BREAKING! U.S. NIAID Suppresses Study Results Showing Natural Infection By SARS-CoV-2 Boost Antibodies Against HCoV-OC43 Virus But Not Vaccination!

In a related development, it has come to light that the study findings by a research team from Geisel School of Medicine at Dartmouth College-USA, Johns Hopkins School of Medicine, Hadassah University Medical Center-Israel, Université libre de Bruxelles-Belgium and CHU St Pierre Hospital-Belgium that also included medical scientists from the U.S. National Institute of Allergy and Infectious Diseases-National Institutes of Health were deliberately prevented from being released to the media as per instructions given to the communications department at the U.S.NIAID by 'higher ups'. However due to pressure by partners in the research team, a version of the study findings was released on a preprint server with the communications departments of the various entities involved, instructed to not to send out any PR releases or arrange for any media coverage of the study!

 
The study findings showed that natural infection by SARS-CoV-2 boost antibodies against HCoV-OC43 virus but not vaccination!
 
According to the study abstract, “Pre-existing antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse.”
 
Interestingly in this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, the study team tested for cross reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the β-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross react.
 
Although further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity.
 
The study findings provide evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity.
 
The study findings were published on the preprint server: medRxiv https://www.medrxiv.org/content/10.1101/2021.10.27.21265574v1
 
Why the U.S. NIAID is suppressing the mainstream media from covering about the study results is anyone’s guess. It should also be noted that that this is not the first time that it has come to light that the U.S. NIAID has been trying to suppress media coverages of studies or even suppressing studies from being published.
 
The study team led by Dr Margaret E. Ackerman from the department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth College, Hanover observed elevated cross-reactive antibodies to endemic coronaviruses (CoVs), particularly to β-CoV OC43, in severe acute respiratory coronavirus 2 (SARS-CoV -2) natural infection cohorts when compared to naive controls.
 
Importantly pre-existing antibodies to endemic CoVs that cross-react with SARS-CoV-2 have the potential to influence the antibody response to the SARS-CoV-2 vaccination and infection. The magnitude of cross-reactive antibodies found in the current study correlated well with responses to the SARS-CoV-2 spike protein and the S2 subdomain.
 
Key Question As To Whether SARS-CoV-2 Infections Lead To ‘Original Antigenic Sin’ And ‘Antibody-Dependent Enhancement’ Arises?
 
It has been found that the human immune system tends to preferentially utilize immunological memory based on a primary infection when a secondary and slightly different variant of that pathogen is encountered, thus resulting in a biased response to the novel strain.
 
This phenomenon, which is otherwise known as original antigenic sin, may reduce the formation of neutralizing antibodies, thereby dampening the effective clearance of the novel virus.
 
While this phenomenon has been established for influenza and dengue viruses, it has only recently been suggested to exist for SARS-CoV-2 infection. This implies that lower titers of neutralizing antibodies against SARS-CoV-2 may result from the boosting of pre-existing cross-reactive viruses. https://pubmed.ncbi.nlm.nih.gov/19648276/
 
https://pubmed.ncbi.nlm.nih.gov/28192418/
 
https://pubmed.ncbi.nlm.nih.gov/20980526/
 
Interestingly another phenomenon that has been proposed to exist for SARS-CoV-2 infection is an antibody-dependent enhancement (ADE). ADE is described as when cross-reactive antibodies induced by previous exposure to a related pathogen promote infection of cell types bearing antibody Fc receptors, thus potentially raising morbidity and mortality.
 
Although observed in vitro, there has not been abundant evidence for the existence of ADE in the context of the SARS-CoV-2 in vivo. https://www.medrxiv.org/content/10.1101/2020.10.08.20209114v1
 
https://pubmed.ncbi.nlm.nih.gov/34242577/
 
However, the establishment of ADE in cases of dengue fever has motivated concerns about the coronavirus disease 2019 (COVID-19) enhancement. https://pubmed.ncbi.nlm.nih.gov/29097492/
 
In the study, the spike protein sequences of endemic CoVs were aligned with that of SARS-CoV-2 to compare the sequence conservation across human CoVs. Structural conservation was evaluated by superimposing SARS CoV-2 S1 and S2 domains with the most well conserved widely circulating endemic human CoV strain of OC43.
 
Importantly three diverse cohorts were included in the current study to assess the antibody profiles in this observational study. The first small cohort consisted of COVID-19 convalescent individuals, for which serum and mucosal samples were available.
 
A larger second cohort consisted of convalescent plasma donors, acutely infected individuals, and pregnant women infected in their third trimester.
 
Lastly, the third cohort consisted of subjects for whom pre- and post-infection samples were available. A cohort of healthy adults was included that consisted of individuals vaccinated with the SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine, as well as pregnant women who were vaccinated in their third trimester. All samples were analyzed alongside samples from naive and historical negative controls.
 
Interestingly the N-terminal domain (NTD) of SARS-CoV-2 that contains the receptor-binding domain (RBD) showed lower sequence homology to the corresponding subdomains of endemic CoVs as compared to the S2 subdomains.
 
However, superimposition of the SARS CoV-2 S1 and S2 domains with the most well conserved widely circulating endemic human CoV OC43 showed high structural conservation in S2 and the NTD, as well as a complete lack of homology in the RBD.
 
From data based on both structural and sequence homology, the study team suggested that preexisting antibodies raised against endemic human CoVs are more likely to target the better-conserved regions of SARS-CoV-2 like S2, and less likely to recognize the RBD.
 
Significantly, detailed examination of antibody responses against endemic and pandemic human CoVs in subjects one month after SARS-CoV-2 infection found heightened OC43-specific antibody responses in SARS-CoV-2 convalescents compared to naive controls. The magnitude of these responses correlated with responses to SARS-CoV-2 spike protein and the S2 subdomain.

Antibody responses to SARS-CoV-2 and endemic CoV spike proteins were measured in diverse cohorts. While antibodies to SARS-CoV-2 were induced across all isotypes, only IgA and IgG responses to endemic CoV were robustly boosted, and only among naturally-infected but not vaccinated individuals. These recalled, cross-reactive responses to endemic CoV primarily recognized the better conserved S2 domain and were non-neutralizing. While other antiviral activities of broadly cross-reactive S2-specifc antibodies are not known, the differing antigenicity of natural infection and vaccination with stabilized pre-fusion spike has potential implications for the breadth and level of protection afforded by each.

The study team also found OC43-specific immunoglobulin G (IgG) in both the serum and mucosal samples, as well as mucosal IgA, but not IgM, in acutely infected subjects two weeks post-COVID-19 diagnosis.
 
This new finding indicates that these elevated responses were real and not due to newly induced antibody lineages with cross-reactivity to OC43.
 
Detailed testing of serum samples pre- and post- SARS-CoV-2 infection reinforced the hypothesis that pre-existing clonal families were boosted by the SARS-CoV-2 infection.
 
It was further found that the SARS-CoV-2 S2 domain and whole spike (S-2P) specific antibodies isolated from convalescent serum were cross-reactive to the spike of OC43; however, RBD-specific antibodies were not. Similarly, antibodies isolated using OC43 were cross-reactive with SARS-CoV-2 S-2P and S2 but not the RBD, thereby indicating that cross-reactivity between these viral spike proteins has a link to the more conserved S2 domain. Both OC43 S-specific and SARS-CoV-2 S2-specific antibodies were non-neutralizing, which is consistent with the fact that neutralizing antibodies tend to target the RBD of SARS-CoV-2.
 
Alarmingly as compared to naturally infected and vaccinated subjects representing exposure to unstabilized and proline stabilized S antigens, respectively, the immunogens starkly contrasted. The immune response generated from vaccination with the SARS-CoV-2 spike protein stabilized in the pre-fusion conformation had either very weak or no cross-reactive profiles, thus suggesting critical importance of the conformational state of the spike protein to resulting humoral responses.
 
Furthermore, the high levels of neutralization activity resulting from vaccination suggest favorable antigenicity of the pre-fusion conformation of the spike protein, and that the costs of original antigenic sin might be avoided by immunogen design.
 
Dr Ackerman told Thailand Medical News, “In sum, this study provides evidence that antibodies targeting OC43 are robustly boosted in response to SARS-CoV-2 infection but not vaccination with stabilized S, and that the S2 subdomain of the spike protein is likely responsible for triggering a recalled, IgG-dominated response.”
 
Most importantly, it should be noted that neutralization is not the only mechanism by which antibodies confer protection, as cross-reactive antibodies could also interact with the receptors for Fc region of antibodies found on the surface of innate immune cells and promote protective effector functions.
 
Hence the study team emphasizes the need for further work aimed at characterizing the effector function potential of these antibodies. Future work should also be focused on understanding their role in vaccine-mediated protection to provide a more complete picture of the relative risks and benefits of this recall response relevant to vaccine design, particularly in the context of viral variants of concern.
The study team concluded, “Whereas numerous studies have focused on the antibody responses elicited from vaccination towards the SARS-CoV-2 S protein and specifically the RBD, little is known about the effect previous exposure to endemic CoV may have on vaccination. However, our observations of limited boosting agree with two recent reports.”
https://www.nature.com/articles/s41467-021-25167-5
 
https://www.medrxiv.org/content/10.1101/2021.10.27.21265574v1.full.pdf
 
They added, “Further evaluation of a cohort vaccinated with a nonstabilized form of S will be required to begin to elucidate whether this is a feature of the stabilization itself, the mRNA-based vaccine modality, or if some other aspect of the vaccine formulation is responsible. Most importantly, this evidence of cross-reactivity has implications for the design of vaccines targeting SARS-CoV-2 variants. There is a risk that subsequent antibody responses might disregard the novel epitopes in favor of those already more familiar, although it should be emphasized that cross-reactivity was not a deterrent to the development of multiple highly efficacious SARS-CoV-2 vaccines.”
 
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