Wednesday, March 4, 2020

Does Coronavirus - COVID-19 - Promote Re-Infection or is it Bi-Phasic?

Can you recover from Covid 19 and then become reinfected?

The answer - unclear. What is clear is that a few people have been cleared of the infection and then became sick again with same, but potentially worse symptoms.

The question is whether this is a re-infection or whether the virus produces bi-phasic infection, or two-phase infection.

If re-infection occurs, then there is a risk that the second infection may be much worse because coronavirus may, although it is not entirely clear, enhance re-infection through a mechanism called "antibody-dependent enhancement."

The answers are unclear, but questions about re-infection are critical when considering risk impacts and mitigation strategies:
Apoorva Mandavilli (Feb. 29, 2020). They recovered from the coronavirus. Were they infected again? The New York Times

Coronaviruses are on the whole poorly understood, she said. Before the SARS epidemic, coronaviruses were not known to cause serious illnesses...

....Dr. Perlman’s research with MERS has shown that the strength of the immune response depends on the severity of the infection, but that even in those with severe disease — which should produce the strongest immune responses — the immunity seemed to wane within a year....

...One worrisome possibility is that the coronavirus follows what is known as a biphasic infection: the virus persists and causes a different set of symptoms than observed in the initial bout....
Stanway, D., & Kelland, K. (2020, February 28). Explainer: Coronavirus reappears in discharged patients, raising questions in containment fight. Reuters. 
Other experts have also raised the possibility of “antibody-dependent enhancement”, which means exposure to viruses might make patients more at risk of further infections and worse symptoms.

China has so far discharged 36,117 patients, according to data from the National Health Commission released on Friday, which represents almost 46% of the total cases on the Chinese mainland. If the 14% rate of reinfection is accurate and remains consistent, it could pose a wider health risk.

“I would say that it is less about if it is possible that re-infection can occur than how often it occurs,” Cheng said.  

Wan, Y., Shang, J., Sun, S., Jai, W., Chen, J., Geng, Q, He, L., Chen, Y., Wu, J., Shi, Z., Zhou, Y., Du, L., Li, F. (2020). Molecular mechanism for anti-body dependent enhancement of coronavirus. Journal of Virology, 94 (5) e02015-19; DOI: 10.1128/JVI.02015-19.

Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that MAb binds to the virus surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, MAb binds to cell surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized MAb dosages in viral-receptor-dependent, Fc-receptor-dependent, and both-receptors-dependent viral entry pathways, delineating guidelines on MAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.

IMPORTANCE Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses.
Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.
Chun-Sheng Yeh, Jyh-Yuan Yang, Wu-Tse Liu, Jason C. Huang, Yi-Ming Arthur Chen, Sheng-Fan Wang (2016) SARS coronavirus has antibody-dependent enhancement (ADE) effect through the autologous antibodies against envelope spikes on Fcγ receptor expressing cells. Supplement : Abstracts of the 2016 International Symposium on HIV and Emerging Infectious Diseases (ISHEID) Journal of Virus Eradication 2016; 2 supplement 1Abstract No : P84
Abstract :

Background: Severe acute respiratory syndrome coronavirus (SARS-CoV) had an outbreak in 2003. Even though SARS-CoV now remains in the natural bat reservoir, it still has the reemergence threat. Vaccination is a prophylactic strategy for this disease control and prevention. Antibody-dependent enhancement (ADE) is a mechanism by which viruses such as, dengue virus, feline coronavirus, and HIV, as alternative strategies, apply to infect host cells to gain entry into the target cells by taking advantage of anti-viral humoral immune responses. The ADE effect of SARS-CoV infection is controversial.

Materials: SARS-CoV TW1 strain (GenBank accession no., AY291451) was obtained from Taiwan CDC and SARS-CoV pseudotyped virus particles harboring the SARS-CoV S protein with HIV core structure virus were constructed for infectivity assay... 
Results: We found that SARS-CoV uses ADE to enhance its infectivity towards a human promonocyte cell line-HL-CZ. Quantitative-PCR and immunofluorescent staining indicated that SARS-CoV can replicate in HL-CZ and display virus-induced cytopathic effect as well as increased TNF-α, IL-4 and IL-6 two days postinfection. 
Results from flow-cytometry indicate HL-CZ cells express angiotensin converting enzyme 2 (ACE2), a SARS-CoV receptors and higher level of FcrRII receptors. Our data demonstrated that higher diluted sera from SARS-CoV infection patients promote SARS-CoV infection and induced higher level of apoptosis. 
Infectivity assay demonstrated that ADE of SARS-CoV is majorly mediated by diluted antibodies against envelope spikes rather than nucleocapsid proteins. We further generated monoclonal antibodies against spike proteins of SARS-CoV and found that most monoclonal antibodies promote SARS-CoV infection.

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