Making Universal Influenza Vaccines: Lessons From the 1918 Pandemic

Abstract

The year 2018 marked the 100th anniversary of the deadliest event in human history. In 1918-1919, pandemic influenza spread globally and caused an estimated 50-100 million deaths associated with unexpected clinical and epidemiological features. The descendants of the 1918 virus continue to circulate as annual epidemic viruses causing significant mortality each year. The 1918 influenza pandemic serves as a benchmark for the development of universal influenza vaccines. Challenges to producing a truly universal influenza vaccine include eliciting broad protection against antigenically different influenza viruses that can prevent or significantly downregulate viral replication and reduce morbidity by preventing development of viral and secondary bacterial pneumonia. Perhaps the most important goal of such vaccines is not to prevent influenza, but to prevent influenza deaths.

Keywords: influenza; pandemic; pathogenesis; vaccine.

Figure 1.

The 1918 pandemic caused so many deaths, so quickly, that in some hospitals bodies were stacked up layers deep; hasty burials, and burials in mass graves, were common.

Figure 2.

Influenza A viruses and mechanisms of antigenic change. Hemagglutinin (HA) and neuraminidase (NA) are the major surface glycoproteins that elicit protective humoral immunity. Antigenic change can occur via several different mechanisms [7], as diagrammed here. A, Antigenic shift, or gene segment reassortment with another influenza A virus (following mixed infection), can lead to viruses with novel gene segment combinations. In the example shown, reassortment of the pre-1957 human H1N1 virus with one or more unknown avian H2N2 influenza A viruses led to the emergence of the 1957 pandemic virus containing 3 novel avian influenza–derived gene segments, PB1, HA, and NA. B, Intrasubtypic reassortment in which 2 co-circulating human influenza viruses of the same HA subtype can undergo reassortment to create a novel genotype, as occurred in both the postpandemic H1N1 and H3N2 viruses [5]. In the example shown, 2 clades of H3N2 viruses reassorted and led to the antigenically variant 2003 Fujian-like epidemic [6]. C, Antigenic drift, where coding mutations in the antigenic regions of HA and NA lead to continual antigenic alteration of circulating influenza viruses [8] (see Figure 3).

Figure 3.

The evolution of, and annual mortality associated with, 4 pandemic influenza viral descendants of the 1918 pandemic virus that arose by antigenic shift, 1955–2016. A, Antigenic changes in postpandemic viruses. The colored bars represent prevalence of the 1957 H2N2 pandemic virus (red); the 1968 H3N2 pandemic virus (blue); the unexpected return of a 1950s-era descendant of the 1918 pandemic virus, presumably released accidentally from viral storage (amber); and the 2009 H1N1 pandemic virus (green). Antigenic drift changes of sufficient magnitude to require reformulation of the annual vaccine for use in the Northern Hemisphere are represented on the y-axis. Notably, the 1968 H3N2 has been drifting at a greater rate (an average 0.70 significant genetic changes per year) than the other 3 pandemic viruses (an average of 0.27 genetic changes per year for the 3 combined). Antigenic changes in postpandemic influenza viruses have been associated with antigenic drift, which introduces new epitopes or new glycosylation sites, and by intrasubtypic reassortment of an antigenically different HA of the same subtype, represented by vertical hash marks. B, Annual excess mortality rates attributed to influenza. Data are missing for some early years. The figures are obtained from or extrapolated from Centers for Disease Control and Prevention data to reflect excess all-cause mortality, the most common calculation method available for all of the years, although arguably represent overestimations of mortality. Figure updated and modified from Morens et al [15].