Common cold rhinovirus combats COVID-19

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Exposure to the rhinovirus, the most frequent cause of the common cold, can protect against infection by the virus which causes COVID-19, Yale researchers have found.

In a new study, the researchers found that the common respiratory virus jump-starts the activity of interferon-stimulated genes, early-response molecules in the immune system which can halt replication of the SARS-CoV-2 virus within airway tissues infected with the cold.

Triggering these defenses early in the course of COVID-19 infection holds promise to prevent or treat the infection, said Ellen Foxman, assistant professor of laboratory medicine and immunobiology at the Yale School of Medicine and senior author of the study. One way to do this is by treating patients with interferons, an immune system protein which is also available as a drug.

“But it all depends upon the timing,” Foxman said.

The results were published June 15th in the Journal of Experimental Medicine.

Previous work showed that at the later stages of COVID-19, high interferon levels correlate with worse disease and may fuel overactive immune responses. But recent genetic studies show that interferon-stimulated genes can also be protective in cases of COVID-19 infection.

Foxman’s lab wanted to study this defense system early in the course of COVID-19 infection.

Since earlier studies by Foxman’s lab showed that common cold viruses may protect against influenza, they decided to study whether rhinoviruses would have the same beneficial impact against the COVID-19 virus.

For the study, her team infected lab-grown human airway tissue with SARS-CoV-2 and found that for the first three days, viral load in the tissue doubled about every six hours. However, replication of the COVID-19 virus was completely stopped in tissue which had been exposed to rhinovirus.

If antiviral defenses were blocked, the SARS-CoV-2 could replicate in airway tissue previously exposed to rhinovirus.

The same defenses slowed down SARS-CoV-2 infection even without rhinovirus, but only if the infectious dose was low, suggesting that the viral load at the time of exposure makes a difference in whether the body can effectively fight the infection.

The researchers also studied nasal swab samples from patients diagnosed close to the start of infection. They found evidence of rapid growth of SARS-CoV-2 in the first few days of infection, followed by activation of the body’s defenses. According to their findings, the virus typically increased rapidly for the first few days of infection, before host defenses kicked in, doubling about every six hours as seen in the lab; in some patients the virus grew even faster.

“There appears to be a viral sweet spot at the beginning of COVID-19, during which the virus replicates exponentially before it triggers a strong defense response,” Foxman said.

Interferon treatment holds promise but it could be tricky, she said, because it would be mostly effective in the days immediately after infection, when many people exhibit no symptoms. In theory, interferon treatment could be used prophylactically in people at high risk who have been in close contact with others diagnosed with COVID-19. Trials of interferon in COVID-19 are underway, and so far show a possible benefit early in infection, but not when given later.

These findings may help explain why at times of year when colds are common, rates of infections with other viruses such as influenza tend to be lower, Foxman said.

There are concerns that as social distancing measures ease, common cold and flu viruses – which have been dormant over the past year – will come back in greater force. Interference among respiratory viruses could be a mitigating factor, creating an “upper limit” on the degree to which respiratory viruses co-circulate, she said.

“There are hidden interactions between viruses that we don’t quite understand, and these findings are a piece of the puzzle we are just now looking at,” Foxman said.


Edward Jenner, was an English surgeon, who is credited with creating the first vaccine, in 1798, which was used to combat the Smallpox virus. Jenner employed the zoonotic Cowpox virus (as a live vaccine). Using the observation that milkmaids were somehow protected against Smallpox, he hypothesized that the pus from the milkmaid’s skin blisters could be used as a vaccine to inoculate other people, to protect against Smallpox. His successful clinical trial, of 23 patients, ultimately led the English Parliament to pass the Vaccination Act in 1840, making vaccination a new public health policy. His approach was used all over the world and ultimately led to the eradication of Smallpox by the WHO (World Health Organization) in 1980, nearly 40 years ago.

What can we learn today from Jenner’s observations that could be useful for designing a vaccine against SARS-CoV-2? Are there any less pathogenic viruses that could be used as a vaccine against SARS-CoV-2? The answer is probably yes.

For example, there are four human coronaviruses that are known to cause the common cold, namely 229E, NL63, OC43, and HKU1, which lead to mild upper respiratory infections (URI’s) [1–4]. According to the CDC, their route of transmission appears to be similar to SARS-CoV-2, but the onset of symptoms is quite mild in comparison. https://www.cdc.gov/coronavirus/general-information.html

All five viruses contain a viral spike glycoprotein (VSG), which is the main target of SARS-CoV-2 vaccine development world-wide.

One attractive hypothesis is that inoculation with the common cold coronavirus (229E, NL63, OC43, or HKU1) or, more likely, an attenuated version, could provide immunity against SARS-CoV-2. If that was the case, then we might already have a naturally-occurring vaccine at hand, that could soon be implemented, off the shelf.

To begin to test this hypothesis, we retrieved the protein sequences of the relevant viral spike glycoproteins from a variety of available databases, such as UniProt/FASTA, and analysed their shared protein sequence similarity and identity using BLASTP.

Table 1 summarizes the results of this brief analysis.

Table 1

Protein sequence identity of the viral spike glycoproteins of SARS-Cov-2 and the common cold corona viruses (229E, NL63, OC43, or HKU1).

Common Cold VSGSARS-Cov-2 VSG
229E27.78%
NL631.27%
OC4337.65%
HKU136.66%

Based on this simple analysis, the viral spike glycoprotein of coronavirus OC43 appears to be the most similar to that of SARS-CoV-2, with nearly 38% identity and up to 53% similarity (Figure 1). In fact, the viral spike glycoproteins of coronavirus OC43 and HKU1 are also quite similar to each other, sharing 64% identity (Figure 2). So, both OC43 and HKU1 would possibly be good candidates for developing a potential vaccine to SARS-CoV-2.

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Object name is aging-12-104166-g001.jpg
Figure 1
Protein sequence alignments of the Viral Spike Glycoproteins (VSGs) from SARS-CoV-2 and the related Human Coronavirus OC43. Areas of high sequence homology are highlighted in color, which may represent potentially shared epitopes for immune recognition. Generated using the online program BLASTP, by pairwise sequence analysis.
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Object name is aging-12-104166-g002.jpg
Figure 2
Protein sequence alignments of the Viral Spike Glycoproteins (VSGs) from two related Human Coronaviruses, namely OC43 and HKU1. Note the high homology between OC43 and HKU1, with up to 78% similarity. Generated using the online program BLASTP, by pairwise sequence analysis. The same potentially shared epitopes, highlighted in color in Figure 1, are also highlighted here, for comparison.

Is there any clinical evidence to support these assertions?

Three recent papers published in Nature, Science and Cell have begun to look at the existence of cross-reactive immunity in a variety of patient populations, especially patients infected with the SARS-CoV-2 (with frank COVID-19 or asymptomatic) and uninfected patients. The results are all quite encouraging, directly demonstrating cross-reactive T-cell immunity between SARS-CoV-2 and the existing known human cold coronaviruses (229E, NL63, OC43, and HKU1) [5–7]. One of the papers also detected cross-reactive serum IgG as well.

These reports clearly provide tantalizing clinical evidence for the feasibility of using a human cold coronavirus, such as attenuated OC43 or HKU1, as a potential vaccine for the prevention of COVID-19. What would Edward Jenner suggest, if he was living today?.

Further support for this idea has recently appeared in the popular press and was supported by data from the National Institutes of Health (NIH), because there is significant shared serological cross-reactivity between SARS-CoV-2, OC43 and HKU1 [8, 9].

Fortunately, two live coronaviruses, OC43 and 229E, associated with the common cold, are actually commercially available from the American Type Culture Collection (ATCC), which could greatly facilitate their potential use in new, off-the-self, vaccine development.

https://www.lgcstandards-atcc.org/products/all/VR-1558.aspx

https://www.lgcstandards-atcc.org/products/all/VR-740.aspx

Moreover, the VSGs from OC43 and HKU1, may also be sufficient to convey cross-reactive immunity, when recombinantly-inserted in another non-pathogenic viral vector, specifically designed for live or attenuated vaccine immunizations (Figure 3).

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Figure 3
Schematic diagram summarizing the possible use of Human Coronaviruses that cause the common cold as naturally-occurring vaccines for targeting SARS-CoV-2 and preventing COVID-19. A brief flow-diagram is presented, outlining a vaccine development strategy.

Ultimately, this may be a safer approach, than using the VSG from SARS-CoV-2, which may have mild negative, or even pathogenic, side-effects. Only time will tell.

Nature may have already done the “experiment” or “clinical trial” for us, as so many people that are SARS-CoV-2 virus-positive, are asymptomatic and show evidence of cross-reactive immunity, to both SARS-CoV-2 and the common cold coronaviruses.

These findings have been independently confirmed now, in several different laboratories world-wide.

UNIPROT accession numbers for 5 relevant protein sequences:

P0DTC2,

SPIKE_SARS2 Spike glycoprotein, Severe acute respiratory syndrome coronavirus 2

https://www.uniprot.org/uniprot/P0DTC2.fasta

Q6TUL7,

CVH22 Spike glycoprotein Human coronavirus 229E

https://www.uniprot.org/uniprot/Q6TUL7.fasta

Q6Q1S2,

SPIKE_CVHNL Spike glycoprotein Human coronavirus NL63

https://www.uniprot.org/uniprot/Q6Q1S2.fasta

P36334,

SPIKE_CVHOC Spike glycoprotein Human coronavirus OC43

https://www.uniprot.org/uniprot/P36334.fasta

Q0ZME7,

SPIKE_CVHN5 Spike glycoprotein Human coronavirus HKU1

https://ebi10.uniprot.org/uniprot/Q0ZME7.fasta

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732292/


More information: Nagarjuna Cheemarla et al, Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics, Journal of Experimental Medicine (2021). DOI: 10.1084/jem.20210583

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