With the COVID-19 pandemic beginning to show signs of resurgence in several spots, it is evident that the only way out of continued lockdowns, social distancing, and the accompanying economic woes is to develop an effective vaccine. A new study published on the preprint server medRxiv* in August 2020 reports on the human antibody response in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is key to developing vaccines and managing the pandemic, as well as designing and executing serologic testing and interpreting their results.
Antibodies attacking SARS-CoV-2 virus. Illustration Credit: Kateryna Kon / Shutterstock
Antibodies Vs. Protective Immunity
Most studies that aim to predict the pandemic rely on the presence of immune individuals, assuming that natural infection results in protective immunity. Many clinical measures, as well as planned and present health policies targeting the pandemic, operate on this hypothesis, such as the famed ‘immunity passports’ or certifications of immunity that allow the bearer to move around freely since they have antibodies against the virus, or the use of convalescent plasma to treat COVID-19 patients, or even simple epidemiologic studies and prevalence studies, as well as COVID-19 surveillance based on serology.
Knowledge of human immune response to the virus even determines how people will respond to a vaccine, once it is available, and how the vaccine should be prioritized. Earlier research on other coronaviruses shows that infection causes partial and short-term immunity, in most cases. Still, the SARS-CoV elicited robust and long-lasting immunity with neutralizing antibodies being detectable even 17 years after infection.
Studies from the early days of the pandemic show that SARS-CoV-2 induces a more transient antibody response, mostly directed against the nucleocapsid (N) or spike (S) proteins. It also seems that antibodies against different antigens may arise at different points, last for varying periods, and have different neutralizing capabilities. Thus, it would appear that the general population level protection from reinfection wanes over time, fairly rapidly, but less so if the initial infection was a severe one.
The current study focuses on understanding the dynamics and role of neutralizing antibodies (nAbs) in COVID-19, as well as their mechanism of action, the titer required for protection, and the specific antigens they target in such a scenario.
Overview of the Included Studies
The paper reviews 150 studies, 108 of them relating to antibody response, and 70 to protective immunity. Most of the studies had been carried out in patients with severe disease who were in hospital. Only 11 studies focused on asymptomatic infections, and only 5 of these evaluated the development of protective immunity in this group.
Time-Frame of Humoral Immunity in COVID-19
The researchers found that most individuals in these studies developed specific antibodies in the acute phase of illness; in many cases, up to 100% of patients. The rate of antibody detection depended on the time of testing, the type of patient, the serology test used, and the target antigens. However, while studies recorded the time taken to seroconvert, the time from symptom onset or first positive polymerase chain reaction (PCR) test was not always available. The target antigens were also not always clear. This restricted the ability to trace the development of antibodies to specific viral proteins.
Many researchers have reported seroconversion in terms of the development of combined or total antibody, namely, IgG, IgM, and IgA. The current paper presents the mean or median time of IgG development as 12-15 days from the first symptom, though the latest detection was at 73 days. For IgM, it was 4-14 days, and for IgA, though only a few studies are available, it is 4-24 days.
Pattern of Antibody Development
Most studies reported the earliest detected antibody to be IgM, as expected, followed by IgG. Still, one recorded the pattern IgA/IgM simultaneously, and then IgG, while another showed IgG to be the first detected, and then IgM. A study in African green monkeys reports that IgM and IgG developed simultaneously. The issue here may relate, the researchers suggest, to variable assays, in different species, and the lack of standardization.
Changes in Antibodies with Time
The investigators found that IgG antibodies traced a path of peak, plateau, and persistence, with the peak being variously reported as occurring at 3-7 weeks from the earliest symptom. The plateau is not well described, but the decline is reported to occur from the eight weeks from the onset of symptoms. However, one study has shown that IgG is detectable at 12 weeks, which is the most extended available period of follow up. Detection dates were thus defined by the study period rather than the absence of detectable antibody titers.
IgM first rose to a peak at 2-5 weeks, and then fell over time to become undetectable by 6 weeks. IgA peaks at 16-22 days from the first symptom, but these studies are few.
Factors that Influence Antibody Response
The researchers found it difficult to trace a connection between disease phenotype and antibody response due to significant inconsistency in study methods, controls, and study design. Antibody response appeared to be independent of age, sex, ethnicity, and other demographic factors in most studies, or inconclusive overall.
The study also shows that most individuals did seroconvert, demonstrating neutralizing antibodies against SARS-CoV-2, but a significant though the low proportion of subjects had low titers of nAbs. Two high-quality studies show that the vast majority of participants did have nAbs, but the titer was less than 1:80 in 25% of them, and in another study, almost 80% of a sample of mild COVID-19 patients had low titers.
The receptor-binding domain (RBD) elicited potent antibodies in all cases, indicating its ability to elicit specific nAbs even though the total plasma neutralizing capacity is low. Such antibodies were detected at 7-15 days, peaked over days 14-22, and then declined over the next 6 weeks or so. Since most research now available is of moderate quality, the researchers suggest the need for better studies to understand why nAbs wane over time, and to evaluate its occurrence in the upper respiratory tract, of which no study has yet been made.
Factors that Determine NAb Production
Researchers also found that disease severity was key to nAb development, with asymptomatic individuals being much less likely to develop such responses. The presence of specific IgG to the viral S protein or the RBD was positively linked to higher neutralization ability. The latter was shown to correlate with blockade of the ACE2 viral receptor on the host cell. B memory cells were induced with clonal B cell expansion in hospitalized patients, mostly in the naïve B cells, with a clear correlation to disease severity.
Anti-N IgG is also significantly linked to a lower viral load and lower mortality. These high-quality studies seem to show that viral RNA remains detectable in recovered patients, though at low levels, for up to 50 days from the earliest detection.
Reinfection Following Recovery
Only a few animal studies followed re-exposure to the virus. Most showed that the animals were protected to some extent from reinfection, with lower viral titers and milder symptoms.
After transferring antiviral antibodies, in two studies, higher potency of nAbs was associated with lower viral titer and symptoms, but after less potent antibodies were transferred, only partial neutralization occurred.
The researchers summarize their findings, “Although nAb may be detectable, high-quality studies suggest that titers are generally low, and the response is short-lived.”
A massive gap in immunology was uncovered, being the lack of evidence about the immune response to COVID-19. Much data is either inconsistent or unreliable, and there are no validated assumptions about the association with demographic data or coexisting diseases. However, the nAb titer is higher in males, even though males typically suffer worse outcomes.
The medium quality of much of the research limits the accuracy of the findings. However, the researchers draw out two findings that may shape future policy. One, without a firm knowledge of viral immunology, it will be tough to define what is a normal and acceptable seropositive test. Secondly, at the population level, validated serology will be challenging to carry out to maintain control and surveillance of the viral spread unless pre-assigned.
The researcher points out, “With regard to control, the evidence here for lasting protective immunity, or lack thereof, may suggest it is too early to recommend the use of ‘immunity passports.” Instead, they put forth a battery of other ways to understand how the antibody, host cell, and virus interact, and what a future vaccine strategy may look like.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.