Preventing Smallpox, Influenza, and Tuberculosis
Smallpox, influenza, and tuberculosis have each had a marked impact on medicine and society. These three different diseases have one very important aspect in common: the development of technology to prevent them. The development of the smallpox vaccine ushered in a new era in disease prevention (1), but similar success with an influenza vaccine has so far eluded researchers (6). Despite the development of a vaccine, preventing tuberculosis relies on the use of prophylactic antibiotics and reducing exposure (4). While smallpox has been eradicated globally, influenza and tuberculosis continue to kill hundreds of thousands to millions of people each year (7,8).
Smallpox has been around for centuries and spread along with civilization as people began to travel throughout the world. Early prevention strategies relied on variolation, a precursor to vaccination, that required exposure to fluid or scabs containing the virus from the pustules of smallpox patients. While ultimately causing infection, the severity of the illness and mortality rate were reduced in variolated individuals compared to those who acquired smallpox naturally. Building upon this success, Edward Jenner famously observed that milkmaids did not develop smallpox symptoms after variolation if they had previously been infected by cowpox. This observation and subsequent experimentation led to the development of the smallpox vaccine still used today (3).
Published in 1801, Jenner viewed his vaccine as the key to eradicating smallpox globally. The World Health Organization (WHO) launched a global campaign to realize Jenner’s goals that began in 1966. Utilizing the vaccine throughout the world, the WHO finally declared smallpox eradicated on December 9, 1980. Vaccination of the public was discontinued in the United States in 1972. This was the first disease to have ever been eradicated through a global health initiative. However, smallpox still exists as known samples in two laboratories and unknown samples that may be held elsewhere. Its history as a biological weapon has led to vaccination for smallpox to be required for all military personnel who could be exposed and stockpiling of the vaccine for emergency use (1).
In contrast to the successful vaccination campaign against smallpox, influenza (flu) vaccination has faced a number of issues that have yet to be overcome. Each year, scientists and public health officials must work to predicted which strains of the influenza virus will be prevalent for the upcoming flu season before vaccine production begins. Where the smallpox viral genome is relatively stable double-stranded DNA, influenza viruses have a negative-sense single-stranded RNA genome. This leads to mutations from replication errors that changes existing strains (antigenic drift) and the existence of multiple strains provides the opportunity for recombination (antigenic shift). Determining which strains will be spreading in any given flu season is an inexact science with varying success rates (2).
The evolution of influenza strains has also made the creation of a universal vaccine exceedingly difficult. Current flu vaccines utilize inactivated viruses to induce an immune response that targets the specific form of the hemagglutinin (H) protein on the surface of the virus in the strains predicted to be circulating. Since each subtype of influenza can also have different configurations of this protein, the H protein of the most likely strain to be prevalent is targeted. This strategy is effective when the circulating strain matches the strain used for the vaccine, but the frequent mutations of the virus can render the vaccine essentially useless before the flu season even begins. Universal flu vaccine candidates have looked at alternative ways to confer immunity by utilizing subunits of the virus to create an immune response to a wide range of H protein configurations. While there are several candidates for a universal flu vaccine in clinical trials, further investigation is still being conducted into their safety and efficacy (6).
Vaccine efficacy has also been a problem in tuberculosis (TB) prevention. As the leading infectious cause of death throughout the world, preventing the spread of TB is a critical public health concern. Due to problems with the current TB vaccine, prevention efforts rely on reducing exposure to the bacteria through public health campaigns and prophylactic antibiotic therapy for those exposed. In endemic areas, avoiding contact with infected individuals can be difficult and reinfection can occur after prophylactic treatment has been completed. Additionally, the emergence of multiple antibiotic resistance in Mycobacterium tuberculosis can complicate treatment of both latent and active tuberculosis infections (4).
Challenges with prevention and treatment have created a growing need for an effective TB vaccine, especially as tuberculosis continues to be a grave concern for HIV/AIDS patients. In the past century since the Bacille Calmette-Guerin (BCG) vaccine was first used, an alternative has not been successfully developed. The BCG vaccine’s use is currently restricted to vulnerable infants or healthcare workers to prevent TB complications and does not provide immunity to M. tuberculosis. However, recent research conducted in macaque monkeys has produced promising results in the prevention of pulmonary tuberculosis. The BCG vaccine is currently administered under the skin of infants, but researchers administered the vaccine intravenously to the macaques and found an increased immune response as well as reduced incidence of pulmonary TB. This change to the method of administration could provide greater protection to infants and shift TB vaccine development toward more complete protection (5).
Vaccines have been used with varying success in the prevention of respiratory infections that have long plagued society. The development of the smallpox vaccine and its use in the global eradication of the disease is the epitome of vaccine success. However, the varying efficacy of the seasonal flu vaccine and the need for annual administration demonstrates the challenges faced in vaccine science. New technology is enabling the development of universal flu vaccine candidates while research into alternative administration methods show promise for an effective tuberculosis vaccine. While neither may achieve the same success as Jenner dreamed of for smallpox, both provide hope for increased prevention of these respiratory diseases.
References
(1) Bradford, A. (2019 Apr 23). Smallpox: The world’s first eradicated disease. LiveScience. https://www.livescience.com/65304-smallpox.html
(2) Centers for Disease Control and Prevention. (2018 Sep 4). Influenza (flu): Selecting viruses for the seasonal influenza vaccine. https://www.cdc.gov/flu/prevent/vaccine-selection.htm
(3) Centers for Disease Control and Prevention. (2016 Aug 30). Smallpox: History of smallpox. https://www.cdc.gov/smallpox/history/history.html
(4) Centers for Disease Control and Prevention. (2016 Mar 15). Tuberculosis (TB): TB prevention. https://www.cdc.gov/tb/topic/basics/tbprevention.htm
(5) Darrah, P. A., Zeppa, J.J., Maiello, P., Hackney, J.A., Wadsworth II, M.H., Hughes, T.K., Pokkali, S., Swanson II, P.A, Grant, N.L., Rodgers, M.A., Kamath, M., Causgrove, C.M., Laddy, D.J., Bonavia, A., Casimiro, D., Lin, P.L., Klein, E., White, A.G., Scanga, C.A., Shalek, A.K., Roederer, M., Flynn, J.L., Seder, R.A. (2020). Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature, 577, 95-102. https://doi.org/10.1038/s41586-019-1817-8
(6) National Institute of Allergy and Infectious Diseases. (2019 Sept 5). Universal influenza vaccine research. National Institutes of Health. https://www.niaid.nih.gov/diseases-conditions/universal-influenza-vaccine-research
(7) Paget, J., Spreeuwenberg, P., Charu, V., Taylor, R.J., Iuliano, A.D., Bresee, J., Simonsen, L., Viboud, C. (2019). Global mortality associated with seasonal influenza epidemics: New burden estimates and predictors from the GLaMOR Project. Journal of Global Health, 9(2), 020421. https://doi.org/10.7189/jogh.09.020421
(8) World Health Organization. (2020 Mar 24). Tuberculosis. https://www.who.int/news-room/fact-sheets/detail/tuberculosis
