Seroconversion

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 ==

Serological assays 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. 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. 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 (and when they do, it generally indicates immunosuppression). 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 (primary infection) phase of the infection, the immune system responds by generating weakly binding immunoglobulin M (IgM) 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. 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 (SARS-CoV-2, the virus causing COVID-19) 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. == In HIV ==

Most individuals infected with HIV will begin to produce antibodies within a few weeks after their initial exposure to HIV. During the window period, the antibody assay cannot detect unbound anti-HIV antibodies and will indicate that the individual is seronegative. The length of the window period depends on the individual's immune response and the particular parameters of the test. An individual in the window period can still infect others despite appearing seronegative on tests because the individual still carries the virus. The average window period for the development of antibodies to p24 antigen, the standard for testing, is about two weeks. However, the window periods used for the assays are based on capturing as many people as possible. More recent, fourth-generation assays that assess for both the antibody and the antigen can have a window period as short as six weeks to detect more than 99% of infections, while third-generation tests that assess only for unbound antibody tend to have a longer window period of eight to nine weeks. Rapid tests procurable at a consumer level often fail to detect antibody until at least three months have passed since the initial infection. Thus, individuals who test negative for HIV before the window period ends for that specific test will usually need to be retested after the window period, as they may fall into the minority who take more time to develop antibodies. Because not all individuals experience the symptoms of seroconversion, and because they are non-specific, individuals should receive testing for HIV if they are high-risk or have possibly had an exposure to HIV. Likewise, if an individual suspects exposure for HIV, a lack of symptoms does not indicate that seroconversion has not occurred. 20–30% of people undergoing HIV seroconversion lack symptoms entirely or have mild symptoms. == In COVID-19 ==

As with other viruses, seroconversion in COVID-19 refers to the development of antibodies in the blood serum against COVID-19 antigens. An individual is seropositive, or has seroconverted for COVID-19, once standard techniques are able to detect COVID-19 antibodies in the blood. Seroconversion testing is primarily used to detect individuals who have been infected with COVID-19 in the past who have already resolved their infections. Due to the time delay of seroconversion compared to viral load, seroconversion is not sufficiently timely to diagnose a current case of COVID-19. However, seroconversion may be helpful for individuals with suspected infections who are negative by RT-PCR testing for viral load. Some individuals can become seropositive without ever experiencing symptoms of COVID-19 or knowing that they were exposed to COVID-19 at any point. Some asymptomatic individuals can still transmit COVID-19 to others. However, it is unclear whether all asymptomatic individuals who seroconvert to COVID-19 had transmissibility at any point (active infection), or whether an individual can seroconvert to COVID-19 without undergoing a period during which they can infect others. Concentrations of antibodies develop after several days and reach their maximal value approximately two to three weeks after infection. Some individuals have detectable levels of both IgG and IgM as early as within the first week after symptoms begin. Becoming seropositive for COVID-19 antibodies can occur due to either infection with COVID-19 itself or due to becoming vaccinated to COVID-19. Being seropositive for COVID-19 does not intrinsically confer immunity or even resistance. However, higher rates of seroconversion are linked to greater clinical efficacy of vaccines. This suggests that for most individuals, seroconversion does lead to resistance. Younger individuals tend to have more robust responses to vaccinations compared to older individuals. The difference in the robustness of the response increases with the second dose. Younger individuals tend to have much higher and more sustained peaks of anti-spike IgG antibodies following the second dose. On the other hand, individuals with weakened immune systems, such as due to immunosuppressive medications or leukemia, can exhibit decreased rates of seroconversion for currently available vaccines. The different vaccines currently utilized do not appear to have significant differences in seroconversion rates when compared in similar population groups. Seroconversion does not necessarily occur at the same rate to all COVID-19 antigens. Individuals who seroconvert more rapidly to different antigens may have different disease courses. Individuals infected with COVID-19 who developed primarily anti-spike antibodies rather than anti-nucleocapsid antibodies are less likely to have a severe disease course. Studies suggest that anti-spike antibodies confer greater resistance to COVID-19 than anti-nucleocapsid antibodies. A higher ratio of anti-spike antibodies to anti-nucleocapsid antibodies thus serves as a predictor of disease course and patient mortality. Significantly older patients of greater than eighty years old are more likely to have higher quantities of IgG antibodies compared to younger patients at the time of infection. This is consistent with the fact that older patients tend to have more severe COVID-19 infections and thus have higher viral loads compared to younger patients. Several studies have demonstrated that individuals who recovered from COVID-19 infections and are seropositive for COVID-19 at the time of vaccination produce significantly more anti-spike IgG antibodies in response to vaccination than individuals who are not seropositive for COVID-19, while individuals who have recovered from COVID-19 infections but never seroconverted and are seronegative respond similarly to individuals who have never been exposed to COVID-19. Specifically, individuals who are seropositive for COVID-19 at the time of their first dose of vaccination have a response similar to the general population's response to the second dose, due to this increased concentration of IgG antibodies. == In hepatitis B ==

Seroconversion plays a major role in the diagnosis and treatment of hepatitis B infections. As in other viral infections, seropositivity indicates that an individual has a sufficiently high concentration of antibody or antigen in the blood to be detectable by standard techniques. While assays for other infections such as COVID-19 and HIV primarily test for seroconversion of antibodies against antigens, assays for HBV also test for antigens. The standard serology panel for seroconversion include hepatitis B surface antigen, hepatitis B surface antibody for IgM and IgG, hepatitis B core antibody for IgM and IgG, and hepatitis B e-antigen. In the typical disease course for hepatitis B, the individual will first seroconvert for hepatitis B surface antigen (HBsAg). While some can convert within one week, most individuals take about four weeks after initial infection to convert. Anti-core antibodies (anti-HBc) are the first antibodies produced by the body, first in short-term IgM (anti-HBc IgM), and subsequently in long-term IgG; while levels of IgM anti-HBc will peak around sixteen weeks after exposure and fall within about seven to eight months, IgG anti-HBc will remain detectable in the serum as a sign of chronic infection for years. IgM anti-HBc concentration will fall regardless of whether or not the individual clears the infection. During this time, serology assays can test for total anti-HBc. An individual who is infected with HBV and who never becomes seropositive for HBeAg can likewise be infective, because not all HBV infections produce HBeAg. For most individuals, those who seroconvert positive for HBeAg during their disease course and subsequently serorevert negative as their infection progresses are no longer infective. Seroreversion from HBeAg is thus used as one marker of resolution of infection. For these individuals, a booster is recommended. However, those who are immunocompetent may forego testing or boosters after the five-year period. Individuals who receive vaccination for HBV should undergo serology testing to confirm seroconversion following the initial vaccine series as well as any boosters. == See also ==