WHAT'S NEW - COVID-19 | Mutation, Virulence and Immunity

COVID-19 | Mutation, Virulence and Immunity

Headlines

More febrile reporting is afoot. Apparently the virus has mutated to be less deadly but more infectious, and antibodies to it don’t last so a vaccine can’t work. Which all sounds bad. 

• Viruses do have a tendency to mutate and become less deadly. That hasn’t happened to this one yet; mortality is falling but not because the virus has changed – other factors are at play;

• The REACT-2 study from Imperial suggests protective antibodies in people wane "quite rapidly" - but reports that this means immunity can’t last or a vaccine won’t be protective are premature. 

Let’s have a delve behind the headlines and work out what the science is actually telling us. 

Has the Virus Muted?

Yes and no. SARS-CoV-2 is an RNA virus. RNA viruses in general tend to mutate lots - they lack the internal proofreading and error correcting kit DNA has. And if you think human reproduction is sloppy it’s nothing compared with viral reproduction. 

The inevitable errors introduced during replication are the major source of genetic variation in all virus populations, and the coronavirus genomes are among the largest known - so we should expect them to have many and frequent mutations. But it turns out they don’t (1). 

Coronaviruses have an error-correcting protein that was unknown amongst RNA viruses prior to its discovery in SARS-CoV-1. This rather nifty trick contributes to a replication error rate more than 10-fold lower than that of other RNA viruses (2).

This is good. Because SARS-CoV-2’s genetic diversity and mutation rate is remarkably low this bodes well for the development of a broadly protective vaccine. It’s not like flu which mutates constantly, making vaccine design each season very challenging. 

But what about D614G?

Early in the pandemic a mutation cropped up in China called D614G. It’s called that because at position 614 in the virus spike protein a mutation caused a switch from aspartate (D) to glycine (G).

It seems this switch made the virus more transmissible - but not more or less dangerous. 

By June this was the strain that was dominant pretty much everywhere on the planet – but critically was also the strain responsible for the early outbreaks in Europe so it’s not this mutation that’s causing the lower mortality and morbidity we’re seeing now. This strain is not a newcomer.

Is It Getting Weaker / Less Dangerous?

A central dogma of virology is viruses tend to become less deadly over time. Viruses want to use you, not kill you. This is why outbreaks of really deadly viruses such as Ebola, hantavirus or Lassa tend to burn out quickly – evolution favours viruses that don’t rapidly kill their hosts. 

Many mutations will have no impact on a virus’s ability to spread or cause disease because they don’t alter the shape of any protein, whereas those mutations that do change proteins are more likely to harm the virus than improve it. Mutations are far more likely to break something than they are to improve or fix it. 

Ꙭ | HCoV-229E and HCoV-OC43 (3)

It turns out two of the ‘common cold’ coronaviruses we already knew about - HCoV-229E and HCoV-OC43 – started out as absolute shockers but over time have evolved to be less deadly. 

In 1889 ‘Russian Flu’ was a serious pandemic killing over a million, including Queen Victoria's grandson and second in line to the throne, Prince Albert Victor. It now seems ‘Russian Flu’ was in fact coronavirus OC43. 

Some rather clever research has shown 229E left bats on its path to people sometime between 1686 and 1800. It has a trajectory similar to MERS; it originated in African bats and moved to camels, before infecting people in or around the late 18th century. 

So, viruses including coronaviruses tend to evolve to become less virulent. But there’s no evidence this virus has done that yet. 

Yes, mortality is high but not that high. We need to look elsewhere to explain why mortality is dropping. And it is dropping, even in patients admitted to intensive care.

Data from the UK Intensive Care National Audit and Research Centre show that the proportion who died within 28 days of admission fell from 39% in the months to August 31st to 27% after September 1st. 

Another study looking at the case fatality rate in the New York region from March to August found that the death rate for cases admitted to hospital dropped from 27% to 3% (4). 

This can’t be explained by changes to the virus itself, so what’s happening? It seems there are two primary factors. 

1. There has been a very steep learning curve in terms of case management. 

For example doctors have learned from direct experience it’s better to rest critical patients on their stomach, to delay ventilation as long as possible and that steroids can reduce the risk of cytokine storm (this is where the immune system goes into overdrive, often with disastrous consequences). This is a good reason for a decrease in mortality. 

2. In the early stages many of the most vulnerable people caught it and died. 

Now there are quite simply fewer of them to catch it and younger people who are healthier at baseline are getting it. 

They naturally have a higher survival rate even if they become sick enough to end up in hospital. 

Certainly if we look at New York or Sweden the elderly and people with chronic conditions such as asthma, obesity or hypertension took a huge hit. This is a bad reason for a decrease in mortality. 

Yes, testing does have an effect on some of the numbers but we can control for that. 

now seemsThere are other factors too. It now seems that protective measures such as masking and distancing leading to lower exposure (getting a lower infectious dose) correlates with risk of death. 

So if you’re exposed to less virus the course of the infection is less severe. This has been long-suspected but the data is now supporting that. 

What About Immunity?

The Imperial College REACT-2 (5) study looked at 365,000 people across England. 

It reported:

• Only 6% of people were found to have antibodies in late June, falling to 4.8% in August and further still to 4.4% in mid-September.

• Overall, people with detectable antibodies fell by 26% across England in the three months to September. 

• Antibodies start diminishing 3-4 weeks after first becoming detectable, and drop more quickly in the elderly and those with asymptomatic infections.

So, there are regional variations but overall REACT-2 suggests fewer than 1 in 20 has any detectable level of antibodies going into the current spike of infections. This is not encouraging. Nor are reports of reinfections – plus we still don’t have a handle on the level of antibody required to sustain protective immunity. 

It seems immunity to SARS-CoV-2 follows a similar trajectory to other coronaviruses but it’s not all doom and gloom, despite early reporting on the REACT-2 data. 

Before digging a little deeper, it’s important to realise REACT-2 is a snapshot. It’s asking a simple question – are antibodies present – of a large sample of people. And the test itself is not hugely sophisticated. 

The key point is they are asking this question of DIFFERENT people each time they do it. It’s a big random sample, it’s not tracking antibody levels over time in the same people, it’s tracking antibody presence in the population – which is very different. 

What REACT-2 Tells Us

It suggests the level of immune response declines over a relatively short period indicating we can’t take for granted any protective effects of previous infection – and, as we have said before, any strategy reliant on herd immunity without a vaccine lacks credibility. Interestingly there was no significant decline for healthcare workers, likely because they may well have been repeatedly exposed. 

What REACT-2 Doesn’t Tell Us

It’s too early to assume that this means that immunity to SARS-CoV-2 does not last - importantly the study doesn’t look at trajectory of antibody levels in the same individuals over time. 

Also the simple, finger-prick test used had the advantage of being able to target a huge sample (good) but doesn’t tell us about antibody concentrations, how effective they are at neutralising the virus or other aspects such as T cell immunity.

What Does This Mean for Reinfection or Effectiveness of a Vaccine?

Despite reports, the results of REACT-2 are not a showstopper for immunity or for a protective vaccine. 

When people are infected antibody levels rise. As they get better antibody levels fall – but this is not exactly the same thing as ‘losing’ immunity. 

What we don’t know is how quickly the immune system might mount an adaptive (specific) response to being challenged to the virus a second time either through IgG or T cells. 

Even if a rapid, finger-prick antibody test is negative, the person may still be protected from re-infection resulting in a milder illness or complete protection. We just don’t know yet, and in fairness, that’s not a question REACT-2 was asking. 

This also doesn’t mean a vaccine might only give short term protection. There are some very interesting vaccines in the pipeline including RNA vaccines which may offer longer-term immunity plus traditional vaccines contain adjuvants to provoke a more durable immune response. 

What Else Do We Know?

There was a study in Iceland (6) using far more sensitive assays that found antibodies remained stable over the 4 months after diagnosis they were looking at. And this was a ‘longitudinal’ study, examining the same people over time. It showed the rise and early decay of antibodies that one would expect but with limited loss of antibodies at later time points. The study population was largely from a single ethnic origin and geographic region which isn’t ideal but it offers more encouragement than the ‘snapshots’ in the Imperial studies. 

Another study (7) tracking 30,082 individuals in New York found that over 90% of the sample had detectible neutralizing antibody responses. These titres remained relatively stable for several months after infection.

So, it remains unclear if infection with SARS-CoV-2 in humans protects from reinfection and for how long, but it does suggest SARS-CoV-2 behaves in a similar way to other coronaviruses - where neutralizing antibodies are induced and these antibodies can last for years and provide protection from reinfection or attenuate disease, even if an individual does get reinfected. 

Conclusion

• SARS-CoV-2 does not mutate as rapidly as other RNA viruses. 

This is useful when designing vaccines: the more ‘conserved’ areas on the viral coat are, the more chance you have of raising a vaccine with longer-term potential rather than needing a new one each season. 

• Viruses do tend to evolve to be less serious but that hasn’t happened to this one yet. 

The decreases we’re seeing in morbidity and mortality are in part due to a very steep learning curve in treating cases but it’s more that in many places the virus ripped through the most vulnerable very quickly with disastrous consequences. 

Now it’s spreading amongst groups better able to deal with it, plus it’s very likely that distancing and masking mean – to those that do catch it - exposure to lower amounts of virus are leading to a less serious disease progression. 

The latest REACT-2 results are not a huge surprise. 

They are discouraging but many media reports are reading a bit too much into it. 

Overall nothing here has turned previous assumptions on their head

Some previous assumptions are being confirmed by the data, some not so much. 

The immunity question remains elusive but the direction of travel is that SARS-CoV-2 immunity is in the same ballpark as other coronaviruses. But that does not speak to the potential effectiveness of future vaccines, nor does it cause us to change current advice.  


References

1. Low genetic diversity may be an Achilles heel of SARS-CoV-2. Rausch, Jason W, et al. 40, 6 October 2020, PNAS, Vol. 117, pp. 24614-24616.

2. Discovery of an RNA virus 3′→5′ exoribonuclease that is critically involved in coronavirus RNA synthesis. Minskaia, Ekaterina, Hertzig, Tobias and Alexander E. Gorbalenya, Valérie Campanacci, Christian Cambillau, Bruno Canard, John Ziebuhr. 28 March 2006, PNAS.

3. King, Anthony. An uncommon cold. New Sci. 2 May 2020, Vol. 246, 3280, pp. 32-35.

4. Trends in Covid-19 risk-adjusted mortality rates in a single health system. Horowitz, Leora, et al. 14 August 2020, medRxiv.

5. Ward, Helen, et al. Declining prevalence of antibody positivity to SARS-CoV-2: a community study of. Imperial College London. 2020.

6. Humoral Immune Response to SARS-CoV-2 in Iceland. Gudbjartsson, Daniel F, et al. September 2020, NEJM.

7. Wajnberg, Ania, et al. Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science. 28 October 2020.


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