2. Marco teórico
2.6 Enfoques de gestión Pública
for influenza had its origin in the James D. Bruce memorial lecture given by Dr. Thomas Francis Jr. to the American College of Physicians in 1953 (Francis 1953). Involved in the identification of influenza strains and early attempts at vaccine development, Francis was also interested in determining what factors may have contributed to the unusual young adult mortality of the 1918 flu pandemic. Using the work of Collins in the 1930s, Francis determined that the infection rates for influenza were similar across all ages but that young adults (whom he considered to be 25 to 40) were more likely to die from secondary pneumonias. Young adults were more susceptible to bacterial complications due to the more severe damage done to their lungs by the initial influenza infection. He saw that those aged 5 to 9 are generally the most likely to contract influenza and that “they develop a relatively specific immunity against recent strains of virus, reflected in the low point of incidence from 15 to 24 years [when the same, or only moderately changed virus is still in circulation]” (Francis 1953:210). Francis’ hypotheses about the relationship between immunity and age can be seen in Figure 2.2. In 1918, he reasoned that those people over
mortality where she says that “if the baby is nursed by its mother the chances are great that it will live. If the baby is fed in any other way the chances are great that it will die” (1910:5). Infant mortality was blamed on working mothers who were not able to breastfeed, such that “where the mother works, the baby dies . . . she cannot nurse the baby if she works” (1910:17). Since the subject period of birth for individuals in this study was before the 1900, and due to the high levels of mortality for bottle-fed infants, for the purposes of this research it will be assumed that all individuals who survived to age 23 were breast-fed in some regard and thus were under the protection of the maternal immune response to a certain extent.
21
First called so in Francis (1955) and Davenport and Hennessy (1956). It is now more useful to refer to this theory as ‘antigenic imprinting’ (Ma et al. 2011) or ‘antigenic seniority’ (Lessler et al. 2012, Miller et al. 2013, Gagnon et al. 2015). Antigenic imprinting implies that the virus an individual is first exposed to may be similar (but not identical) to the one encountered later in life.
the age of 40 had a more successful immunity to the 1918 strain and those under 40 had a less successful immunity. Importantly, “the more virulent a strain, the greater, presumably, is its ability to override the lesser degrees of resistance [immunity]” (Francis 1953:214).22 Francis explains the elevated immunity of young adults as a byproduct of the immunity to influenza of those over the age of 40 (resulting in less likelihood of dying from pneumonia), creating the ‘W’ shaped mortality curve which otherwise would have been a linear increase from the age of around 20 (1953:214). He explains that,
The combined effect is that the middle age group possessed a lower margin of the physiologic tolerance which protected the five to 24 year group from pneumonia and a less complete resistance to the virus than that which protected the older ages against the essential virus injury (Figure 6). It shows, instead, the results of a high incidence of influenza and the increased liability of its age to pneumonia and fatality following influenza virus infection. [Francis 1953:215].
Francis’ Figure 6 is reproduced as Figure 2.3. Francis states that “the data support the conclusion that the primary determining factor in the development of fatal infection is the viral constitution and the degree of injury it creates.” (1953:217).
22 Francis was writing only twenty years after the influenza virus had first been identified and the isolation of various
strains was only in its initial phases. He is working under the assumption that there was a similar viral strain circulating before 1918 while more recent research claims that “the 1918 virus appears to be an avianlike influenza virus derived in toto from an unknown source” (Taubenberger and Morens 2006:18). Contrastingly, Worobey and colleagues suggest that both the H1 and N1 strains had been circulating for at least 5 years and that they had joined together by 1915 (2014).
Source: Francis (1953:210, Figure 3).
Source: Francis (1953:215, Figure 6).
Figure 2.2 - Relation of Age to Features of Incidence and Immunity in Influenza.
Davenport, Hennessy and Francis expanded this in an article later in 1953. Experimenting with blood samples from individuals of different ages and using different strains of influenza, they were able to hypothesize about the strains that were circulating in the years prior to 1953. Additionally, by focusing on the ages of the individuals and the types and amount of antibodies to certain strains produced, they came to three important conclusions. First, the antibodies that an individual obtains from their first exposure to influenza in early life (influenza infections being ubiquitous among the very young) are specific to that strain encountered; however, the long-term immunity gained from this experience is of limited strength. Second, exposure to various different types of influenza over the lifecourse will result in a broader range of antibodies to help protect individuals against antigenic shift.23 Finally, however,
The antibody-forming mechanisms appear to be oriented by the initial infections of childhood so that exposures later in life to antigenically related strains result in a progressive reinforcement of the primary antibody. The highest cumulative antibody levels detectable in a particular age group tend, therefore, to reflect the dominant antigens of the virus responsible for the childhood infections of that group. [Davenport et al. 1953]
The finding that upon vaccination, individuals will produce antibodies to the virus first encountered in childhood was reinforced by Davenport and Hennessy using experimental data in 1956 (Davenport and Hennessy 1956). Similarly, from experiments with both humans and ferrets, Jensen and colleagues reported that “whatever the mechanism may be, it [is] clear that each antibody response to the various strains is dependent on preexisting immunologic factors and that antigenic similarities are emphasized in human hosts rather than slight antigenic differences which can be demonstrated among influenza viruses” (Jensen et al. 1956:208).
In response to authors who found little evidence for original antigenic sin in experimental studies (Gulati et al. 2005 and Wrammert et al. 2008) and to a lack of consensus over the existence of original antigenic sin among researchers, Kim and colleagues (2009)
23
However, recent longitudinal analyses have shown that exposure to variant strains later in life that share similar proteins may actually reinforce the immunological response to the strain the individual first encountered in life (Miller et al. 2013).
conducted experiments in mice finding that “original antigenic sin could be a potential strategy by which variant influenza viruses subvert the immune system” (2009:3294). Using live rather than inactivated viruses, they found a profound effect of original antigenic sin but note that the original strain and the more recent strain must be antigenically similar for the phenomenon to occur (2009:3300). They admit that the mechanisms that cause original antigenic sin are still unknown.
In 2012, Shanks and Brundage (2012) attempted to explain the mortality of young adults using immunological theories and previous exposure to the 1890 influenza. As with other theorists, they try to explain elevated young adult mortality using a range of 18-43. They use 43 as the upper bound, since they believe that the 1890 pandemic strain was circulating in a less virulent from as early as 1875. Likewise, 18 is the lower age bound, as they attribute the 1899-1900 epidemic to the same strain as was circulating in 1890. They argue that “mortality rates during the lethal second wave were highest among persons with prior exposures to heterosubtypic influenza strains that enhanced immunopathogenic effects when a person was infected with the 1918 pandemic strain and had limited exposures to other respiratory infectious agents” (2012:205). They explain their finding that medical personnel and those who had been in the army for longer periods of time were as likely as non-medical personnel and new recruits to contract influenza, but they were less likely to die during the second wave. They argue that both previous exposure to a strain similar to pandemic influenza as well as limited exposure to the bacteria that cause pneumonia resulted in higher death rates in 1918 (for example, in those recruits raised in rural areas who had less exposure to the bacteria that cause pneumonia throughout their lives). Once these individuals were exposed to pandemic influenza, it resulted in “high viral loads, dysregulated and pathogenic cell mediated immune responses, and transient increases in susceptibility to invasive bacterial infections” (2012:205). If those individuals also contracted a strain of bacteria to which they had no immunity, they were more likely to die.
This argument is not accepted by Morens and Taubenberger (2012) who state that the knowledge of the 1890 virus and its circulation in the 1890s is speculative at best, and it is hard to base immunological arguments on it. They conclude that the ‘W’ shape of
mortality is as of yet unexplained and that there are still missing pieces to understand the puzzle of the 1918 influenza pandemic. This dissertation, focusing on the young adult age category specifically onto the ages of 28 and 30, adds a piece to that puzzle (Chapter 5).