same or similar strains, most people do not encounter the same strain repeatedly in their lifespan, suggesting that enhancement of natural immunity is required to improve influenza vaccines. It is clear that transformative change of influenza vaccines requires a rethink of how we immunize. In this study, we review the problems associated with the changing nature of the virus, and highlight some of the approaches being employed to improve influenza vaccines.

Repeated Antigen Exposure Extends the Durability of Influenza-Specific Lung-Resident Memory CD8+ T Cells and Heterosubtypic Immunity

“…These vaccines aim at inducing neutralizing antibodies against surface antigens, such as HA. High mutation rate and antigenic plasticity of the main antibody targets can severely compromise the efficacy of seasonal influenza vaccines and preclude their efficacy against pandemic influenza (Boni, 2008; Kim et al, 2018). Thus, much effort is currently directed toward the concept of universal influenza vaccines.…”

“…However, the HA protein undergoes high rates of mutation (antigenic drift) (Doherty et al, 2006) that enables successful escape from the immunological pressure of vaccination-induced antibodies and dramatically limits vaccine efficacy (Boni, 2008; de Jong et al, 2000). Additionally, reassortment of the segmented influenza virus genome in animal reservoirs can result in new HA sequences (antigenic shift) (Kim et al, 2018) that have not previously circulated in humans and have the potential for pandemic infections (Kim et al, 2018). It has been well documented in humans and rodent models that influenza-specific CD8 + T cells targeting conserved internal proteins of the virus can control virus titers and limit disease development in the absence of neutralizing antibodies (Altenburg et al, 2015; Kreijtz et al, 2007; McMichael et al, 1983; Sridhar et al, 2013).…”

Influenza Viruses in Mice: Deep Sequencing Analysis of Serial Passage and Effects of Sialic Acid Structural Variation

“…We have the greatest knowledge of outbreaks that occurred during the past 100 years, which in 70 humans include the H1N1, H2N2, H3N2 human seasonal viruses that were first recognized in 1918, 1957, and 1968, respectively, as well as of the second human H1N1 pandemic strain that spread worldwide in 2009, replacing the circulating seasonal H1N1 clade (7,8). The emergence of IAV in new hosts involves the natural selection of mutations involved in host adaptation, which may alter binding to the sialic acid (Sia) receptor by the Hemagglutinin (HA), cleavage of 75 the Sia by the Neuraminidase (NA), host specific nuclear transport and replication processes that involve the polymerase subunits, and evasion of the host immune responses (reviewed by 2,[9][10][11]. Some of these processes and mutations that impact mammalian transmission and disease have also been identified during experimental host passages, in which IAVs are passaged in new hosts such as ferrets (12)(13)(14).…”

Current and Next Generation Vaccines Against Influenza

“…Since antibodies against HA can neutralize the virus, HA has been used as antigen for influenza vaccines. Influenza viruses have two major mechanisms of antigenic evolution: antigenic drift and antigenic shift [9]. Antigenic drift occurs when the virus accumulates mutations at antigenic sites during replication through the actions of the inherently error-prone RNA polymerase, producing variant viruses that can escape existing immunity.…”