Seroconversion


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.
Seroconversion rates are one of the methods used for determining the efficacy of a vaccine. The higher the rate of seroconversion, the more protective the vaccine for a greater proportion of the population. Seroconversion does not inherently confer immunity or resistance to infection. Only some antibodies, such as anti-spike antibodies for COVID-19, confer protection.
Because seroconversion refers to detectability by standard techniques, seropositivity status depends on the sensitivity and specificity of the assay. As a result, assays, like any serum test, may give false positives or false negatives and should be confirmed if used for diagnosis or treatment.

Mechanism

The physical structure of an antibody allows it to bind to a specific antigen, such as bacterial or viral proteins, to form a complex. Because antibodies are highly specific in what they bind, tests can detect specific antibodies by replicating the antigen which that antibody binds to. Assays can likewise detect specific antigens by replicating the antibodies that bind to them. If an antibody is already bound to an antigen, that antibody and that antigen cannot bind to the test. Antibody tests therefore cannot detect that specific antibody molecule. Due to this binding, if the amounts of antigen and antibody in the blood are equal, each antibody molecule will be in a complex and be undetectable by standard techniques. The antigen, which is bound as well, will also be undetectable. The antibody or antigen is only detectable in the blood when there is substantially more of one than the other. Standard techniques require a high enough concentration of antibody or antigen to detect the amount of antibody or antigen; therefore, they cannot detect the small amount that is not bound during seroconversion.
The immune system may take several days or weeks to detect antigen in tissue, begin to create antibodies, and ramp up the production of antibodies to counter the antigen. As a result, the antigen molecules outnumber the antibody molecules in the early stages of an infection. Because there are more antigen molecules than antibody molecules, the majority of the antibody molecules are bound to antigen. Thus, tests at this stage are unable to detect sufficient unbound antibodies. On the other hand, there may be unbound antigen that can be detectable. As seroconversion progresses, the amount of antibody in the blood gradually rises. Eventually the amount of antibody outnumbers the amount of antigen. At this time, the majority of the antigen molecules is bound to antibodies, and the antigen is undetectable. Conversely, there is a substantial amount of unbound antibodies, allowing standard techniques to detect these antibodies.

Terminology

are tests that detect specific antibodies and are used to determine whether those antibodies are in an organism's blood; such tests require a significant concentration of unbound antibody in the blood serum. Serostatus is a term denoting the presence or absence of particular antibodies in an individual's blood. An individual's serostatus may be positive or negative. During seroconversion, the specific antibody being tested for is generated. Therefore, before seroconversion, the serological assay will not detect any antibody, and the individual's serostatus is seronegative for the antibody. After seroconversion, sufficient concentration of the specific antibody exists in the blood, and the serological assay will detect the antibody. The individual is now seropositive for the antibody.
During seroconversion, when the amounts of antibody and antigen are very similar, it may not be possible to detect free antigen or free antibody. This may give a false negative result when testing for the infection. The time during which the amount of antibody and antigen are sufficiently similar that standard techniques will be unable to detect the antibody or antigen is referred to as the window period. Since different antibodies are produced independently of one another, a given infection may have several window periods. Each specific antibody has its own window period.
Similarly, because standard techniques utilize assumptions about the specificity of antibodies and antigens and are based on chemical interactions, these tests are not completely accurate. Serological assays may give a false positive result, causing the individual to appear to have seroconverted when the individual has not. False positives can occur due to the test reacting to, or detecting, an antibody that happens to be sufficiently similar in structure to the target antibody. Antibodies are generated randomly, so the immune system has a low chance of generating an antibody capable of weakly binding to the assay by coincidence. More rarely, individuals who have recently had some vaccines or who have certain autoimmune conditions can temporarily test falsely seropositive. Due to the possibility of false positives, positive test results are usually reported as "reactive." This indicates that the assay reacted to antibodies, but this does not mean that the individual has the specific antibodies tested for.
Seroreversion is the opposite of seroconversion. During seroreversion, the amount of antibody in the serum decreases. This decrease may occur naturally as a result of the infection resolving and the immune system slowly tamping down its response, or as a result of loss of the immune system. Different infections and antigens lead to the production of antibodies for differing periods of time. Some infections may lead to antibodies that the immune system produces for years after the infection resolves. Others lead to antibodies that the immune system only produces for a few weeks following resolution. After seroreversion, tests can no longer detect antibodies in a patient's serum.
The immune system generates antibodies to any antigen, so seroconversion can occur as a result of either natural infection or as a result of vaccination. Detectable seroconversion and the timeline of seroconversion are among of the parameters studied in evaluating the efficacy of vaccines. A vaccine does not need to have a 100% seroconversion rate to be effective. As long as a sufficient proportion of the population seroconverts, the entire population will be effectively protected by herd immunity.
An individual being seropositive means that the individual has antibodies to that antigen, but it does not mean that that individual has immunity or even resistance to the infection. While antibodies form an important part of the immune system's ability to fight off and resolve an infection, antibodies and seropositivity alone do not guarantee that an individual will resolve the infection. An individual who is seropositive for anti-HIV antibodies will retain that infection chronically unless treated with medications specific to HIV. Conversely, seroconversion in other infections may indicate resistance or immunity. For example, higher concentrations of antibodies after seroconversion in individuals vaccinated against COVID-19 predicts reduced chance of breakthrough infection.
Although seroconversion refers to the production of sufficient quantities of antibodies in the serum, the word seroconversion is often used more specifically in reference to blood testing for anti-HIV antibodies. In particular, "seroconverted" has been used to refer to the process of having "become HIV positive". This indicates that the individual has a detectable amount of anti-HIV antibodies. An individual may have a transmittable HIV infection before the individual becomes HIV positive due to the window period.
In epidemiology, seroconversion is often used in reference to observing the evolution of a virus from a host or natural reservoir host to the human population. Epidemiologists compare archived human blood specimens taken from infected hosts before an epidemic and later specimens from infected hosts at later stages of the epidemic. In this context, seroconversion refers to the process of anti-viral antibodies becoming detectable in the human population serum.

Background

The immune system maintains an immunological memory of infectious pathogens to facilitate early detection and to confer protective immunity against a rechallenge. This explains why many childhood diseases never recur in adulthood.
It generally takes several days for B cells to begin producing antibodies, and it takes further time for those antibodies to develop sufficient specificity to bind strongly to their specific antigen. In the initial phase of the infection, the immune system responds by generating weakly binding immunoglobulin M antibodies; although they individually bind weakly, each IgM antibody has many binding regions and can thus make for an effective initial mobilization of the immune system. Over time, immunoglobulin class switching will result in IgM-generating B-cells switching to more specific IgG-generating B-cells. Levels of IgM then gradually decline and eventually become undetectable by immunoassays, while levels of immunoglobulin G levels rise and become detectable. After the infection resolves, levels of IgM antibodies generally fall to completely undetectable levels as the immune response self-regulates, but some plasma cells will remain as memory cells to produce levels of IgG that will frequently remain detectable for months to years after the initial infection.
Upon reinfection, levels of both IgM and IgG rise, with IgM antibodies having a more rapid but smaller and less sustained peak, and IgG antibodies having a slightly slower, but far greater peak sustained over a longer period of time compared to IgM antibodies. Subsequent infections will demonstrate similar patterns, with initial IgM peaks and significantly stronger IgG peaks, with the IgG peak occurring more rapidly during subsequent infections. Thus an elevated IgM titre indicates recent primary infection or acute reinfection, while the presence of IgG suggests past infection or immunization.
Severe acute respiratory syndrome coronavirus 2 sometimes does not follow the usual pattern, with IgM sometimes occurring after IgG, together with IgG, or not occurring at all. Generally, however, median IgM detection occurs 5 days after symptom onset, and IgG is detected a median 14 days after symptom onset.