In 1918 a new strain of influenza spread around the world, infecting millions. Medical personnel were stretched to their limit as they tried to prevent people from falling victim to this deadly virus. When the dust settled, over 20 million people had died in what became known as the Spanish influenza pandemic.  At the time, vaccinations for Smallpox, Rabies and even the Plague were available but a “flu shot” was still several years away.  If an influenza vaccination program had existed, could have it prevented the Spanish influenza pandemic? In order to answer this question properly we have to understand the function of a vaccine and what constitutes an effective vaccination program.
The immune system is made up of a complex arrangement of specialized cells and proteins whose role is to neutralize organisms that are perceived as foreign entities. The immune system has some basic protective functions that allow it to recognize threatening organisms and to effectively eliminate them from the body. The problem is that many infectious organisms are quite stealthy and can cause us to become ill before our bodies have the opportunity to fight them off. It takes time for our immune system to respond to these organisms and to produce protective proteins called antibodies. An antibody binds to a specific feature on the surface of the organism and acts like a name tag by which the immune system identifies the organism so that it can be destroyed. It is important to note that antibodies are specific to an organism and if appropriate antibodies are not present, the infectious organism overwhelms the immune system and makes the body sick. Fortunately the immune system can ‘learn’ from previous exposures to a threat and be prepared to fight any subsequent infections from the same organism.  An excellent example of the immune system’s ability to ‘learn’ is its response to the Chickenpox virus. The first time someone is exposed to Chickenpox, his/her immune system lacks the defenses against that particular organism; therefore the virus has the opportunity to infect the body before it is destroyed. From that very first exposure, however, the body creates antibodies specific to the virus. Therefore, successive exposures are recognized immediately and the organism is destroyed before it can mount a significant immune response. We take advantage of this adaptive nature of the immune system to protect ourselves against certain organisms using vaccines.
A vaccination is a way of introducing one’s immune system to an infectious agent without causing illness, and possible death, to that individual. The vaccine primes the immune system to produce antibodies to a specific infectious agent, so that the body immediately recognizes and destroys it during the next exposure to that organism.  Influenza vaccinations are available in two forms. The form that is considered by most to be the safest and is recommended for people of all ages is the inactivated (killed) form. Vaccines prepared using this method contain viral particles that are killed chemically and then processed so that only the features that are necessary for antibody recognition are injected into the body. Occasionally an additive is used to stimulate a slightly more aggressive response by the immune system, resulting in enhanced immunity.[4-8] The second form that is available, though not in Canada, is called the live attenuated influenza vaccine (LAIV). [9, 10] This method involves culturing the virus in conditions that weakens it to the point where it cannot replicate efficiently outside of the culture medium. The culture is virulent enough to produce an immune response but weak enough that symptoms of infection do not appear.  This particular influenza vaccine is administered as a nasal mist and is almost always accompanied by an additive to enhance the immune response. LAIV is considered to be a more risky option due to the fact that it is a live virus; it is therefore not recommended for children under the age of 5 or for people with compromised immune systems. 
Some vaccinations convey lifelong immunity but influenza vaccinations tend to lose their efficacy in approximately a year, one reason why you have to get vaccinated yearly. [9, 11] Annual vaccinations for influenza are also required due to the many subtypes of influenza that exist. Viruses are extremely adaptive and mutate quite frequently; new isolates are identified each year. To make matters even more complicated, more than one influenza subtype can be present during the flu season which is why the vaccines are usually made up of three influenza subtypes. [4-7, 11] The immune system produces antibodies that recognize several features of influenza. The two features of influenza that contribute the most to an immune response are proteins on the surface of the virus called hemagglutinin (HA) and neuraminidase (NA). [11, 12] Several variations of HA and NA have been identified; the subtype of an influenza isolate is determined primarily on the variations of HA and NA present. The numerous combinations of the two surface proteins make selecting the correct subtype for a vaccine quite difficult. The World Health Organization (WHO) along with local officials (the Public Health Canada and the Center for Communicable Diseases in the United States, for example) analyze the subtypes that were most prevalent the previous season and make an educated guess as to which subtypes should be included in the new vaccine.[4-6, 13]
The vaccination programs currently in effect rely heavily on including the correct subtypes in the vaccine. In the last 15 years the WHO has been correct approximately 80% of time in predicting the correct subtypes for North America. In the 2003-2004 flu season, the vaccine was quite ineffective due to the appearance of a new subtype of influenza early in the season which rendered the vaccine ineffective. The vaccine for the 2004-2005 season was only marginally effective due to the appearance of a new isolate which was similar to the one included in the vaccine but was not identical; therefore, the vaccine did not provide much protection. [4-6, 13] It is critical that subtype selection be done early enough to give time for the development and production of the vaccine. New techniques using reverse genetics are being developed that allow for a shorter development time and a longer lasting vaccine. Thus, in the future, the development process may be reduced sufficiently to allow for a more accurate tailoring of the vaccine for the upcoming season.[12, 14, 15] Research is also being done on the safety of LAIV vaccines as they tend to provide better protection; at least one study has determined that the vaccine is safe for healthy children under the age of 5. [9, 10]
An effective vaccination program must take into account when the vaccination is available and who receives the vaccination. It takes two weeks for a vaccination to be fully effective once it has been administered; therefore a vaccination has to be available well before the flu season actually starts to allow time for people to receive their vaccinations and for them to take full effect. If the vaccine is in short supply, as it was in the United States during the 2004-2005 season, the collective coverage of the population is decreased significantly. For the program to work, it is essential that people at high risk for contracting influenza be vaccinated to prevent the spread of the virus. While it is recommended that everyone receive a vaccination, the high risk categories include children under 5, the elderly, anyone with an impaired immune system, public health workers, and essential service personnel. It is important to vaccinate the first three groups because they are the most likely to become ill from the virus; the lack of previous exposure in young children causes a greater threat as does the decreased natural immunity typically seen in the elderly. The remaining two groups are important because they are likely to be in contact both with the virus, as well as with those individuals more at risk of becoming ill. Vaccination reduces the likelihood of them contracting the virus and spreading it further.[4-7, 13, 16]
Some questions regarding the wisdom of vaccinating the entire public have come up recently. Viruses mutate and adapt quickly and it has been suggested that immunizing the masses to one type of influenza leaves the door open for another strain to fill the niche. It is possible that a vaccination program is unwittingly selecting for new and possibly more virulent subtypes of the virus. That is why programs are in place to monitor influenza outbreaks for potential mutations and to report to public health officials any strains that show abnormal and highly contagious symptoms. If detected in time it may be possible to act quickly to contain the outbreak to a very small population. Antiviral drugs are also available to help contain an outbreak of influenza but care must be exercised in the selection and use of these drugs to prevent the virus from developing resistance. [4-6] In addition, work is being done to explore the possibility of using a different feature of the virus for antibody identification; this feature is highly conserved among influenza types and therefore less prone to the variability that is present in the HA and NA proteins. The conservation of this feature across influenza subtypes raises the prospect of a universal influenza vaccination.
Outbreaks of avian influenza and SARS in human populations suggest that the monitoring of viral agents should be expanded to include animal viruses as well. SARS is thought to have originated as an animal virus that somehow gained the ability to infect humans. [17, 18] There was little to no natural protection against this new virus because it had never been seen before and therefore no one had the opportunity to develop any immunity. Fortunately the virus was not life threatening to most healthy people. The symptoms of avian influenza, however, are quite severe. It has lead to death and, with many documented cases of transmission to humans, the WHO is keeping a very close eye for possible mutations. So far, human cases of avian influenza have been linked to exposure to infected birds; human to human transmission is not common. [3-5] By monitoring outbreaks of avian influenza we hope to rapidly identify any mutations that could lead to a pandemic.
Pandemics are usually the result of a rapid mutation of a virus, one that is new and unique enough to bypass what is sometimes referred to as herd immunity. Herd immunity is the idea that there will be a large percentage of individuals immune to a given organism and therefore spread of the disease is impeded. The individuals that are at the highest risk in this model are the sick, the elderly and the youngest; from a purely biological perspective these are the same individuals that would fall victim to natural predators in the wild. The number of people in their twenties to forties who died during the Spanish influenza pandemic took the world by surprise because it was unusual for an organism to infect a typically healthy age group so readily. If a virus mutates faster than the collective immunity of the population, the chance of another pandemic rises significantly. Of course we have a variety of antiviral agents that were not available back in 1918 that may help reduce the number of casualties, but that in itself may not stop a pandemic.
The WHO recognizes at least two pandemics that have occurred since 1918, one in 1955 and another in 1968. This was despite the development of influenza vaccines in 1945. The influenza virus will continue to mutate as long as a selection pressure exists, be it through drug, vaccine or some other mechanism. We have developed new techniques to monitor the virus, to reduce the development time required to make a vaccine and to create more robust vaccines, yet we are still looking over our shoulder for the next pandemic. We may not be able to stop an outbreak of a new influenza strain but if we stay alert we may be able to contain and treat it within a small community.
1. Canada, L.a.A. Spanish Influenza Epidemic — Fall 1918. Tragedy on the Home Front [cited 2005-09-28];
2. Timeline of vaccines. [cited 2005-09-28].
3. Roitt, I., Brostoff,J., Male,D., Immunology. 1985, Toronto: The C.V. Mosby Company.
4. Canada Communicable Disease Report, H. Canada, Editor. 2004. p. 1-32.
5. Canada Communicable Disease Report, H. Canada, Editor. 2004. p. 1-6.
6. Canada Communicable Disease Report, H. Canada, Editor. 2005. p. 1-32.
7. Canada, P.H.A.o. Vaccine Preventable Diseases – Influenza. 2002 2002-10-23 [cited 2005-09-28].
8. Canada, P.H.A.o. Pandemic Influenza. 2005 2005-04-26 [cited 2005-09-28].
9. Harper, S.A., Fukuda, Keiji., Cox, Nacy J., Bridges Carolyn B., Using Live, Attenuated Influenza Vaccine for Prevention and Control of Influenza, C.f.D. Control, Editor. 2003. p. 1-8.
10. Piedra, P.A., et al., Live Attenuated Influenza Vaccine, Trivalent, Is Safe in Healthy Children 18 Months to 4 Years, 5 to 9 Years, and 10 to 18 Years of Age in a Community-Based, Nonrandomized, Open-Label Trial. Pediatrics, 2005. 116(3): p. e397-407.
11. Diseases, C.f.C. [cited 2005-09-28].
12. De Filette, M., et al., The universal influenza vaccine M2e-HBc administered intranasally in combination with the adjuvant CTA1-DD provides complete protection. Vaccine. In Press, Corrected Proof.
13. Weely epidemiological record, in Weekly epidemiological record. 2005, World Health Organization. p. 71-76.
14. Hoffmann, E., et al., Role of specific hemagglutinin amino acids in the immunogenicity and protection of H5N1 influenza virus vaccines. PNAS, 2005. 102(36): p. 12915-12920.
15. Lee, C.-W., D.A. Senne, and D.L. Suarez, Generation of reassortant influenza vaccines by reverse genetics that allows utilization of a DIVA (Differentiating Infected from Vaccinated Animals) strategy for the control of avian influenza. Vaccine, 2004. 22(23-24): p. 3175-3181.
16. Helms, C.M., et al., Strengthening the Nation’s Influenza Vaccination System: A National Vaccine Advisory Committee Assessment. American Journal of Preventive Medicine, 2005. 29(3): p. 221-226.
17. Lee PJ, K.L., When animal viruses attack: SARS and avian influenza. Pediatr Ann., 2005. 34(1): p. 42-52.
18. LJ., S., Animal coronavirus vaccines: lessons for SARS. Dev Biol (Basel). , 2004(119): p. 129-40.
19. Billings, M. The Influenza Pandemic of 1918 1997 February, 2005 [cited 2005-09-28].