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Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic

Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza... P AT H O G E N E S I S R E V I E W Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic 1 2 3 Rafi Ahmed , Michael B A Oldstone & Peter Palese The influenza pandemic of 1918 killed nearly 50 million people worldwide and was characterized by an atypical W-shaped mortality curve, where adults between the ages of 30–60 years fared better than younger adults aged 18–30 years. In this review, we will discuss why this influenza virus strain was so virulent and how immunological memory to the 1918 virus may have shaped the W mortality curve. We will end on the topic of the ‘honeymoon’ period of infectious diseases—the clinically documented period between the ages of 4–13 years during which children demonstrate less morbidity and/or mortality to infectious diseases, in general, compared with young adults. The very young and the very old are the most susceptible to infectious diers’ immune systems, thereby increasing their vulnerability to disease. diseases. One of the main reasons for this is that the young are often However, similar mortality rates were seen in young men and women immunologically naive and the old are undergoing immune senes- not involved in the war. Thus, one must consider the possibility that the cence. This pattern of susceptibility is characteristic of most infections >30 year olds may have had some degree of protective immunity against (Fig. 1a). These data show the death rate from influenza virus during the the 1918 influenza virus pandemic strain and that this immunity was years 1911–1915 and illustrate the typical U-shaped curve of mortality lacking in the younger adults (18–30 year olds) (Fig. 1c). In this review, as a function of age. These historical data from 1911–1915 highlight the we will address this issue and consider how immunological memory markedly different mortality curve that was observed during the influ- may have shaped the W mortality curve of the 1918 influenza pandemic. enza pandemic of 1918 that killed over 50 million people worldwide, We will also discuss why this 1918 pandemic flu strain was so virulent. making it one of the deadliest plagues ever experienced by mankind Finally, we will end on one of the great mysteries of infectious diseases: (Fig. 1b) . The most notable difference between the mortality curves of why did children (ages 4–12) fare much better than young adults did 1918 compared with those of 1911–1915 is that the 1918 pandemic was during the 1918 influenza pandemic? particularly deadly for young adults between the ages of 18–30, whereas, quite surprisingly, adults in the 30–60-year-old age group fared better. Virulence of the influenza pandemic strain As expected, the very young (<2 years) and the elderly (>70 years) had a Influenza viruses belong to the orthomyxovirus family and come in three high mortality rate. This pattern of susceptibility resulted in the unique types: A, B and C. Only influenza A and B viruses are important for caus- W mortality curve of the 1918 influenza pandemic. ing disease in humans. These viruses have a negative-sense, segmented There has been much debate about the reasons for this W-shaped RNA genome and can code for up to 11 proteins . By virtue of possessing curve and why the young adults were more susceptible than the >30- a segmented genome, influenza viruses can easily reassort (exchange year-old adults. Because many of these deaths were among young men RNA segments between human and animal viruses), and thereby acquire fighting in World War I, it has been suggested that battle conditions new antigenic properties (antigenic shift). The fact that influenza viruses (stress, fatigue, chemical exposure, etc.) may have weakened the sol- have an error-prone RNA-dependent RNA polymerase explains the fact that mutations occur frequently and that, through selection, new anti- genic variants emerge (antigenic drift). The 1918 virus was responsible Emory Vaccine Center and Department of Microbiology and Immunology, for one of the most devastating pandemics in recorded history, and a Emory University School of Medicine, Atlanta, Georgia 30322, USA. Viral- question of great interest has been why this particular influenza virus Immunobiology Laboratory, Molecular and Integrative Neurosciences strain was so virulent. Department, The Scripps Research Institute, 10550 N. Torrey Pines Road, A major breakthrough toward addressing this question was made La Jolla, California 92037, USA. Departments of Microbiology and Medicine, when available pathology materials from patients who had died dur- Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, New York ing the 1918 pandemic were used to obtain the entire sequence of the 10029, USA. 1918 virus and to subsequently reconstruct the extinct strain in the 4,5 Correspondence should be addressed to R.A. (ra@microbio.emory.edu). laboratory using reverse genetics . The virus turned out to be highly Published online 19 October 2007; doi:10.1038/ni1530 virulent in intranasally inoculated mice, with a lethal dose 50 (LD ) that 1 1 8 8 VOLUME 8 NUMBER 11 NOVEMBER 2007 NATURE IMMUNOLOGY © 2007 Nature Publishing Group http://www.nature.com/natureimmunology R E V I E W an increased influx of neutrophils and alveolar macrophages and an a 2,000 Interpandemic period increase in the production of cytokines and chemokines were observed in lung tissues with a virus expressing only two proteins, hemagglutinin (HA) and neuraminidase (NA), from the 1918 strain . In mice infected 1,500 with a virus expressing all eight genes from the 1918 virus, a marked activation of pro-inflammatory and cell death pathways was observed, which was less pronounced in reassortant viruses that only contained a 1,000 7 subset of genes from the 1918 virus . A question of substantial interest is whether the enhanced production of inflammatory cytokines and asso- ciated pathology that was seen after infection with the 1918 pandemic influenza virus strain is due to some specific interactions of the viral genes of the 1918 virus with the immune system or if this is primarily a reflection of the rapid growth and spread of this virus. The two possibili- ties are not mutually exclusive, and it is conceivable that both contribute to the complex pathogenesis that is seen in vivo. b 2,000 1918 Pandemic Pathogenicity of the pandemic strain was also studied in the cyno- molgus macaque (Macaca fascicularis) model. Macaques infected with the 1918 virus became symptomatic within 24 h of infection and had to 1,500 be euthanized by day 8 as a result of the severity of the symptoms. The animals showed severe respiratory signs, with an increase in respiration rate and a decrease in lung function, as measured by a decrease in blood 1,000 oxygen saturation. Also, interleukin-6 (IL-6), IL-8 and the chemokines CCL2 (monocyte chemotactic protein 1) and CCL5 (RANTES) were elevated in infected animals. Notably, compared with a control non-1918 influenza virus, the 1918 virus demonstrated reduced activation of the RNA helicase sensor proteins RIG-I and MDA-5 in infected macaques. These data suggest that the NS1 protein of the 1918 virus, which is an interferon antagonist, has an important immunomodulatory role. By c effectively downregulating the innate immune response of the host, 2,000 Theoretical the NS1 protein may very well have contributed to the extraordinary virulence of the 1918 virus in humans. Although one can measure the contribution to virulence of individual genes of the 1918 virus (as, for 1,500 example, in the case of the 1918 virus NS1 gene and the 1918 HA and NA genes), it appears that the interplay—or combination of the natural biological functions—of all eight 1918 genes results in a virus with the 1,000 highest virulence. Thus, the 1918 virus is a unique influenza virus strain by virtue of its ‘matching’ genes or because of genes that express viral proteins that affect hundreds of cellular proteins during replication. By the same token, any reassortment of genes in the 1918 virus with RNAs from other influenza viruses has, in most cases, led to a decrease in virulence, highlighting the extraordinary gene constellation of the 4–7 1918 virus . 1–4 5–14 15–24 25–34 35–44 45–54 55–64 65–74 75–84 >85 Age groups Genetic variation in influenza virus and immune memory Prior to addressing the important issue of immunological memory and Figure 1 Deaths per 100,000 in the United States caused by influenza- the 1918 pandemic influenza virus strain, it is essential to first consider pneumonia. (a) A U-shaped mortality curve was observed for different the degree of genetic variation in influenza viruses and the epidemiol- age groups for the interpandemic period of 1911–1915. (b) A W-shaped ogy of the various influenza virus strains that have been in circulation mortality curve was observed for the pandemic year 1918. (c) A V-shaped mortality curve might have been observed in 1918, if the population had among the human population. not been exposed previously (before 1889) to an H1-like influenza virus (the A hallmark of influenza viruses is their ability to undergo genetic specific death rates were taken from ref. 50). shift and drift. Specifically, reassortment can lead to influenza viruses acquiring RNA segments, most likely from avian influenza viruses, that was more than 1,000-fold lower than that of other human (non–mouse can lead to new pandemic (globally epidemic) strains. The pandemic adapted) influenza virus strains. In embryonated eggs, the 1918 virus 1957 strain sported a new HA (subtype 2) and a new NA (subtype 2) and was 10 -fold more virulent than the human control strain, as measured caused worldwide morbidity and mortality. In 1968, a new pandemic by the dose required to kill an 8-d-old embryo, and the 1918 influenza strain had only the HA (subtype 3) exchanged, and in 1977 an H1N1 strain grew to titers that were at least one log unit higher than those of virus appeared that had circulated around 1950 in the human population control influenza viruses in tissue culture of human bronchial epithelial (Fig. 2). In 1977, it was mostly young people born after the end of the H1 cells . Further studies in mice showed excessive immune-cell infiltration period (1957 and later) that came down with the disease when infected in the lung following infection with viruses containing genes from the with this new (recycled) virus. Individuals older than 20–25 years of age 1918 strain and higher lung virus titers than in the controls. Specifically, had ostensibly been exposed to similar H1 strains and were thus partially NATURE IMMUNOLOGY VOLUME 8 NUMBER 11 NOVEMBER 2007 1 1 8 9 © 2007 Nature Publishing Group http://www.nature.com/natureimmunology Specific death rate Specific death rate Specific death rate R E V I E W Table 1 The 1918 influenza pandemic: age distribution, immune status and disease susceptibility of the human population Age distribution Immune status Disease susceptibility 0–2 years old Immunologically naive to the 1918 H1N1 influenza virus strain Very high mortality rate 4–12 years old Immunologically naive to H1N1 Substantially decreased mortality; much lower than the 15–30–year-old group 15–30 years old Immunologically naive to H1N1 High mortality rate 30–60 years old Evidence of immunological memory to the H1N1 influenza pandemic Decreased mortality rate compared with the strain. Most likely due to an H1 influenza virus that was in circulation 15–30-year-old group in 1889 >70 years old Immunity compromised as a result of the effects of aging Increased mortality protected. It is likely that an antigenic shift also occurred in 1918, when the A/Solomon Islands/3/2006 (H1N1) virus isolated in 2006 replaced an H1N1 virus caused the major pandemic of the 20th century (Fig. 2) . the A/New Caledonia/20/1999 (H1N1) virus in the vaccine preparations As for the subtype strain circulating before 1918, only indirect evidence from the previous seasons; the latter virus was first isolated in 1999, and from serologic patient data are available that suggest an H3-like virus thus does not adequately protect against the new antigenic drift variants circulated in humans starting in 1889 (ref. 8). Viruses circulating before circulating in the human population at the present time. 9–12 1889 were postulated to be of the H1 subtype . In each case in 1889, 1918, 1957, 1968 and 1977, a large segment of the population lacked Immunological memory to the 1918 influenza virus protective antibodies against these previously unknown (reassortant) Why were adults in the 30–60-year-old group more resistant to the viruses, and it is thought that this single antigenic shift is the single most 1918 pandemic influenza virus strain than the 18–30-year-old young important factor responsible for the outbreaks of pandemics. adults? Did people older than 30 years in 1918 have some level of pro- However, influenza viruses also undergo antigenic drift and can tective immunity to the influenza virus pandemic strain, and could this change their surface glycoproteins by accumulation of nucleotide muta- immune memory explain the W-shaped 1918 mortality curve? tions in the glycoprotein gene. Such drift variants can re-infect and cause If, as postulated (Fig. 2), an H3 influenza strain was in circulation disease in individuals who were infected just 2–4 years earlier with a from 1889–1918 and H1-type viruses were present before 1889, then virus belonging to the same subtype. Why influenza viruses undergo people born in or after 1889 would have been immunologically naive antigenic drift remains unclear. Measles and mumps viruses are also to the 1918 H1 pandemic strain (that is, at least to the HA of the 1918 negative-sense RNA viruses and their RNA-dependent RNA polymer- H1 strain). In contrast, individuals born before 1889 (>30 year olds in ases are probably as error-prone as that of influenza virus. However, 1918) would have had prior exposure to H1-type influenza viruses. How these viruses stay more or less the same antigenically, as evidenced by would this encounter have resulted in protective immunity 30 years our present day use of measles and mumps vaccine strains that were first later? The viral proteins that are immunologically relevant for protec- 13–15 introduced in humans in the 1960s. Although we have no satisfactory tive antibody responses are HA and, to a much lesser extent, NA , explanation for the molecular basis of the continuing antigenic change both of which are viral surface glycoproteins, and are thus targets for in influenza viruses, we nevertheless recognize this by changing the vac- protective antibodies. cine formulation of the three influenza virus components on an annual Pre-existing antibody is the first level of defense against pathogens, or biannual schedule. Thus, the trivalent influenza virus vaccine for the and if there were individuals in 1918 with circulating HA-specific 2007–2008 season contains A/Wisconsin/67/2005(H3N2), A/Solomon antibody that was reactive against the H1 pandemic strain, then those Islands/3/2006(H1N1) and B/Malaysia/2506/2006) components. As a individuals would have fared better during the pandemic. It is now well- direct demonstration of the consequences of antigenic drift in influenza, established that circulating antibody can be detected in the serum for decades after acute viral infections and even after some subunit protein 16–18 vaccines, such as tetanus and diphtheria . Thus, it is plausible that some of the individuals in the 30–60-year-old group still had some cir- culating antibody against the pandemic strain. Several studies have now shown that one of the major mechanisms for maintaining antibody H3N2 H3? levels in the serum for extended periods of time is the long-lived plasma 16,17,19–21 cell that resides in the bone marrow . Plasma cells are end-stage H2N2 differentiated cells that constitutively produce antibody in the absence H1N1 of antigen. Antigen is, of course, needed for the differentiation of naive H1N1 H1? or memory B cells into antibody-secreting cells, but it is not required for maintaining antibody production by fully differentiated plasma cells. Not all plasma cells are long-lived, but a proportion of these cells can 1889 1900 1918 1940 1960 1980 2000 2020 live for extended periods of time in the bone marrow and constitute the Year major source of long-term antibody production after infection or vac- Figure 2 Influenza A and B viruses circulating in the human population. cination. These long-lived plasma cells are not only the major source of Influenza A viruses with three different hemagglutinin subtypes (H1, H2 antibody in the serum, but can also contribute to antibody in the mucosa and H3) and two different neuraminidase subtypes (N1 and N2) have been by the process of transudation. identified, and the introductions of these (antigenic shift as a result of In addition to plasma cells, memory B cells can also be involved in reassortment) strains were associated with pandemics. All influenza viruses protective immunity by making rapid recall responses and producing also undergo continuing antigenic change (antigenic drift as a result of 17,22 mutation) during interpandemic years. Broken lines indicate that no virus high-affinity antibody . Memory B cells cannot prevent infection, isolates are available from that time period. but can control the spread of virus infection by rapidly differentiating 1 1 9 0 VOLUME 8 NUMBER 11 NOVEMBER 2007 NATURE IMMUNOLOGY © 2007 Nature Publishing Group http://www.nature.com/natureimmunology R E V I E W have been of much benefit during the pandemic. However, in individuals that still had residual humoral immunity against the H1 virus, memory T cells could have acted in concert with the H1-specific plasma cells and memory B cells to confer some degree of protection against the pandemic flu strain. Infectious diseases and the honeymoon period The influenza epidemic reached Alaska by the end of 1918 and took a terrible toll on the local population. Because of the geographic isola- tion of Alaska, it is likely that most of the natives had not been exposed to the 1889 H1 influenza virus and, consequently, a large percentage of the local population was immunologically naive. As a result of this, the Alaskan natives showed almost no resistance to the H1N1 pandemic strain, and there were many instances where villages lost their entire adult population (the W mortality curve was not observed among these isolated populations). Notably, the only survivors were the children in some of these villages. A photograph of the ‘Flu Orphans’ is shown in Figure 3. Why did the children survive and the parents die during this Figure 3 The Flu Orphans. Children in the remote Alaskan village of epidemic? This pattern of susceptibility, so dramatically illustrated Nushagak survived the 1918–1919 influenza pandemic. However, most of among the immunologically naive population of Alaska, was also their parents and grandparents succumbed to the 1918 pandemic virus, seen in other parts of the world. The general trend was that children probably because they had not been exposed to an earlier H1-like influenza between the ages of 4 and 12 showed a substantially decreased mor- virus as a result of their geographic isolation. The photograph was taken in tality rate during the 1918 pandemic (Fig. 1 and Table 1). It should the summer of 1919. Printed with permission from the Alaska State Library, be emphasized that these children were not protected from infection, Core: Nushagak-People-4, Alaskan Packers Association, PCA 01-2432. but, for reasons that are as mysterious today as they were in 1918, into antibody-secreting cells and producing antibody that neutralizes they were able to cope with the disease much better than their adult the virus. A notable feature of the memory B cell response is its longev- counterparts. ity. Several studies have demonstrated that memory B cells induced by This pattern of disease susceptibility, where children fare better than our commonly used childhood vaccines (tetanus, measles, polio, etc.) adults, is not unique to influenza virus and is also seen in other infections. 16–18,22 persist for years in humans . In one of the most striking examples, A classic example is that of tuberculosis, where it is well documented it was shown that memory B cells generated after smallpox vaccina- that children between the ages of 5 and 14 have a lower clinical case rate 23,24 10,29 tion were still detectable 40–50 years after immunization . This is compared with any other segment of the population (Fig. 4) . In particularly noteworthy, as smallpox was eradicated in the 1970s and fact, in the older German literature, this age period (5–14 years of age) is smallpox–specific memory B cells were maintained for >30 years in the absence of re-exposure to the pathogen. In light of these extensive 2.0 studies demonstrating the longevity of human memory B cells, it is very likely that individuals who were exposed to the H1 virus in 1889 or 1.5 earlier would have still have had some memory B cells that were specific for H1 influenza virus in 1918, and it is possible that these memory B 1.0 cells also contributed toward protective immunity against the pandemic flu strain. 0.5 Immune memory and protective immunity against infectious dis- eases consist of three key components: pre-existing antibodies in the blood and at mucosal sites, memory B cells and memory T cells. Both + + CD4 and CD8 memory T cells provide a critical second line of defense 2.0 against pathogens as a result of their higher numbers (compared with their naive counterparts), faster responses (can elaborate effector func- 1.5 tions much faster than naive T cells) and better location (present in both 22,25 lymphoid and nonlymphoid tissues) . Could memory T cells have 1.0 had any role in protection against the 1918 pandemic strain? Infection + + with influenza virus generates a broad range of CD4 and CD8 T cells 0.5 that are reactive against most of the viral proteins , and many of these T cell epitopes are conserved across the various influenza virus strains. Substantial progress has been made in understanding the mechanisms 0–4 5–9 10–14 15–19 20–24 25–34 by which influenza virus–specific T cells control infection in the lung Age groups (years) (reviewed in refs. 13,26). Also, several studies in animal models have shown that memory T cells do contribute to protective immunity against influenza virus, and there are also human clinical data that are con- Figure 4 The honeymoon period of tuberculosis. Age-specific death rates 13,27,28 sistent with this notion . But given the extreme virulence of the from tuberculosis (all forms) in England and Wales for 1913 and 1918. Note pandemic flu strain and the rapid appearance of clinical disease after that the 5–14-year-old group had a lower mortality rate than the other age groups (data from ref. 10). infection with this virus, it is unlikely that memory T cells alone would NATURE IMMUNOLOGY VOLUME 8 NUMBER 11 NOVEMBER 2007 1 1 9 1 © 2007 Nature Publishing Group http://www.nature.com/natureimmunology Age-specific death rates per 1,000 from tuberculosis R E V I E W The outcome of viral infections is greatly influenced by early innate 1,600 1,500 responses: in particular, the production of type 1 interferons that not 1,300 only provide a critical early check on viral growth, but also activate natural killer cells and enhance the development of specific immune 1,100 44,45 responses . It is conceivable that the type 1 interferon response after viral infection is more efficient in children than in adults. From this perspective, it would be interesting to examine Toll-like receptor or MDA-5/RIG-I expression on dendritic cells from children versus adults and to look at the numbers and function of plasmacytoid dendritic 46,47 cells, the major interferon-producing cells . Also, it would be useful to quantitate antigen-specific T and B cell responses and to determine if the quality of these specific responses is different between adults and 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 children. In fact, a recent study analyzing the immune response to the human papilloma virus vaccine has shown that pre-adolescent girls Age at enrollment (years) (9–12 years old) made higher antibody responses than 18–23-year-old 48,49 young women (Fig. 5). Number of subjects evaluable (n) Although the phenomenon of the honeymoon period has been rec- Age 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 68 129 166 141 166 148 109 85 137 440 511 624 576 564 400 ognized for nearly a hundred years, there have been few, if any, studies directly addressing this issue. It is important to try and understand the Figure 5 Antibody responses to the human papillomavirus (HPV) vaccine. underlying mechanisms of this pattern of disease susceptibility. It should Note that 9–12-year-old girls made higher antibody responses than young be possible to address some of the questions directly in human studies, women (18–23 year olds). The data shown in this figure are for HPV type 6 but it will also be necessary to start developing small animal models at 7 months after vaccination. A similar trend in the antibody responses was 48,49 seen for the other three HPV types present in the vaccine . to carry out more mechanistic studies. Also, valuable information and insight will come from studies in nonhuman primates using the same referred to as the ‘favorable school age period’. Similarly, morbidity and pathogens that have shown a difference in their ability to cause disease mortality to several viruses, such as mumps, measles, Varicella-Zoster in children versus adults. The knowledge gained from these studies will virus (chicken pox, VZV), poliomyelitis, Epstein Barr virus (EBV) and provide a better understanding of host-pathogen interactions and better hepatitis E virus (HEV), are much more pronounced if the infection is prepare us for dealing with future epidemics and emerging infections. acquired for the first time as an adult (or during adolescence) than they ACKNOWLEDGMENTS 29,30 are if the infection is acquired as a child . The severe manifestations We thank S. Sarkar for discussions and for his help in preparing the manuscript. of EBV infection (for example, infectious mononucleosis) are rarely, if We also thank D. Lewis for helpful discussions about disease susceptibility in ever, seen in children. Also, chicken pox is a relatively mild disease, but children. We are grateful to E. Barr and M. Esser of Merck Research Laboratories for providing the immunogenicity data on the HPV vaccine. it can be disfiguring and even life threatening if the infection is first acquired as an adult. It is also worth noting that in the 2003 severe acute 1. Johnson, N.P. & Mueller, J. Updating the accounts: global mortality of the 1918–1920 respiratory syndrome (SARS) epidemic, the death rate was much lower “Spanish” influenza pandemic. Bull. Hist. Med. 76, 105–115 (2002). 31,32 in children than in adults . 2. Palese, P. & Shaw, M.L. Orthomyxoviridae: the viruses and their replication. in Fields’ Virology (eds. Fields, B.N., Knipe, D.M. and P.M. 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Rev. 211, 310–319 (2006). rivariant (Type 6, 11, 16, 18) Human Papilloma Virus–like particle vaccine. J. Infect. 34. Oldstone, M.B. The role of cytotoxic T lymphocytes in infectious disease: history, criteria Dis. 196, 1153–1162 (2007). and state of the art. Curr. Top. Microbiol. Immunol. 189, 1–8 (1994) 50. Linder, F.E. & Grove, R.D. Vital statistics rates in the United States: 1900–1940. (US 35. Brooks, D.G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Government Printing Office, Washington, D.C., 1947) < http://www.cdc.gov/nchs/data/ Nat. Med. 12, 1301–1309 (2006). vsus/vsrates1900_40.pdf>. NATURE IMMUNOLOGY VOLUME 8 NUMBER 11 NOVEMBER 2007 1 1 9 3 © 2007 Nature Publishing Group http://www.nature.com/natureimmunology http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Immunology Pubmed Central

Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic

Nature Immunology , Volume 8 (11) – Oct 19, 2007

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Abstract

P AT H O G E N E S I S R E V I E W Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic 1 2 3 Rafi Ahmed , Michael B A Oldstone & Peter Palese The influenza pandemic of 1918 killed nearly 50 million people worldwide and was characterized by an atypical W-shaped mortality curve, where adults between the ages of 30–60 years fared better than younger adults aged 18–30 years. In this review, we will discuss why this influenza virus strain was so virulent and how immunological memory to the 1918 virus may have shaped the W mortality curve. We will end on the topic of the ‘honeymoon’ period of infectious diseases—the clinically documented period between the ages of 4–13 years during which children demonstrate less morbidity and/or mortality to infectious diseases, in general, compared with young adults. The very young and the very old are the most susceptible to infectious diers’ immune systems, thereby increasing their vulnerability to disease. diseases. One of the main reasons for this is that the young are often However, similar mortality rates were seen in young men and women immunologically naive and the old are undergoing immune senes- not involved in the war. Thus, one must consider the possibility that the cence. This pattern of susceptibility is characteristic of most infections >30 year olds may have had some degree of protective immunity against (Fig. 1a). These data show the death rate from influenza virus during the the 1918 influenza virus pandemic strain and that this immunity was years 1911–1915 and illustrate the typical U-shaped curve of mortality lacking in the younger adults (18–30 year olds) (Fig. 1c). In this review, as a function of age. These historical data from 1911–1915 highlight the we will address this issue and consider how immunological memory markedly different mortality curve that was observed during the influ- may have shaped the W mortality curve of the 1918 influenza pandemic. enza pandemic of 1918 that killed over 50 million people worldwide, We will also discuss why this 1918 pandemic flu strain was so virulent. making it one of the deadliest plagues ever experienced by mankind Finally, we will end on one of the great mysteries of infectious diseases: (Fig. 1b) . The most notable difference between the mortality curves of why did children (ages 4–12) fare much better than young adults did 1918 compared with those of 1911–1915 is that the 1918 pandemic was during the 1918 influenza pandemic? particularly deadly for young adults between the ages of 18–30, whereas, quite surprisingly, adults in the 30–60-year-old age group fared better. Virulence of the influenza pandemic strain As expected, the very young (<2 years) and the elderly (>70 years) had a Influenza viruses belong to the orthomyxovirus family and come in three high mortality rate. This pattern of susceptibility resulted in the unique types: A, B and C. Only influenza A and B viruses are important for caus- W mortality curve of the 1918 influenza pandemic. ing disease in humans. These viruses have a negative-sense, segmented There has been much debate about the reasons for this W-shaped RNA genome and can code for up to 11 proteins . By virtue of possessing curve and why the young adults were more susceptible than the >30- a segmented genome, influenza viruses can easily reassort (exchange year-old adults. Because many of these deaths were among young men RNA segments between human and animal viruses), and thereby acquire fighting in World War I, it has been suggested that battle conditions new antigenic properties (antigenic shift). The fact that influenza viruses (stress, fatigue, chemical exposure, etc.) may have weakened the sol- have an error-prone RNA-dependent RNA polymerase explains the fact that mutations occur frequently and that, through selection, new anti- genic variants emerge (antigenic drift). The 1918 virus was responsible Emory Vaccine Center and Department of Microbiology and Immunology, for one of the most devastating pandemics in recorded history, and a Emory University School of Medicine, Atlanta, Georgia 30322, USA. Viral- question of great interest has been why this particular influenza virus Immunobiology Laboratory, Molecular and Integrative Neurosciences strain was so virulent. Department, The Scripps Research Institute, 10550 N. Torrey Pines Road, A major breakthrough toward addressing this question was made La Jolla, California 92037, USA. Departments of Microbiology and Medicine, when available pathology materials from patients who had died dur- Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, New York ing the 1918 pandemic were used to obtain the entire sequence of the 10029, USA. 1918 virus and to subsequently reconstruct the extinct strain in the 4,5 Correspondence should be addressed to R.A. (ra@microbio.emory.edu). laboratory using reverse genetics . The virus turned out to be highly Published online 19 October 2007; doi:10.1038/ni1530 virulent in intranasally inoculated mice, with a lethal dose 50 (LD ) that 1 1 8 8 VOLUME 8 NUMBER 11 NOVEMBER 2007 NATURE IMMUNOLOGY © 2007 Nature Publishing Group http://www.nature.com/natureimmunology R E V I E W an increased influx of neutrophils and alveolar macrophages and an a 2,000 Interpandemic period increase in the production of cytokines and chemokines were observed in lung tissues with a virus expressing only two proteins, hemagglutinin (HA) and neuraminidase (NA), from the 1918 strain . In mice infected 1,500 with a virus expressing all eight genes from the 1918 virus, a marked activation of pro-inflammatory and cell death pathways was observed, which was less pronounced in reassortant viruses that only contained a 1,000 7 subset of genes from the 1918 virus . A question of substantial interest is whether the enhanced production of inflammatory cytokines and asso- ciated pathology that was seen after infection with the 1918 pandemic influenza virus strain is due to some specific interactions of the viral genes of the 1918 virus with the immune system or if this is primarily a reflection of the rapid growth and spread of this virus. The two possibili- ties are not mutually exclusive, and it is conceivable that both contribute to the complex pathogenesis that is seen in vivo. b 2,000 1918 Pandemic Pathogenicity of the pandemic strain was also studied in the cyno- molgus macaque (Macaca fascicularis) model. Macaques infected with the 1918 virus became symptomatic within 24 h of infection and had to 1,500 be euthanized by day 8 as a result of the severity of the symptoms. The animals showed severe respiratory signs, with an increase in respiration rate and a decrease in lung function, as measured by a decrease in blood 1,000 oxygen saturation. Also, interleukin-6 (IL-6), IL-8 and the chemokines CCL2 (monocyte chemotactic protein 1) and CCL5 (RANTES) were elevated in infected animals. Notably, compared with a control non-1918 influenza virus, the 1918 virus demonstrated reduced activation of the RNA helicase sensor proteins RIG-I and MDA-5 in infected macaques. These data suggest that the NS1 protein of the 1918 virus, which is an interferon antagonist, has an important immunomodulatory role. By c effectively downregulating the innate immune response of the host, 2,000 Theoretical the NS1 protein may very well have contributed to the extraordinary virulence of the 1918 virus in humans. Although one can measure the contribution to virulence of individual genes of the 1918 virus (as, for 1,500 example, in the case of the 1918 virus NS1 gene and the 1918 HA and NA genes), it appears that the interplay—or combination of the natural biological functions—of all eight 1918 genes results in a virus with the 1,000 highest virulence. Thus, the 1918 virus is a unique influenza virus strain by virtue of its ‘matching’ genes or because of genes that express viral proteins that affect hundreds of cellular proteins during replication. By the same token, any reassortment of genes in the 1918 virus with RNAs from other influenza viruses has, in most cases, led to a decrease in virulence, highlighting the extraordinary gene constellation of the 4–7 1918 virus . 1–4 5–14 15–24 25–34 35–44 45–54 55–64 65–74 75–84 >85 Age groups Genetic variation in influenza virus and immune memory Prior to addressing the important issue of immunological memory and Figure 1 Deaths per 100,000 in the United States caused by influenza- the 1918 pandemic influenza virus strain, it is essential to first consider pneumonia. (a) A U-shaped mortality curve was observed for different the degree of genetic variation in influenza viruses and the epidemiol- age groups for the interpandemic period of 1911–1915. (b) A W-shaped ogy of the various influenza virus strains that have been in circulation mortality curve was observed for the pandemic year 1918. (c) A V-shaped mortality curve might have been observed in 1918, if the population had among the human population. not been exposed previously (before 1889) to an H1-like influenza virus (the A hallmark of influenza viruses is their ability to undergo genetic specific death rates were taken from ref. 50). shift and drift. Specifically, reassortment can lead to influenza viruses acquiring RNA segments, most likely from avian influenza viruses, that was more than 1,000-fold lower than that of other human (non–mouse can lead to new pandemic (globally epidemic) strains. The pandemic adapted) influenza virus strains. In embryonated eggs, the 1918 virus 1957 strain sported a new HA (subtype 2) and a new NA (subtype 2) and was 10 -fold more virulent than the human control strain, as measured caused worldwide morbidity and mortality. In 1968, a new pandemic by the dose required to kill an 8-d-old embryo, and the 1918 influenza strain had only the HA (subtype 3) exchanged, and in 1977 an H1N1 strain grew to titers that were at least one log unit higher than those of virus appeared that had circulated around 1950 in the human population control influenza viruses in tissue culture of human bronchial epithelial (Fig. 2). In 1977, it was mostly young people born after the end of the H1 cells . Further studies in mice showed excessive immune-cell infiltration period (1957 and later) that came down with the disease when infected in the lung following infection with viruses containing genes from the with this new (recycled) virus. Individuals older than 20–25 years of age 1918 strain and higher lung virus titers than in the controls. Specifically, had ostensibly been exposed to similar H1 strains and were thus partially NATURE IMMUNOLOGY VOLUME 8 NUMBER 11 NOVEMBER 2007 1 1 8 9 © 2007 Nature Publishing Group http://www.nature.com/natureimmunology Specific death rate Specific death rate Specific death rate R E V I E W Table 1 The 1918 influenza pandemic: age distribution, immune status and disease susceptibility of the human population Age distribution Immune status Disease susceptibility 0–2 years old Immunologically naive to the 1918 H1N1 influenza virus strain Very high mortality rate 4–12 years old Immunologically naive to H1N1 Substantially decreased mortality; much lower than the 15–30–year-old group 15–30 years old Immunologically naive to H1N1 High mortality rate 30–60 years old Evidence of immunological memory to the H1N1 influenza pandemic Decreased mortality rate compared with the strain. Most likely due to an H1 influenza virus that was in circulation 15–30-year-old group in 1889 >70 years old Immunity compromised as a result of the effects of aging Increased mortality protected. It is likely that an antigenic shift also occurred in 1918, when the A/Solomon Islands/3/2006 (H1N1) virus isolated in 2006 replaced an H1N1 virus caused the major pandemic of the 20th century (Fig. 2) . the A/New Caledonia/20/1999 (H1N1) virus in the vaccine preparations As for the subtype strain circulating before 1918, only indirect evidence from the previous seasons; the latter virus was first isolated in 1999, and from serologic patient data are available that suggest an H3-like virus thus does not adequately protect against the new antigenic drift variants circulated in humans starting in 1889 (ref. 8). Viruses circulating before circulating in the human population at the present time. 9–12 1889 were postulated to be of the H1 subtype . In each case in 1889, 1918, 1957, 1968 and 1977, a large segment of the population lacked Immunological memory to the 1918 influenza virus protective antibodies against these previously unknown (reassortant) Why were adults in the 30–60-year-old group more resistant to the viruses, and it is thought that this single antigenic shift is the single most 1918 pandemic influenza virus strain than the 18–30-year-old young important factor responsible for the outbreaks of pandemics. adults? Did people older than 30 years in 1918 have some level of pro- However, influenza viruses also undergo antigenic drift and can tective immunity to the influenza virus pandemic strain, and could this change their surface glycoproteins by accumulation of nucleotide muta- immune memory explain the W-shaped 1918 mortality curve? tions in the glycoprotein gene. Such drift variants can re-infect and cause If, as postulated (Fig. 2), an H3 influenza strain was in circulation disease in individuals who were infected just 2–4 years earlier with a from 1889–1918 and H1-type viruses were present before 1889, then virus belonging to the same subtype. Why influenza viruses undergo people born in or after 1889 would have been immunologically naive antigenic drift remains unclear. Measles and mumps viruses are also to the 1918 H1 pandemic strain (that is, at least to the HA of the 1918 negative-sense RNA viruses and their RNA-dependent RNA polymer- H1 strain). In contrast, individuals born before 1889 (>30 year olds in ases are probably as error-prone as that of influenza virus. However, 1918) would have had prior exposure to H1-type influenza viruses. How these viruses stay more or less the same antigenically, as evidenced by would this encounter have resulted in protective immunity 30 years our present day use of measles and mumps vaccine strains that were first later? The viral proteins that are immunologically relevant for protec- 13–15 introduced in humans in the 1960s. Although we have no satisfactory tive antibody responses are HA and, to a much lesser extent, NA , explanation for the molecular basis of the continuing antigenic change both of which are viral surface glycoproteins, and are thus targets for in influenza viruses, we nevertheless recognize this by changing the vac- protective antibodies. cine formulation of the three influenza virus components on an annual Pre-existing antibody is the first level of defense against pathogens, or biannual schedule. Thus, the trivalent influenza virus vaccine for the and if there were individuals in 1918 with circulating HA-specific 2007–2008 season contains A/Wisconsin/67/2005(H3N2), A/Solomon antibody that was reactive against the H1 pandemic strain, then those Islands/3/2006(H1N1) and B/Malaysia/2506/2006) components. As a individuals would have fared better during the pandemic. It is now well- direct demonstration of the consequences of antigenic drift in influenza, established that circulating antibody can be detected in the serum for decades after acute viral infections and even after some subunit protein 16–18 vaccines, such as tetanus and diphtheria . Thus, it is plausible that some of the individuals in the 30–60-year-old group still had some cir- culating antibody against the pandemic strain. Several studies have now shown that one of the major mechanisms for maintaining antibody H3N2 H3? levels in the serum for extended periods of time is the long-lived plasma 16,17,19–21 cell that resides in the bone marrow . Plasma cells are end-stage H2N2 differentiated cells that constitutively produce antibody in the absence H1N1 of antigen. Antigen is, of course, needed for the differentiation of naive H1N1 H1? or memory B cells into antibody-secreting cells, but it is not required for maintaining antibody production by fully differentiated plasma cells. Not all plasma cells are long-lived, but a proportion of these cells can 1889 1900 1918 1940 1960 1980 2000 2020 live for extended periods of time in the bone marrow and constitute the Year major source of long-term antibody production after infection or vac- Figure 2 Influenza A and B viruses circulating in the human population. cination. These long-lived plasma cells are not only the major source of Influenza A viruses with three different hemagglutinin subtypes (H1, H2 antibody in the serum, but can also contribute to antibody in the mucosa and H3) and two different neuraminidase subtypes (N1 and N2) have been by the process of transudation. identified, and the introductions of these (antigenic shift as a result of In addition to plasma cells, memory B cells can also be involved in reassortment) strains were associated with pandemics. All influenza viruses protective immunity by making rapid recall responses and producing also undergo continuing antigenic change (antigenic drift as a result of 17,22 mutation) during interpandemic years. Broken lines indicate that no virus high-affinity antibody . Memory B cells cannot prevent infection, isolates are available from that time period. but can control the spread of virus infection by rapidly differentiating 1 1 9 0 VOLUME 8 NUMBER 11 NOVEMBER 2007 NATURE IMMUNOLOGY © 2007 Nature Publishing Group http://www.nature.com/natureimmunology R E V I E W have been of much benefit during the pandemic. However, in individuals that still had residual humoral immunity against the H1 virus, memory T cells could have acted in concert with the H1-specific plasma cells and memory B cells to confer some degree of protection against the pandemic flu strain. Infectious diseases and the honeymoon period The influenza epidemic reached Alaska by the end of 1918 and took a terrible toll on the local population. Because of the geographic isola- tion of Alaska, it is likely that most of the natives had not been exposed to the 1889 H1 influenza virus and, consequently, a large percentage of the local population was immunologically naive. As a result of this, the Alaskan natives showed almost no resistance to the H1N1 pandemic strain, and there were many instances where villages lost their entire adult population (the W mortality curve was not observed among these isolated populations). Notably, the only survivors were the children in some of these villages. A photograph of the ‘Flu Orphans’ is shown in Figure 3. Why did the children survive and the parents die during this Figure 3 The Flu Orphans. Children in the remote Alaskan village of epidemic? This pattern of susceptibility, so dramatically illustrated Nushagak survived the 1918–1919 influenza pandemic. However, most of among the immunologically naive population of Alaska, was also their parents and grandparents succumbed to the 1918 pandemic virus, seen in other parts of the world. The general trend was that children probably because they had not been exposed to an earlier H1-like influenza between the ages of 4 and 12 showed a substantially decreased mor- virus as a result of their geographic isolation. The photograph was taken in tality rate during the 1918 pandemic (Fig. 1 and Table 1). It should the summer of 1919. Printed with permission from the Alaska State Library, be emphasized that these children were not protected from infection, Core: Nushagak-People-4, Alaskan Packers Association, PCA 01-2432. but, for reasons that are as mysterious today as they were in 1918, into antibody-secreting cells and producing antibody that neutralizes they were able to cope with the disease much better than their adult the virus. A notable feature of the memory B cell response is its longev- counterparts. ity. Several studies have demonstrated that memory B cells induced by This pattern of disease susceptibility, where children fare better than our commonly used childhood vaccines (tetanus, measles, polio, etc.) adults, is not unique to influenza virus and is also seen in other infections. 16–18,22 persist for years in humans . In one of the most striking examples, A classic example is that of tuberculosis, where it is well documented it was shown that memory B cells generated after smallpox vaccina- that children between the ages of 5 and 14 have a lower clinical case rate 23,24 10,29 tion were still detectable 40–50 years after immunization . This is compared with any other segment of the population (Fig. 4) . In particularly noteworthy, as smallpox was eradicated in the 1970s and fact, in the older German literature, this age period (5–14 years of age) is smallpox–specific memory B cells were maintained for >30 years in the absence of re-exposure to the pathogen. In light of these extensive 2.0 studies demonstrating the longevity of human memory B cells, it is very likely that individuals who were exposed to the H1 virus in 1889 or 1.5 earlier would have still have had some memory B cells that were specific for H1 influenza virus in 1918, and it is possible that these memory B 1.0 cells also contributed toward protective immunity against the pandemic flu strain. 0.5 Immune memory and protective immunity against infectious dis- eases consist of three key components: pre-existing antibodies in the blood and at mucosal sites, memory B cells and memory T cells. Both + + CD4 and CD8 memory T cells provide a critical second line of defense 2.0 against pathogens as a result of their higher numbers (compared with their naive counterparts), faster responses (can elaborate effector func- 1.5 tions much faster than naive T cells) and better location (present in both 22,25 lymphoid and nonlymphoid tissues) . Could memory T cells have 1.0 had any role in protection against the 1918 pandemic strain? Infection + + with influenza virus generates a broad range of CD4 and CD8 T cells 0.5 that are reactive against most of the viral proteins , and many of these T cell epitopes are conserved across the various influenza virus strains. Substantial progress has been made in understanding the mechanisms 0–4 5–9 10–14 15–19 20–24 25–34 by which influenza virus–specific T cells control infection in the lung Age groups (years) (reviewed in refs. 13,26). Also, several studies in animal models have shown that memory T cells do contribute to protective immunity against influenza virus, and there are also human clinical data that are con- Figure 4 The honeymoon period of tuberculosis. Age-specific death rates 13,27,28 sistent with this notion . But given the extreme virulence of the from tuberculosis (all forms) in England and Wales for 1913 and 1918. Note pandemic flu strain and the rapid appearance of clinical disease after that the 5–14-year-old group had a lower mortality rate than the other age groups (data from ref. 10). infection with this virus, it is unlikely that memory T cells alone would NATURE IMMUNOLOGY VOLUME 8 NUMBER 11 NOVEMBER 2007 1 1 9 1 © 2007 Nature Publishing Group http://www.nature.com/natureimmunology Age-specific death rates per 1,000 from tuberculosis R E V I E W The outcome of viral infections is greatly influenced by early innate 1,600 1,500 responses: in particular, the production of type 1 interferons that not 1,300 only provide a critical early check on viral growth, but also activate natural killer cells and enhance the development of specific immune 1,100 44,45 responses . It is conceivable that the type 1 interferon response after viral infection is more efficient in children than in adults. From this perspective, it would be interesting to examine Toll-like receptor or MDA-5/RIG-I expression on dendritic cells from children versus adults and to look at the numbers and function of plasmacytoid dendritic 46,47 cells, the major interferon-producing cells . Also, it would be useful to quantitate antigen-specific T and B cell responses and to determine if the quality of these specific responses is different between adults and 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 children. In fact, a recent study analyzing the immune response to the human papilloma virus vaccine has shown that pre-adolescent girls Age at enrollment (years) (9–12 years old) made higher antibody responses than 18–23-year-old 48,49 young women (Fig. 5). Number of subjects evaluable (n) Although the phenomenon of the honeymoon period has been rec- Age 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 68 129 166 141 166 148 109 85 137 440 511 624 576 564 400 ognized for nearly a hundred years, there have been few, if any, studies directly addressing this issue. It is important to try and understand the Figure 5 Antibody responses to the human papillomavirus (HPV) vaccine. underlying mechanisms of this pattern of disease susceptibility. It should Note that 9–12-year-old girls made higher antibody responses than young be possible to address some of the questions directly in human studies, women (18–23 year olds). The data shown in this figure are for HPV type 6 but it will also be necessary to start developing small animal models at 7 months after vaccination. A similar trend in the antibody responses was 48,49 seen for the other three HPV types present in the vaccine . to carry out more mechanistic studies. Also, valuable information and insight will come from studies in nonhuman primates using the same referred to as the ‘favorable school age period’. Similarly, morbidity and pathogens that have shown a difference in their ability to cause disease mortality to several viruses, such as mumps, measles, Varicella-Zoster in children versus adults. The knowledge gained from these studies will virus (chicken pox, VZV), poliomyelitis, Epstein Barr virus (EBV) and provide a better understanding of host-pathogen interactions and better hepatitis E virus (HEV), are much more pronounced if the infection is prepare us for dealing with future epidemics and emerging infections. acquired for the first time as an adult (or during adolescence) than they ACKNOWLEDGMENTS 29,30 are if the infection is acquired as a child . The severe manifestations We thank S. 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Published: Oct 19, 2007

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