Live-attenuated vaccines are very effective vaccines used in the prevention of a variety of diseases including influenza, chickenpox, measles, polio and TB.

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What are live-attenuated vaccines?

Live-attenuated vaccines differ from traditional inactivated vaccines where the pathogen is “killed”, and as the name suggests the pathogen (typically a virus) remains active in live vaccines, however, is attenuated or modified in a way that the pathogen is not able to cause disease itself but can produce a robust immune response. Typically, live vaccines lead to a stronger, more prolonged and robust immune response in comparison to inactivated vaccines.

Live-attenuated vaccines can be produced by reverse genetics including RNAi. Briefly, reverse genetic tools are used to create live-attenuated vaccines. Genes from current (novel) viruses are combined with previously altered (attenuated) viruses belonging to the same generic strain.

However, due to these live viruses being attenuated, they are unable to replicate to the same extent as live unattenuated viruses. This means that they are no longer able to sufficiently infect the host, but can do so enough for the host to develop broad and robust immunity.

The immunological mechanism of live-attenuated vaccines usually involves a broad immune response including the involvement of CD4+ & CD8+ T lymphocytes (T-cells) as well as antibodies against the pathogen (produced by B-cells). Live-attenuated vaccines usually result in long-term (potentially life-long) protection without requiring additional doses in adulthood.

Advantages of live-attenuated vaccines over some other forms of vaccines (such as inactivated) include the production of a robust, strong antibody and cell-mediated immune response, long-lasting immunity, with a relatively quick onset of action. Disadvantages may include production, maintenance & transport considerations due to the use of live pathogens and the fact that because they are live pathogens it could lead to issues in immunocompromised individuals (see considerations below).

Examples of live-attenuated vaccines

The most common live-attenuated vaccines include:

• Live-attenuated Influenza (flu) vaccines (LAIV)
• Measles, Mumps & Rubella (MMR)
• Polio – nearing global eradication due to mass vaccination
• Smallpox – officially eradicated due to mass vaccination
• Chickenpox
• Yellow Fever
• Japanese encephalitis
• Shingles
• Rotavirus

Whilst the majority of these vaccines are for viruses, some do exist for specific bacterial infections. These include cholera, TB and oral typhoid vaccines. Two of the most common live-attenuated vaccines are discussed below: influenza & MMR vaccines.

Live-attenuated influenza vaccines (LAIV)

Influenza causes worldwide seasonal epidemics each year (see influenza). To combat influenza, a variety of different vaccines are available to use including inactivated vaccines and live-attenuated. The LAIV can provide up to 90% protection in adults under 65 years of age, and up to 40% of adults over 65 (though inactivated vaccines are preferred for older individuals). LAIVs are usually administered via the nose – mimicking the natural infection route of the influenza virus.

The influenza A virus has 8 RNA segments. In the live attenuated vaccine, a combination of 6 attenuated segments combined with 2 normal (WT) segments – engineered into plasmids – creating a 6:2 reassortment LAIV. LAIVs are typically produced in 10–11-day old chicken embryonated eggs using a WHO-approved virus variant and a master donor virus (MDV).

The 6:2 reassorted virus is passaged in the presence of neutralizing antibodies against the MDV at low temperatures so that it becomes cold-adapted & temperature-sensitive. This means it no longer replicates in the lower-respiratory tract, which is warmer and where influenza causes disease. Instead, it allows it to replicate in the slightly colder upper respiratory tract to elicit an immune response without causing the disease.

Mumps, measles & rubella (MMR) vaccine

The MMR vaccine offers a high level of protection (over 90% effective overall) against mumps, measles and rubella and is usually given as part of a 2-dose regimen in toddlers. Due to the MMR vaccine, the levels of mumps, measles and rubella infections and fatalities are incredibly low, though cases have increased in unvaccinated populations.

The MMR vaccine usually contains an attenuated rubella virus grown in human cell strains, whereas the attenuated measles and mumps viruses are grown using chicken embryo cells (not chicken embryonated eggs). The MMR vaccine may also incorporate attenuated varicella virus; chickenpox, in the MMRV vaccine. Whilst these vaccines are incredibly safe, they do come with some side effects, and the MMRV vaccine has a higher rate of side effects compared to the MMR vaccine.

One of the biggest and potentially most damaging aspects of the MMR vaccine was the false & fraudulent claim by Andrew Wakefield; a disgraced former doctor, that the MMR vaccine leads to autism. This fuelled anti-vaccine sentiment, conspiracy theories and inevitably led to a rise in cases of mumps, measles and rubella in unvaccinated groups who believed the claims.

There is absolutely no credible scientific evidence to back up Wakefield’s claims, and all legitimate scientific studies are to the contrary. This highlights the damage baseless misinformation can create where the MMR vaccine is an incredibly safe and effective vaccine and has saved (and continues to save) millions of lives worldwide.

Considerations of live-attenuated vaccines

Whilst live-attenuated vaccines lead to strong, robust and long-term immunity to viruses (and some bacteria) in most healthy individuals, there may be cases where such vaccines may not be appropriate. Specifically, individuals with compromised immune systems – either due to chemotherapy, HIV infection, or primary disorders of immunodeficiency should not be given live-attenuated vaccines.

Compared to inactivated vaccines, live-attenuated vaccines also need to be carefully prepared, stored, transported and administered. These normally need to be kept uninterruptedly at cold temperatures, and this may present a challenge to more remote areas of the world or where such facilities do not exist.

In summary, live-attenuated vaccines are highly effective and safe vaccines used in the prevention of a variety of viral diseases (including influenza, measles, mumps, rubella & chickenpox) as well as some bacterial diseases (such as cholera and TB). In these vaccines, the pathogen remains viable, but altered in a way that it can cause an immune response, but not lead to infection. Generally, these vaccines produce more robust and broader immune responses compared to inactivated (killed pathogen) vaccines.

References

• Minor, 2015. Live attenuated vaccines: Historical successes and current challenges. Virology. 479-480:379-92. https://pubmed.ncbi.nlm.nih.gov/25864107/
• Blanco-Lobo, 2019. Novel Approaches for The Development of Live Attenuated Influenza Vaccines. Viruses. 11(2):190. https://pubmed.ncbi.nlm.nih.gov/30813325/
• La Torre et al, 2017. The effectiveness of measles-mumps-rubella (MMR) vaccination in the prevention of pediatric hospitalizations for targeted and untargeted infections: A retrospective cohort study. Hum Vaccin Immunother. 13(8):1879-1883. https://pubmed.ncbi.nlm.nih.gov/28604255/

Further Reading

• All Vaccine Content
• What are Vaccines?
• Vaccine History
• Vaccine Schedule
• Vaccine Effectiveness

Written by

Dr. Osman Shabir

Osman is a Postdoctoral Research Associate at the University of Sheffield studying the impact of cardiovascular disease (atherosclerosis) on neurovascular function in vascular dementia and Alzheimer's disease using pre-clinical models and neuroimaging techniques. He is based in the Department of Infection, Immunity & Cardiovascular Disease in the Faculty of Medicine at Sheffield.