Antibodies COVID-19: Another Study Shows That Antibodies Not Effective In Treating COVID-19 And Warns Of Vaccines Focusing Only On Spike Proteins

Antibodies COVID-19: Another study by researchers from Nanjing University Medical School -China led by Dr Chao Wu and Dr Rui Huang, both infectious disease and immunology specialists show that various factors contribute to the fact that antibodies might not be a good solution to treat COVID-19 coupled with the fact that most convalescent treatments did not produce positive results due to lack of the right types and amounts of antibodies.


 
The study also warns that vaccines not producing the right potent immune responses and also only using one type of spike protein could lead to adverse conditions of both increased inflammatory issues and also antibody-dependent enhancement (ADE) phenomenon. The study team said that a comprehensive analysis of antibody responses in COVID-19 patients could inform the development of an effective vaccine
 
The study findings were published in the journal: PLOS Pathogens https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008796
 
The study results showed that the neutralizing activity of antibodies from recovered patients is typically not strong, and declines sharply within one month after hospital discharge.
 
For the study, the researchers continuously monitored SARS-CoV-2-specific antibody responses in 19 non-severe and seven severe COVID-19 patients for seven weeks from disease onset.
 
It was observed that most patients generated antibody responses against SARS-CoV-2, including the viral nucleoprotein and three parts of the spike protein: the receptor-binding domain, S1 protein, and ectodomain. Although 80.7% of recovered COVID-19 patients had varying levels of antibody neutralization activity against SARS-CoV-2, only a small portion of patients elicited a potent level of neutralization activity.
 
The study findings highlights the importance of carefully selecting blood samples from recovered patients using antibody neutralization assays prior to transfusion into other COVID-19 patients.

Significantly, it was observed that three to four weeks after hospital discharge, the neutralizing activity of antibodies from recovered patients declined significantly, suggesting that recovered COVID-19 patients might be susceptible to reinfection with SARS-CoV-2.
 
Furthermore the study found that severe COVID-19 patients had a large amount of non-neutralizing antibodies, which may contribute to antibody-dependent enhancement of infection.
 
Utilizing four recombinant SARS-CoV-2 related antigens, the team was able to monitor the dynamic antibody responses with various specificities. The team demonstrated that the kinetics profile of IgM or IgG responses specific for four antigens might be distinct in time and magnitude aspects.
 
The study suggested that combined detection of NP-specific IgM and ECD-specific IgG could greatly improve the sensitivity of serological assay especially during the first 2 weeks after symptom onset, compared to the mere inclusion of either the NP-specific antibody or RBD-specific antibody.
 
A small portion of non-severe COVID-19 patients was still identified as seronegative. This was consistent with recent findings. First, it is well-est ablished that the non-severe COVID-19 patients generated significantly lower level of viral-specific humoral response compared to that in severe patients. Besides, asymptomatic SARS-CoV-2 carrier patients had a remarkably reduced level of virus specific IgG levels, compared to symptomatic group, accompanied by prolonged presence of viral RNA and remarkable reduction of IgG and neutralizing activities. The differential pattern of specific humoral responses elicited by SARS-CoV-2 might be contributed by host factors such as age and host inflammatory responses. https://pubmed.ncbi.nlm.nih.gov/32221519/
and https://academic.oup.com/clinchem/article/66/8/1102/5855668 and https://www.nature.com/articles/s41591-020-0965-6?fbclid=IwAR2C_zNQA7_N_A8RV3Q5ZzWriY-Vf01rOC7Nb-nlRNbGt9W6nmIxKKem4BI and https://www.nature.com/articles/s41586-020-2355-0
 
It must be noted that it is unclear whether clinically recovered patients acquire the protective immunity from re-infection. Limited information regarding the neutralization activities of the clinically recovered patients are available.
 
The study team reported that 80.7% of convalescent sera had varying degrees of neutralization activities, and only a small portion of patients elicited a potent level of neutralization activity. Preliminary studies indicated that the major factor associated with the efficacy of convalescent plasma therapy is the neutralizing antibody titer of the convalescent plasma obtained from the donor. The research data also demonstrated the importance of prior selection of convalescent serum using neutralization assays. Additionally, the rapidly declined neutralizing activities in COVID-19 clinically recovered patients within 28 days after discharge, suggesting that the circulating anti-SARS-CoV-2 neutralizing antibodies might have a relatively short half-life.
 
This was consistent with previous studies demonstrating that the humoral immunity rapidly waned over time in patients that recovered from SARS-CoV and MERS-CoV infections. https://pubmed.ncbi.nlm.nih.gov/17855683/
and https://pubmed.ncbi.nlm.nih.gov/27532807/
 
The study also revealed a pivotal role of mucosal immunity in humoral protection against SARS-CoV-2. First, the team discovered that the neutralization activities were strongly associated with S1-specific IgA and ECD-specific IgA responses, and moderately correlated with RBD-specific IgA and IgG responses, suggesting that mucosal immunity might contribute greatly to viral neutralization. Even though the current temporal antibody profile did not include the IgA responses, previous studies demonstrated the presence of NP or RBD-specific IgA responses in the early phase during SARS-CoV-2 infection, whereas the systemic IgM and IgG responses occurred later. Of note, the RBD-specific IgA response declined sharply after hospital discharge, accompanied by the rapidly waned neutralization activities. Due to the relatively short half-life of IgA , the study finding of rapidly declined RBD-specific IgA response is not surprising, which might be responsible for the clinical observation of prolonged viral RNA shedding in fecal samples or re-occurrence of positive viral RNA in rectal swabs .
 
Significantly higher level of IgA response was detected from the clinically recovered severe patients in comparison to non-severe patients. Consistent with the findings, vaccine-induced potent mucosal IgA was associated with lower level of viral load and reduced pulmonary pathological damages upon challenge with SARS-CoV. The beneficial role of IgA during the COVID-19 disease course still requires thorough investigation. It is important to further analyze the magnitude of IgA responses between the survivor and non-survivor groups in a large cohort. https://pubmed.ncbi.nlm.nih.gov/18178835/
 
The ADE or antibody-dependent enhancement phenomenon has been a major concern in viral infections. Antibody specificity, concentration, neutralization ability, and isotype might define the ability of antibody to neutralize virions and protect the host or promote ADE and acute inflammation. https://www.nature.com/articles/s41577-020-0321-6?fbclid=IwAR2OHhAhzFzJpqZOEI_ifMLBpihW-beWYoGQ0L4XJ5cDQRpleOQ5kQ9lH28
and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478436/ and https://pubmed.ncbi.nlm.nih.gov/29097492/
and https://pubmed.ncbi.nlm.nih.gov/27627203/
 
Past animal studies of SARS-CoV indicated that the spike protein RBD region or HR2 domain-specific antibodies might exert a beneficial role in viral clearance, whereas the antibodies specific for NP and other S protein epitopes other than the RBD and HR2 domain might induce ADE and escalate acute inflammation [29, 30]. https://pubs.acs.org/doi/10.1021/acsinfecdis.6b00006 and https://www.jimmunol.org/content/181/9/6337
 
IgG isotype also controls the effector function, in which IgG1 and IgG3 engage FcrRIIa and FcrRIIb with high affinity leading to the possible occurrence of ADE.
 
The study data showed that severe patients generated significantly higher level of antibody titers, especially for NP-specific IgG1 and RBD-specific IgG1 and IgG3 compared to the non-severe patients. Consistently, the team did not identify any correlation between the binding antibody titers and the neutralizing activities from the convalescent sera of severe COVID-19 patients, suggesting that a large amount of non-neutralizing antibodies might have been present in the severe group.
 
Whether such higher magnitude of NP-specific IgG1 or RBD-specific IgG1 and IgG3 contributed to the severity of COVID-19 disease progression remains to be determined.
 
The study data also have important implications for the current development of the COVID-19 vaccine. The majority of patients generated potent humoral responses recognizing spike protein-related antigens, including RBD, S1 and ECD proteins, implying their high immunogenicity makes them vaccine candidates.
 
Additionally, the study correlation analyses showed that the neutralizing activities were strongly correlated with ECD-specific IgA and S1-specific IgA responses compared to RBD-specific IgA responses. Several human neutralizing monoclonal antibodies (mAbs) isolated from convalescent COVID-19 patients were not exclusively targeted at RBD region. For example, the epitope of a potent neutralizing mAb, 4A8, is within N terminal of spike protein, while other mAbs targeted at cryptic epitopes on spike trimeric interface. https://science.sciencemag.org/content/369/6504/650.abstract
and https://pubmed.ncbi.nlm.nih.gov/32413276/
 
This study and others suggested that the antibodies targeting at diverse domains of the spike protein might greatly contribute to higher neutralization activities. Consequently, the inclusion of the full-length spike protein might be ideal to elicit humoral responses targeting to the major neutralizing targets.
 
Furthermore, the IgG subclass responses in COVID-19 patients were skewed toward IgG1 and IgG3, and induction of optimal antibody isotypes such as IgA and certain IgG subclasses such as IgG2 might be desired in vaccine studies of SARS-CoV-2.
 
The study had some limitations. It only included a small number of recovered COVID-19 patients and did not have the deceased COVID-19 patients. Second, the cytokines and antigen-specific cellular responses were not serially monitored, which could facilitate the understanding of innate and adaptive immune responses during COVID-19 disease. Thirdly, the mucosal IgA responses such as the IgA responses in saliva warrant further investigation.
 
The team concludes that the study demonstrated that the majority of COVID-19 patients generated a distinct profile of immune response against NP and spike protein-related antigens in both time and magnitude aspects. Therefore, combining NP and ECD as detecting antigens could further enhance the sensitivity of the serological assay.
 
Also, 80.7% of the convalescent sea from COVID-19 patients displayed varying levels of neutralization activities against SARS-CoV-2, which correlated with S1-specific and ECD-specific IgA responses in non-severe patients. A rapid decline in these neutralizing activities was observed, accompanied by a sharply reduced RBD-specific IgA response.
 
The study team says that the study provides important insights for serological testing, antibody-based intervention, and vaccine design.
 
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