What is Live Attenuated Vaccines?

Live attenuated vaccines are created by weakening infectious organisms that can still replicate and induce protective immune responses without causing disease in the host. Vaccination with the live but attenuated organism generates an immune response that protects the vaccinated person against severe disease or even infection.

Overview

Live attenuated vaccines use live organisms that have been weakened so that they are avirulent, meaning they are unable to cause disease. Attenuation can be achieved in several ways:

  • Naturally occurring related organisms that are avirulent in humans, including host range restricted organisms or naturally occurring avirulent strains
  • Multiple rounds of growth of virulent organisms under conditions that weaken the organism such as in tissue culture or harsh physical conditions
  • Genetic manipulation of the organism to reduce virulence

Live attenuated vaccines represent one of the first successful methods of vaccination. In the 18th century, the British doctor Edward Jenner used cowpox virus to vaccinate children against the devastating disease smallpox. This vaccination strategy was based on the observation that milkmaids, who were often exposed to cowpox in their work, rarely got smallpox. Eventually cowpox was replaced by the related vaccinia virus. The vaccinia and cowpox viruses are highly related to the smallpox virus but cause minimal or mild disease in humans with a high degree of cross protection against smallpox. Using the vaccinia virus-based vaccine, smallpox was successfully eradicated in the late 1970s.

Existing Products

There are numerous live attenuated vaccines currently in use. Examples of successful live attenuated vaccines are listed here.

Vaccine Description Impact
Measles Attenuation for the measles vaccine is achieved by culture of virulent virus in duck and human cells. The measles vaccine was FDA approved in 1968. In the U.S., measles vaccination reduced the incidence of measles by 99% and is estimated to have prevented 52 million infections and 5,200 deaths in the first 20 years of use.
Polio (Sabin vaccine) Attenuation of virulent polio virus by culture in monkey cells was used by Sabin to develop the first oral polio vaccine. The vaccine was first approved by the FDA in 1961 and the preferred tri-valent oral vaccine was approved in 1963. The Sabin vaccine represented a significant advance over the Salk inactivated vaccine for polio as it was extremely stable and could be administered orally. This improved uptake of the vaccine in resource poor settings. The use of both the Salk inactivated and Sabin live attenuated polio vaccines has decreased the worldwide incidence of polio from 350,000 cases in 1988 to 1,652 cases in 2007. Because of these highly effective vaccines, polio is poised for eradication.
Rotavirus Current rotavirus vaccines include a bovine virus expressing proteins from human rotavirus and a human virus attenuated by cell culture. These vaccines were FDA approved in 2006. Rotavirus vaccine is not yet widely available in the developing world where it could have significant health impact. Further roll out and studies of the impact of the current vaccines are needed.
Smallpox Smallpox vaccination uses the related vaccinia virus and was first used by Edward Jenner experimentally in 1796. Aggressive vaccination campaigns led to the eradication of smallpox in the late 1970s.
Tuberculosis The only tuberculosis vaccine uses attenuation of the related organism Mycobacterium bovis by culture in bile containing media to create the Bacillus Calmette-Guerin (BCG) vaccination strain. It was first used experimentally in 1921 by Albert Calmette and Camille Guerin and is currently in widespread use outside of the United States. BCG vaccine protects newborns against tuberculosis-related meningitis and other systemic tuberculosis infections, but it has limited protection against active pulmonary disease.
Varicella zoster (chicken pox) The chicken pox vaccine uses the human Oka isolate of the virus attenuated by passage in human cells. It was FDA approved in 1995. As the chicken pox vaccine is still relatively new and expensive its cost benefit has not been fully assessed. It is not yet recommended for use in developing countries.
Yellow fever The yellow fever vaccine was produced by attenuation of yellow fever virus by passage in duck embryos. The vaccine was first described by Max Theiler in the 1930s. Mass vaccination campaigns conducted between 1933 and 1961 result in a near disappearance of yellow fever disease. Reemergence of the disease started in the 1990s most likely due to waning immunity in previously vaccinated persons and a reduced focus on new vaccination campaigns.

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Pipline

Analysis

Live attenuated vaccines benefit from a long history of use for a variety of infectious diseases. The overall strengths and weaknesses for live attenuated vaccines for viral, bacterial, and parasitic protozoan neglected tropical diseases are summarized here.

Strengths Weaknesses
Long history of successful use for a variety of infectious diseases Difficult to achieve balance between immunogenicity and attenuation of virulence
Clear regulatory pathway Live organisms often require cold chain (including current rotavirus vaccines) which is challenging in resource poor settings
Mimics natural infection and presents antigens in native conformation to biologically relevant immunologic compartment  Live organisms have risks of causing symptoms or reverting to virulent form

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Tools for the development of live attenuated vaccines vary widely based on the nature of the infectious organism. See tools tables regarding the availability of culture systems and techniques for genetic manipulation in the individual disease profiles. Attenuation based on stressing organism during serial passage can be achieved by a variety of mechanism including physical, host-range, temperature, chemical, and radiation modalities.

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To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.