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 A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
has failed to provide complete
immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity desc ...
against the
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
(currently only
virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...
es). Breakthrough infections have been identified in individuals immunized against a variety of diseases including
mumps MUMPS ("Massachusetts General Hospital Utility Multi-Programming System"), or M, is an imperative, high-level programming language with an integrated transaction processing key–value database. It was originally developed at Massachusetts Gener ...
, varicella (
Chickenpox Chickenpox, also known as varicella, is a highly contagious disease caused by the initial infection with varicella zoster virus (VZV). The disease results in a characteristic skin rash that forms small, itchy blisters, which eventually scab ...
),
influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
, and
COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
. 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. Causes of breakthrough infections include biological factors in the recipient, improper administration or storage of vaccines, mutations in viruses,
blocking antibody A blocking antibody is an antibody that does not have a reaction when combined with an antigen, but prevents other antibodies from combining with that antigen. This function of blocking antibodies has had a variety of clinical and experimental uses. ...
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. The
measles vaccine 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 ...
fails to provide immunity to 2% of children that receive the vaccine. However, if
herd immunity Herd immunity (also called herd effect, community immunity, population immunity, or mass immunity) is a form of indirect protection that applies only to contagious diseases. It occurs when a sufficient percentage of a population has become imm ...
exists, it typically prevents individuals who are ineffectively vaccinated from contracting the disease. Accordingly, herd immunity reduces the number of breakthrough infections in a population.


By disease


Varicella

The
varicella vaccine 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 t ...
is 85% effective at preventing varicella (chickenpox) infection. However, 75% of individuals that are diagnosed with breakthrough varicella exhibit milder symptoms than individuals that are not vaccinated. These individuals with mild varicella have low fevers, fewer than 50 lesions on their skin, and a
maculopapular rash A maculopapular rash is a type of rash characterized by a flat, red area on the skin that is covered with small confluent bumps. It may only appear red in lighter-skinned people. The term "maculopapular" is a compound: ''macules'' are small, flat ...
. In contrast, unvaccinated individuals typically have a fever of 102, 200-500 skin lesions, and macules (lesions that are not elevated) evolve to
papule A papule is a small, well-defined bump in the skin. It may have a rounded, pointed or flat top, and may have a dip. It can appear with a stalk, be thread-like or look warty. It can be soft or firm and its surface may be rough or smooth. Some h ...
s and vesicular lesions. Additionally, infection in unvaccinated individuals tends to last for a longer period of time than in individuals who have been vaccinated. The majority of cases of breakthrough varicella are attributed to the failure of an individual to uptake the varicella vaccine. 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.


Mumps

The mumps vaccine is a component of the Measles, Mumps and Rubella vaccine (MMR). The mumps vaccine, specifically, is 88% effective at preventing mumps. Individuals with breakthrough cases of mumps have fewer serious complications from the infections as compared to individuals unvaccinated for mumps. These complications include the development of
aseptic meningitis Aseptic meningitis is the inflammation of the meninges, a membrane covering the brain and spinal cord, in patients whose cerebral spinal fluid test result is negative with routine bacterial cultures. Aseptic meningitis is caused by viruses, myco ...
and
encephalitis Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations, ...
. The cause of breakthrough mumps is not currently completely understood. Evolution of the virus (
antigenic drift Antigenic drift is a kind of genetic variation in viruses, arising from the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies recognize. This results in a new strain of virus particles that is ...
) is thought to explain the majority of breakthrough cases. Other theories suggest that memory T lymphocytes play a role in the development of breakthrough infections.


Hepatitis B

Breakthrough cases of
Hepatitis B Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. Fo ...
are primarily attributed to mutations in the
Hepatitis B virus ''Hepatitis B virus'' (HBV) is a partially double-stranded DNA virus, a species of the genus ''Orthohepadnavirus'' and a member of the ''Hepadnaviridae'' family of viruses. This virus causes the disease hepatitis B. Disease Despite there bein ...
(HBV) that make HBV surface proteins unrecognizable to antibodies produced from the HBV vaccine. Viruses with such mutations are called "vaccine escape mutants". Breakthrough infections may also be caused by delayed vaccination,
immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...
, and maternal viral load. It is possible for an individual to have breakthrough infection of HBV but be asymptomatic.


COVID-19

In April 2021, scientists reported that in a
cohort Cohort or cohortes may refer to: * Cohort (educational group), a group of students working together through the same academic curriculum * Cohort (floating point), a set of different encodings of the same numerical value * Cohort (military unit ...
of 417 vaccinated persons, two women had breakthrough infections as of publication and identified their variants' viral mutations. In the same month, the
CDC The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
reported that in the United States, there were 5,814
COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
breakthrough infections and 74
deaths Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
among the more than 75 million people fully vaccinated for the
COVID-19 virus Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a p ...
. In July 2021, scientists reported that in an outbreak of the
SARS-CoV-2 Delta variant The Delta variant (B.1.617.2) was a variant of SARS-CoV-2, the virus that causes COVID-19. It was first detected in India in late 2020. The Delta variant was named on 31 May 2021 and had spread to over 179 countries by 22 November 2021. The ...
, associated with large public gatherings, 74% of infections occurred in fully vaccinated people.


Characteristics


Age

As a person ages, their immune system undergoes a series of changes, in a process referred to as
immunosenescence Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. A 2020 review concluded that the adaptive immune system is affected more than the innate immune system. Immunosenescence involves both the ...
. Notable among these changes is a decreased production of
naive T cell In immunology, a naive T cell (Th0 cell) is a T cell that has differentiated in the thymus, and successfully undergone the positive and negative processes of central selection in the thymus. Among these are the naive forms of helper T cells ( CD ...
s and
naive B cell A naive B cell is a B cell that has not been exposed to an antigen. These are located in the tonsils, spleen, primary lymphoid follicles in lymph nodes Once exposed to an antigen, the naive B cell either becomes a memory B cell In immunology, a ...
s. The reduced number of naive lymphocytes (T and B cells) is attributed to the fact that the
telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
s in
hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
s (HSCs), degenerate over time and, consequently, limit the proliferation of HSCs and production of
lymphoid progenitor cell __NOTOC__ A lymphoblast is a modified naive lymphocyte with altered cell morphology. It occurs when the lymphocyte is activated by an antigen (from antigen-presenting cells) and increased in volume by nucleus and cytoplasm growth as well as new mRN ...
s. This is compounded by the fact that, with time, HSCs tend to favor the production of
myeloid progenitor cells Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
over lymphoid progenitor cells. Mature lymphocytes are also unable to proliferate indefinitely. 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. Indeed, vaccines, including the influenza vaccine,
Tdap The DPT vaccine or DTP vaccine is a class of combination vaccines against three infectious diseases in humans: diphtheria, pertussis (whooping cough), and tetanus. The vaccine components include diphtheria and tetanus toxoids and either kille ...
, and
pneumococcal ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They are ...
vaccines, are less effective in adults over the age of 65. 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.


Antibody interference

The presence of
maternal antibodies 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 h ...
in infants limits the efficacy of inactivated, attenuated and subunit vaccines. Maternal antibodies can bind to
epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
s on the proteins produced by the virus in the vaccination. The recognition of viral proteins by maternal antibodies neutralizes the virus. 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. 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. 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. In most infants, maternal antibodies disappear 12–15 months after birth, so vaccines administered outside this window are not compromised by maternal antibody interference.


Longevity of memory B cells

When an individual is vaccinated against a disease, the individual's immune system is triggered and
memory B cell In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescen ...
s store the specific antibody response. 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. 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. 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.


Virus evolution

When a person is vaccinated, their immune system develops antibodies that recognize specific segments (
epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
s) viruses or viral-induced proteins. Over time, however, viruses accumulate
genetic mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mit ...
which can impact the 3D structure of viral proteins. If these mutations occur in sites that are recognized by antibodies, the mutations block antibody binding which inhibits the immune response. This phenomenon is called antigenic drift. Breakthrough infections of Hepatitis B and mumps are partially attributed to antigenic drift.


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. Similarly, appropriate vaccine dosage is essential to ensuring immunity. Vaccine dosage is dependent on factors including a patient's age and weight. 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. 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 Immunological memory is the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. Generally, these are secondary, tertiary and other subs ...
. It is possible for an individual to neutralize and clear a pathogen through the humoral response without activating the adaptive immune response. 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.


References


External links


COVID-19 Vaccine Breakthrough Case Investigation and Reporting
CDC

CDC * ttp://adam.about.com/reports/000082_4.htm Shingles and Chickenpox (causes, diagnosis, treatment, and prevention) {{portal bar, Biology, Medicine, Viruses Immunology