Type Of Antibodies, Proportion And Quantities Of Antibodies, Duration Of Antibodies-All Determine COVID-19 Severity Contrary To Previous Studies
For the past few weeks we have been constantly been bombarded with half-baked research studies mostly by greedy researchers or institutions that are often funded directly or indirectly by the U.S. Government agencies like NIH, CDC etc or by the pharmaceutical and biotech companies that have a vested interested in the current vaccines and antibody therapeutics making claims that antibodies provide protection for 6 months or 8 months etc or that reinfections would be unlikely due to the presence of these antibodies etc.
The key thing is that finding antibodies in the blood and doing some in vitro studies does not really reflect the way things really work in the human body. and guarantee protection against the SARS-CoV-2 coronavirus. The whole process is very complicated and dynamic in the human host body.
Most importantly, the new and most accurate hypothesis by Thailand Medical News
is that is that different types of antibodies are at play at different stages of the SARs-CoV-2 pathogenesis in the human host and even host factors determine which types of antibodies are being produced (Sometimes wrongly), and the proportion and quantity of these antibodies are also critical coupled with the duration of the availability of these antibodies. To make things more complicated for the already very dynamic process, different viral strains with various mutations on them also affect the type of antibodies that may or may not be produced due to issues like immune evasion strategies of these mutations or antibody resistant mechanisms etc. (We are basing this new hypothesis based on years on work in the field of oncology.)
A new study by Stanford University partially substantiates or hypothesis.
The study team certain COVID-19 antibodies preferentially target a different part of the virus in mild cases of COVID-19 than they do in severe cases, and wane significantly within several months of infection.
The news study findings identify new links between the course of the disease and a patient's immune response. They also raise concerns about whether people can be re-infected, whether antibody tests to detect prior infection may underestimate the breadth of the pandemic and whether vaccinations may need to be repeated at regular intervals to maintain a protective immune response.
The study findings were published in the peer reviewed journal: Science Immunology. https://immunology.sciencemag.org/content/5/54/eabe0240
SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, can neutralize the virus. It is, however, unknown which features of the serological response may affect clinical outcomes of COVID-19 patients.
The Stanford study team analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Within this cohort, 25 patients died of their illness. Higher ratios of IgG antibodies targeting S1 or RBD domains of spike compared to nucleocapsid antigen were seen in outpatients who had mild illness versus severely ill patients.
Plasma antibody increases correlated with decreases in viral
RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes. Pseudovirus neutralization assays and a scalable ELISA measuring antibodies blocking RBD-ACE2 interaction were well correlated with patient IgG titers to RBD. Outpatient and asymptomatic individuals’ SARS-CoV-2 antibodies, including IgG, progressively decreased during observation up to five months post-infection.
Dr Scott Boyd, MD, Ph.D., associate professor of pathology told Thailand Medical News, "This is one of the most comprehensive studies to date of the antibody immune response to SARS-CoV-2 in people across the entire spectrum of disease severity, from asymptomatic to fatal. We assessed multiple time points and sample types, and also analyzed levels of viral RNA in patient nasopharyngeal swabs and blood samples. It's one of the first big-picture looks at this illness."
The team found that individuals with severe COVID-19 have low proportions of antibodies targeting the spike protein used by the virus to enter human cells compared with the number of antibodies targeting proteins of the virus's inner shell.
Dr Boyd is a senior author of the study and other senior authors are Dr Benjamin Pinsky, MD, Ph.D., associate professor of pathology, and Dr Peter Kim, Ph.D., the Virginia and D. K. Ludwig Professor of Biochemistry. The lead authors are research scientist Dr Katharina Röltgen, Ph.D.; postdoctoral scholars Dr Abigail Powell, Ph.D., and Dr Oliver Wirz, Ph.D.; and clinical instructor Dr Bryan Stevens, MD.
The team studied 254 people with asymptomatic, mild or severe COVID-19 who were identified either through routine testing or occupational health screening at Stanford Health Care or who came to a Stanford Health Care clinic with symptoms of COVID-19. Of the people with symptoms, 25 were treated as outpatients, 42 were hospitalized outside the intensive care unit and 37 were treated in the intensive care unit. Twenty-five people in the study died of the disease.
The SARS-CoV-2 binds to human cells via a structure on its surface called the spike protein. This protein binds to a receptor on human cells called ACE2. The binding allows the virus to enter and infect the cell.
Once inside, the virus sheds its outer coat to reveal an inner shell encasing its genetic material. Soon, the virus co-opts the cell's protein-making machinery to churn out more viral particles, which are then released to infect other cells.
Certain antibodies that recognize and bind to the spike protein block its ability to bind to ACE2, preventing the virus from infecting the cells, whereas antibodies that recognize other viral components are unlikely to prevent viral spread. Current vaccine candidates use portions of the spike protein to stimulate an immune response.
Dr Boyd and his colleagues analyzed the levels of three types of antibodies ie IgG, IgM and IgA and the proportions that targeted the viral spike protein or the virus's inner shell as the disease progressed and patients either recovered or grew sicker. They also measured the levels of viral genetic material in nasopharyngeal samples and blood from the patients.
Finally, they assessed the effectiveness of the antibodies in preventing the spike protein from binding to ACE2 in a laboratory dish.
Dr Boyd explained, "Although previous studies have assessed the overall antibody response to infection, we compared the viral proteins targeted by these antibodies. We found that the severity of the illness correlates with the ratio of antibodies recognizing domains of the spike protein compared with other nonprotective viral targets. Those people with mild illness tended to have a higher proportion of anti-spike antibodies, and those who died from their disease had more antibodies that recognized other parts of the virus."
The study team cautioned that although the study identified trends among a group of patients, there is still substantial variability in the immune response mounted by individual patients, particularly those with severe disease.
Dr Boyd said, "Antibody responses are not likely to be the sole determinant of someone's outcome. Among people with severe disease, some die and some recover. Some of these patients mount a vigorous immune response, and others have a more moderate response. So, there are a lot of other things going on. There are also other branches of the immune system involved. It's important to note that our results identify correlations but don't prove causation."
Interestingly as in other studies, the research team found that individuals with asymptomatic and mild illness had lower levels of antibodies overall than did those with severe disease. After recovery, the levels of IgM and IgA decreased steadily to low or undetectable levels in most patients over a period of about one to four months after symptom onset or estimated infection date, and IgG levels dropped significantly.
Dr Boyd said, "This is quite consistent with what has been seen with other coronaviruses that regularly circulate in our communities to cause the common cold. It's not uncommon for someone to get re-infected within a year or sometimes sooner. It remains to be seen whether the immune response to SARS-CoV-2 vaccination is stronger, or persists longer, than that caused by natural infection. It's quite possible it could be better. But there are a lot of questions that still need to be answered."
Dr Boyd is a co-chair of the National Cancer Institute's SeroNet Serological Sciences Network, one of the nation's largest coordinated research efforts to study the immune response to COVID-19.
He is the principal investigator of Center of Excellence in SeroNet at Stanford, which is tackling critical questions about the mechanisms and duration of immunity to SARS-CoV-2.
Dr Boyd explained, "For example, if someone has already been infected, should they get the vaccine? If so, how should they be prioritized? How can we adapt seroprevalence studies in vaccinated populations? How will immunity from vaccination differ from that caused by natural infection? And how long might a vaccine be protective? These are all very interesting, important questions."
The study team concluded, “One implication of our finding of waning antibody levels is that seroprevalence studies may, over time, underestimate the proportion of the investigated population which has been previously infected with SARS-CoV-2. The decrease in antibodies after infection also raises the question of how long antibodies elicited by vaccination will last, and whether frequent boosting will be needed to maintain protection, assuming that safe and effective vaccines are identified. The current vaccination strategies undergoing clinical trials differ from natural infection in a variety of ways, including the method for generating or introducing viral antigens into the body, the site of exposure, and the presence of adjuvants . It is possible that some of the vaccine approaches may generate more potent and long-lasting antibodies than natural infection, in which the virus may have currently unknown mechanisms for subverting humoral immune responses. Further detailed study of the generation of memory B cell populations, short- or long-lived plasma cells, and T cell memory to SARS-CoV-2 as well as other coronaviruses should begin to clarify some of these key mechanistic points.”
Thailand Medical News will be providing more emerging studies in the next few weeks that substantiated our hypothesis.
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