User:Tlevit/Attenuated vaccines

An attenuated vaccine (or a live attenuated vaccine) is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or "live"). Attenuation takes an infectious agent and alters it so that it becomes harmless or less virulent. These vaccines contrast to those produced by "killing" the virus (inactivated vaccine).

Attenuated vaccines stimulate a strong and effective immune response that is long-lasting. In comparison to inactivated vaccines, attenuated vaccines produce a strong immune response and have a quick immunity onset. However, they may not be safe for use in immunocompromised and pregnant individuals. Common examples of live attenuated vaccines are measles, mumps, rubella, yellow fever, and influenza vaccines.

Mechanism section: These vaccines function by encouraging the body to create antibodies and memory immune cells in response to the specific pathogen which the vaccine protects against.

Talk Page Introduction
Hello everyone, we are focusing on this article as a WikiEducation project. We are planning to increase the quality of this article by improving the lead section, adding missing references, updating older information/sources, as well as re-arranging and possibly adding new sections (e.g., History, Vaccine Safety). The sections we are planning to improve are “development” and “administration”, and we also plan to combine the “advantages” and disadvantages” sections into one. Does anyone have any questions, concerns, or ideas they would like to bring up? We would appreciate any help and feedback, and are excited to work with all of you on improving this article! ~

History
Potential sources:

https://link-springer-com.libaccess.lib.mcmaster.ca/chapter/10.1007/978-3-662-45024-6_1#Sec73

https://www-sciencedirect-com.libaccess.lib.mcmaster.ca/science/article/pii/S0042682215001725

The history of vaccine development started with the creation of the smallpox vaccine by Edward Jenner in the late 18th century. Jenner discovered that inoculating a human with an animal pox virus would grant immunity against smallpox, a disease considered to be one of the most devastating in human history. Although the original smallpox vaccine is sometimes considered to be an attenuated vaccine due to it's live nature, it was not strictly-speaking attenuated since it was not derived directly from smallpox. Instead, it was based on the related and milder cowpox disease. The discovery that diseases could be artificially attenuated came in the late 19th century when Louis Pasteur was able to derive an attenuated strain of chicken cholera. Pasteur applied this knowledge to develop an attenuated anthrax vaccine and demonstrating it's effectiveness in a public experiment. The first rabies vaccine was subsequently produced by Pasteur and Emile Roux by growing the virus in rabbits and drying the affected nervous tissue. The technique of cultivating a virus repeatedly in artificial media and isolating less virulent strains was pioneered in the early 20th century by Albert Calmette and Camille Guérin who developed an attenuated tuberculosis vaccine called the BCG vaccine. This technique was later used by several teams when developing the vaccine for yellow fever, first by Sellards and Laigret, and then by Theiler and Smith. The vaccine developed by Theiler and Smith proved to be hugely successful and helped establish recommended practices and regulations for many other vaccines. These include the growth of viruses in primary tissue culture (e.g., chick embryos), as opposed to animals, and the use of the seed stock system which uses the original attenuated viruses as opposed to derived viruses (done to reduce variance in vaccine development and decrease the chance of adverse effects). The middle of the 20th century saw the work of many prominent virologists including Sabin, Hilleman, and Enders, and the introduction of several successful attenuated vaccines, such as those against polio, measles, mumps, and rubella.

Development
Viruses may be attenuated via passage of the virus through a foreign host, such as:


 * Tissue culture
 * Embryonated eggs
 * Live animals

The initial virus population is applied to a foreign host. Through natural genetic variability or induced mutation, a small percent of the viral particles should have the capacity to infect the new host. These strains will continue to evolve within the new host and the virus will gradually lose its efficacy in the original due to lack of selection pressure. This process is known as "passage" in which the virus becomes so well adapted to the foreign host that it is no longer harmful to the vaccinated subject. This makes it easier for the host's immune system to eliminate the agent and create the immunological memory cells which will likely protect the patient if they are infected with a similar version of the virus in "the wild".

Administration
Paragraph moved from previous administration:

Live attenuated vaccines are administered via a viral transport media containing the relevant viral particles. The media may be given orally, injected via a hypodermic needle or by inhalation with the method often dependent upon the source phage's virulence factors.

Attenuated vaccines can be administered in a variety of ways:


 * Injections:
 * Subcutaneous (e.g. measles, mumps and rubella vaccine, varicella vaccine, yellow fever vaccine)
 * Intradermal (e.g. tuberculosis vaccine, smallpox vaccine)
 * Mucosal:
 * Nasal (e.g. Live Attenuated Influenza Vaccine)
 * Oral (e.g. oral polio vaccine, recombinant live attenuated cholera vaccine, oral typhoid vaccine, oral rotavirus vaccine)

There is also a transcutaneous vaccine which is administered via a patch being developed for a live attenuated measles vaccine currently in development. (should this be included?)

question: should we only link a page once in the article or every time we mention it? (e.g. I link MMR vaccine here and it's also linked in the examples)

Administration
Original:

Live attenuated vaccines are administered via a viral transport media containing the relevant viral particles. The media may be given orally, injected via a hypodermic needle or by inhalation with the method often dependent upon the source phage's virulence factors.

A vaccine works by encouraging the creation of memory B and T cells specific for an antigen associated with the pathogen in question. Accordingly, a vaccine is only effective for as long as the body maintains a population of these cells. Non-Attenuated Vaccines typically require boosters to resubmit the antigen to these memory leukocytes, in a sense, this alerts the body that the pathogen is still a threat and that the population of specific memory leukocytes should be maintained rather than allowing them to die-off. This is much less of a concern for attenuated vaccines because the virus will reproduce, albeit at a severely reduced rate, resulting in constant antigen presence.

Updated:

Live attenuated vaccines are administered via a viral transport media containing the relevant viral particles. The media may be given orally, injected via a hypodermic needle or by inhalation with the method often dependent upon the source phage's virulence factors.

Vaccines function by encouraging the creation of cells, such as CD8+ and CD4+ T lymphocytes, or molecules, such as antibodies, that are specific to the pathogen. The cells and molecules function in various ways to either prevent or reduce infection, such as by killing infected cells or producing interleukins. The specific effectors that are evoked differ based on the vaccine. In particular, live attenuated vaccines tend to induce the production of CD8+ cytotoxic T lymphocytes and T-dependent antibody responses. Accordingly, a vaccine is only effective for as long as the body maintains a population of these cells. Live attenuated vaccines are unique in their ability to induce long-term, possibly lifelong, immunity without requiring re-exposure to the pathogen through multiple vaccine doses. Live attenuated vaccines are also unique in their ability to induce cellular immune responses, which do not rely solely on antibodies but also involve immune cells such as cytotoxic T cells or macrophages.

Suggestion for a sentence to add in mechanisms (need to paraphrase, from WHO Vaccine Safety module): Attenuated vaccines "provide continual antigenic stimulation giving sufficient time for memory cell production"

Advantages

 * Activates all phases of the immune system (for instance IgA local antibodies are produced)
 * Provides more durable immunity; boosters are required less frequently
 * Low cost
 * Quick immunity
 * Some are easy to transport and administer (for instance OPV for polio can be taken orally, rather than requiring a sterile injection by a trained healthworker, as the inactivated form IPV does)
 * Attenuated vaccines can have strong beneficial non-specific effects. That is effects which go beyond the specific protective effects against the targeted diseases.

Disadvantages

 * In extremely rare cases, natural mutations can cause a reversion to virulence.In this case, the virus can revert to wild type or develop into an entirely new strain.
 * Live vaccines are not usually recommended for immunocompromised patients due to the risk of potentially severe complications.
 * Live strains typically require advanced maintenance, such as refrigeration and fresh media, making transport to remote areas difficult and costly.

Potential sources:
https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf

https://pubmed.ncbi.nlm.nih.gov/25864107/

https://vaccine-safety-training.org/live-attenuated-vaccines.html

Advantages

 * Accurately imitate natural infections.
 * Are effective at evoking both strong antibody and cell-mediated immune reactions.
 * Can elicit long-lasting or life-long immunity.
 * Often only one or two doses are required.
 * Quick immunity onset.
 * Cost-effective (compared to some other health interventions).
 * Can have strong beneficial non-specific effects.



Disadvantages

 * In extremely rare cases natural mutations can cause a virus to revert to its wild-type form or mutate to a new strain, potentially resulting in the new virus being infectious, pathogenic, or dangerous.
 * Often not recommended for immunocompromised patients due to the risk of potentially severe complications.
 * Live strains typically require advanced maintenance, such as refrigeration and fresh media, making transport to remote areas difficult and costly.

Safety
Live-attenuated vaccines stimulate a strong and effective immune response that is long-lasting. Given pathogens are attenuated, it is extremely rare for pathogens to revert to their pathogenic form and subsequently cause disease. Additionally, within the five WHO-recommended live attenuated vaccines (tuberculosis, polio, measles, rotavirus, and yellow fever) severe adverse reactions are extremely rare. However, similar to any medication or procedure, no vaccine can be 100% safe or effective.

Individuals with compromised immune systems (e.g., HIV-infection, chemotherapy, combined immunodeficiencies) typically should not receive live-attenuated vaccines as they may not be able to produce an adequate and safe immune response. Household contacts of immunodeficient individuals are still able to receive most attenuated vaccines since there is no increased risk of infection transmission, with the exception being the oral polio vaccine.

As precaution, live-attenuated vaccines are not typically administered during pregnancy. This is due to the risk of transmission of virus between mother and fetus. In particular, the varicella and yellow fever vaccines have been shown to have adverse effects on fetuses and nursing babies.

Some live attenuated vaccines have additional common, mild adverse effects due to their administration route. For example, the live attenuated influenza vaccine is given nasally and is associated with nasal congestion.

Compared to inactivated vaccines, live-attenuated vaccines are more prone to immunization errors as they must be kept under strict conditions during the cold chain and carefully prepared (e.g., during reconstitution).

Potential sources:

https://www.who.int/vaccine_safety/initiative/tech_support/Part-2.pdf

https://vaccine-safety-training.org/live-attenuated-vaccines.html

https://www.cdc.gov/flu/professionals/acip/safety-vaccines.htm

https://pubmed.ncbi.nlm.nih.gov/28824613/

https://www-sciencedirect-com.libaccess.lib.mcmaster.ca/topics/immunology-and-microbiology/attenuated-vaccine (List of book chapters, one discusses advantages/disadvantages as well)

Bacterial vaccines

 * Anthrax vaccine
 * Cholera vaccine
 * Plague vaccine
 * Salmonella vaccine
 * Tuberculosis vaccine
 * Typhoid vaccine

Viral vaccines

 * Influenza vaccine
 * Japanese encephalitis vaccine
 * Measles vaccine
 * Mumps vaccine
 * MR vaccine


 * MMR vaccine
 * MMRV vaccine
 * Polio vaccine
 * Rotavirus vaccine
 * Rubella vaccine
 * Smallpox vaccine
 * Varicella vaccine
 * Yellow fever vaccine
 * Zoster/Shingles vaccine

Bacterial vaccines

 * Enterotoxigenic Escherichia coli vaccine

Viral vaccines

 * Tick-Borne encephalitis vaccine