Back to the Future for Influenza Preimmunity-Looking Back at Influenza Virus History to Infer the Outcome of Future Infections

Abstract

The influenza virus-host interaction is a classic arms race. The recurrent and evolving nature of the influenza virus family allows a single host to be infected several times. Locked in co-evolution, recurrent influenza virus infection elicits continual refinement of the host immune system. Here we give historical context of circulating influenza viruses to understand how the individual immune history is mirrored by the history of influenza virus circulation. Original Antigenic Sin was first proposed as the negative influence of the host's first influenza virus infection on the next and Imprinting modernizes Antigenic Sin incorporating both positive and negative outcomes. Building on imprinting, we refer to preimmunity as the continual refinement of the host immune system with each influenza virus infection. We discuss imprinting and the interplay of influenza virus homology, vaccination, and host age establishing preimmunity. We outline host signatures and outcomes of tandem infection according to the sequence of virus and classify these relationships as monosubtypic homologous, monosubtypic heterologous, heterosubtypic, or heterotypic sequential infections. Finally, the preimmunity knowledge gaps are highlighted for future investigation. Understanding the effects of antigenic variable recurrent influenza virus infection on immune refinement will advance vaccination strategies, as well as pandemic preparedness.

Keywords: Spanish influenza; antigenic drift; antigenic shift; immune response; imprinting; influenza virus; original antigenic sin; orthomyxoviridae; pandemic; preimmunity.

Figure 1

Influenza immune background development following recurrent infections and vaccinations. The schematic illustrates possible immune fluctuations following influenza virus infection or vaccination. Immune fluctuations and potential protection can be conceptualized at both the individual or population level. The heterogeneity of the immune background is dependent on the sequence of virus exposures and their genetic and antigenic relatedness. Immune specificity that is gained during influenza virus immune imprinting during infancy or childhood leading to the generation of virus-specific T and B cells are retained at some level throughout life. T = T cell; B = B cells; Y = antibodies.

Figure 2

Schematic of Influenza A, B, and C virus structure. Influenza A is defined by its surface proteins hemagglutinin (HA) and neuraminidase (NA) of which there are 18 HA and 11 NA. Influenza B viruses are categorized into two lineages (B/Yamagata and B/Victoria). The surface of both A and B viruses contains HA, NA, and the M2 proteins. Internally, A and B viruses both have eight genomic segments. Influenza C viruses have only one external spike protein (HEF) which functions both in viral entry and egress and an ion channel M2 protein. Type C viruses have 7 internal genomic segments. M1 protein line the envelope internally adjacent nuclear export protein (NEP) proteins for type A, B, and C viruses. The genomic segments are encapsidated by the NP protein and form the ribonucleocapsid with the polymerase proteins Polymerase acidic (PA), Polymerase basic 1 (PB1), and Polymerase basic 2 (PB2).

Figure 3

Timeline of the history of influenza virus circulation in humans since 1890s. The timeline shows the history of influenza virus type A and B circulation since 1890. There have been 6 presumptive pandemics in this time period. The Russian pandemic of ~1891 occurred prior to the discovery of the influenza virus and is known only by historical medical records. Seroarcheology has suggested that this outbreak was caused by an H3N8 virus. In 1918 what was known as the Spanish Influenza Pandemic took place. The H1N1 virus which had caused the pandemic was not definitively identified until lung samples from victims of the pandemic were sequenced in 2005. It is estimated that 50 to 100 million deaths were caused by this virus. H1N1 viruses circulated until 1957 when H1N1 was replaced with an H2N2 pandemic virus during the Asian pandemic. The H2N2 virus was replaced with H3N2 during the 1968 Hong Kong pandemic. In 1977, H1N1 resurfaced and since then, H1N1 and H3N2 have co-circulated. In 2009, the emergence of an H1N1 strain of swine origin replaced the former seasonal H1N1 virus ‘lineage’ which was in circulation from the 1977 lineage. In addition to circulating seasonal influenza viruses, avian virus spillover events also lead to human infection. Major avian virus spillover events occurred in 1997 and 2013 for the influenza A viruses H5N1 and H7N9, respectively. During this time period, influenza B viruses have also co-circulated in humans. *Image credit CDC for the 1918 pandemic and the influenza virion [79].

Figure 4

Influenza immune imprinting and the history of circulating influenza viruses. The timeline illustrates the relationship between virus circulation and influenza virus immune imprinting at infancy. Several published studies have shown that antibodies reactive toward the imprinting virus can last throughout the host’s lifetime. Human studies investigating imprinting serology, epidemiology, or cell reactivity are noted in the figure for the time period of imprinting. The author’s last name and publication date are given. The date in parentheses refers to study subjects’ date of birth if it is not easily deduced from the timeline.