Breakthrough infection

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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 (currently only viruses). [1] Breakthrough infections have been identified in individuals immunized against a variety of diseases including mumps, varicella (Chickenpox), influenza, and COVID-19. [2] [3] [4] 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. [5]

Contents

Causes of breakthrough infections include biological factors in the recipient, improper administration or storage of vaccines, mutations in viruses, blocking antibody formation, and other factors. For these reasons, vaccines are rarely 100% effective. A 2021 study found the common flu vaccine provided immunity to the flu in 58% of recipients. [6] The measles vaccine fails to provide immunity to 2% of children that receive the vaccine. However, if herd immunity exists, it typically prevents individuals who are ineffectively vaccinated from contracting the disease. [7] Accordingly, herd immunity reduces the number of breakthrough infections in a population. [8]

By disease

Varicella

The varicella vaccine is 85% effective at preventing varicella (chickenpox) infection. [9] However, 75% of individuals that are diagnosed with breakthrough varicella exhibit milder symptoms than individuals that are not vaccinated. [5] These individuals with mild varicella have low fevers, fewer than 50 lesions on their skin, and a maculopapular rash. In contrast, unvaccinated individuals typically have a fever of 102, 200-500 skin lesions, and macules (lesions that are not elevated) evolve to papules and vesicular lesions. [5] [10] Additionally, infection in unvaccinated individuals tends to last for a longer period of time than in individuals who have been vaccinated. [5]

The majority of cases of breakthrough varicella are attributed to the failure of an individual to uptake[ clarification needed ] the varicella vaccine. [9] Therefore, to prevent breakthrough infections, it is proposed that children receive a second dose of varicella vaccine less than a year after getting their first dose. [9]

Mumps

The mumps vaccine is a component of the Measles, Mumps and Rubella vaccine (MMR). [11] The mumps vaccine, specifically, is 88% effective at preventing mumps. [12] Individuals with breakthrough cases of mumps have fewer serious complications from the infections as compared to individuals unvaccinated for mumps. [13] These complications include the development of aseptic meningitis and encephalitis. [13]

The cause of breakthrough mumps is not currently completely understood. Evolution of the virus (antigenic drift) is thought to explain the majority of breakthrough cases. [13] Other theories suggest that memory T lymphocytes play a role in the development of breakthrough infections. [13]

Hepatitis B

Breakthrough cases of Hepatitis B are primarily attributed to mutations in the Hepatitis B virus (HBV) that make HBV surface proteins unrecognizable to antibodies produced from the HBV vaccine. [14] [15] [16] Viruses with such mutations are called "vaccine escape mutants". Breakthrough infections may also be caused by delayed vaccination, immunosuppression, and maternal viral load. [15] It is possible for an individual to have breakthrough infection of HBV but be asymptomatic. [14]

COVID-19

In April 2021, scientists reported that in a cohort of 417 vaccinated persons, two women had breakthrough infections as of publication and identified their variants' viral mutations. [17] [18] In the same month, the CDC reported that in the United States, there were 5,814 COVID-19 breakthrough infections and 74 deaths among the more than 75 million people fully vaccinated for the COVID-19 virus. [19] [20] [21] [22] [23] [24] In July 2021, scientists reported that in an outbreak of the SARS-CoV-2 Delta variant, associated with large public gatherings, 74% of infections occurred in fully vaccinated people. [25] [26] In August 2022, a study that followed up 648 vaccinated individuals found that 40% had at least one breakthrough infection. The incidence was higher in those with long term side effects of vaccination. [27]

Characteristics

Age

As a person ages, their immune system undergoes a series of changes, in a process referred to as immunosenescence. [28] Notable among these changes is a decreased production of naive T cells and naive B cells. [29] The reduced number of naive lymphocytes (T and B cells) is attributed to the fact that the telomeres in hematopoietic stem cells (HSCs), degenerate over time and, consequently, limit the proliferation of HSCs and production of lymphoid progenitor cells. [28] [29] This is compounded by the fact that, with time, HSCs tend to favor the production of myeloid progenitor cells over lymphoid progenitor cells. [29] Mature lymphocytes are also unable to proliferate indefinitely. [28] Compounded, the reduction in number of naive lymphocytes and limitations of the proliferative abilities of mature lymphocytes contribute to a limited number and variety of lymphocytes to respond to pathogens presented in a vaccine. [29]

Indeed, vaccines, including the influenza vaccine, Tdap, and pneumococcal vaccines, are less effective in adults over the age of 65. [29] [30] Nevertheless, the CDC recommends that elderly adults get the flu vaccine because influenza infection is particularly dangerous in this population and vaccine provides at least a moderate level of immunity to the flu virus. [30]

Antibody interference

The presence of maternal antibodies in infants limits the efficacy of inactivated, attenuated and subunit vaccines. [31] Maternal antibodies can bind to epitopes on the proteins produced by the virus in the vaccination. The recognition of viral proteins by maternal antibodies neutralizes the virus. [32] Further, the maternal antibodies outcompete B cell receptors on the infant's B cells for binding to the antigen. Thus, an infant's immune system is not highly activated and the infant produces fewer antibodies. [8] [31] Even when B cells do bind to the pathogen, immune response is still frequently repressed. If B cell receptors bind to the antigen and Fc receptors simultaneously bind to the maternal antibody, the Fc receptors send a signal to B cell receptors that inhibits cell division. [32] Because the infant's immune system is not stimulated and B cell division is inhibited, few memory B cells are produced. The level of memory B-cells is not adequate to ensure an infant's lifelong resistance to the pathogen. [31] [32]

In most infants, maternal antibodies disappear 12–15 months after birth, so vaccines administered outside this window are not compromised by maternal antibody interference. [8]

Longevity of memory B cells

When an individual is vaccinated against a disease, the individual's immune system is triggered and memory B cells store the specific antibody response. [8] These cells remain in circulation until the pathogen infection is cleared. Because the telomeres in genes degenerate after each successive cell division, lymphocytes, including memory B cells are not capable of proliferating indefinitely. [28] Typically, the cells live for multiple decades, but there is variation in the longevity of these cells depending on the type of vaccine they were stimulated with and the vaccine dosage. [32] The reason for the differences in the longevity of memory B cells is currently unknown. However, it has been proposed that the differences in memory B cell longevity are due to the speed at which a pathogen infects the body and, accordingly, the number and type of cells involved in the immune response to the pathogen in the vaccine. [33]

Virus evolution

When a person is vaccinated, their immune system develops antibodies that recognize specific segments (epitopes) viruses or viral-induced proteins. Over time, however, viruses accumulate genetic mutations which can impact the 3D structure of viral proteins. [34] If these mutations occur in sites that are recognized by antibodies, the mutations block antibody binding which inhibits the immune response. [35] This phenomenon is called antigenic drift. Breakthrough infections of Hepatitis B and mumps are partially attributed to antigenic drift. [13] [15]

Vaccine quality and administration

Vaccines may fail to provide immunity if the vaccine is of poor quality when administered. A vaccine loses potency if it is stored at the incorrect temperature or if it is kept after the expiration date. [36] Similarly, appropriate vaccine dosage is essential to ensuring immunity. Vaccine dosage is dependent on factors including a patient's age and weight. [36] Failure to account for these factors can lead to patients receiving an incorrect amount of vaccination. Patients that receive a lower dose than recommended of a vaccine do not have an adequate immune response to the vaccine to ensure immunity. [32]

In order for a vaccine to be effective, an individual must respond to the pathogens in a vaccine through the adaptive branch of the immune system and that response must be stored in an individual's immunological memory. [8] It is possible for an individual to neutralize and clear a pathogen through the humoral response without activating the adaptive immune response. [8] Vaccines with weaker or fewer strains of a pathogen, as is the case when a vaccine is of poor quality when administered, may primarily elicit the humoral response, and, thus, fail to ensure future immunity. [8]

Related Research Articles

<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">Antiviral drug</span> Medication used to treat a viral infection

Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.

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

Mumps is a 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 of the parotid glands, called parotitis, which is the most common symptom of a mumps infection. Symptoms typically occur 16 to 18 days after exposure to the virus and resolve within two weeks. About one third of infections are asymptomatic.

<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.

<span class="mw-page-title-main">Varicella zoster virus</span> Herpes virus that causes chickenpox and shingles

Varicella zoster virus (VZV), also known as human herpesvirus 3 or Human alphaherpesvirus 3 (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting children and young adults, and shingles in adults but rarely in children. VZV infections are species-specific to humans. The virus can survive in external environments for a few hours.

<span class="mw-page-title-main">Seroconversion</span> Development of specific antibodies in the blood serum as a result of infection or immunization

In immunology, seroconversion is the development of specific antibodies in the blood serum as a result of infection or immunization, including vaccination. During infection or immunization, antigens enter the blood, and the immune system begins to produce antibodies in response. Before seroconversion, the antigen itself may or may not be detectable, but the antibody is absent. During seroconversion, the antibody is present but not yet detectable. After seroconversion, the antibody is detectable by standard techniques and remains detectable unless the individual seroreverts, in a phenomenon called seroreversion, or loss of antibody detectability, which can occur due to weakening of the immune system or decreasing antibody concentrations over time. Seroconversion refers the production of specific antibodies against specific antigens, meaning that a single infection could cause multiple waves of seroconversion against different antigens. Similarly, a single antigen could cause multiple waves of seroconversion with different classes of antibodies. For example, most antigens prompt seroconversion for the IgM class of antibodies first, and subsequently the IgG class.

<span class="mw-page-title-main">Original antigenic sin</span> Immune phenomenon

Original antigenic sin, also known as antigenic imprinting, the Hoskins effect, immunological imprinting, or primary addiction is the propensity of the immune system to preferentially use immunological memory based on a previous infection when a second slightly different version of that foreign pathogen is encountered. This leaves the immune system "trapped" by the first response it has made to each antigen, and unable to mount potentially more effective responses during subsequent infections. Antibodies or T-cells induced during infections with the first variant of the pathogen are subject to repertoire freeze, a form of original antigenic sin.

<span class="mw-page-title-main">Vertically transmitted infection</span> Infection caused by pathogens that use mother-to-children transmission

A vertically transmitted infection is an infection caused by pathogenic bacteria or viruses that use mother-to-child transmission, that is, transmission directly from the mother to an embryo, fetus, or baby during pregnancy or childbirth. It can occur when the mother has a pre-existing disease or becomes infected during pregnancy. Nutritional deficiencies may exacerbate the risks of perinatal infections. Vertical transmission is important for the mathematical modelling of infectious diseases, especially for diseases of animals with large litter sizes, as it causes a wave of new infectious individuals.

Pox parties, also known as flu parties, are social activities in which children are deliberately exposed to infectious diseases such as chickenpox. Such parties originated to "get it over with" before vaccines were available for a particular illness or because childhood infection might be less severe than infection during adulthood, according to proponents. For example, measles is more dangerous to adults than to children over five years old. Deliberately exposing people to diseases has since been discouraged by public health officials in favor of vaccination, which has caused a decline in the practice of pox parties, although flu parties saw a resurgence in the early 2010s.

<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.

Correlates of immunity or correlates of protection to a virus or other infectious pathogen are measurable signs that a person is immune, in the sense of being protected against becoming infected and/or developing disease.

In immunology, passive immunity is the transfer of active humoral immunity of ready-made antibodies. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and it can also be induced artificially, when high levels of antibodies specific to a pathogen or toxin are transferred to non-immune persons through blood products that contain antibodies, such as in immunoglobulin therapy or antiserum therapy. Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. Passive immunization can be provided when people cannot synthesize antibodies, and when they have been exposed to a disease that they do not have immunity against.

<span class="mw-page-title-main">Varicella vaccine</span> Vaccine to prevent chickenpox

Varicella vaccine, also known as chickenpox vaccine, is a vaccine that protects against chickenpox. One dose of vaccine prevents 95% of moderate disease and 100% of severe disease. Two doses of vaccine are more effective than one. If given to those who are not immune within five days of exposure to chickenpox it prevents most cases of disease. Vaccinating a large portion of the population also protects those who are not vaccinated. It is given by injection just under the skin. Another vaccine, known as zoster vaccine, is used to prevent diseases caused by the same virus – the varicella zoster virus.

An attenuated vaccine is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable. 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 pathogen.

<span class="mw-page-title-main">Hepatitis B vaccine</span> Vaccine against hepatitis B

Hepatitis B vaccine is a vaccine that prevents hepatitis B. The first dose is recommended within 24 hours of birth with either two or three more doses given after that. This includes those with poor immune function such as from HIV/AIDS and those born premature. It is also recommended that health-care workers be vaccinated. In healthy people, routine immunization results in more than 95% of people being protected.

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

Chickenpox, or chicken pox, also known as varicella, is a highly contagious, vaccine-preventable disease caused by the initial infection with varicella zoster virus (VZV), a member of the herpesvirus family. The disease results in a characteristic skin rash that forms small, itchy blisters, which eventually scab over. It usually starts on the chest, back, and face. It then spreads to the rest of the body. The rash and other symptoms, such as fever, tiredness, and headaches, usually last five to seven days. Complications may occasionally include pneumonia, inflammation of the brain, and bacterial skin infections. The disease is usually more severe in adults than in children.

<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 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 decrease. 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.

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

References

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