Attenuated vaccine

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An attenuated vaccine (or a live attenuated vaccine, LAV) is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or "live"). [1] Attenuation takes an infectious agent and alters it so that it becomes harmless or less virulent. [2] These vaccines contrast to those produced by "killing" the pathogen (inactivated vaccine).

Contents

Attenuated vaccines stimulate a strong and effective immune response that is long-lasting. [3] In comparison to inactivated vaccines, attenuated vaccines produce a stronger and more durable immune response with a quick immunity onset. [4] [5] [6] They are generally avoided in pregnancy and in patients with severe immunodeficiencies. [7] Attenuated vaccines function by encouraging the body to create antibodies and memory immune cells in response to the specific pathogen which the vaccine protects against. [8] Common examples of live attenuated vaccines are measles, mumps, rubella, yellow fever, and some influenza vaccines. [3]

Development

Attenuated viruses

Viruses may be attenuated using the principles of evolution with serial passage of the virus through a foreign host species, such as: [9] [10]

The initial virus population is applied to a foreign host. Through natural genetic variability or induced mutation, a small percentage of the viral particles should have the capacity to infect the new host. [10] [11] These strains will continue to evolve within the new host and the virus will gradually lose its efficacy in the original host, due to lack of selection pressure. [10] [11] 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 subject that is to receive the vaccine. [11] This makes it easier for the host 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". [11]

Viruses may also be attenuated via reverse genetics. [12] Attenuation by genetics is also used in the production of oncolytic viruses. [13]

Attenuated bacteria

Bacteria is typically attenuated by passage, similar to the method used in viruses. [14] Gene knockout guided by reverse genetics is also used. [15]

Administration

Attenuated vaccines can be administered in a variety of ways:

Oral vaccines or subcutaneous/intramuscular injection are for individuals older than 12 months. Live attenuated vaccines, with the exception of the rotavirus vaccine given at 6 weeks, is not indicated for infants younger than 9 months. [19]

Mechanism

Vaccines function by encouraging the creation of immune cells, such as CD8+ and CD4+ T lymphocytes, or molecules, such as antibodies, that are specific to the pathogen. [8] The cells and molecules can either prevent or reduce infection by killing infected cells or by producing interleukins. [8] The specific effectors evoked can be different based on the vaccine. [8] Live attenuated vaccines tend to help with the production of CD8+ cytotoxic T lymphocytes and T-dependent antibody responses. [8] A vaccine is only effective for as long as the body maintains a population of these cells. [8]

Attenuated vaccines are “weakened” versions of pathogens (virus or bacteria). They are modified so that it cannot cause harm or disease in the body but are still able to activate the immune system. [20] This type of vaccine works by activating both the cellular and humoral immune responses of the adaptive immune system. When a person receives an oral or injection of the vaccine, B cells, which help make antibodies, are activated in two ways: T cell-dependent and T-cell independent activation. [21]

In T-cell dependent activation of B cells, B cells first recognize and present the antigen on MHCII receptors. T-cells can then recognize this presentation and bind to the B cell, resulting in clonal proliferation. This also helps IgM and plasma cells production as well as immunoglobulin switching. On the other hand, T-cell independent activation of B cells is due to non-protein antigens. This can lead to production of IgM antibodies. Being able to produce a B-cell response as well as memory killer T cells is a key feature of attenuated virus vaccines that help induce a potent immunity. [21]

Safety

Live-attenuated vaccines are safe and stimulate a strong and effective immune response that is long-lasting. [3] Given pathogens are attenuated, it is extremely rare for pathogens to revert to their pathogenic form and subsequently cause disease. [22] Additionally, within the five WHO-recommended live attenuated vaccines (tuberculosis, oral polio, measles, rotavirus, and yellow fever), severe adverse reactions are extremely rare. [22]

Individuals with severely compromised immune systems (e.g., HIV-infection, chemotherapy, immunosuppressive therapy, lymphoma, leukemia, combined immunodeficiencies) typically should not receive live-attenuated vaccines as they may not be able to produce an adequate and safe immune response. [3] [22] [23] [24] 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. [24]

As precaution, live-attenuated vaccines are not typically administered during pregnancy. [22] [25] This is due to the risk of transmission of virus between mother and fetus. [25] In particular, the varicella and yellow fever vaccines have been shown to have adverse effects on fetuses and nursing babies. [25]

Some live attenuated vaccines have additional common, mild adverse effects due to their administration route. [25] For example, the live attenuated influenza vaccine is given nasally and is associated with nasal congestion. [25]

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). [3] [22] [23]

History

The history of vaccine development started with the creation of the smallpox vaccine by Edward Jenner in the late 18th century. [26] 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. [27] [28] Although the original smallpox vaccine is sometimes considered to be an attenuated vaccine due to its 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. [29] [30] 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. [29] Pasteur applied this knowledge to develop an attenuated anthrax vaccine and demonstrating its effectiveness in a public experiment. [31] The first rabies vaccine was subsequently produced by Pasteur and Emile Roux by growing the virus in rabbits and drying the affected nervous tissue. [31]

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. [26] 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. [26] [29] [32] 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). [29] [32] 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. [33] [34] [35] [36]

Advantages and disadvantages

Advantages

Disadvantages

List of attenuated vaccines

Currently in-use

For many of the pathogens listed below there are many vaccines, the list below simply indicates that there are one (or more) attenuated vaccines for that particular pathogen, not that all vaccines for that pathogen are attenuated.[ citation needed ]

Bacterial vaccines

Viral vaccines

In development

Bacterial vaccines

Viral vaccines

Related Research Articles

<span class="mw-page-title-main">Vaccination</span> Administration of a vaccine to protect against disease

Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating the body's adaptive immunity, they help prevent sickness from an infectious disease. When a sufficiently large percentage of a population has been vaccinated, herd immunity results. Herd immunity protects those who may be immunocompromised and cannot get a vaccine because even a weakened version would harm them. The effectiveness of vaccination has been widely studied and verified. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the elimination of diseases such as polio and tetanus from much of the world. However, some diseases, such as measles outbreaks in America, have seen rising cases due to relatively low vaccination rates in the 2010s – attributed, in part, to vaccine hesitancy. According to the World Health Organization, vaccination prevents 3.5–5 million deaths per year.

<span class="mw-page-title-main">Vaccine</span> Pathogen-derived preparation that provides acquired immunity to an infectious disease

A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.

<span class="mw-page-title-main">Measles</span> Viral disease affecting humans

Measles is a highly contagious, vaccine-preventable infectious disease caused by measles virus. Symptoms usually develop 10–12 days after exposure to an infected person and last 7–10 days. Initial symptoms typically include fever, often greater than 40 °C (104 °F), cough, runny nose, and inflamed eyes. Small white spots known as Koplik's spots may form inside the mouth two or three days after the start of symptoms. A red, flat rash which usually starts on the face and then spreads to the rest of the body typically begins three to five days after the start of symptoms. Common complications include diarrhea, middle ear infection (7%), and pneumonia (6%). These occur in part due to measles-induced immunosuppression. Less commonly seizures, blindness, or inflammation of the brain may occur. Other names include morbilli, rubeola, red measles, and English measles. Both rubella, also known as German measles, and roseola are different diseases caused by unrelated viruses.

<span class="mw-page-title-main">Mumps</span> Human disease caused by paramyxovirus

Mumps is a highly contagious viral disease caused by the mumps virus. Initial symptoms of mumps are non-specific and include fever, headache, malaise, muscle pain, and loss of appetite. These symptoms are usually followed by painful swelling around the side of the face, which is the most common symptom of a mumps infection. Symptoms typically occur 16 to 18 days after exposure to the virus. About one third of people with a mumps infection do not have any symptoms (asymptomatic).

<span class="mw-page-title-main">MMR vaccine</span> Any of several combined vaccines against measles, mumps, and rubella

The MMR vaccine is a vaccine against measles, mumps, and rubella, abbreviated as MMR. The first dose is generally given to children around 9 months to 15 months of age, with a second dose at 15 months to 6 years of age, with at least four weeks between the doses. After two doses, 97% of people are protected against measles, 88% against mumps, and at least 97% against rubella. The vaccine is also recommended for those who do not have evidence of immunity, those with well-controlled HIV/AIDS, and within 72 hours of exposure to measles among those who are incompletely immunized. It is given by injection.

<span class="mw-page-title-main">Herd immunity</span> Concept in epidemiology

Herd immunity is a form of indirect protection that applies only to contagious diseases. It occurs when a sufficient percentage of a population has become immune to an infection, whether through previous infections or vaccination, thereby reducing the likelihood of infection for individuals who lack immunity.

<span class="mw-page-title-main">Rubella</span> Human viral disease

Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and last for three days. It usually starts on the face and spreads to the rest of the body. The rash is sometimes itchy and is not as bright as that of measles. Swollen lymph nodes are common and may last a few weeks. A fever, sore throat, and fatigue may also occur. Joint pain is common in adults. Complications may include bleeding problems, testicular swelling, encephalitis, and inflammation of nerves. Infection during early pregnancy may result in a miscarriage or a child born with congenital rubella syndrome (CRS). Symptoms of CRS manifest as problems with the eyes such as cataracts, deafness, as well as affecting the heart and brain. Problems are rare after the 20th week of pregnancy.

<span class="mw-page-title-main">Immunization</span> Process by which an individuals immune system becomes fortified against an infectious agent

Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an infectious agent.

In biology, immunity is the state of being insusceptible or resistant to a noxious agent or process, especially a pathogen or infectious disease. Immunity may occur naturally or be produced by prior exposure or immunization.

ATC code J07Vaccines is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System, a system of alphanumeric codes developed by the World Health Organization (WHO) for the classification of drugs and other medical products. Subgroup J07 is part of the anatomical group J Antiinfectives for systemic use.

<span class="mw-page-title-main">Childhood immunizations in the United States</span>

The schedule for childhood immunizations in the United States is published by the Centers for Disease Control and Prevention (CDC). The vaccination schedule is broken down by age: birth to six years of age, seven to eighteen, and adults nineteen and older. Childhood immunizations are key in preventing diseases with epidemic potential.

The MMRV vaccine combines the attenuated virus MMR vaccine with the addition of the varicella (chickenpox) vaccine. The MMRV vaccine is typically given to children between one and two years of age.

<span class="mw-page-title-main">Mumps vaccine</span> Vaccine which prevents mumps

Mumps vaccines are vaccines which prevent mumps. When given to a majority of the population they decrease complications at the population level. Effectiveness when 90% of a population is vaccinated is estimated at 85%. Two doses are required for long term prevention. The initial dose is recommended between 12 and 18 months of age. The second dose is then typically given between two years and six years of age. Usage after exposure in those not already immune may be useful.

A breakthrough infection is a case of illness in which a vaccinated individual becomes infected with the illness, because the vaccine has failed to provide complete immunity against the pathogen. Breakthrough infections have been identified in individuals immunized against a variety of diseases including mumps, varicella (Chickenpox), influenza, and COVID-19. The characteristics of the breakthrough infection are dependent on the virus itself. Often, infection of the vaccinated individual results in milder symptoms and shorter duration than if the infection were contracted naturally.

Immunization during pregnancy is the administration of a vaccine to a pregnant individual. This may be done either to protect the individual from disease or to induce an antibody response, such that the antibodies cross the placenta and provide passive immunity to the infant after birth. In many countries, including the US, Canada, UK, Australia and New Zealand, vaccination against influenza, COVID-19 and whooping cough is routinely offered during pregnancy.

<span class="mw-page-title-main">Measles vaccine</span> Vaccine used to prevent measles

Measles vaccine protects against becoming infected with measles. Nearly all of those who do not develop immunity after a single dose develop it after a second dose. When the rate of vaccination within a population is greater than 92%, outbreaks of measles typically no longer occur; however, they may occur again if the rate of vaccination decreases. The vaccine's effectiveness lasts many years. It is unclear if it becomes less effective over time. The vaccine may also protect against measles if given within a couple of days after exposure to measles.

<span class="mw-page-title-main">Rubella vaccine</span> Vaccine used to prevent rubella

Rubella vaccine is a vaccine used to prevent rubella. Effectiveness begins about two weeks after a single dose and around 95% of people become immune. Countries with high rates of immunization no longer see cases of rubella or congenital rubella syndrome. When there is a low level of childhood immunization in a population it is possible for rates of congenital rubella to increase as more women make it to child-bearing age without either vaccination or exposure to the disease. Therefore, it is important for more than 80% of people to be vaccinated. By introducing rubella containing vaccines, rubella has been eradicated in 81 nations, as of mid-2020.

<span class="mw-page-title-main">Inactivated vaccine</span> Vaccine using a killed version of a disease pathogen

An inactivated vaccine is a vaccine consisting of virus particles, bacteria, or other pathogens that have been grown in culture and then killed to destroy disease-producing capacity. In contrast, live vaccines use pathogens that are still alive. Pathogens for inactivated vaccines are grown under controlled conditions and are killed as a means to reduce infectivity and thus prevent infection from the vaccine.

<span class="mw-page-title-main">Non-specific effect of vaccines</span> Unintended side effects of vaccines which may be beneficial or bad

Non-specific effects of vaccines are effects which go beyond the specific protective effects against the targeted diseases. Non-specific effects can be strongly beneficial by increasing protection against non-targeted infections. This has been shown with two live attenuated vaccines, BCG vaccine and measles vaccine, through multiple randomized controlled trials. Theoretically, non-specific effects of vaccines may be detrimental, increasing overall mortality despite providing protection against the target diseases. Although observational studies suggest that diphtheria-tetanus-pertussis vaccine (DTP) may be highly detrimental, these studies are at high risk of bias and have failed to replicate when conducted by independent groups.

Live recombinant vaccines are biological preparations that stimulate immune responses to a pathogen through the use of genetically modified live bacteria or viruses. These live pathogens are biologically engineered to express exogenous antigens in the cytoplasm of target cells, thereby triggering immune responses. This form of vaccine combines the beneficial features of attenuated and recombinant vaccines, providing the long-lasting immunity of attenuated vaccines’ with recombinant vaccines’ genetically engineered precision and safety.

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