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SARS-CoV-2 reinfection: What does it mean?

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coronavirus

Not only the popular press but even some of my distinguished science colleagues are claiming that the recent report of reinfection of a COVID-19 patient is the end of the world. Nothing could be farther from the truth.

First, the facts. The patient is a healthy Hong Kong male who was diagnosed by PCR with SARS-CoV-2 infection on 26 March 2020, after developing cough, fever, sore throat and headache. He was hospitalized for two weeks and discharged on 14 April after two consecutive negative SARS-CoV-2 PCR tests done 24 h apart.

Upon returning to Hong Kong from Spain on 15 August 2020, the patient was tested by PCR for SARS-CoV-2 and found to be positive. He was hospitalized but remained asymptomatic. Oropharyngeal viral loads gradually decreased during his hospital stay. Patient was IgG negative for SARS-CoV-2 nucleoprotein 10 days after symptom onset for the first infection, and 1 day after hospitalization for the second episode. However a serum specimen taken 5 days after the second hospitalization was positive. I conclude that the first IgG test was likely negative because it was too soon after infection; an IgM test should have been done. It is very likely that the patient eventually became IgG positive after the first infection. However, levels of IgG appear to have decreased substantially in the ensuing months, allowing the second infection. IgG positivity on day 5 after the second infection is a classic memory response.

Whole genome sequence analysis of viruses isolated during the patient’s first and second infections clearly revealed that he was infected with two different isolates.

I am convinced that this patient was infected twice by two different isolates of SARS-CoV-2. The second infection is likely a consequence of waning anti-viral IgG antibodies. However, patient T cells were not studied. Such an analysis would have been useful because if virus-specific T cells had been found, it would have suggested why he did not develop disease upon reinfection.

This re-infection is the first of which I am convinced; the others are anecdotal and not supported by laboratory evidence. That gives us one reinfection with SARS-CoV-2 in the nearly 25 million that have been detected so far. To be fair, there are likely other reinfections, and as time passes and antibody levels wane, there will be more. Should we worry?

As long as reinfections with SARS-CoV-2 do not cause disease, I am not worried. Could this patient transmit virus? He was clearly shedding virus the second time; whether it was enough to transmit is not known as PCR Ct values are not given in the manuscript. But if reinfections remain asymptomatic, it doesn’t matter if these infections transmit. Let’s say in the coming months, as antibodies to SARS-CoV-2 wane in the population, more and more reinfections occur. If none or few of them are symptomatic, why do we care about them? If SARS-CoV-2 continues to circulate and causes little disease, it would have little impact.

Reinfection with SARS-CoV-2 in the absence of symptoms is reminiscent of the four seasonal coronaviruses. These viruses circulate widely and infect nearly everyone. Antibody levels appear to wane after each infection. Reinfections occur, but they are generally mild.

As the human population approaches 90% infection with SARS-CoV-2, we will likely see a pattern of waning immunity and reinfection in the absence of symptoms. As I’ve said before, SARS-CoV-2 will become the fifth common cold coronavirus.

Some have suggested that this reinfection story bodes ill for SARS-CoV-2 vaccines. This conclusion is not necessarily true. First, we don’t yet know what kind of immunity the experimental vaccines will produce. There are a few possibilities. The vaccines might not work at all to prevent infection or disease. In this case we would have to depend on other approaches to limit mortality (Mina-style susceptibility testing, quarantine, perhaps antivirals). At the either extreme, some vaccines might prevent both infection and disease. I find this scenario highly unlikely, because not even natural infection can do that. Some of the vaccines in development might produce immunity approximating that of a natural infection – that is, it wanes soon after vaccination. Reinfection will likely occur, but in the absence of disease. The virus will continue to circulate, even in a population that has been widely vaccinated. This scenario will make the vaccine unnecessary at some point in the future.

The reinfected COVID-19 patient simply reinforces what we already knew about the pattern of infection caused by common cold coronaviruses: immunity wanes after infection, reinfection occurs, and there no disease.

Note added 9/1/20: A second reinfected patient has been identified in Nevada.

The future of SARS-CoV-2

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coronavirus

What does the future hold for SARS-CoV-2? Will it remain in its current configuration, with 20% of infections causing serious damage? Will everyone on Earth need to be vaccinated regularly to prevent infection? Allow me to indulge in some speculation and suggest that SARS-CoV-2 will eventually become the fifth common cold coronavirus (CoV).

There are five CoV that regularly cause mild upper respiratory tract infections in most humans. Called OC43, HKU1, 229E and NL63, they infect children in their first years of live and cause little disease. Immunity wanes within a year and reinfections occur regularly, but with little consequence.

OC43, HKU1, 229E and NL63 were originally viruses that infect bats and rodents. Hundreds of years ago these viruses spilled over into humans and eventually became the viruses we know today. It is likely that the initial emergence of these viruses from bat and rodent reservoirs led to epidemics that were not noticed. There was no medicine or science or public health to record such epidemics, and given the much smaller human population, they likely spread slowly and were not noticed amid the generally poor state of human health.

It is likely that since their emergence hundreds of years ago, OC43, HKU1, 229E and NL63 slowly underwent change and became less pathogenic for humans. I base this assumption on the fact that contemporary spillovers of CoVs have led to serious disease in humans. In 2003, SARS-CoV emerged from bats into humans and caused severe atypical respiratory disease; however we were able to eradicate this virus after only 8000 known human infections. In 2013, MERS-CoV emerged from camels into humans, but this virus has never been able to establish itself in humans. Every small outbreak is, for the most part, the consequence of a new spillover of virus from camels into humans. These short chains of infection eventually terminate.

However in late 2019 SARS-CoV-2 emerged from bats into humans and established itself as a human virus. It transmits very well among humans and because 80% of infections are mild, it spreads silently. The more serious infections that require hospitalization contribute little to transmission of the virus in the human population. Indeed, these seriously ill patients have problems because their own immune response has gone awry. SARS-CoV-2 is no longer their problem.

It seems likely that with time, SARS-CoV-2 will change so that infected patients no longer develop serious disease. This assumption is based on the fact that causing serious disease is absolutely not required for virus transmission. As the virus moves through humans over the years, its genome will slowly accumulate mutations as a consequence of error-prone replication. Some of these mutations will be lethal and cause viral replication to cease. Other mutations will be tolerated, and among these will be changes that alter the viral reproduction cycle so that serious disease no longer occurs in 20% of infected patients. Although viral reproduction in seriously ill patients is very low, it is likely that some virus-mediated event early in infection sets the stage for the later immune dysregulation. I submit that mutations will eventually accumulate in the viral genome that prevent these late sequelae.

There is good reason to think that SARS-CoV-2 will eventually lose the ability to cause serious disease. The main selective force for viral evolution is transmission; little else matters (viruses can be selected to become drug resistant but such events play a minuscule role in the bigger scheme of viral evolution). Put another way, there is simply no selective advantage for the virus to remain pathogenic as this property contributes nothing to transmission. With no selection to maintain pathogenicity, SARS-CoV-2 will eventually become benign. It will become the fifth common cold CoV.

Why does SARS-CoV-2 cause severe disease in 20% of infected people? Recall that the ancestors of this virus originated in bats where have likely circulated for many thousands of years. These viruses became well adapted to their bat hosts, such that they replicated efficiently and were transmitted effectively to new hosts. Their genome had evolved to co-exist with the unusual immune system of bats, which is tuned to deal with the damage caused by high oxygen usage during flight. Then one day late in 2019 one of these viruses encounters a human host. It replicates well in that host but in the face of a very different immune response, problems such as cytokine storms arise. It will be some years before the genome of SARS-CoV-2 changes sufficiently so that it no longer triggers aberrant immune reactions in the human host.

How long it will take before SARS-CoV-2 changes sufficiently to become common cold CoV #5 is unknown. It depends in part on how well the experimental vaccines currently under development work. I suspect that none of these vaccines will completely block viral reproduction, although they may mitigate disease. Consequently SARS-CoV-2 will continue to circulate and the mutations that will eventually reduce its virulence will arise. I do think that at one day in the future we will no longer need any of the SARS-CoV-2 vaccines that are currently in development, because the virus will no longer cause serious disease. For this reason we do not have vaccines against the four common cold CoVs – there is no medical need for them.

To put this another way, here we have a pandemic virus whose emergence could have been stopped had we invested a few billion dollars in development of pan-CoV antiviral drugs. Instead, many companies and governments are spending billions of dollars to develop vaccines that will one day be obsolete. This lack of vision should infuriate every human on Earth.

Pandemic viruses will continue to emerge from animal reservoirs in the coming years. Will we be ready for them? I doubt it.

Children transmit SARS-CoV-2

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Among the mountains of false information being peddled during the current pandemic, one of the most offensive is being used to drive opening of schools in the fall: that children do not transmit SARS-CoV-2. The results of multiple studies have shown that this assertion is incorrect. I’ll review two of them here.

One study examined 59,073 contacts of 5,706 COVID-19 patients in South Korea during January 20–March 27, 2020. The 5,706 index patients were grouped by age and the numbers of cases associated with that individual were identified. COVID-19 was detected in 11.8% of household contacts, and the rates were higher for contacts of children than for adults. The highest transmission rate, 18.6%, was observed for household contacts of school-aged children (10-19 years), and the lowest, 5.3%, for household contacts of children 0–9 years. This study was conducted in the middle of school closure; transmission rates are expected to be higher when school resumes.

A second study examined the presence of SARS-CoV-2 nucleic acids in nasopharyngeal swabs at a pediatric tertiary medical center in Chicago. The cohort, which included individuals less than a year of age to 65, all tested positive for SARS-CoV-2. Viral nucleic acid was detected by RT-PCR and the cycle threshold (CT) values for each individual were calculated. The CT value is inversely related to the quantity of nucleic acid present: the higher the number, the fewer copies of nucleic acid present in the sample.

The results show that young children (less than 5 years old) have as much or more SARS-CoV-2 nucleic acids in their upper respiratory tracts compared with older children (5-17 years old) or adults (over 18). While infectious virus was not measured, these differences mean that young children could have 10 to 100 times more infectious virus in their upper respiratory tracts.

The findings of these two studies show that young children are likely to be important drivers of SARS-CoV-2 transmission. Given the behavioral habits of young children in schools and day care centers, they will serve to efficiently amplify the virus among themselves, teachers, and their parents.

Schools may be opened only if stringent precautions are taken, including wearing of face masks, physical distancing, and most importantly, frequent testing. As discussed by Dr. Michael Mina on TWiV 640, the availability of a rapid and daily $1 test would make it possible to identify infected students and keep them at home. Unfortunately, such tests will not be widely ready for school opening this fall. Write your elected officials to demand that such tests be made available as soon as possible. There is no valid reason why we cannot achieve this goal.

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No evidence for increased human transmission of SARS-CoV-2

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coronavirus Spike

Don’t believe the headlines that SARS-CoV-2 is becoming more transmissible! Virologists are making conclusions that are not justified by the data.

SARS-CoV-2 virus isolates from many parts of the world have a single amino acid change in the spike protein, D614G. This observation in itself doesn’t mean very much. It could be that the change arose early in the outbreak and as this virus spread to other areas it was maintained because it has no fitness cost. We call this behavior ‘founder effect’. Whether the change has been selected for – what we would call ‘positive selection’, as claimed by many virologists, needs to be proven by experiments that have not been done.

The D614G change appears to make the virus more infectious in cells in culture. However, there are limitations to the conclusions that may be drawn from these data. First, cells that have been used are irrelevant to human transmission, such as a kidney cell line (VERO) from Vervet monkeys. I would like to see data from cultures of human respiratory epithelial cells, including airway-liquid cultures and lung organoids. Second, SARS-CoV-2 was not used for these experiments, but pseudotyped viruses – recombinant retroviruses or vesicular stomatitis virus with the SARS-CoV-2 spike glycoprotein gene inserted. The reason for this approach is that working with SARS-CoV-2 requires a BSL-3 laboratory which is not easy to come by. Nevertheless, even if all these issues were addressed, do we really think that results in cell culture tell us anything about human to human transmission? Seriously, virology colleagues? A monolayer of cells in culture in no way compares with the architecturally complex respiratory epithelium with mucus, antibodies, innate and adaptive responses.

I don’t mention using an animal model to assess SARS-CoV-2 transmission potential because there are no good models (yet) for animal to animal transmission of the virus.

I can think of experiments that could be done to determine if viruses with D614G behave differently in humans, but they have not been done. One approach would be to determine if the change leads to higher shedding of infectious virus from the upper tract. One study reported higher levels of viral RNA in the upper tract of patients infected with 614G compared with patients infected with 614D. This observation is meaningless, because everyone knows that nucleic acids detected by PCR does not always mean that infectious virus is present. Increased RNA might be a consequence of a change in the viral RNA polymerase caused by another mutation that accompanies the spike change. What needs to be done is to measure the levels of INFECTIOUS VIRUS shed from the upper respiratory tract of humans infected with either variant. Even then I would argue that the results cannot be interpreted, because we do not know how much of an increase in virus shedding would lead to an increase in transmission. Would twofold more virus be enough? Fivefold? Tenfold? A thousand fold? Anyone who says they know is wrong.

We know that the dispersion factor, k, of SARS-CoV-2 is 0.1, which means that about 10% of cases lead to 80% of spread. Which virus are these individuals transmitting, 614D or 614G? The results would contribute to an understanding of the role of this amino acid change in transmission.

It’s unfortunate that during a serious outbreak, rigorous science appears to be relegated to the back seat. You might remember during the 2015 Ebolavirus outbreak in West Africa, a viruses with a single amino acid change in the spike protein arose early and predominated. This change made the virus more infectious in cells in culture in the laboratory, but was never shown to have any effect on human transmission. In a nonhuman primate model, the change actually reduced virulence of the virus. Whether the predominance of virus isolates with the amino acid change was a founder effect or positive selection was never determined.

An important consideration is to identify the selection pressure for SARS-CoV-2 viruses with increased transmission. By the time the virus was detected in China late in 2019, it was already very good at transmitting among humans. I fail to see what selection pressure would lead to the emergence of such a variant.

The D614 change does not appear to change the virulence of SARS-CoV-2, nor its ability to be neutralized by antibodies. Let’s toss all the above arguments aside and assume that D614G increases human transmission. What should we do? Wear face masks, avoid large gatherings of people, embrace physical distancing. All of which are already being done – or are they?

Trial By Error: My Letter to Peer Reviewer of BMJ’s CBT-Music Therapy Paper

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By David Tuller, DrPH

I have recently written a few posts–here, here and here–about a study in BMJ Paediatrics Open that appears to be marred by multiple methodological and ethical problems. This is certainly not a one-time occurrence when it comes to BMJ journals. Last week, I sent a letter to the study’s senior author inviting him to send me his response for posting in full on Virology Blog. I have not heard back.

[Read more…] about Trial By Error: My Letter to Peer Reviewer of BMJ’s CBT-Music Therapy Paper

The SARS-CoV-2 pandemic could have been prevented

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coronavirusThe 3,250,000 cases of COVID-19 and 233,000 deaths caused by SARS-CoV-2 (numbers as of this writing) could have largely been prevented. The viral outbreak could have been stopped in December in Wuhan had we had the foresight and financial support to develop antiviral drugs or vaccines.

In the aftermath of the SARS-CoV pandemic of 2003, wildlife sampling taught us that bats harbor many SARS-like coronaviruses. Subsequent research revealed that some of these bat viruses have pandemic potential. We knew that CoVs lurked in bats in China with the potential to cause an outbreak. But no one would invest the money needed to make antiviral drugs or vaccines.

After SARS-CoV, a number of laboratories continued their research on the virus, but big Pharma lost interest in the virus – because it had disappeared from the face of the Earth. There was no money to be made in SARS-CoV antivirals or vaccines, so none were made. As a result, when SARS-CoV-2 emerged in late 2019, humanity was completely unable to stop its inexorable spread around the globe.

What could have been done? To start, we should have made antiviral drugs that inhibit a broad range of bat SARS-like CoVs. One protein encoded in the genome of these viruses – the RNA dependent RNA polymerase, essential for the synthesis of all viral RNAs – is the most highly conserved protein among all of these viruses. It would have been straightforward to take a sample of these RdRps from bat CoVs, produce them in cell culture, and find small molecule compounds that inhibit all of them. A pan-CoV antiviral drug could have been developed through human phase I trials, and stockpiled for the next pandemic. But there was no money to support such work – neither in the halls of big Pharma or forthcoming from the under-funded NIH.

It might have even been possible to make a pan-CoV vaccine, although in my view this would be much harder and less certain than a pan-CoV antiviral drug. One approach, similar to that being taken to make universal influenza vaccines, is to identify conserved epitopes (the amino acids to which antibodies are directed) on the viral spike protein. It would be straightforward to examine the spike proteins of many bat SARS-like CoVs to identify such conserved epitopes and either design vaccines to target them, or produce monoclonal antibodies agains such targets to be used therapeutically.

All of this research and more is taking place after the fact – too late to impact the pandemic. Companies are now motivated because the profit to be had is clear. Until such therapies are available – too late to impact the 2020 outbreak – we are left with testing antiviral drugs that were developed for other purposes, and they are not ideal. One that is being highly touted is Remdesivir, a drug that must be given intravenously (it is not sufficiently absorbed after oral administration) which means it is typically given only to very sick patients. By that time, virus loads in the lung are already low and giving an antiviral drug will have little impact. We could have had so much more than this.

How would all of this research have impacted the SARS-CoV-2 pandemic? In one scenario, we have stockpiles of a pan-CoV antiviral drug, enough to treat millions of people. When SARS-CoV-2 is first identified in Wuhan, the drug is immediately given a large phase II efficacy trial. We treat not only sick people but all their contacts and contacts of contacts. We also treat health care personnel. The drug will substantially drop virus levels in lung, impairing transmission. A larger phase III trial could follow with even more participants. It is likely that with such an approach, the virus would never have left China; but if it had, we could track it down and use the antiviral to stop spread. This scenario depends, of course, on extensive testing and contact tracing, a process not sufficiently done in the US and for which that country should be ashamed for not responding quickly enough.

It’s easy to blame bats for unwittingly giving humanity SARS-CoV-2. But I also blame both big Pharma and the US government for failing to come up with a pan-CoV antiviral or vaccine. Big Pharma because they are blind to anything that doesn’t enhance their bottom line. And the US government for severely under-funding the NIH so that essential research could not even be done in academic laboratories. It is very difficult to get money from Congress for research on a virus that is not a big human problem. That situation needs to end.

Every American should be outraged that the US has cut off funding for EcoHealth Alliance, an organization that supports wildlife sampling to discover viruses with pandemic potential in bats and other species. It is exactly that type of work that is needed to prepare therapeutics for the next pandemic. There is no scientific justification for such a move, only political motives.

I would also like to point out that due to pressure from a number of individuals who felt that determining the pandemic potential of SARS-like CoV in bats was too dangerous, a research moratorium on certain kinds of this research was imposed in 2014. I do hope the authors of that moratorium feel at least a small amount of regret as they look at the rising COVID-19 numbers. After all, Nature does not observe our moratoriums.

Now, as a consequence of this lack of vision, many people have died, economies have been destroyed, and the social structure of the world has changed. The US alone is spending trillions of dollars on recovery assistance. It would have been far cheaper to spend just billions for prevention.

Our model of how we make life-saving vaccines and antiviral drugs has to change. We cannot be dependent on for-profit companies and governments with lack of vision to save our lives. A new breed of non-profit organization is emerging that hopes to fund the development of vaccines and antiviral drugs that would not be otherwise possible. They include the likes of CEPI and READDI. Give them your support – our lives depend on it.

I would like to think that this pandemic will at least improve government support for research on viruses that are currently not harming humans, but have the potential to do so. But that would require that those in Congress who dole out the money look beyond politics. I do not think that will happen. Human health, and the viruses that impact it, will always be a political issue.